Process Validation Guidance

This article
provides an The FDA’s Draft Process Validation
overview of the
draft guidance, Guidance – A Perspective from
the key changes
in relation to the Industry
1987 guidance,
and reviews
its potential by Nuala Calnan, Alice Redmond, and Stan O’Neill
impact on the
current industry
approaches to
science- and
risk-based
design and Abstract

T
validation. It sets out the approaches that the
qualification he long anticipated draft of the FDA’s FDA consider to be appropriate elements of
Guidance for Industry on Process Valida- process validation for the manufacture of human
activities tion should be welcomed for the clarity and veterinary drugs, including biologicals and
which support of its integrated three stage lifecycle APIs. No specific mention is made within the
the process process, its emphasis on the need for effective scope to investigational medicinal products or
validation scientific knowledge led programs, and the medical devices, for which CDRH has published
elimination of the “Three Golden Batches” its own guidance through the Global Harmoni-
program. concept. zation Task Force.
This article provides an overview of the
Introduction draft guidance, the key changes in relation to
In November 2008, the FDA published the long the 1987 guidance, and reviews its potential
anticipated draft of its Guidance for Industry impact on the current industry approaches to
on “Process Validation: General Principles and science- and risk-based design and qualification
Practices.” This draft, which has just completed activities which support the process validation
its public comment period, will replace the FDA’s program.
1987 “Guideline on General Principles of Process
Validation” when finalized and represents the The Lifecycle Approach
FDA’s current thinking in regard to process The guidance states at the outset that it has
been written to promote “modern
manufacturing principles, process
Basic Principles of Quality Assurance improvement, innovation, and sound
science” and is significantly aligned
Effective Process Validation contributes significantly
with the Product Lifecycle Ap-
to assuring drug quality.
proach described in the ICH Guid-
The basic principle of Quality Assurance is that a
ance Q8 (R1), Q9, and Q101 and the
drug should be produced that is fit for its intended use;
Quality by Design (QbD) initiative.
this principle incorporates the understanding that the
This lifecycle approach emphasizes
following conditions exist:
the importance of the links between
• Quality, safety, and efficacy are designed or built the following:
Reprinted from
into the product.
PHARMACEUTICAL • Quality cannot be adequately assured merely by in- 1. product and process design and
ENGINEERING® process and finished-product inspection or testing. development
The Official Magazine of ISPE
• Each step of a manufacturing process is controlled 2. qualification of the commercial
to assure that the finished product meets all design manufacturing equipment and
May/June 2009, characteristics and quality attributes including speci- process
Vol. 29 No. 3 fications. 3. maintenance of the process in a
©Copyright ISPE 2009 Ref: Guidance for Industry Process Validation: General Prin- state of control during routine
www.ISPE.org ciples and Practices (Nov 2008). commercial production

Continued on page 10.

8 PHARMACEUTICAL ENGINEERING May/June 2009
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 Process Validation Guidance
tion is then used to develop the approach to process vali-
Three Stages of Process Validation dation, and the scientific knowledge is verified by testing
(in-process, release, characterization) of each significant
Process validation involves a series of activities taking
step of the commercial manufacture process.
place over the lifecycle of the product and process.
• The significant emphasis in the lifecycle is on maintaining
Stage 1 – Process Design: The commercial process is the process in a state of control over the life of the process,
defined during this stage based on knowledge gained which will require ongoing data analysis of both intra-batch
through development and scale-up activities. and inter-batch variability, and appropriate provisions to
Stage 2 – Process Qualification: During this stage, address deviations and nonconforming data.
the process design is confirmed as being capable of • It emphasizes the importance of both QA professionals and
reproducible commercial manufacturing. line operators in providing feedback for continued process
Stage 3 – Continued Process Verification: Ongoing verification.
assurance is gained during routine production that the • Not surprisingly, the guidance focuses on the importance
process remains in a state of control. of demonstrating, documenting, and utilizing process un-
derstanding in designing effective validation programs. It
Ref: Guidance for Industry Process Validation: General
Principles and Practices (Nov 2008). provides a strong lead in acknowledging that qualification
programs devoid of process understanding will not guar-
antee the assurance of quality required.
One of the key messages from this draft is that validation of
the process is not a “one off ” event, but represents an ongoing Significant Recommendations
continuum of scientific knowledge development and ongoing The main body of the guidance is provided under section IV
assurance. There is a real emphasis throughout the draft on Recommendations, where very useful general considerations
the importance of acquiring this knowledge about the process on the three stages of process validation and their associated
from the early process design stage right throughout com- activities are outlined.
mercial manufacture, which is a significant departure from This is where we see the most significant alignment with
the convention of (essentially) testing the process outputs. current industry thinking for implementation of science- and
Success relies on the establishment of a comprehensive risk-based lifecycle approaches and where the most signifi-
science-based process design, which focuses on understanding cant departures from the prescriptive approaches of the 1987
the sources of variability in achieving process understanding guidance are noted.
and recognizes that more knowledge will be gained during Under “General Considerations for Process Valida-
product commercialization. The draft emphasizes that the tion,” it emphasizes the importance of making the entire
key to this success will lie in an organizations proficiency “in process validation program more effective and efficient through
the collection and evaluation of information and data about the following:
the performance of the process,” and outlines specific guid-
ance relating to the use of quantitative statistical methods • good project management
to enhance understanding of process performance. • robust scientific knowledge collection, management, and
From this, the guidance defines Process Validation activi- archiving
ties in three stages identified in Figure 1. • uniform collection and assessment of information meth-
Key tenets of the lifecycle approach outlined are: ods
• reducing the burden of redundant information gathering
• A manufacturer should have gained a high degree of as- • use of an integrated team approach
surance in the performance of the manufacturing process
before any batch from the process is commercially distrib-
uted for use by consumers.
• This assurance should be obtained from objective informa-
tion and data from laboratory, pilot, and/or commercial­
scale studies – this implies a need for greater scrutiny of
process performance during the early stages of commercial
manufacture.
• A successful validation program depends upon the skilled
interpretation of the information and knowledge gained
from product and process development regarding sources
of variation, its impacts, and the associated risks.
• This knowledge and understanding is cited as the basis
for establishing the appropriate control strategy for the
manufacturing process.
Figure 1. Process validation lifecycle activities shown in three
• The product and process design and development informa- stages.
Continued on page 12.
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 Process Validation Guidance
conditions so that the process output remains constant and
Key Definition: Process Validation (PV) reproducible. However, it does indicate that in the case of PAT,
the approach to process qualification will be different from
“The collection and evaluation of data, from the process
that for other process designs by focusing on the qualification
design stage throughout production, which establishes
of the measurement system and control loop.
scientific evidence that a process is capable of consis-
Significantly, by grouping the recommendations for product
tently delivering quality products”
and process design together in this stage, it further endorses
Ref: Guidance for Industry Process Validation: General an integrated approach. Within this integrated approach,
Principles and Practices (Nov 2008). while it acknowledges that the full spectrum of input vari-
ability typical of the commercial production is not generally
known at this stage, it directly recommends that the team
• appropriately documented Project Plans responsible for process design take early consideration of the
• the support of senior management functionality and limitations of commercial manufacturing
• statistical assessment of data equipment by utilizing their knowledge about measurement
systems in a production setting, contributions to process
The draft recommends the “integrated team approach” as variability from different raw materials or component lots,
presented in the FDA’s 2006 guidance entitled, “Quality production operators or environmental conditions. This ethos
Systems Approach to Pharmaceutical Current Manufacturing will no doubt be welcomed by many involved in the start up
Principles,” involving expertise from a variety of disciplines, of regulated commercial manufacturing facilities who have
including process engineering, industrial pharmacy, analytical dealt with the challenges posed when this early integration
chemistry, microbiology, statistics, manufacturing, and quality of commercial production and process design has not been
assurance. Furthermore, both here and throughout the docu- successful.
ment, it emphasizes the need for effective and efficient pro-
grams and supports the move away from overly bureaucratic Stage 2: Process Qualification
traditional qualification practices and in doing so provides This stage of the process validation lifecycle is undoubtedly
good alignment with the key principles of the recent ASTM going to generate the most comment and perhaps lead to some
standard E2500-07.2 initial confusion, due to its use and definition of terminology
In “Specific Stages and Activities of Process Validation in relating to Process and Performance qualification.
the Product Lifecycle,” the guidance gives specific direction The stated goal of this key stage is that “the process design
on each of the three stages of process validation. is confirmed as being capable of reproducible commercial
manufacture.” The guidance further divides this stage into
Stage 1: Process Design the following two elements:
The stated goal of this stage is to “design a process suitable
for routine commercial manufacturing that can consistently 1. design of the facility and qualification of the equipment
deliver a product that meets its Critical Quality Attributes and utilities
(CQAs).” The guidance again makes reference to ICH Q10, 2. Performance Qualification (PQ)
Pharmaceutical Quality Systems, and draws some distinctions
around the varying levels of controls required related to the Stage 2-1: Design of the Facility and
product development lifecycle activities. Qualification of Utilities and Equipment
The focus of this stage is on developing methods and com- This section of the guidance opens with a welcome reference
petencies for building and capturing process knowledge and to the essential role that proper facility design and commis-
understanding and in using this scientific knowledge as the sioning play in the start-up of a facility and cites them as
basis for establishing an approach to effective process control. prerequisites to the commencement of PQ.
It states that the “Design of Experiment (DOE) studies can help Most significantly, the guidance gives a key definition for
develop process knowledge by revealing relationships, including qualification as shown below:
multi-factorial interactions, between the variable inputs (e.g., The draft guidance states that qualification of utilities and
component characteristics or processing parameters) and the equipment generally includes the following activities:
resulting outputs (e.g., in-process material, intermediates, or
the final product).” Risk analysis tools can be used to minimize
the total number of experiments conducted while maximiz- Key Definition: Qualification
ing knowledge gained. The results of the DOE studies should “Activities undertaken to demonstrate that utilities and
be used to establish ranges of incoming component quality, pieces of equipment are suitable for their intended use
equipment parameters, and in­ process material quality at- and perform properly is referred to in this guidance as
tributes. qualification”
The draft draws attention to the recent advances with Pro-
Ref: Guidance for Industry Process Validation: General
cess Analytical Technology (PAT), which may be used for real
Principles and Practices (Nov 2008).
time analysis, facilitating control loops to adjust the processing
Continued on page 14.
12 PHARMACEUTICAL ENGINEERING May/June 2009
 Process Validation Guidance
• selecting utilities and equipment based on whether they • The manufacturing conditions set for the PQ are established
are appropriate for their specific use based on the cumulative data from all relevant studies (e.g.,
• verifying that the utility system and equipment are built/ designed experiments; laboratory, pilot, and commercial
installed in compliance with the design specifications and batches).
operate in accordance with the process requirements in • Objective measures (e.g., statistical metrics) are used to
all anticipated operating ranges for routine production evaluate the outputs and justify that adequate assurance
• challenging the equipment or system functions while has been achieved.
under loads comparable to that expected during routine • Greater scrutiny of process performance is undertaken
production during PQ through the use of enhanced levels of sampling
• performance of interventions, stoppage, and start-up as is and testing. This enhanced level of monitoring and testing
expected during routine production should be capable of confirming uniform product quality
is achieved throughout the batch during processing.
The guidance requires that these qualification activities
are covered either under an individual plan or as part of an It will be important to understand and assess the impact of
overall project plan. In line with the ICH Q9, Quality Risk these expectations relating to PQ early in the overall lifecycle
Management guidance, the plan should consider the use of as they may affect process development activities, system
risk management to prioritize certain activities and to identify design, equipment selection, or team selection considerations
the appropriate level of effort for both the performance and and will certainly influence the development of methods and
the documentation of these qualification activities. procedures.
Finally, it confirms the requirement for the qualification In relation to the number of PQ batches required, to date
activities to be documented in a report with conclusions product PQ was typically followed by the traditional “three
that specifically address the criteria set out in the plan. It PV batches.” Now no fixed number of new PQ batches are
is important to note this draft’s expectation that the quality prescribed and manufacturers must provide justification
control unit must review and approve both the qualification for any rationale used in asserting that assurance has been
plan and the report. There is divergence here with the recently achieved. However, it is noted that the words “commercial
published ASTM E2500-072 standard, which seeks Quality batches” are used, which would suggest the use of more than
Unit preapproval of the qualification acceptance criteria rather one batch.
than the plan, but concurs on the Quality Unit post approval Furthermore, it is important to note the expectation that
of the qualification report. the greater scrutiny accompanied by the enhanced level of
sampling undertaken during the PQ batches should continue
Stage 2-2: Performance Qualification (PQ) initially into the continued process verification stage.
Performance Qualification (PQ) is the phrase used to described Of particular note in the document is the recommendation
the second element of the overall process qualification and that the PQ lots should be manufactured under normal con-
combines the actual qualified facility, utilities, and com- ditions. Thus, a matrix approach with extremes of operating
mercial manufacturing process equipment with the trained conditions is not expected for this phase of validation.
personnel using cGMP compliant control procedures (SOPs), The guidance provides specific recommendations on the
and all raw materials and components necessary to produce format and content of the PQ protocol and the report includ-
commercial batches. ing as follows:
The use of the phrase Performance Qualification (PQ) in
the context of producing commercial batches may present • manufacturing conditions, such as operating parameters,
divergence from what is widely understood to be within the process limits, and raw materials inputs are document-
scope of a “traditional” PQ, which currently focuses on equip- ed
ment and process performance for clean utilities, cleaning, and • details of the data to be collected, including when and how
sterilization processes. In the 1987 guide, this was described it is evaluated
as Process Performance Qualification and was distinguished • details of the in-process, release, and characterization tests
from that which was referred to as Product Performance to be performed, as well as the acceptance criteria for each
Qualification. This draft combines the two efforts within significant step
this stage in order to achieve the stated goal of overall Per- • the sampling plan, including sampling points, the number
formance Qualification (PQ) which is to “confirm the process of samples, and the frequency of sampling for each unit
design and demonstrate that the commercial manufacturing operation, based on statistical confidence incorporating
process performs as expected.” risk analysis
Success at this stage is cited as an important milestone • criteria showing the processes consistently produce quality
in the product lifecycle and must be completed before a batches, including a description of the statistical methods
manufacturer commences commercial distribution of the drug used to define both intra-batch and inter-batch variability,
product. and provisions to address deviations and nonconforming
The draft requires that the design of the PQ study should data
ensure that: • design of facilities and qualification of utilities and equip-

14 PHARMACEUTICAL ENGINEERING May/June 2009

 Process Validation Guidance
1987 PV Guidance 2008 Draft
Defines validation as “establishing documented evidence” Defines validation in terms of “establishing scientific evidence”
Principles of quality assurance wording revision from “cannot be inspected or to “cannot be adequately assured merely by in-process and finished product
tested into the finished product” inspection or testing”
Principles of quality assurance wording revision from “designed and built into the to “is designed or built”
product”
Wording revision from “maximize the probability that” to “is controlled to assure”
Introduction of “integrated team approach”
Introduction of “product lifecycle” concept
exclusion of “revalidation” and “retrospective process validation”
Introduction of Process Analytical Technology (PAT) concepts for PV
Introduction of “root cause” (e.g., review of customer complaints and impact on
process)
Removes validation information for medical devices
Emphasizes Science Based Knowledge development
Emphasizes the use of qualitative statistical methods to monitor, evaluate and
justify assurance of process performance
Table A. Key changes between 1987 PV Guidance and 2008 Draft.

ment, training, and verification of source materials port their relaxation.

• validation status of analytical methods used to measure It is noted that data gathered during this stage may identify
the process, materials, and product ways to improve and/or optimize the process and appropriate
• review and approval by the appropriate department and procedures to control and manage these changes must be in
the quality unit
Concludes on page 16.

Finally, the draft elaborates on the opportunities presented

for manufacturers utilizing PAT systems to support activities
undertaken in the next stage.

Stage 3: Continued Process Verification

The stated goal of the third process validation stage is to “con-
tinually assure that the process remains in a state of control
(the validated state) during commercial manufacture.” This
will require robust systems for detecting unplanned depar-
tures (drift) from the designed process, and there is a strong
emphasis on the use of statistically trended data, which is
reviewed in a timely manner by trained personnel, such as
statisticians or persons with adequate training in statistical
process control techniques.
The development of a Data Collection Plan is recommend
ensuring that the information collected can verify that the
critical quality attributes are being controlled throughout the
process.
This production data also should evaluate process stability
and capability and the scrutiny should include both intra-
batch as well as inter-batch variation. The quality unit should
evaluate this data, discuss possible trends or drifts in the
process, and coordinate any correction or follow-up actions
with production personnel.
As referred to previously, the draft recommends that the
enhanced monitoring and/or sampling initially established
during the process qualification stage continue until sufficient
data is available to generate significant variability estimates
and justification, using statistical metrics, is available to sup-

May/June 2009 PHARMACEUTICAL ENGINEERING 15

 Process Validation Guidance
place. It highlights that maintenance of the facility, utilities, and Verification of Pharmaceutical and Biopharmaceutical
and equipment is another important aspect of ensuring that Manufacturing Systems and Equipment, July 2007.
a process remains in control. While the document discusses 3. Notes for Guidance on Process Validation; CPMP/
the use of continued process verification to identify variability QWP/848/96, EMEA/CVMP/598/99 September 2001.
and improve the process, no mention is made to the possible
implications on already commercialized batches. About the Authors
Finally, it states a fundamental tenet that following the Nuala Calnan is a Principal Consultant
scientific based approach requires that information transpar- with PM Group, Ireland and has more than
ency and accessibility are essential so that organizational units 17 years of experience in the pharmaceuti-
responsible for the process can make informed, science-based cal industry. Currently, she is a member of
decisions that ultimately support the ongoing commercial the ISPE International Board of Directors
release of a product. and was a member of the Author Task Team
which produced the recent ASTM E2500-07
Conclusion International Standard. Calnan also is a
It is the opinion of the authors that this guide will be welcomed member of the document development task team currently
for many reasons, primarily for the clarity and simplicity of writing the ISPE Baseline Guide: Science and Risk-Based Ap-
the integrated three stage lifecycle process, but also for the proach for the Delivery of Facilities, Systems, and Equipment.
emphasis on the need for effective and efficient science-based She graduated in 1991 with a BSc in engineering (BSc Eng)
programs, which seek to reduce unnecessary duplication in and achieved her MBA in 2002. She is a regular contributor
activities through the application of product and process at ISPE conferences. She can be reached by telephone: 353-
knowledge throughout the lifecycle. 14040700 or by email: nuala.calnan@pmg.ie.
From a facility, utility, and equipment qualification per- PM Group, Kilakee House, Belgard Square, Tallaght, Dublin
spective the welcomed avoidance of traditional, prescriptive 24, Ireland.
terminology such as DQ, IQ, and OQ offer teams real opportu-
nities to look behind the prepared templates and design and Alice Redmond is CQ Technical Director
execute qualification and validation programs which are not with PM Group, has more than 20 years
only valid, but valuable to the ongoing operation and continu- of experience in the R&D, pharmaceutical
ous improvement. There is only one minor exception to this (API, formulation fill, solid dosage), and
relating to an external cross reference in the introduction to biotechnology industry. She graduated with
the very prescriptive validation approach for APIs found in a BSc in biotechnology in 1987, a PhD in
the ICH Q7A guidance. This is likely to add confusion rather biotechnology in 1991 and a MBs in 2001.
than clarity and which hopefully will be dealt with through Current responsibilities include oversight of
the public comment phase. regulatory compliance, GEP, quality, commissioning, qualifi-
Upon first review, this draft in itself does not appear to cation and validation strategies on a corporate level for PM
have any new implications for the preparation and submis- Group. Redmond is an active member of ISPE and PDA. She
sion of regulatory filings. co-chaired and presented at the ISPE GEP ICQ Conference in
However, for many organizations, aligning this FDA pro- Copenhagen in 2006, and the Singapore ISPE Conference in
cess validation guidance with the current EMEA legislative July 2008. She can be contacted by telephone: 353-214358922
requirements and recommendations for process validation or by email: alice.redmond@pmg.ie.
would be very beneficial.3 PM Limited, Loughmahon Technology Park, Blackrock,
Finally, from an ISPE Technical Documents perspective, Cork, Ireland.
due to the revised use of terminology and the welcome step
back from prescriptive qualification practices, final publica- Stan O’Neill is the Managing Director of
tion of this guidance will provide an opportunity to review the Compliance Group. After qualifying as
several current ISPE Guidance documents for alignment. This a pharmacist, he spent more than five years
will impact both the Baseline® Pharmaceutical Engineering working in the pharmaceutical industry in
Guides series and Good Practices Guide series, many of which Regulatory Affairs, marketing, and Quality
are already under revision for alignment with recent ICH Assurance (QP), and then joined the Irish
guidance. Medicines Board (IMB) for a period of 10
years. In his capacity as a Senior Inspec-
References tor, he performed GMP inspections throughout the world,
1. See the FDA/International Conference on Harmonisation represented Ireland at European level for the negotiation of
(ICH) guidance for industry: standards of inspection for medicinal products, and trained
a. Q8 Pharmaceutical Development Inspectors at Irish, European, and International levels. He
b. Q9 Quality Risk Management can be contacted by telephone: 353-866032297 or by email:
c. Q10 Pharmaceutical Quality Systems stanoneill@compliancegroup.eu
2. ASTM E2500-07: Standard Guide for Specification, Design, The Compliance Group, 22 Earlsfort Terrace, Dublin 2,
Ireland.
16 PHARMACEUTICAL ENGINEERING May/June 2009
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 Process Validation Q&A
This article
presents the The Draft Process Validation
questions and
answers from Guidance – A Perspective from the
a recent ISPE
Webinar focused FDA
on the FDA’s
draft process
validation
guidance.

Introduction
In January 2009 Grace McNally of the US FDA
provided a first time public view and under-
A Yes, Q7A has a very prescriptive specific sec-
tion about validation. That is the standard
for APIs. If there appears to be any conflict
standing on the new draft Guidance for Industry between that and this guidance, I would cer-
– Process Validation in a live ISPE Webinar. tainly ask that you submit those comments to
Paul D’Eramo, Executive Director, Johnson & us and we will consider them as we revise the
Johnson, hosted a question and answer session guidance for final.
which gave attendees the chance to submit their
questions and have them directly answered by
McNally. The following is a transcript of some
of the highlights of that Q&A session:
Q When you implement this, is there a plan for
how you will be training the FDA investiga-
tors to make sure everybody’s consistent?

Q Do we have any idea on when it might get

finalized? A Yes, that’s a very good question. We haven’t
done that in a formal comprehensive way.
We have the basic drug school or courses geared

A Once we get the comments in we’ll have

to empanel a group of experts to evaluate
them, make some decisions, write responses, and
toward our pharmaceutical inspectorate. Myself
and others involved in this working group have
given talks about this new guidance – it wasn’t
adopt suggestions if appropriate or not. I can’t published because we weren’t distributing it at
tell you exactly how long that process will take that point – and the concepts in it, discussing
but it’s certainly our intention to get that done the principles and how they should be thinking
and get a final published this year, 2009. about process validation, which isn’t terribly
different than the thinking we had under the

Q Did you discuss this draft with other regula-

tory bodies such as in Europe, to see what
their reaction might be in regards to harmoniz-
1987 guidelines. A careful reading of the 1987
guidelines is very revealing. It is not fundamen-
tally different in its basic principles.
ing some of their documents? But yes, the investigative staff will need to be
trained and we will be developing a formal train-

A No, this was an FDA effort only and it did not

involve other regulatory agencies. Certainly,
it’s available to them. I’ve been to conferences
ing program. Certainly this is just a draft and
there may be revisions, so we are not prepared
to do that quite yet until we have the final. As
where representatives from other regulatory far as the implementation phase, it’s important
bodies have asked about it, so they are aware to remember that this is a guidance, it’s not a
Reprinted from that it was in draft. Of course, it’s on the Web regulation. These are recommendations. This
PHARMACEUTICAL and it’s available for everybody to take a look is the current thinking about what we believe
ENGINEERING® at and comment on. are useful practices for process validation in
The Official Magazine of ISPE this day and time. So an implementation phase
May/June 2009,
Vol. 29 No. 3 Q It’s clear in the document you’ve referenced
Q8, Q9, and Q10. It’s not as clear as how
doesn’t really apply to this guidance.

©Copyright ISPE 2009

www.ISPE.org
this relates to Q7, especially because there are
sections in Q7 that discuss validation. So should
we defer to that?
Q How does this guide relate to the aseptic
processing guide? Does that processing guide
take precedent for sterile products?
Continued on page 20.
18 PHARMACEUTICAL ENGINEERING May/June 2009
 Process Validation Q&A

A Yes, that’s a good point. The aseptic

processing guide is as direct and
prescriptive for that activity and that
that is performing well, and there’s no
indication, there’s no quality indicator
data that suggests to you something is
A While it’s true that references to
statistical criteria and procedures
are prominently featured in this guid-
manufacturing operation. So if there is amiss, I’m not suggesting that you run ance, I will say that that’s not new …
a guidance out there that specifically out and begin R&D all over for each of It’s a topic that we need to shine light
addresses a type of manufacturing these product and process lines. on and put on the table. It is my belief
activity, that is what you want to look It would make sense to me that as that it has been somewhat ignored as
at. This guidance is not intended to part of your overall quality system, of late. Certainly it has to be wrestled
conflict with the aseptic processing and certainly as part of the periodic with. It raises a lot of questions about
guide or any of the guidances out there. evaluation of all product lines, that how to do this.
I know in the biological realm there are whatever your procedures dictate that But I would say it really is not new.
specific guidances for viral clearance or you consider each of these products I’m looking at the old guidance, second
other technical manufacturing aspects and processes as part of your periodic to last section. It’s talking about testing,
and those should be your primary evaluation procedures. You can cer- test data, and ...process monitoring.
reference. tainly take for example, you may want It says, “specific results on the other
to consider some sort of risk analysis hand can be statistically analyzed and

Q Can you explain the major differ-

ences between the old guide and
the new as it relates to existing (or
of each of your product lines and pro-
cesses and see what can and should be
done to improve them if that appears
a determination can be made of what
variance and data can be accepted.”
So those ideas have been around for a
legacy) products? For example, if we necessary, based our your data and long time. In Stage 3, you can use Six
have to revalidate an existing product, evaluation. There’s no move afoot on Sigma. We’re not going to prescribe
should I use the new guideline or the our part to send investigative teams what statistical tools to use and really
old principles? out to go through a company’s product we’re just looking for a scientific basis
line, find the five year old process that and objective measures, and statistics

A Process validation is a lifecycle and

if you’re in a position of revalidating,
for whatever reason... I would direct
seems to be doing quite well and start
digging into R&D records … that’s not
the goal and it won’t be part of any ac-
are one of them.
In this day and age, I understand
from many people in industry that there
your attention to Stage 3. If you have tion on the field’s part. are a lot of good software packages out
an existing product in process and But I would say to you as the com- there and they can be very valuable. And
you’re revalidating it, I would assume pany to think about your processes and even in Stage 2, you have limited data
there’s been some trigger for that. It product lines. You do and are required at that point and so the power of those
would make sense to me that the trig- and certainly want to have in place analyses may not be as great because
ger for that is information you gath- these periodic evaluation procedures. you have much more accumulative data
ered during what we’re calling Stage So when an older and existing process in Stage 3, once you’re making a lot of
3, commercialization activities that comes up, my question then to you, is commercial batches … but they would
you do under 211.180 (e), part of your do you think you should apply these be very useful. We’re not going to dictate
periodic evaluation. (That information) new principles. And they’re really not which statistical tools to use, but you
brought to your attention something that new actually. I would recommend as a company should select what works
that needs to be changed or checked. that everybody who is concerned about for you and be able to defend why it’s
So it would make sense at that point to this new guidance being different than scientific and objective.
incorporate the principles in this new the old should sit down with the new
guidance. And remember they’re not
that different. If I was to go back, and
I do have the old guideline here in front
one and the old one and carefully read
them. Q Was a there a reason why risk
analysis was not discussed in the
document?
of me, it also calls for a maintenance of
a state of control.
So I would say good companies con-
Q Someone made the comment, it
seems our industry lags somewhat
in process monitoring/statistical pro- A Yes, we made a deliberate effort
to not explore topics that have
cerned about quality are going to use cess control. It is now clear that this is already been thoroughly covered in
revalidation for whatever the impetus an expectation. Another asks, can you other guidelines or guidances. Risk
was... to adopt a modern view. As a com- use Six Sigma concepts to rationalize management is thoroughly discussed
pany you also want to be philosophically process validation being in a state in ICH Q9 and we’ve referenced it. But
congruent. If companies are embracing of control. Can you elaborate on that to avoid retread on already established
an attitude of continuous improve- Continued Verification, Stage 3, the concepts – we mention it and there is
ment it seems to me that that would monitoring part, and how you foresee an expectation that risk analysis will
permeate their thinking for all their that? be used throughout the lifecycle and all
product lines. Now, having said that I’m of the stages – felt it was not necessary
not saying if you have an old process to go into detail. That is expected, and

20 PHARMACEUTICAL ENGINEERING May/June 2009

 Process Validation Q&A
Need
use the guidances available on it.
Q Is there value in executing PQ at
ranges versus a target or should
Knowledge?
Q Will a glossary be added? There are
terms such as process verification
and product performance. Criticality
this be carried out in the development
phase? No Budget for
Travel?
is not really defined anywhere. Do you
think you’ll go back and put some of
those terms into a glossary?
A That’s a great question and that
really speaks to the old guideline.
In the old guideline you certainly get
the impression that the boundary con-

A A few thoughts on criticality. We

actually in our earlier versions
used the word critical throughout the
ditions (worst case challenges, edge of
the operating parameters that have
been established, whatever you want
document. The definition of criticality to call it, edge of operating limits) in
has been greatly debated. We’ve seen the old guidance to me and my read-
many definitions, whether individual ing of it is that that’s something you’re
companies prefer a definition, whether going to do as your making commercial
a regulatory body has a certain slant batches, this performance qualification
on their definition. In the interest of stage or what we would call it, Stage 2.
getting this guidance done, we did not It seems to me that while that knowl-
put a glossary in because so many of edge should be pursued, it would make
the terms are debatable in terms of sense that that would be in the Stage 1
what they mean. Criticality, we took arena, or I should at least say, it’s not
out of there and went back to our source something you want to do when you’re
document which is the GMP and chose
to use the word “significant.” So you’ll
ultimately confirming your process
design and working with product you
No Problem.
see in those places that term instead intend to sell. I would agree with the
of criticality. inquiry statement that before you ready ISPE Online Learning
But the comment about the glossary what you think is commercial product
in general, there isn’t a glossary. But you’ve probably already explored that delivers critical
if the comments we get back strongly
suggest that that is indispensible or
and have some understanding of what
those limits are and what their impact
knowledge and
absolutely necessary in order to pre- is on the product quality and process. I training to you
vent confusion or make this guidance agree that you would want to explore
meaningful and useful then we’ll take that up front. anytime, anywhere,
that into consideration.
and at a price to fit
And I should just say as an aside,
there’s no magic to the terminology
that we chose to use for this guidance:
Q Please elaborate on the following –
“to have sufficient understanding of
the commercial process, the manufac-
your budget.
Stage 1, Stage 2, Stage 3. They’re just turer will need to consider the effects
terms we chose and then laid out what of scale; however, it is not typically nec-
they meant. That’s something each of essary to explore the entire operating
your individual companies probably range at commercial scale if assurance
do as well. Certainly there’s value in can be provided by other data.” Can you
everybody using and having the same clarify what is sufficient understanding
meaning but to expect that to happen, and what is the agency’s thinking there
I wouldn’t bet money on it. I think the and the same for scale? Does this need
key about terminology is, whenever you to be done at full scale batches?
get involved in a discussion with some-
body, whether it’s in an audit, or your
collaborating on something, as long as
that group understands what is meant
A ...as far as sufficient data, there
are certain words that the Agency
will use, such as “appropriate” or “suf-
Visit www.ISPE.org/
onlinelearning for a
by certain terms, then you can make ficient.” Because it’s going to differ from
complete list of Online Learning
progress and have a successful meeting company to company and product to
or inspection, or move forward. But the product… it’s a judgment call that the
opportunities or call ISPE
glossary issue, I would say we will look manufacturer must make and then be Member Services at tel:
at that in terms of the comments that able to explain why they feel this is +1-813-960-2105.
we get back from everybody. adequate from a science perspective...
Concludes on page 22.
May/June 2009 PHARMACEUTICAL ENGINEERING 21
 Process Validation Q&A
the key there, is people will talk in terms a procedure. I don’t want to say protocol some cogent, appropriate manner that
of how many commercial size batches because I don’t want to give people the I really think will differ from product
do I have to make. The more important idea that this is what you have to do. to product and process to process. The
question is, having made these batches, But doesn’t it make sense, if you’re go- agency isn’t going to dictate that. As
however many there are, what is it that ing to assess performance over time, to far as number ... there is this element
you’re looking (for). That’s the criteria. establish some criteria and some sort of of reproducibility, so right off the bat
That’s what you want to specify in your procedure and then execute it, gather you know you’ve got to have more than
protocol, your plan. The real question that data and do those analyses. And put one. And when I say one I don’t mean
is, but what about them, what are you numbers, I mean that’s mainly where one batch. I mean, I’d rather say data
doing with them, what is the data you’re we’re coming from, the statistics that you point, or for whatever the data points
looking at, what is the information? Is see in this new guidance are “objective that are important or for whatever the
it during processing, are you looking at measures,” I think it maybe only says attributes or parameters are important,
the controls and the process parameters, it once in there. But if you’re going to reproducibility is an element that needs
how tight they are or not. Are you looking assert that you have confidence in this to be demonstrated.
at attributes of the in-process material unit operation, this process overall, this
in the final product and what about it,
are you going to do some analysis of
that data. It’s not about the number of
particular attribute, can you put a num-
ber on it. I think more and more today
you can if you use the right tools.
Q Why doesn’t the guide talk about
revalidation?

batches, it’s what data are you gleaning

and how are you handling that data and
what are your expectations.
Confidence intervals, how sure am I
about this data point or this statistical
metric I just calculated. How confident
A We didn’t use “revalidation” because
really Stage 3, the output of those
monitoring activities, is going to give
am I. It’s going to depend on sample you the impetus to revisit potentially

Q Does the Continued Process Veri-

fication Program for a given drug
product require formal protocol, similar
size, it’s going to depend on a lot of
things. But you can put a label on how
confident you are on some of your data
design or revisit Stage 2. So revalidation
is really a function of what you find in
Stage 3. It’s covered in concept, we just
in fashion to Performance Qualifica- … I think this inquirer’s insight is a fine didn’t use the word. It’s something Stage
tion? Should this data be collected, one and makes sense. Again, Stage 3, 3 will dictate what you need to do.
analyzed, summarized (and approved) if you’re trying to maintain things in a
by the QA – Validation Department? state of control you want to be able to
measure what it’s doing, what is that Q Can you please comment on the
responsibilities of manufacturers

A That’s a very good question. I am

not saying it’s required but it makes
rational sense. If you have a new prod-
process doing over time. It’s really the
essence of that 211.180 (e), Periodic
Evaluation, when you say you’re doing
of record and contract manufacturers?
Who’s responsible for the validation?

uct or process for which you don’t have

a lot of history and you don’t have a
similar product or process from which
a Periodic Evaluation, what tools are
you employing to do that. So really what
the inquirer is getting at is what tools
A Ultimately the manufacturer or the
company’s name that’s on the label
is responsible. Having said that, it’s im-
you could leverage information; I think do we want to devise to do our Periodic possible for the contract manufacturer
that’s one of the holes in the way things Evaluation. I think it’s a great idea. not to be involved. I know that there
are operated right now. You have the are these quality agreements that the
pre-approval and post-approval and it
goes from getting approval and launch
to automatically, oversight is at routine
Q You purposely did not use the
number three in batches in the
document, but there are a few ques-
contract manufacturer and the actual
manufacturer of record will negotiate
and the responsibilities should be laid
levels. Well the routine levels may not tions asking if it would be appropriate out in these quality agreements. So
be appropriate immediately. to mention a minimum number? there are special considerations. And
To answer this person’s question, it’s that’s very prevalent. There are lots of
not required, but I think it’s an excel-
lent idea, sort of a transition; things
aren’t on and off, like flipping a light
A Here’s the key word you have to
think about. You have to demon-
strate reproducibility. As far as a mini-
contract manufacturers even within one
company so that has to be worked out
and transferred, whether to a site in
switch. And I suspect companies don’t mum number, again it’s not the number India or in the US... Both parties are go-
just say it’s a new process, and so now of batches, it’s what is the data. That’s ing to have some responsibility because
once it’s approved we’ll just treat it like the key criteria that you’re looking at, they will each be inspected on their own
the one that’s been running for three and how are you going to analyze that merit; they are registered drug compa-
years seamlessly. I think there is more data using what tools. You have two con- nies. If you’re responsible for transfer of
oversight and appropriately so. siderations, the product attributes, and a process to another location, that needs
So under Stage 3 I can envision and you have the process parameters and to be one of your primary concerns in
would certainly recommend that you the ability to control them. So any crite- getting those responsibilities laid out
would have formal protocols, or at least ria needs to account for both of those in and understood by all parties.

22 PHARMACEUTICAL ENGINEERING May/June 2009

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 Defining Regulatory Expectations
This article
provides a A Comparison of the FDA’s Draft
comparison of
the provisions Process Validation Guidance and
ASTM E2500
found in ASTM
E2500 versus
the expectations
for equipment
qualification by Robert E. Chew, PE
as enunciated
in the FDA’s
recent draft
process validation
guidance.
Introduction

T
management to focus on those aspects of the
he pharmaceutical/biotechnology in- facility, equipment, and automation that provide
dustry has shown great interest in the control of risk to the patient, or otherwise help
ASTM Standard E25001 for the Design, assure manufacture of a quality product.
Specification, and Verification of facili- The EU GMPs Annex 15 on Qualification
ties, equipment, and systems. Many companies and Validation, published in 2001, states that
are attempting to implement this standard. In “A risk assessment approach should be used to
quite a few instances, organizations responsible determine the scope and extent of validation.”
for compliance are concerned that this standard The document then prescribes use of Design
represents a significant change from how indus- Qualification (DQ), Installation Qualification
try has practiced qualification in the past. There (IQ), Operational Qualification (OQ), and Per-
is a further concern regarding terminology formance Qualification (PQ) as being precursors
(what certain documents need to be called) and to process validation. These terms are defined
the structure of documents with respect to EU and general content is specified. These terms
regulatory expectations. The FDA’s new draft and provisions are echoed in the more recent
process validation guidance includes expecta- ICH Q7A, GMPs for manufacture of active
tions for equipment qualification. How do the pharmaceutical ingredients, which has been
expectations in this new guidance compare with adopted by the US, EU, and Japanese regulators
the approach defined by ASTM E2500, and how as either regulation or official guidance.
can the EU expectations be reconciled with these In July 2007, ASTM E55 committee (which
documents? This article provides an analysis of is developing standards related to pharmaceuti-
these provisions and a recommended approach cal manufacturing) issued its Standard E2500
to equipment qualification. covering the design, specification, verification,
and acceptance of facilities, equipment, and as-
History sociated automation for use in pharmaceutical
ICH Q9, Quality Risk Management, was final- and biotechnology manufacturing. The purpose
ized at Step 4 in November 20052 and has been of this standard is to describe how to implement
adopted by the Japanese, EU, and US regulators the ICH Q9 principles of quality risk manage-
as either guidance or incorporated into regula- ment in a controlled and documented manner
tions. This document provides principles and ex- that meets regulations and demonstrates
Reprinted from amples of tools of quality risk management that manufacturing systems are suitable for their
PHARMACEUTICAL can be applied to all aspects of pharmaceutical intended use.
ENGINEERING® quality, including development, manufacturing, In November 2008, the FDA issued its draft
The Official Magazine of ISPE update to the 1987 Process Validation Guidance.
distribution, and the inspection and submis-
May/June 2009, sion/review processes. One way (out of many) In January, the FDA delivered a webinar on this
Vol. 29 No. 3 that risk management can be used is to focus subject, hosted by ISPE. See related article on
the facility and equipment design and opera- page 8 in this issue for a full discussion of the
©Copyright ISPE 2009 tion around risk to the patient. A qualification contents of this draft guidance. Industry has
www.ISPE.org approach also can make use of quality risk been provided with an opportunity to comment
Continued on page 26.
24 PHARMACEUTICAL ENGINEERING May/June 2009
 Defining Regulatory Expectations
on this draft guidance, and it remains to be seen the degree medical device and other industries: Verification is the act
to which comments and changes will be incorporated into the of confirming, through objective evidence, that a particular
final guidance. feature or specification has been met. This definition fits with
ISPE has under development a new Baseline® Guide Vol- the use of the term verification in ICH Q7A, in that DQ, IQ,
ume 12: Science and Risk-Based Approach for the Delivery of OQ, and PQ are defined in terms of “documented verification
Facilities, Systems, and Equipment, which will provide details that…”
on how to implement a program based on ASTM E2500. ISPE The third related term is Commissioning. The FDA draft
also is developing a Good Practice Guide that will provide guidance states, “It is essential that activities performed to
further options and approaches to qualification, including assure proper facility design and commissioning precede PQ.”
how to evolve practices based on the original Baseline® Guide Commissioning is widely used in many industries, particularly
Volume 5: Commissioning and Qualification, toward an ASTM the construction industry; therefore, it is a definition that is
E2500-based approach. readily understood by many parties and is of benefit to project
teams.
Terminology For purposes of this article, the following terminology will
For many years, a Qualified system meant that there existed be invoked. For additional discussion of this choice of defini-
a QA pre-approved, executed, and QA post-approved set of tions, please see related article in the July/August 2008 issue
documents consisting of an IQ and OQ (and in many cases a of Pharmaceutical Engineering.3
PQ) protocol. For computer systems, and later most systems, Verification – the act of confirming, through objective
this set of documents was expanded to include user require- evidence, that a particular specification has been met.
ments, functional requirements, traceability matrices, etc. The Commissioning – a well-planned, documented, and man-
content of these protocols more often than not was dictated by aged engineering approach to the start-up and turnover of
local procedures. It did not matter whether the protocol con- facilities, systems, and equipment to the end-user that results
tent actually corresponded to critical aspects of the system or in a safe and functional environment that meets established
whether the qualification process actually yielded equipment design requirements and stakeholder expectations.
that was fully functional and ready to manufacture quality Qualification – a state, or determination, that the equip-
product. What mattered was whether the local procedure ment has been found to be suitable for its intended use.
was followed to develop, execute, and approve each protocol.
Today, there are projects where money is being wasted and Basis for Qualification
time is being lost as decisions are made to address procedural What defines or what constitutes suitability for use? Neither
issues that are oblivious to good engineering and science and the FDA guidance, nor EU GMPs, address this question in
the impact on product quality. general terms, but instead merely provide examples of quali-
This is changing. The most important change is what it fication activities. See Content and Execution below. ICH Q7A
means to Qualify a manufacturing system. This change began has the general requirement to comply with the approved
with ISPE’s Baseline® Guide Volume 5: Commissioning and design and to operate and perform as intended.
Qualification. This Guide defined IQ, OQ, and PQ in terms The ASTM E2500 standard provides a much clearer defini-
of “aspects…that can affect product quality.” This is a more tion of what suitability for use is, and how it is assured. While
focused approach than the traditional approach of inspecting both the FDA draft guidance and the ASTM standard discuss
and testing against all engineering specifications (which can understanding the process science behind manufacturing, the
yield very thick protocols, a measure of success for some). ICH standard goes further to define critical aspects as “functions,
Q7A defines DQ as “verification that the proposed design… features, abilities, and performance characteristics necessary
is suitable for the intended purpose.” ASTM E2500 defines for the manufacturing process and systems to ensure consistent
verification as “a systematic approach to verify that manu- product quality and patient safety.” The standard requires the
facturing systems…are fit for intended use…” The FDA’s new definition of product and process requirements, and the use
draft Process Validation guidance states, “activities under- of risk assessments to identify appropriate controls through
taken to demonstrate that utilities and pieces of equipment design solutions and other means. Collectively, the process
are suitable for their intended use and perform properly is requirements and risk assessments can be used to derive the
referred to as Qualification.” The draft guidance also states, critical design and operating characteristics; these constitute
“Focusing on qualification efforts without understanding the “suitability for use.”
manufacturing process may not lead to adequate assurance The ASTM E2500 standard prescribes a lifecycle approach:
of quality.” In short, a Qualified system no longer means one “Assurance that manufacturing systems are fit for intended
with signed off protocols created and executed per a rigid use should not rely solely upon verification after installation,
procedure, but rather a system that has been shown to be but be achieved by a planned and structured approach applied
suitable for its intended use. throughout the system lifecycle.” The standard prescribes
This use of the term Qualification to mean a demonstra- a series of steps necessary to design, specify, and verify the
tion of suitability for use is equivalent to how ASTM E2500 manufacturing systems. The FDA guidance includes a brief
uses the term Verification. The author believes that the term mention of the need to assure proper facility design and com-
Verification has a more narrow and specific meaning in the missioning, but does not carry this idea to any greater detail.
Continued on page 28.
26 PHARMACEUTICAL ENGINEERING May/June 2009
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 Defining Regulatory Expectations
The determination, via the ASTM process requirements • Operate in accordance with process requirements in all
and risk assessment process, of what constitutes suitability anticipated operating ranges. This is further amplified
for use is a more robust and process-science driven approach to include challenges under load, performance of inter-
than the FDA guidance “examples.” While one cannot argue ventions, start and stoppage as expected during routine
with the general thrust of these examples, the potential is operations, and ability to hold operating ranges as long as
that industry will focus on these perceived requirements necessary during routine production operations.
to the detriment of good science and good test engineering
practices. The author feels the above attempts by regulators to engage
in the practice of defining the approach and scope of inspec-
Planning for Qualification tions and testing are overly prescriptive. For example, the
Both the ASTM E2500 standard and the FDA draft guidance last sentence regarding the ability to hold operating ranges
are remarkably similar with respect to planning, the only dif- as long as would be necessary during routine production
ference being use of Verification Plan (ASTM) vs. Qualification could lead a team to conclude they have to show the ability
Plan (FDA). The EU GMPs also contain similar requirements. to control bioreactor temperature, pH, dissolved oxygen,
Table A illustrates the respective requirements for “plans.” etc., over a time period equal to a normal cell culture batch,
which could be days or weeks. A test engineer would not as-
Content and Execution sess this as being necessary, but would instead understand
The EU GMPs are the most prescriptive, defining DQ, IQ, the science of the process and test those control loops under
OQ, and PQ. Neither the FDA draft guidance nor the ASTM expected worst case challenge conditions for heat transfer or
standard defines how the design review and inspection and test oxygen uptake, etc. Eventually, of course, such control is by
programs should be structured; during ISPE’s webinar with default demonstrated during development batches or process
FDA, the FDA presenter stated that there is no expectation for validation lots. However, teams may interpret the guidance
IQ/OQ/PQ per se. The EU GMPs prescribe content of IQ, OQ, regarding qualification of equipment preceding PQ lots as
and PQ with IQ having the most prescriptive detail. The FDA being a hard requirement and endeavor to execute such tests
draft guidance states, “Qualification of utilities and equipment in a non-optimal manner.
generally includes the following activities.” The examples are The ASTM standard prescribes that specific methods,
similar to the EU content examples and include: performance, and documentation of inspection and testing
activities are to be determined by subject matter experts. The
• selection of materials of construction (note the words are verification activities should be conducted using a systematic
selection, not verification!) approach and documented, the extent of which is scaled based
• operating principles and performance characteristics ap- on risk to patient, risk to product quality, and the complexity
propriate for their specific use and novelty of the equipment. This is a science and risk-based
• built and installed per design specifications – and it clari- engineering approach. The use of subject matter experts, as
fies this by stating “built as designed with proper materi- defined by the standard, is in complete agreement with 21
als, capacity, and functions, and properly connected and CFR 211.25, Personnel Qualifications.
calibrated.”

Plan Element ASTM FDA EU

Strategy/studies or tests to use/timing or sequence/scheduling X X X
Define acceptable documentation of detailed activities X X X
QA approval (for systems with critical aspects) X X Note 1
Acceptance criteria X X
Developed and approved by subject matter experts X
Responsibilities/organizational structure X X
Incorporate risk management to prioritize activities and adjust level of effort in both performance and documentation X X Note 2
thereof
Choice to use system-based planning or one overall project plan X X X
Managing change during the project Note 3 X X
Validation policy, and reference to existing documents X
Note 1: Common expectation is that the validation master plan be approved by QA.
Note 2: The Principle (preamble) states “A risk assessment approach should be used to determine the scope and extent of validation.” It is presumed that the scope
and extent are discussed in the validation plan.
Note 3: ASTM positions Change Management as a required supporting process to the project, but does not mention it in the context of the verification plan. It is likely
teams would choose to include such a subject in their verification plans.
Table A. Comparison of ASTM, FDA, and EU expectations for contents of a “Qualification Plan (FDA/EU)” or “Verification Plan (ASTM E2500).”

28 PHARMACEUTICAL ENGINEERING May/June 2009

 Defining Regulatory Expectations
Review, Approval, and Release Summary and Recommendations
ASTM E2500, the EU GMPs, and the FDA draft guidance Table B summarizes the similarities and differences between
document all require a summary report following the field the US FDA, EU GMPs, and ASTM E2500 with respect to
inspections and testing. This report is to summarize the demonstrating manufacturing systems are suitable for their
findings, highlight any deviations, and describe any changes intended use.
to the plan/protocol that may have occurred. The ASTM It is this author’s opinion that if a project team follows
standard describes a two-step process, Verification Review, the requirements of the ASTM E2500 standard, it will have
which is performed by an independent (second check) subject met the expectations of both US FDA and EU regulators for
matter expert, followed by an Acceptance and Release, which demonstrating manufacturing system suitability for use. While
includes the quality unit for systems with critical aspects. In project teams may choose to be sensitive as to what labels are
other words, technical experts review the technical results attached to what documents and to a few particulars of the
and make a determination as to suitability for use, while the regulations, overall the ASTM standard provides the most
quality unit provides a final approval of this determination robust, science- and risk-based methodology of any of the
and official release for manufacturing, at which point the documents discussed.
system is placed under QA pre-approved change control (vs. For those who feel more comfortable having documents
change management during the project). labeled “DQ, IQ, OQ, and PQ,” the following is suggested with
It should be noted that NONE of the three documents respect to documents typically produced during an ASTM
describe the typical onerous and formal deviation resolution E2500-based project.
process present in most projects today. Only the EU GMPs
and the ASTM standard mention deviations, and both discuss • The final risk assessment and identification of critical
them in terms of documentation via the final summary report. aspects/acceptance criteria and confirmation that the
While the FDA draft guidance does not specifically mention design includes all process requirements could be labeled
deviations, the subject can be inferred under the contents the DQ.
of the qualification plan: “the criteria appropriate to assess • A checklist of these critical aspects and their acceptance
outcomes [should include how to deal with deviations].” criteria could be used to review the verification/commission-
ing work to confirm all critical aspects have been checked.

Concludes on page 30.

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 Defining Regulatory Expectations
Qualification Expectation ASTM FDA EU
Focus on science-based process understanding and meeting process requirements X X
Equipment and facilities suitable for intended use X X
QA approves [qualification] [verification] plan X X
QA approves [qualification] [verification] report X X
QA approves protocols Note 1 Note 1 Note 2
Risk assessment to “scale” effort, documentation X X X
Flexibility on how effort is structured X X
Specific aspects to check are spelled out X X
Critical aspects derived from risk assessments and process requirements X
Use of project change management X X X
Use of subject matter experts: how to verify, adjudicate departures from specification X
Use of vendor documents X
Design and testing of facility, process, equipment based on process understanding X X X
Final report to summarize findings and deviations X X X
Note 1: The QA unit is to approve the acceptance criteria and other high level aspects of the qualification planning effort as discussed under Planning for Qualification.
Note 2: QA approval is inferred. EU Annex 15 requires approval of protocols, but does not state by whom.
Table B. Summary comparison of key expectations of ASTM E2500 program, FDA process validation guidance, and EU GMP Annex 15.

These checklists could be labeled “IQ/OQ” protocols. These References

checklists could actually be created or copied from the final 1. ASTM E2500-07: Standard Guide for Specification, Design,
risk assessment and list of critical aspects, eliminating a and Verification of Pharmaceutical and Biopharmaceutical
separate protocol pre-approval step – the approval of the Manufacturing Systems and Equipment, July 2007.
DQ also could serve as the approval of these checklists. 2. See the FDA/International Conference on Harmonisation
• A similar approach could be taken for PQ work or a more (ICH) guidance for industry:
traditional PQ protocol could be used that includes the a. Q8 Pharmaceutical Development
specific test cases and instructions for execution. b. Q9 Quality Risk Management
• These checklists that are labeled IQ/OQ protocols also could c. Q10 Pharmaceutical Quality Systems
be used as the final verification report and the approval 3. Adamson, R., Calnan, N., Chew, R., Wisniewski, S., “Com-
thereof would constitute the acceptance and release phase missioning, Qualification, and Verification: A Review
of ASTM standard. Solving the Terminology Conundrum,” Pharmaceutical
Engineering, July/August 2008, Vol. 28 No. 4.
As a cautionary note, it is the author’s experience that teams
attempting to implement ASTM E2500 with respect to risk About the Author
assessments and contents of protocols spend significant effort Robert E. Chew, PE is President and CEO
trying to understand and spell out the detailed mechanics of of Commissioning Agents, Inc. and has 20
documentation format, structures, what goes where, etc. It years of experience in the pharmaceutical
also is the author’s experience that teams tend to view risk industry. He was a member of the Author
assessments solely through the lens of focusing on the inspec- Task Team which produced the recent ASTM
tion and testing (verification/qualification) effort. That is not E2500-07 International Standard. Chew also
the intent of ICH Q9, Quality Risk Management. Instead, it is a member of the team currently writing the
is the author’s recommendation that teams approach risk ISPE Baseline Guide Volume 12: Science and
assessments with a holistic view – conduct risk assessments Risk-Based Approach for the Delivery of Facilities, Systems,
with the idea of identifying, assessing, and controlling risk and Equipment. He is a former member of ISPE’s Interna-
to the patient through a variety of means (engineering and tional Board of Directors, and has been a frequent speaker for
other quality system-related means). The risk assessments ISPE globally. He graduated in 1981 with a BS in chemical
should commence at a high level starting with conceptual engineering from Case Western Reserve University. He can be
design, continuing through more detail as the design devel- reached by telephone: +1-317-710-1530 or by email: Robert.
ops. It will then become apparent to teams as to how to use Chew@Cagents.com.
these results – to improve the design, to improve procedures, Commissioning Agents, Inc. P.O. Box 34320, Indianapolis,
to improve training, to improve other aspects of the quality Indiana 46234 USA.
system, not to mention providing a focus on the critical design
and operating aspects of the manufacturing systems.

30 PHARMACEUTICAL ENGINEERING May/June 2009

 Defining Regulatory Expectations
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06.03.2009 09:06:49 31
 Industry Interview
Jean-Louis
Robert talks
Pharmaceutical Engineering Interviews
candidly about
his role with the
Dr. Jean-Louis Robert, Head of Luxembourg’s
International
Conference on
Laboratoire National de Santé, Service du
Harmonization Contrôle des Medicaments
(ICH), the
continued
importance of by Dr. John C. Berridge
harmonizing
quality
standards both
within the ICH

T
regions and he following is a recent interview with System (Q10), and currently he is Rapporteur
beyond, and the Jean-Louis Robert, Head of Luxem- for the implementation of ICH Q8, Q9, Q10. At
bourg’s Laboratoire National de Santé, the European Pharmacopoeia, he is a member
need for global Service du Contrôle des Medicaments, of the Commission and of the group of experts
implementation conducted by ISPE’s European Regulatory Af- 10 B (synthetic products). Currently he chairs
of initiatives fairs Advisor, who was a European Industry the Steering Committee of the Certificate of
such as Quality Representative at the International Conference Suitability of the European Pharmacopoeia.
on Harmonisation (ICH) from its inception He also serves as a pharmaceutical expert at
by Design until 2007. WHO.
(QbD), design
space, and risk
management.
Dr. Jean-Louis Robert
studied chemistry at
Q Jean-Louis, today you contribute to a wide
variety of activities associated with public
health protection. For example, you are the
the University of Basle
quality representative to the EMEA’s Commit-
(CH) and obtained his
tee on Human Medicinal Products (CHMP) and
PhD from there in 1976.
the Chairman of the Quality Working Party
He had a post-doctoral
(QWP). For many years, you and I worked closely
training at the Pharma-
together as members of a variety of ICH Expert
ceutical Institute of the
Working Groups. Your latest ICH contribution
“Eidgenössische Technis-
has been the completion of the Annex to ICH
che Hochschule” (ETH) in
Q8 in November 2008. Congratulations! This
Zurich (CH). He spent one year with a pharma-
surely represents the conclusion of another very
ceutical company before joining the National
valuable ICH guideline.
Health Laboratory (LNS) in Luxembourg. In

A
his current position, he is Head of the Depart- Yes, thank you. I was very happy to take
ment of Control of Medicines, an Official Medi- over the completion of this guideline after
cines Control Laboratory (OMCL) at the LNS, you had led the Expert Working Group through
member of the European Directorate for the to Step 2 in the ICH process. While principles
Quality of Medicines OMCL (Council of Europe, of Quality by Design (QbD) were not totally
Strasbourg) network. He has been a member of new in Europe, it is extremely useful to have a
the Committee for Human Medicinal Products guideline such as Q8(R1) to explain an enhanced
(CHMP) since 1995 (co-opted since 2004) at the approach to pharmaceutical development and
Reprinted from
European Medicines Agency (EMEA) in London all the opportunities linked to it.
PHARMACEUTICAL
and Chairman of the CHMP/CVMP Quality

Q
ENGINEERING® Can you tell me more about your role and
Working Party since 1995. Within the Interna-
The Official Magazine of ISPE responsibilities as Head of the Laboratoire
tional Conference on Harmonization (ICH), he is
May/June 2009, National de Santé, Service du Contrôle des
or was involved in following topics: Validation of
Vol. 29 No. 3 Medicaments in Luxembourg?
Analytical Procedures (Q2), Common Technical

A
Document-Quality, revision of the guidelines I am responsible for the laboratory which
©Copyright ISPE 2009
on impurities (Q3A and Q3B), Pharmaceutical deals primarily in the quality control of the
www.ISPE.org
Development (Q8), Pharmaceutical Quality medicines sold in Luxembourg. This monitoring

32 PHARMACEUTICAL ENGINEERING May/June 2009

 Industry Interview
is done in close collaboration with the
Division of Pharmacy and Medicines
(Luxembourg Inspectorate) at the na-
nominated to the CPMP, as it was then,
in January 1995 and became a co-opted
member of the CHMP in 2003. The har-
A Right now, our priorities can be
seen by reviewing the work pro-
grammed on our Web site. In the recent
tional level, and they are responsible monization of quality standards across past, we have significantly increased
for the review and approval of human Europe is the responsibility of the Qual- our collaboration with the Inspectors’
and veterinary dossiers in Europe. The ity Working Party (QWP). I have chaired working party where we are planning
laboratory is also involved in developing the QWP since March 1995. As an EU greater involvement of assessors with
methods to characterize the chemical expert, I support the activities of the inspectors as we review and approve
and physical properties of drugs at European Directorate for the Quality of new marketing authorization applica-
pharmacopoeial level. The laboratory is Medicines (EDQM) European Pharma- tions. We work very closely with the
a member of the European Official Medi- copoeia, OMCL network, and represent Biological Working Party and this has
cines Control Laboratories (OMCL) Europe in the International Conference been especially so with the development
network, coordinated by the European on Harmonisation (ICH). of the recent ICH guidelines. Looking
Directorate of Quality of Medicines further into the future, of course we will
(Council of Europe, Strasbourg). It is
also engaged in anti-counterfeiting
Q Tell us more about the role of the
QWP and why is it so important
to have an organization such as the
continue to adapt to new scientific prog-
ress and work across Europe to support
activities. the training of assessors, where there
QWP?
may be opportunities to work together

Q Please tell me more about the role

and responsibilities of an OMCL.
A As Europe continues to grow, it is
vitally important to have a coordi-
with organizations such as ISPE. We
do also have a very active PAT team,

A An OMCL is an official laboratory

that supports the regulatory au-
thorities and complements the inspec-
nating organization that oversees the
development, implementation, and
application of common standards and
addressing specific issues with regard
to PAT, Quality by Design, giving advice
to industry on product related issues.
tion services in controlling the quality quality systems across all the member This group chaired by Dr. Keith Pugh
of medicinal products on the market states. Where we see the need to develop from MHRA includes experts from QWP,
by independent testing. It is an inde- a guideline for industry regarding a qual- BWP, and GMDP IWP.
pendent laboratory responsible for the ity matter, we address it through a well-
quality control of medicines for human
and veterinary use in member states of
documented and rigorous procedure. We
actively seek input from industry and
Q Tell us more about your role in ICH.
I believe you are the longest serving
member of the Quality Expert Working
the Convention on the elaboration of other interested parties across the whole
Groups?
the European Pharmacopoeia and the of the community and are always willing
observer states. The Commission of the
European communities and the Council
of Europe set up the network in May
to hear comments and suggestions on
how we can improve quality standards
in Europe, and internationally, for the
A With your recent retirement, I
think I am now the longest serv-
ing member supporting the quality
1994 and the European Secretariat took benefit of patients. topics! Clearly, my primary role is to
on this new responsibility. The main pur- The QWP also represents a single represent the EU in this area. I have
pose of the European network of OMCLs source of scientific advice for indus- really enjoyed working for the past 15
is the mutual recognition of tests carried try. We hold regular meetings with years and still enjoy supporting the
out at the national level from countries companies who seek our input as they harmonization of quality standards
that belong to the European Union and progress their candidates through the both within the ICH regions and those
the sharing of expertise, standardiza- later stages of development. observer countries that adopt the ICH
tion, and international collaboration for In addition, the QWP provides a guidelines. One of the more demanding
the other countries. Among the many central point of contact and liaison roles is that of the rapport. Generally,
things the network does, it has set up a with other regulatory authorities. For industry acts as the rapport until a
coordinated European approach for the example, we recently collaborated with guideline reaches step two, after which
surveillance of marketed products. It Health Canada in the elaboration of a the regulatory authority from the same
is also responsible for the coordination guideline for inhaled products, and we region will take over the responsibility.
of the official batch release of vaccines, frequently welcome visitors from the Personally, I have led the development
for example. FDA or other agencies to our QWP meet- of the guidelines concerning analyti-
ings. For instance, Swissmedic and the cal validation, impurities (revision),

Q As an EU expert with the EMEA

and representative to the CHMP,
what are the main areas that you focus
European Pharmacopoeia participate
as observers to our meeting.
pharmaceutical development part of,
the quality aspects of the CTD-Q, and
currently Q8, Q9, and Q10 IWG.
on and contribute to?
Q What are your current key priorities
as Chairman of the QWP? How do
Q There are many different initiatives

A At the CHMP level, my main contri-

butions are for the pharmaceutical
quality aspects of submissions. I was
you see the role and priorities of QWP
changing or developing over the next
(FDA’s initiative on Pharmaceutical
Quality Systems for the 21st Century,
decade? ICH Guidelines, industry association
Concludes on page 34.
May/June 2009 PHARMACEUTICAL ENGINEERING 33
 Industry Interview
initiatives, etc.) that share the same arena, especially in global implementa- in industry at Merck in Darmstadt. I
concepts (some of which are not so tion of these many initiatives? then moved to the laboratory in Lux-
“new”), such as QbD, design space, risk embourg in 1978 and have been there
management, etc. What do you think is
the best way forward to facilitate global
A I think it is the combination of ex-
pertise and the global reach of orga-
nizations such as ISPE that facilitates
ever since. The most important is not so
much what somebody has studied, but
implementation of those concepts? to continuously improve one’s scientific
global implementation. ISPE, with its
knowledge and to be open minded.

A There are probably two ways which

we can facilitate the global imple-
mentation of these concepts. Starting
Communities of Practice (COPs), Edu-
cation Committees, Regional Affiliates,
and extensive guides and technology Q What has been your most fulfilling
role in your career?
with ICH Q8, we have been focusing based learning, bridges regulators and
more on creating a higher level of guid-
ance that is less prescriptive than was
industry, and is a powerful resource that
can assist everyone whatever region
A I have really enjoyed working in a
small agency because it provided
me with a diverse range of opportuni-
perhaps the case with earlier guidelines. they operate in.
ties, including the chance to review
This means that there then needs to be
agreement on interpretation. Since it
is industry, not regulatory authorities,
Q In your career, what are the most
significant issues or changes you
have seen in the global pharmaceuti-
dossiers (first in the BENELUX regis-
tration), to work as part of the OMCL
network, and to support the European
that develops new drugs, it is important
cal environment and what changes or Pharmacopoeia. I have really enjoyed
for industry to develop and share their
challenges do you anticipate in the next participating in the development of
understanding on the interpretation
few years? the EMEA, the establishment of the
and implementation of these guidelines.
CPMP/CHMP, and the OMCL network.
For example, there have been a number
of groups that have developed and pub-
lished case studies and other training
A There have been so many. What I am
really pleased to see is the move from
assuming quality can be controlled by
Of course working in the ICH also has
been very exciting. Just for the record, I
have not missed a single QWP meeting
materials that support the implementa- end product testing to the appreciation
since it was set up!
tion of these guidelines. The more we can of the importance of product and process
do that and the more that we can jointly
collaborate in their development and
elaboration, the greater will be the adop-
understanding, thereby supporting
continual improvement. The size of the
application file has increased though!
Q What kinds of activities do you enjoy
in your free time?

tion throughout the world. Secondly, we

just need to continue the dialogue. No
I’ve also seen a significant drift away
from localized European manufacture
A I love being with my family. While
I used to play football, jog, and play
squash, I spend more time now on my
guideline is ever 100% complete. There to globalized outsourcing, and I do
bicycle and I really enjoy the wild and
will always be questions. The recently have a concern as to whether industry
rugged scenery of our local Ardennes.
established Implementation Working will be able to maintain their quality
I relax by reading -- thrillers, history,
Group (IWG) has a role to document standards.
and political commentaries.
and answer these questions and thereby
provide a valuable resource to support
the global implementation of the ICH
Q For our readers who might want to
follow in your distinguished foot-
steps, what education and preparation
Q Are there any other comments/last
thoughts you would like to convey
quality guidelines. to our readers?
is needed for a career in a regulatory

Q What is your involvement with

ISPE?
agency, particularly as a pharmaceuti-
cal assessor? A Maybe I can finish this interview
with a message to my industry
friends and colleagues. I think industry

A I have enjoyed many years of involve-

ment with ISPE. In addition to con-
tributing to meetings and workshops in
A Of course there are many routes
that one can take to become a
pharmaceutical assessor. Studying
needs to be its greatest critic. It really
is important for you to do all you can
to achieve the greatest understanding
both Europe and the USA, I participate pharmacy is obviously a good route into
of each other and an understanding of
in the Regulatory Affairs Committee regulatory activities, but the scientific
the authorities that regulate you. Do
meetings and contribute to the Inter- degrees of chemistry or biology are also
what you can to build trust. We, the
national Leadership Forum, which is appropriate. These days, I would rec-
authorities, welcome open discussions
where senior regulators from around ommend that a period in industry to
and transparency, and are always will-
the world and Industry executives can gain a wide exposure to contemporary
ing to receive new ideas and suggestions
share issues relating to quality and pharmaceutical technology is valuable
from you. As you engage in more and
make proposals for their resolution. before considering entering a regulatory
more outsourcing, do pay attention to
agency. I started my career with a BSc

Q In what ways do you believe a global

organization such as ISPE can assist
regulators, pharmaceutical companies,
in chemistry and then did my PhD in
Basle. I stayed in Basle to do a post-Doc
the quality systems throughout the
whole of your supply chain to ensure
the robust quality and sustainability
at the ETH, and then took my first post
and individuals in the international of all your supplies.

34 PHARMACEUTICAL ENGINEERING May/June 2009

 Industry Interview
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 Product Quality Lifecycle Implementation (PQLI)
This article
presents the PQLI® – What is it?
current status
of ISPE’s PQLI
initiative. It by Dr. John C. Berridge
details how
PQLI will
provide the
global industry
with the tools
necessary to Current Status

I
include the provision of a technical framework
implement the SPE launched its Product Quality Lifecycle comprising, for example, explanatory docu-
ICH quality Implementation (PQLI®) initiative in June ments and illustrative examples, supporting
vision. 2007 to help industry find practical ap- the implementation of enhanced science- and
proaches to the global implementation of risk-based approaches to product realization,
recent ICH guidelines. Through PQLI, ISPE technology transfer, commercial manufacture,
is spearheading approaches to assist in the and its continual improvement in both research-
implementation of, in particular, ICH Q8(R1) and generic-based organizations. PQLI clearly
(Pharmaceutical Development), Q9 (Qual- recognizes that there is no one way to implement
ity Risk Management), Q10 (Pharmaceutical the ICH guidelines, rather there are many per-
Quality System) and imminent Q11, and to fectly satisfactory ways to address the concepts
support the work of the ICH Implementation that are described. PQLI is therefore developing
Working Group. ISPE is working with industry a variety of tools to communicate science and
and regulatory leaders worldwide to support risk-based processes, and a growing series of
pragmatic and practical implementation of the publications demonstrates the areas of current
guidelines based on sound scientific, engineer- activity (see References).
ing, and business principles. Key goals of PQLI PQLI encompasses the whole of the product

Figure 1. The strategic

themes, structure, and
status of PQLI.

Reprinted from
PHARMACEUTICAL
ENGINEERING®
The Official Magazine of ISPE

May/June 2009,
Vol. 29 No. 3

©Copyright ISPE 2009

www.ISPE.org

36 PHARMACEUTICAL ENGINEERING May/June 2009

 Product Quality Lifecycle Implementation (PQLI)

“Within PQLI, ISPE has established multi-disciplinary, multi-national teams in support of

these strategic themes, addressing them from the perspectives of both small molecules
(chemically derived) and biotechnology.”

lifecycle and comprises three strategic themes - Figure 1. processes and examples which demonstrate this and show
how their application can result in significant business ben-
• Principles of Quality by Design efits. The paper provides three contrasting case studies which
• Pharmaceutical Quality System Elements indicate a wealth of opportunities to improve processes for
• Enablers existing products through the use of science- and risk-based
approaches, and the subsequent business benefits and regula-
These strategic themes represent the key components of tory opportunities that can accrue.
the ICH quality vision described at the July 2003 meeting The principles of QbD also are equally applicable to
in Brussels which supported the development of the recent biotechnology products. PQLI has an international team of
ICH quality guidelines: industry experts assembling technical guidance and examples
to support this sector of our industry.
“Develop a harmonised pharmaceutical quality system
applicable across the lifecycle of the product emphasiz- Pharmaceutical Quality System
ing an integrated approach to quality risk management As described in ICH Q10, the opportunities to change the
and science.” paradigm of development and manufacturing activities for full
utilisation of enhanced scientific approaches come only with an
Within PQLI, ISPE has established multi-disciplinary, multi- integrated and robust pharmaceutical quality system. At our
national teams in support of these strategic themes, addressing planned conferences in 2009 in Washington, Strasbourg, and
them from the perspectives of both small molecules (chemi- San Diego, PQLI is organizing presentations and workshops to
cally derived) and biotechnology. Ensuring alignment with
Continued on page 38.
the published ICH guidelines and supporting the future IWG
activities is a major focus of PQLI. The PQLI teams benefit
enormously though the presence of past and current mem-
bers of ICH Expert and Implementation working groups and
they have further benefitted from input and feedback from
members of the three ICH regulatory authorities.

Principles of Quality by Design

The principles of Quality by Design (QbD) are described in
ICH Q8(R1). Three multinational, multidisciplinary teams
were set up to address the priority topics of Criticality (Critical
Quality Attributes and Process Parameters), Design Space, and
Control Strategy. Through their deliberations a set of papers
was published in the Journal of Pharmaceutical Innovation
in June 2008. These papers were published with requests for
comments, and from the feedback received it is clear there is
a continuing need for PQLI to demonstrate how the concepts
of the ICH guidelines translate into practical application in
all areas of the product lifecycle. Industry continues to ask
to see the high level ICH concepts made simple, real, and
practical. A more comprehensive explanatory paper is in
preparation to show how the different elements of QbD fit
together. Case studies and worked examples are a helpful
way of exemplifying the principles and the PQLI teams are
actively developing such examples. These examples are all
aimed at providing clearer options that demonstrate there are
many ways of implementing an enhanced, Quality by Design
approach rather than suggesting there is just a single way.
The principles of QbD are applicable throughout the
lifecycle, and a publication in JPI (March 2009) describes

May/June 2009 PHARMACEUTICAL ENGINEERING 37

 Product Quality Lifecycle Implementation (PQLI)

Figure 2. PQLI process to generate technical implementation guidance.

explore the issues and potentially spawn further topic teams Conclusions
to develop the appropriate technical tools. The vision of the ISPE PQLI initiative is to make available
to our global industry the technical and scientific tools and
Enablers understanding that enable comprehensive implementation
The two enablers described in ICH Q10 are knowledge man- of the ICH quality vision. We are fortunate to have on our
agement and quality risk management. PQLI is addressing teams industry experts, current and past members of ICH
quality risk management primarily through the tools being Expert Working Groups, and to receive excellent feedback
developed to support QbD principles. Knowledge management from leading regulators across the ICH regions. Building on
is a vital enabler that has received little attention so far, but a foundation of the principles of QbD, PQLI is strengthen-
represents the key theme of ISPE’s Strasbourg Conference ing this work and now addressing the remaining elements
in September 2009 “Managing Knowledge through Science described in ICH Q10 to provide a unique and comprehensive
and Risk Assessment.” technical framework and set of guides.
ISPE welcomes all contributions, from both members and
Future Plans non-members, who have ideas and examples that describe the
PQLI will continue its efforts to assist in the adoption and practical application of the new ICH quality guidelines. ISPE
implementation of the ICH quality vision. The goal is to is keen to collaborate with colleagues and organizations who
provide a set of resources useful to small, medium, and large share the same objectives towards rapid and comprehensive
innovator companies working on chemical and biotechnology support of the implementation of the ICH quality vision.
active ingredients and products as well as generic companies. If you have any comments, or contributions you wish to
For established concepts, those that are already well-defined make to PQLI, please feel free to email PQLI@ispe.org.
by guidelines and the ICH implementation working group,
PQLI will continue to support and complement implementa- References
tion topics with practical case studies, training opportunities PQLI Publications
and extension of the understanding to global audiences. For 1. Garcia, T., Cook, G., and Nosal, R., PQLI Key Topics -
example, PQLI has in preparation a technical guide which will Criticality, Design Space, and Control Strategy, Journal
describe the continuum of development of a product through of Pharmaceutical Innovation (2008) 3:60–68.
to manufacturing and consideration of opportunities for con-
tinual improvement. Incorporating the feedback received on 2. Nosal, R., and Schultz, T., PQLI Definition of Criticality,
the June 2008 JPI papers, it pulls together the foundation Journal of Pharmaceutical Innovation, (2008) 3:69–78.
work on critical quality attributes and process parameters,
design space, and control strategy, linking to many case stud- 3. Lepore, J., and Spavins, J., PQLI Design Space, Journal
ies and examples illustrating implementation. of Pharmaceutical Innovation, (2008) 3:79–87.
For newer concepts, PQLI will support further debate and
discussion through papers, conference presentations, and 4. Davis, B., Lundsberg, L., and Cook, G., PQLI Control
workshops that involve both industry and regulators: this Strategy Model and Concepts, Journal of Pharmaceutical
well established process is illustrated in Figure 2 and is being Innovation, (2008) 3:95–104.
used to develop implementation guidance around strategic
themes 2 and 3. 5. Bolton, R., and Tyler, S., PQLI Engineering Controls and
Automation Strategy, Journal of Pharmaceutical Innova-
tion, (2008) 3:88–94.

38 PHARMACEUTICAL ENGINEERING May/June 2009

 Product Quality Lifecycle Implementation (PQLI)

6. Berridge, J.C., PQLI®: Current Status and Future Plans,

Journal of Pharmaceutical Innovation, (2009) 4:1–3.
Your Single Source Solution Provider
7. Potter, C., PQLI Application of Science- and Risk-based Director Series
Approaches (ICH Q8, Q9, and Q10) to Existing Products,
Journal of Pharmaceutical Innovation (2009), 4:4–23. Reactor Temperature
Control Module
Other Associated or Referring Publications
8. Ende, D., Bronk, K.S., Mustakis, J., O’Connor, G., Santa
Maria, C.L., Nosal, R., Watson, T. J. N., API Quality by
Design Example from the Torcetrapib Manufacturing
Process, Journal of Pharmaceutical Innovation, (2007)
2:71–86.

9. Somma, R., Development Knowledge Can Increase Manu-

facturing Capability and Facilitate Quality by Design,
Journal of Pharmaceutical Innovation, (2007) 2:87–92.

10. Drennen, J.K., III, Editorial: Introducing PQLI Innovations

from ISPE’s Product Quality Life Cycle Implementation
(PQLI) Initiative, Journal of Pharmaceutical Innovation,
(2008) 3:59.

11. JPI Interviews Moheb Nasr, PhD, Director, Office of New

Drug Quality Assessment (ONDQA), CDER, US FDA,
Journal of Pharmaceutical Innovation, (2007) 2:67–70.

About the Author Features Include:

Dr. John Berridge retired from Pfizer Global � Temperature Range from -80º to +285ºC
Research and Development at Sandwich in
January 2006 as Vice President of Pharmaceu- � Stainless Steel Construction
tical Sciences. He spent more than 31 years at � Sizes from 20 Liter to 500 Gallon Reactors
Pfizer, starting as an Analytical Chemist, and
more recently responsible for all aspects of � Jacket Delivery Pressure Control
chemistry, pharmacy, analytical, and regula- � Single Loop or Cascade Control
tory CMC in Europe. His research interests
have been directed toward high performance liquid chromatog- � General Duty or Explosion Proof
raphy with special emphasis on the use of chemometrics. This Classification
research was recognized by the award of the Chromatographic
� PLC Control, Data Logging & Trending
Society’s Jubilee medal in 1989. Berridge was involved in the
Software, Self Tuning for Accuracy ±1ºC
ICH processes from their inception until November 2007,
representing EFPIA in the Quality topics discussions. He has
contributed to guidelines on impurities in drug substances and Budzar Industries has specialized in process
their dosage forms, specifications, and the Common Technical fluid heat transfer systems since 1975 and has
Document (Quality): he was the Industry rapporteur for the earned a global reputation for quality and
pharmaceutical development guideline (Q8). In 1995, he was ingenuity in the design, engineering, and
presented with an FIP IPS award for his outstanding contri- manufacturing of temperature control systems.
bution to industrial pharmacy and in 1997, he was awarded Budzar Industries systems are found throughout
the Royal Pharmaceutical Society Chiroscience award for his the world, delivering accurate temperature
services to the pharmaceutical industry. Berridge now acts measurement and control to the production of
as an independent consultant and as European Regulatory pharmaceuticals, chemicals, petroleum, rubber,
Affairs Advisor and PQLI project manager to ISPE. He can power, steel, food, and plastics.
be contacted by email: pqli@ispe.org.
Budzar Industries
38241 Willoughby Parkway
Willoughby, Ohio 44094
440-918-0505 • www.Budzar.com

May/June 2009 PHARMACEUTICAL ENGINEERING 39

 Global Regulatory Framework Overview
This article
provides Global Regulatory Framework Overview:
a general
overview of the US FDA, EMEA, PIC/S, and ICH
organizational
structures of the
US FDA, EMEA, by Dr. Kate McCormick
PIC/S, and ICH
as they relate to
pharmaceutical
manufacturing
and regulation.
The content US FDA

T
relevance to the regulation of drugs and biologi-
in this article he Food and Drug Administration (FDA) cal products are discussed below.
is sectioned has responsibility for regulation of
into three drugs and biological products which are Office of Regulatory Affairs
manufactured and/or sold in the US. The The Office of Regulatory Affairs (ORA) is the
Knowledge FDA is part of the Health and Human Services lead office for all field activities of the FDA. The
Briefs, which Department of the US government. Its role is to duties and functions of ORA are divided between
are available guard the welfare of consumers. Full details of four main Offices: Resource Management,
online and the FDA can be found at: www.fda.gov. Regional Operations, Criminal Investigations,
The FDA’s authority is based upon various and Enforcement. ORA regions are the Pacific,
free to ISPE Southwest, Central, Southeast, and Northeast
laws and statutory documents, as shown in
Members. Figure 1. While drugs fall under the Food, Drug, regions of the US. Each region supports a number
and Cosmetic Act, biological products fall under of local FDA offices.
not only the Food, Drug, and Cosmetic Act, but
also the Public Health Service Act. Center for Biologics Evaluation and
While the statutes provide the legal basis Research
for the FDA’s authority, the regulations which The mission of the Center for Biologics Evalu-
they enforce are contained within the Code of ation and Research (CBER) is to protect and
Federal Regulations, Title 21. Of particular enhance public health through the regulation
importance in relation to manufacturing are of certain therapeutic biological products as
parts 210 and 211. These are generally written well as blood products, vaccines, and tissue and
as 21CFR 210 and 21CFR 211. gene therapy products.

Organizational Structure Center for Drug Evaluation and

As Figure 2 shows, the FDA is divided into seven Research
main divisions or Centers. Detailed organization The Center for Drug Evaluation and Research
charts can be found at: http://www.fda.gov/oc/ (CDER) is responsible for the regulation of
orgcharts/orgchart.html. chemically-derived and most therapeutic bio-
The Centers and Offices that have particular logical products, both new drugs and generics.

Figure 1. Statutory and

Regulatory Authorities.
Center for Devices and
Radiological Health
Reprinted from The Center for Devices and Radiologi-
PHARMACEUTICAL cal Health (CDRH) is responsible for
ENGINEERING® the regulation of medical devices and
The Official Magazine of ISPE radiation emitting products.

May/June 2009, Office of Combination

Vol. 29 No. 3 Products
©Copyright ISPE 2009 The Office of Combination Products
www.ISPE.org (OCP) is an office within the FDA’s
Office of the Commissioner, which is
Continued on page 42.
40 PHARMACEUTICAL ENGINEERING May/June 2009
 Global Regulatory Framework Overview
In Phase II, which lasts 2 years, a
small number of patients are voluntarily
given the drug to determine its effective-
ness and to highlight any side effects.
In Phase III, a much larger popula-
tion of patients is given the drug to con-
firm its effectiveness and to identify any
adverse reactions over a longer period of
time. This phase lasts for between 3 and
3.5 years. Once these phases have been
Figure 2. Organizational structure of the FDA.
completed, the company files a New
responsible for general oversight of training in drug development, manu- Drug Application (NDA) or a Biological
the agency’s regulation of combination facturing, quality assurance, and risk Licensing Application (BLA) with the
products. The primary responsibilities management. These investigators, as FDA. The process of assessment and
for regulating specific combination well as other FDA drug investigators, approval by the FDA takes between
products remain in one of the product inspect all facilities that are regulated 1.5 and 2.5 years. Once the drug has
centers – CDER, CBER, or the CDRH. by CDER, including those manufactur- been approved and is marketed, there
The OCP is responsible for assigning an ing therapeutic biological products. The is a much larger potential population
FDA center to have primary jurisdiction Pharmaceutical Inspectorate is often for further testing. Additional post
(lead center) over a particular combina- assigned to inspect the higher risk drug approval testing related to a drug’s
tion product. The OCP also oversees manufacturing facilities. approved indication(s) intended to
multi-center reviews of combination optimize the safe and effective use of
products, ensures consistent and ap- Licensing/Approval Procedure the drug is called Phase IV testing.
propriate post-approval regulation of Figure 3 shows the approval or licens- It can be seen from the bottom of the
combination products, and resolves ing process for a New Chemical Entity figure that each approved drug arises
disputes relating to combination (NCE) by the FDA. The process, which from the evaluation of an average of
products. can take up to 15 years in total, may be 5,000 compounds.
divided into 8 phases. Firstly, there is
Team Biologics the pre-clinical stage, lasting between Pharmaceuticals in the 21st
The FDA Team Biologics was estab- 3.5 and 6.5 years. During this stage Century
lished in 1997 to assure the quality and in-vitro and in-vivo (animal) studies In August 2002, the FDA launched its
safety of biological products. It consists are carried out to assess safety and initiative “Pharmaceutical cGMPs for
of a core team of certified ORA investi- biological activity. At the conclusion of the 21st Century – A Risk-based Ap-
gators, CBER certified inspectors, and this stage, the company files an Inves- proach.” The launch document included
specially trained compliance officers tigational New Drug (IND) application. the following statement:
representing both ORA and CBER. In effect, this is a request for a permit
“FDA resources will be used most ef-
for the drug to be transported across
fectively and efficiently to address the
Pharmaceutical Inspectorate state boundaries for the purposes of
most significant health risks.”
FDA’s Pharmaceutical Inspectorate clinical trials.
was established under the agency’s Clinical trials are carried out on In other words, the agency does not
Pharmaceutical CGMP’s for the 21st humans. In Phase I, which lasts up to have sufficient resources to regularly
Century: A Risk-Based Approach. This 1.5 years, the drug is tested on healthy inspect all the sites around the world
is a group of certified FDA drug inves- volunteers to prove it is safe and to that are making drugs and biological
tigators who have received advanced identify the appropriate dosage. products for the US market. Hence, it
would use risk management to decide
the priorities for inspection.
At the same time, it said it required
from companies:

“The most up-to-date concepts of risk

management and quality systems ap-
proaches to be incorporated, while con-
tinuing to ensure product quality.”

The FDA wants companies to enhance

the scientific approach to GMP to
emphasize risk-based control point
Figure 3. The FDA approval or licensing process for a New Chemical Entity (NCE). analysis and decision-making. In other

42 PHARMACEUTICAL ENGINEERING May/June 2009

 Global Regulatory Framework Overview
words, for each situation, risks should Regulatory Documentation All these references are contained in
be assessed as a precursor to deciding In terms of regulation of manufacture of “The rules governing medicinal prod-
what action, and at what level, is ap- medicinal products, all member States ucts in the European Community.” They
propriate. are bound by a single set of legislation are available at: http://ec.europa.eu/
While this initiative was launched by (Directives) and regulations. In the EU, enterprise/pharmaceuticals/eudralex/
the FDA, it is in line with the philosophy regulation of medicinal products is the eudralex_en.htm.
of both the EU and Japanese regulators. same both for human and veterinary There are currently 10 volumes
It is the basis of recent activities within products. However, the legislation is covering different aspects of medicinal
ICH, culminating in the publication of covered by two Directives, both origi- products from development and regis-
three new guidelines: ICH Q8 (Pharma- nating from 2001: 2001/83/EC relates to tration through to marketing. Volumes
ceutical Development), ICH Q9 (Qual- products for human use and, 2001/82/ 1 and 5 contain all the legislation,
ity Risk Management), and ICH Q10 EC relates to veterinary products. including the directives mentioned
(Pharmaceutical Quality System). Over time, these Directives have previously. The remaining volumes
been amended; most recently, they contain the guidance documents.
EMEA have been expanded to include the Volume 4 is of specific interest as it
The European Medicines Agency manufacture of herbal medicines: concerns good manufacturing practices
(EMEA) (http://www.emea.europa.eu/) for medicines. It is divided into two
has overall responsibility for regulation • Directive 2004/27/EC (amending parts: Part I covers the requirements
of medicinal products within the Euro- Directive 2001/83/EC on human for the manufacture of finished products
pean Union (EU) (http://europa.eu/). medicines). or secondary manufacturing, as it is
The EU is an expanding group of • Directive 2004/28/EC (amending sometimes called, and Part II covers
countries in Europe that have commit- Directive 2001/82/EC on veterinary the requirements for the manufacture
ted to economic and political union. As medicines). of active substances, also known as Ac-
of 1 January 2009, there are 27 Member tive Pharmaceutical Ingredients (APIs)
States. The current members are shown The Directives are expanded and or sometimes as drug substances.
in Figure 4. explained via a series of guidance In addition to Parts I and II, there
documents. are a number of annexes. In some cases,
Continued on page 44.

May/June 2009 PHARMACEUTICAL ENGINEERING 43

Hach-PAT700-inuse-halfpg.indd 1 12/23/2008 11:13:18 AM

 Global Regulatory Framework Overview
• provides independent, science-based
recommendations on the quality,
safety, and efficacy of medicines
and on more general issues relevant
to public and animal health that
involve medicines.
• applies efficient and transparent
evaluation procedures to help bring
new medicines to the market by
means of a single, EU-wide market-
ing authorization granted by the
European Commission.
• implements measures for continu-
ously supervising the quality, safety,
and efficacy of authorized medicines
to ensure that their benefits out-
weigh their risks.
• provides scientific advice and incen-
tives to stimulate the development
and improve the availability of in-
novative new medicines.
• recommends safe limits for residues
of veterinary medicines used in food-
producing animals for the establish-
Figure 4. Member states of the European Union (EU) as of 1 January 2009.
ment of maximum residue limits by
the European Commission.
these represent the requirements relat- of Medicinal Products. It later became • involves representatives of patients,
ing to specific types of products, whereas known as the European Medicines healthcare professionals, and other
others expand on the requirements of Evaluation Agency (hence the acronym stakeholders in its work, to facilitate
Part I or deal with new concepts that EMEA), but has since changed its name dialogue on issues of common inter-
have developed since the main text was to the European Medicines Agency. est.
published. The EMEA is responsible for evalu- • publishes impartial and comprehen-
ation of the safety, efficacy, and quality sive information about medicines
The European Medicines Agency of products which are submitted for a and their use.
The EMEA was set up in 1995 as the marketing authorization within the EU. • develops best practice for medicines
European Agency for the Evaluation The EMEA: evaluation and supervision in Eu-
rope, and contributes alongside
Member States and the European
Commission to the harmonization
of regulatory standards at the in-
ternational level.

The EMEA is a scientific body that

advises individual Member States and
other bodies within the EU and uses a
network of scientists from across the
EU to facilitate the operation of the
evaluation system. It has responsibility
for the procedures to authorize phar-
maceuticals, monitor them once in the
marketplace and withdraw that autho-
rization if there is evidence of a problem.
The EMEA also operates information
sources and electronic communication
in order to enhance the safe use of
pharmaceuticals within the EU.
Figure 5. Organizational structure of the EMEA.

44 PHARMACEUTICAL ENGINEERING May/June 2009

 Global Regulatory Framework Overview
Organizational Structure required, but a full assessment will not application was made.
The EMEA is located in London. Its be carried out.
organizational structure is shown in National Authorizations
Figure 5. Decentralized Procedure It also is possible for a drug to be regis-
The EMEA is divided into five divi- Under the decentralized procedure, tered for sale in a single Member State
sions, three of which involve review which also is applicable for conventional only. This is particularly used for legacy
and approval responsibilities. One drugs, an application is made simulta- products that are imported from third
division focuses on pre-authorization neously to a number of Member States. countries (countries outside of the EU),
(assessment of drugs before they are One State is appointed as the Reference where the license was in place before
launched on the market place) while Member State to carry out the assess- the importing countries had access to
another deals with post-authorization ment. Authorization, if granted, will 26.03.2009
_Anz_Schaltschr190x115en.qxd the EU. 10:35 Uhr Seite 1
of medicines for human use (evaluation apply within the States to which the
Continued on page 46.
of drugs after they have been launched,
primarily through the pharmacovigi-
lance system).
The EMEA inspection section is
in the same division as veterinary
medicines. However, this is for organi-
zational reasons only; the inspections
section relates both to human and
veterinary medicines. Communications
and administration functions round out
the remaining two divisions.
It is important to note that while
the EMEA coordinates GMP inspection
activities across the Member States,
it does not have any inspectors in the
section. Each Member State has one or
more national inspection bodies respon-
sible for carrying out the inspections.
There is mutual recognition of these
inspections across all Member States.

Authorization Procedures
within the EU
There are a number of different ways in
which drugs can be authorized for sale

Ready to install!
in the EU, depending on the nature of
the drug and its supply chain:

Centralized Procedure
For some specific drug types, including
biotechnology products, orphan drugs, The ultimate in one-stop shopping.
and veterinary growth enhancers, it is Pre-assembled, customer-specific
mandatory to use the centralized proce-
dure. A single application is made to the control cabinets, completely equip-
EMEA and authorization, if granted,
applies across all Member States. ped to boost the reliability of your
systems. Designed for fast commis-
Mutual Recognition Procedure
For the majority of conventional drugs, sioning and harsh ambient conditions.
the mutual recognition procedure is
applicable. As the name suggests, an
authorization which has already been
granted by one Member State will be www.festo.com
recognized by other Member States.
In this case, a separate application is

May/June 2009 PHARMACEUTICAL ENGINEERING 45

 Global Regulatory Framework Overview
Summary • to pursue and strengthen the co- document apart from minor changes in
The role of regulatory authorities like operation established between the terminology and one annex.
the European Medicines Agency in the participating authorities in the field Other key guidelines include those
scientific evaluation and oversight of of inspection and related areas with relating to blood establishments and
medicines is critical in the assurance of a view to maintaining their mutual APIs. The guideline on Site Master Files
both public and animal health. To learn confidence and promoting quality includes a template that many compa-
more about the agency and its opera- assurance of inspections nies use to write their own SMF.
tions and purview, please visit their web • to provide the framework for all These and other publications are
site: http://www.emea.europa.eu/. necessary exchange of information available in downloadable PDF formats
and experience from the PIC/S web site.
PIC/S and ICH • to coordinate mutual training for in-
The evaluation and approval of medi- spectors and other technical experts Membership of PIC/S
cines for human use along with responsi- in related fields In order to become a member of PIC/S,
bilities for inspection and oversight of the • to continue common efforts toward the authority in question has to dem-
manufacturing and distribution of these the improvement and harmonization onstrate that it has the organizational
medicines occurs at numerous agencies of technical standards and proce- framework and procedures in place to
around the globe. Manufacturers of phar- dures regarding the inspection of the apply a GMP inspection system that is
maceutical products face substantial manufacture of medicinal products at least on a par with those of the other
challenges in assuring that their prod- and the testing of medicinal products members. This will include a formal
ucts and processes conform to the varied official control laboratories quality management system similar to
requirements of these agencies. These • to continue common efforts for the ISO 9000, although it does not need to
organizations are the Pharmaceutical development, harmonization, and be externally accredited. The author-
Inspection Co-operation Scheme (PIC/S), maintenance of Good Manufacturing ity also has to demonstrate that it has
which is primarily involved in mutual Practice (GMP) trained, competent inspectors who can
recognition of GMP inspection results • to extend the cooperation to other operate the system effectively.
between the regulatory authorities of its competent authorities having the As part of the accession process
members, and the International Confer- national arrangements necessary (and on an ongoing basis) inspectors
ence on Harmonisation (ICH), which to apply equivalent standards and take part in multinational inspection
is primarily involved in harmonized procedures with a view to contribut- teams which provides peer review on
drug regulatory requirements between ing to global harmonization their systems and practices.
Europe, the US, and Japan. There are currently 37 regulatory
The PIC/S Web site, www.picscheme. authorities, from 34 countries, that are
Establishment and Purpose of org, is a very useful reference site. full members of PIC/S, as shown below.
PIC/S (e.g., the Czech Republic and France
PIC was set up in 1970 under the aus- PIC/S Publications have 2 authorities, one dealing with
pices of the European Free Trade As- The documentation that is developed human medicines and the other with
sociation (EFTA). Its full title was “The and published by PIC/S is useful both veterinary products.) Twenty-two of
Convention for the Mutual Recognition for the inspectorates (for whom the the 27 member States of the EU are
of Inspections in Respect of the Manufac- references are primarily intended) and included in this number.
ture of Pharmaceutical Products.” also for industry (who can use the refer- At any time, there also will be other
PIC is a legally binding treaty ences to understand what inspectors regulatory authorities being assessed
between countries. However, under are going to look for). for membership or having expressed
EU law, it is not permissible for indi- The GMP guide PE009-7 was is- an interest in the workings of PIC/S.
vidual Member States to sign treaties sued in its latest form in May 2007. It Although all members of PIC/S have
with countries outside the EU. Only is virtually identical to the EU Part I to operate to an equivalent standard,
the European Commission can sign
such treaties. However, the European
PIC/S Full Members
Commission is not a member of PIC.
Argentina, Australia, Austria, Belgium, Canada, Cyprus, Czech Republic (x2),
If the work of PIC was not to be lost, a
Denmark, Estonia, Finland, France (x2), Germany (x2), Greece, Hungary,
compromise needed to be found.
Iceland, Ireland, Israel, Italy, Latvia, Liechtenstein, Malaysia, Malta, Nether-
The PIC Scheme (PIC/S) was set up
lands, Norway, Poland, Portugal, Romania, Singapore, Slovak Republic, South
in 1995. It differs from PIC in that it is
Africa, Spain, Sweden, Switzerland, United Kingdom
an informal agreement between regula-
tory authorities in Member States and
PIC/S Partners
is not legally binding. However, its goals
European Directorate for the Quality of Medicines and Healthcare (EDQM),
are an extension of those of PIC. The
European Medicines Agency (EMEA) and UNICEF.
purpose of the PIC scheme is:
Concludes on page 48.
46 PHARMACEUTICAL ENGINEERING May/June 2009
 Pharmaceutical
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 Global Regulatory Framework Overview
they are not all using the same refer- The ICH Web site can be found at: 1. Overview of FDA – http://www.
ence documents. For example, the 22 www.ich.org. ispe.org/cs/explore_by_topic/fda_re-
members that also are Member States sources
of the EU will be using Volume 4 Parts ICH Publications 2. What’s New at the FDA – http://
I and II. Unlike PIC/S, publications from ICH www.ispe.org/cs/resourcecenter
Other members, such as Canada and are for direct use in industry. Topics are 3. Recent FDA Slide Presentations –
Australia, will have their own national subdivided into four categories: http://www.ispe.org/cs/fda_section/
documentation. However, if these docu- recent_fda_slide_presentations
ments were examined in detail, it would • Quality topics, relating to chemical 4. What’s New at the EMEA – http://
be very difficult to identify significant and biotechnical active ingredients www.ispe.org/cs/resourcecenter
differences in the principles being ex- and to pharmaceutical products 5. Knowledge Briefs: http://www.ispe.
pressed. • Safety topics, relating to in vitro and org/cs/resource_library_section/
in vivo pre-clinical studies knowledge_briefs
Establishment and Purpose of • Efficacy topics, relating to clinical • “Quality by Design,” by John Ber-
ICH studies in human subjects ridge, KB-0001-Jun08.
The full title of ICH is “The Interna- • Multidisciplinary topics, where ex- • “Risk-Based Approaches to Cross
tional Conference on Harmonisation of perts from more than one discipline Contamination,” by Stephanie
Technical Requirements for Registra- collaborate in the development of Wilkins, KB-0004-Oct08.
tion of Pharmaceuticals for Human guidelines which do not uniquely 6. Product Quality Lifecycle Implemen-
Use.” ICH was set up in 1990 as a joint fit into one of the above categories tation: http://www.ispe.org/pqli
forum between regulatory authorities
and the pharmaceutical industry, with In the first category, Quality topics, a About the Author
a focus on harmonizing the procedures widening of scope has been seen. For ex- Dr. Kate McCor-
used to evaluate the safety, quality, and ample, it was via ICH that the guideline mick of Heathside
efficacy of medicines. At that time, com- for Active Pharmaceutical Ingredient Information Services
panies were experiencing difficulties in (API) manufacturing has been formal- Ltd, United Kingdom,
submitting dossiers for product licenses ized, with the publication of ICH Q7 is a manufacturing
in different countries and regions due to Good Manufacturing Practices for Phar- consultant with ex-
differing regulatory expectations. maceutical Ingredients. This has since tensive strategic and
The purpose of ICH was to identify been incorporated into the regulatory operational manage-
ways in which greater harmonization guidance of the EU, Japan, and the US. ment experience in the pharmaceutical
could be achieved in the interpretation More recently, a new ICH Quality Vision industry, both in the UK and inter-
and application of technical guidelines was developed which spawned guidelines nationally. She has 10 years of line
and requirements for product registra- in support of a greater emphasis on sci- management and 20 years of internal
tion. This would reduce the need for ence and risk-based approaches. and external consulting experience. She
duplicate testing during research and Three key documents have been has worked with multinationals, SMEs,
development of new medicines. produced to date: non-governmental organizations and
The objective was therefore more national regulatory authorities in more
economical use of resources, and elimina- • ICH Q8 (R1) Pharmaceutical Devel- than 50 countries. She is the author
tion of unnecessary delay in the develop- opment of Quality (a textbook within the But-
ment and availability of new medicines • ICH Q9 Quality Risk Management terworth Heinneman pharmaceutical
while maintaining safeguards on quality, • ICH Q10 Pharmaceutical Quality engineering series) and Manufacturing
safety and efficacy, and regulatory obli- System in the Global Pharmaceuticals Industry,
gations to protect public health. the editor of gmp Review and a regular
Since the emphasis was on products These publications have been the cata- speaker at international conferences.
containing new drugs, the scope of the lysts in creating a major transformation McCormick gained a degree in biochem-
activities was limited to registrations in the ways in which the industry will istry and a doctorate in microbiology,
in Western Europe, Japan, and the US, be developing, manufacturing, and over- both at London University. She also has
where the majority of new medicines seeing the quality of future medicines a Masters in Business Administration.
are currently developed. and related products. She is registered as a senior GMP expert
Work occurs within ICH by means of within the EU and is eligible as a QP
Expert Working Groups which are ap- For Further Information under the terms of the EU directive.
pointed to develop guidance on specific For more detailed and related informa- She is currently European Education
topics. In the past few years, the scope tion, the following ISPE resources are Advisor for ISPE. She can be contacted
of ICH discussions has widened to in- available: by telephone: 44-1626-854611 or by
clude not only R&D, but also activities email: kate@heathside.com.
relating to manufacturing.

48 PHARMACEUTICAL ENGINEERING May/June 2009

 Global Regulatory Framework Overview
SM

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May/June 2009 PHARMACEUTICAL ENGINEERING 49

 Barrier Isolation History and Trends
This article
presents the Barrier Isolation History and Trends –
final data
from a survey 2008 Final Data
conducted
on the use of
barrier isolators by Jack Lysfjord and Michael Porter
for automated
fill/finish
operations.

A
s the journey in time of barrier isolation perfection with all data. Numbers are as good
technology went from prototypes in the as the data we get, and they are not absolute.
late 1980s and early 1990s to today, Trends are real and that is what should be used
there have been questions regarding for comparison.
the need for benchmarking the usage of bar- This is the sixth survey on the use of Barrier
rier isolator technology. Another way to say it Isolators for automated fill/finish operations
is; what is everyone else doing in regard to this that began in 1998. The surveys have been done
technology? This survey presents its history and only on the even years because of the energy
trends. We have attempted to gather as much content it requires by both the authors and the
information as possible to use as a database; users. Manual operations in a glovebox are not
however, we also know that we never achieve considered. It is evident that usage of barrier
isolator technology continues to
1998 2000 2002 2004 2006 2008 become much more common in the
84 172 199 256 304 391 industry.
In the advanced aseptic pro-
Table A. Filling barrier isolators (worldwide).
cessing arena a new relative has
evolved called a Restricted Access
1998 2000 2002 2004 2006 2008 Barrier System (RABS). Surveys for
11 19 30 42 50 59 this technology were done in 2005
Table B. Filling barrier isolators (Asia only). and 2007 with the 2007 data to be
presented in another article to be
1998 2000 2002 2004 2006 2008 published.
57 85 97 116 146 196 Table A shows 391 total isolators
worldwide for aseptic fill/finish ap-
Table C. Filling barrier isolators (Europe only). plications (that we know of) in 2008
as well as the progression of number
1998 2000 2002 2004 2006 2008 of units since 1998. Tables B to D
35 49 66 90 105 133 show the major pharmaceutical re-
gion breakouts for Asia, Europe, and
Table D. Filling barrier isolators (North America only).
North America. Figure 1 shows the
global deliveries by year. Figures 2
to 4 again show deliveries by year
Reprinted from for the three regions.
PHARMACEUTICAL Some companies embrace tech-
ENGINEERING® nology while others wait. Figure 5
The Official Magazine of ISPE shows companies who have most
aggressively embraced the use of
May/June 2009, isolators. Figures 6 to 8 show the
Vol. 29 No. 3 regional breakout information. Table
©Copyright ISPE 2009 E displays the increasing number
www.ISPE.org of pharmaceutical companies using
Figure 1. Barrier isolator filling lines – deliveries by year. isolators (99).

50 PHARMACEUTICAL ENGINEERING May/June 2009

 Barrier Isolation History and Trends
Container type is shown in Figures 9 to 12. It is interesting
to see how, for example, the usage of ampoules and syringes
in Asia and in Europe compare to in North America.

Figure 4. Barrier isolator filling lines – deliveries by year (North

America only).

Figure 2. Barrier isolator filling lines – deliveries by year (Asia only).

Figure 3. Barrier isolator filling lines – deliveries by year (Europe only). Figure 5. Barrier isolator filling lines – companies with highest usage.
Continued on page 52.

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May/June 2009 PHARMACEUTICAL ENGINEERING 51
 Barrier Isolation History and Trends
Maximum line speed is shown in the next four graphs 13 ISO 8 in operation with hydrogen peroxide vapor used in
to 16. It is interesting to note the majority of isolator usage in 87% of the reported applications for the biodecontamination
North America is for slow speed operation 1 to 100/minute. agent.
Since 1998, the isolators have been hard wall (stainless Gloves can be one of the most scrutinized areas by regula-
steel and glass). Soft wall applications were used when the tors. Type of glove used is a decision to be made by users of
technology started, but reliability, pressure change issues, the technology. Two piece gloves were preferred by 54% over
sterilant absorption, and outgassing pushed the manufactur- one piece gloves 46%. If gloves are two piece, smooth sleeves
ing to hard wall design. are preferred by 86% over pleated sleeves 14%.
Surrounding room classification is predominately (65%) Glove replacement period data is in Figure 17 with some

1998 2000 2002 2004 2006 2008

32 56 67 83 84 99
Table E. Number of companies using barrier isolation.

Figure 6. Barrier isolator filling lines – companies with highest usage

(Asia only).
Figure 9. Container type.

Figure 10. Container type (Asia only).

Figure 7. Barrier isolator filling lines – companies with highest usage

(Europe only).

Figure 11. Container type (Europe only).

Figure 8. Barrier isolator filling lines – companies with highest usage

(North America only). Figure 12. Container type (North America only).

52 PHARMACEUTICAL ENGINEERING May/June 2009

 Barrier Isolation History and Trends

Figure 13. Maximum speed. Figure 15. Maximum speed (Europe only).

Figure 16. Maximum speed (North America only).

Figure 14. Maximum speed (Asia only).

companies able to use gloves up to six months. Method of 89% of responses indicated usage of a second thin glove with
integrity testing gloves is shown to be predominantly by pres- the glove port (typically placed on the hand prior to entering
sure decay - Figure 18. Visual inspection also should be done. the glove port).

Continued on page 54.

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May/June 2009 PHARMACEUTICAL ENGINEERING 53
 Barrier Isolation History and Trends
Positive overpressure is typically used in these applica-
tions. The concept of “more is always better” does not apply to
systems with mouse holes at exits or depyrogenation tunnels
that are interfaced with the isolator. Too much overpressure
can “blow” the tunnel hot zone air into the washer and melt
many parts. Small vials can be blown out of mouse holes
destroying the product. Figure 19 indicates that the majority
of applications operate between 21 and 40 pascals or ~.1 to
.2 inches of water over pressure.
Tunnel sterilizable cool zone technology was used by 65% Figure 17. Glove replacement period.
of those responding.
Containment was a requirement on 42% of total responses
over the six surveys. The data with this question must be
looked at on a survey by survey basis to look at percent of
containment needed on these responses for a two year period.
Since 2006, 100% of 2008 responses indicated a containment
need.
Those that indicated that they campaigned product fills
within one isolator sterilization event made up 59% of re-
sponses. Figure 20 shows the length of campaign from the Figure 18. Method for integrity testing of gloves.
responses. The maximum campaign length is 28 days.
Finally, cumulative deliveries of isolators are shown in
Figure 21. We believe that isolator usage is increasing even
faster than shown at the time of writing this article based on
equipment manufacturers comments. Data was gathered in
first quarter 2008 and the 2009 increase will be much larger

www.ISPE.org/strasbourgconference
Figure 19. Pressure to washer rooms (12.5 Pascals = .05" Water).

than shown here. 2009 data counted was only for what was
ordered by first quarter 2008 for delivery in 2009. Many more
lines were ordered for 2009 after the data was collected. The
dotted line indicates a change in slope after 2004.
The Trends and Conclusions are:

• Worldwide increase in filling line isolators continues (391)

with significant increase in Europe (50) from 2006.
• Asia (9) and North America (28) showed growth in two
Managing Knowledge through years.
Science and Risk Assessment • Isolators are embraced by some companies and avoided
by others.
• Mergers and facility consolidation impact the number of
28 September - user companies.

1 October 2009
• Number of reported isolator lines in operation increased
(230 to 283) in two years.
Palais de Congrès • Vials continue to be the predominant container.
Holiday Inn Strasbourg City Centre • Hard wall isolators continue to be the preference.
• Smooth sleeve gloves are even stronger than in 2006
(86%).
• Slight preference for two piece gloves (54%).
Sponsorship and Table Top Exhibit • Use of a thin second glove is very strong (89%).
Opportunities Available • Use of depyrogenation tunnels with sterilizable cool zone
increased (65%).

54 PHARMACEUTICAL ENGINEERING May/June 2009

 Barrier Isolation History and Trends

Figure 20. Campaign products (longest run).

The Most Gentle Touch

in Biotechnology
Like a newborn baby, biologically derived products
require careful, precise and tender handling. Our
centrifuges provide this treatment and more:
Figure 21. Barrier isolator filling line – cumulative deliveries (2009 is
partial data). Hydrohermetic feed for gentle product treatment
Hydrostop for highest yields
• Containment need is increasing (42%) (100% in last two
years).
Hygenic design for cleaning-in-place (CIP) and
• Campaigning is increasing (59%). sterilization-in-place (SIP)
Scaled for 2 to 25,000 liter reactors
Benchmarking information for those companies investigat- GMP-compliant documentation
ing the use of isolators is shown below (strongest preferences
from survey): To learn more about GEA Westfalia Separator and
how we can assist you with your separation needs
• hard wall isolator; stainless steel and glass in developing and manufacturing breakthrough
• biodecontamination technology using hydrogen peroxide biotech products, please contact Sean Eicher at
vapor (201) 784-4318 or email Sean.Eicher@geagroup.com.
• ISO 8 in operation surrounding room classification
• gloves only, meaning minimize use of half-suits for inter-
ventions
• two piece gloves with smooth sleeves
• use of a thin second glove
New Patterson, CA full-service repair, parts
• doing glove integrity tests with pressure decay test (plus and training facility now open!
visual)

Capital equipment technology and the accompanying de-

preciation expense last a long time. Remember that today’s
decisions will impact the company for 15 to 25 years. Look at
what is in the pipeline for R&D to make a decision that will
cover future products. Many product candidates will have
the need of aseptic processing and containment in order to
protect both operators and product.

* The author may be contacted for questions or comments by GEA Westfalia Separator, Inc.
telephone: +1-952-546-2082 or by email: jlysfjord@Q.com. 100 Fairway Court · Northvale, NJ 07647
Phone: (201) 767-3900 · Fax: (201) 767-3416
1212H

Service: (800) 509-9299

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May/June 2009 PHARMACEUTICAL ENGINEERING 55
 RABS History and Trends
This article
presents the Restricted Access Barrier System
2007 final data
of a survey (RABS) History and Trends – 2007
conducted on
the use of RABS Final Data
for automated
fill/finish
operations for by Jack Lysfjord and Michael Porter
aseptically filled
injectable drugs.

T
he authors have done surveys on the use conventional cleanroom situation using existing
of barrier isolator technology in 1998, process equipment. The solution was to create a
2000, 2002, 2004, and in 2006. These hard wall barrier with glove ports and transfer
surveys are an attempt to “benchmark” ports for stoppers to separate the operator from
the pharmaceutical industry on a global basis the critical zone or filling closing zone. This bar-
and to look at the historical data and the trends. rier sat in a cleanroom which was class 100 (ISO
The data is for automated fill/finish operations 5) in operation with full ceiling HEPA filters
for aseptically filled injectable drugs. Manual that generated unidirectional airflow on both
operations and hand filling and closing in a glove the outside and inside of the barrier. The top of
box are not considered. In 2004, a question was the barrier was approximately six inches below
asked if it would be possible to get the same type the HEPA filters and extended below the filling
of information for RABS since there seemed to stoppering machine table top with a three inch
be a great deal of interest in this technology. air gap to the table top for air to flow out of the
Due to the energy required to do each survey, barrier with no pressure differential. The doors
the best fit was on the alternate years 2005 and were physically locked to prevent any interven-
2007. The 2004 isolator and 2005 surveys were tions. The operator to product separation was by
presented in conferences, but not published. a hard wall barrier together with air flow with
The 2005 RABS data points are presented here no pressure differential – the first RABS.
along with the RABS data from 2007. Isolators provide separation between the
RABS is a spin off from isolators. Pfizer, Ka- operator and product with a hard wall barrier
lamazoo Michigan (previously Upjohn) in 1992 and pressure differential.
coined the term RABS for “Restricted Access The first RABS was a “Passive RABS.” There
Barrier System.” Their goal was to reduce the also is “Active RABS” and “Closed RABS” today.
contamination risk to a product when filled in a Figures 1 to 3 depict types of RABS.

Reprinted from
PHARMACEUTICAL
ENGINEERING®
The Official Magazine of ISPE

May/June 2009,
Vol. 29 No. 3

©Copyright ISPE 2009

www.ISPE.org
Figure 1. Passive RABS. Figure 2. Active RABS. Figure 3. Closed RABS.

56 PHARMACEUTICAL ENGINEERING May/June 2009

 RABS History and Trends
The use of a RABS implies more than the enclosure since • a quality system
the following must be in place for the concept of separation • proper surrounding room design (ISO 7 minimum)
with air flow to be successful and reduce the contamination - ISO 5 annex for open door interventions
risk to the product: • proper gowning
• proper cGMP training
• properly designed equipment • initial high level disinfection with a sporicidal agent
• management oversight • proper SOP for rare allowed interventions
- disinfection (non sporicidal)
- line clearance
Year Asia Europe North America TOTAL
- documentation of the event
2005 12 40 23 75
2007 23 63 38 124
The S in RABS is for “SYSTEM” and without the systems and
Table A. Number of RABS units. procedures above, a simple enclosure is not a RABS and can
result in increasing the risk to the product.
In 2005, Stewart Davenport from Pfizer, Kalamazoo,
Michigan (part of the team that developed the first RABS)
and Joerg Zimmermann from Vetter, Ravensburg, Germany,
presented data on cumulative RABS lines media fills from
both companies. Each had media fill data that were over one
million media fills with no unexplainable positives. They both
use the philosophy of never opening the doors of their RABS
yielding data equivalent to media fill data of isolators. That
is impressive. Here is the survey of RABS history and trends
for 2007.
We found 124 RABS in the 2007 RABS survey. Table A
gives 2005 and 2007 data and the breakout between Asia,
Europe, and North America.
Continued on page 58.
Figure 4. Number of RABS units delivered by year.

DELABELING SOLUTIONS
for
• SYRINGES*
• CARTRIDGES
• GLASS VIALS
• PLASTIC VIALS
• METAL CANISTERS
*new 2009
Figure 5. Number of RABS units delivered by year (Asia only).
Information:
www.hurstcorp.com

Other HURST products:

Automatic vial TrayLoaders,
plastic vial trays and custom made
stainless steel products.

HURST CORPORATION 610-687-2404

Box 737 - Devon, Pennsylvania 19333 - USA
Figure 6. Number of RABS units delivered by year (Europe only).

May/June 2009 PHARMACEUTICAL ENGINEERING 57

 RABS History and Trends
The number of RABS delivered by year overall and the
three region breakout are shown in Figures 4 to 7. The types
of RABS, passive, active, and closed, are described in Table B.
RABS operating philosophy- never opened, limited open, and
frequent open responses are shown in Table C. The alarming
piece of data indicates many systems (17 companies) frequently
open the doors of their RABS.
A listing of the companies with the highest RABS usage
is shown in Table D. In 2005, 28 companies had RABS. In
2007, the number increased to 36. In 2005, 25 RABS lines
were reported in operation. 36 were in operation in 2007.
Table E shows the RABS lines and the container types that

Figure 8. Maximum line speed/minute.

Figure 7. Number of RABS units delivered by year (North America

only).

Figure 9. Maximum line speed/minute (Asia only).

Year Passive Active Closed TOTAL
2005 16 25 17 58
2007 35 52 39 126
Table B. Types of RABS.

Year Never Opened Limited Open Frequently Open TOTAL

2005 22 29 1 52
2007 31 48 17 96
Table C. Philosophy for using RABS.

2005 2007
# Company # of Rabs Company # of Rabs
1 Vetter Pharma 10 Vetter Pharma 10
Figure 10. Maximum line speed/minute (Europe only).
2 Pfizer 7 Pfizer 10
3 Aventis 5 GSK 7
4 GSK 4 Aventis 5
Table D. Top 4 companies with RABS.

2005 2007
Vial/Bottle 48 77
Ampoule 8 12
Syringe/Cartridge 18 29
Ophthalmic 2 5
IV 0 0
Other (including BFS) 0 2
TOTAL Responses 76 125
Table E. Types of containers processed in RABS. Figure 11. Maximum line speed/minute (North America only).

58 PHARMACEUTICAL ENGINEERING May/June 2009

 RABS History and Trends
Year Autoclave Sanitize in Place Other TOTAL
2005 16 11 4 31
2007 16 21 12 49
Table F. Method of sanitizing gloves.

Year Yes No TOTAL Respondents

2005 29 0 29
2007 31 7 38
Table G. Second inner glove used.

2005 2007
Each Cycle 4 3 Figure 12. Number of days line campaigned.
Every 5 Runs 1 1
Every 15 Cycles 10 10
Every 6 Weeks 1 1
Every 3 Months 4 4
Every 6 Months 0 1
As Needed 8 18
TOTAL Responses 28 38
Table H. Glove replacement time.

2005 2007
Pressure Decay 20 20
Visual 4 18
Other 2 2
None 1 1 Figure 13. RABS.
TOTAL Responses 27 41
Table I. Glove test method. they process. Figure 8, 9, 10, and 11 lists frequency of RABS
use by maximum line speed in total and then breakouts for
2005 2007 the three regions.
Active Oxygen Agent 10 Glove data is listed in Tables F, G, H, and I. The types of
Gas Formaldelhyde 10 sanitizing agents used are listed in Table J.
Spor Klenz 0 6 When RABS lines campaign product, the length of cam-
Chemical Agent and Formaldehyde Gas 5 5 paign in days and frequency are displayed in Figure 12. Six
Peracetic Acids 3 3 of the responses indicated a need for containment of potent
Chemica Agent and VHP Gas 2 2 product to protect the operator.
Decon Quat 100 2 2 Figure 13 displays the cumulative use of RABS and how
Germex B12, Apesin AP3, Apesin Rapid 2 2 the rate of delivery has jumped since 2003. Note that nine
IPA 2 responses did not indicate year of delivery to get total to 124
Rotating Disinfectant Regime 2 units. In summary:
2 Phenols + IPA 1 1
Bleach/Detergent 1 • RABS use is increasing globally.
Disinfectant Medium Level • Europe is ahead of North America-similar to isolator
Alkalidetergent High Level 1 data.
Hydrogen Peroxide 1 1 • Asia started later, but is increasing in use of RABS.
Hypochlorite 5% 2 1 • RABS is an option to consider to improve asepsis particu-
Liquid Disinfectant 1 1 larly with retrofits.
Same as Room Sanitizers, typical 1 • Frequent opening of doors on the barrier is a big caution
Vesphene, LPH 1 1 area since it will compromise asepsis. If this is the routine
VHP Gas 1 1 mode of operation, it is not a RABS.
Alcohol 70%, decon. clean 1
TOTAL Responses 28 38 * The author may be contacted for questions or comments by
telephone: +1-952-546-2082 or by email: jlysfjord@Q.com.
Table J. Types of sanitizing agents.

May/June 2009 PHARMACEUTICAL ENGINEERING 59

 ISPE Update

US FDA Speakers Figure Prominently at ISPE’s Reprinted from

PHARMACEUTICAL
ENGINEERING®

2009 Washington Conference

The Official Magazine of ISPE

May/June 2009,
Vol. 29 No. 3

©Copyright ISPE 2009

www.ISPE.org

N
umerous regulators from the US Food and Drug CDER), Elaine Morefield (Supervisory Chemist, CDER),
Administration (US FDA) were featured speakers at Grace McNally (Senior Compliance Officer, CDER) and
the ISPE 2009 Washington Conference – Engineering Patrick Swann (Deputy Director, Division of Monoclonal
Regulatory Compliance, that took place at the JW Marriott Antibody, CDER) of the US FDA were invited, as well.
in Washington, DC, USA, 1 to 4 June 2009.
Speaker information – along with seminar agendas and • Ilisa Bernstein (Sr. Advisor Pharmacist, CDER) and Steven
training course outlines – for the four-day event are available Silverman (Regulatory Counsel, CDER) were featured US
on the ISPE Web site and include the following listings: FDA speakers at the Global Supply Chain Integrity and
Anti-Counterfeiting seminar. A representative from the
• Richard Friedman (Director, Mfg. and Product Quality, FDA’s Office of Policy and Program Planning, CDER also
CDER), Tara Gooen (Chemical Engineer, CDER), Robert was invited to speak.
Sausville (Supervisory Consumer Safety Officer, CBER),
and Joyce Rockwell (Consumer Safety Officer, CBER) were • Barry Rothman, Consumer Safety Officer for the FDA’s
featured US FDA speakers at the 18th Annual Barrier Division of Manufacturing and Product Quality, CDER
Isolation Technology Forum: Innovation Updates and New was invited to speak at the Current and Future Packaging
Case Studies. Challenges for Investigational Products seminar.

• Helen Winkle (Director, Office of Pharmacy, CDER), Chris- • H. Gregg Claycamp, PhD, the Associate Director of Risk
tine Moore (Deputy Director, CDER), and Sharmista Chat- Analysis and Strategic Policy Assessment, CVM was the
terjee (Staff Fellow/Reviewer, CDER) were featured US FDA featured FDA speaker at the Applied Risk Management
speakers at the PQLI®: Science, Regulatory, Manufacturing, – Addressing Cross Industry Challenges seminar.
and Engineering Working Together for Global Realization
and Implementation of the ICH Quality Vision seminar. • Malcolm Oliver, GMP Inspector for the MHRA, was in-
Joseph Famulare (Deputy Director, Office of Compliance, vited to speak at the Commissioning and Qualification
CDER), Richard Friedman (Director, Mfg. and Product (C&Q): Practical Applications of Science and Risk-based
Quality, CDER), Vibhakar Shah (Consumer Safety Officer, Approaches to Validation seminar, along with several
confirmed leaders of the pharmaceutical manufacturing
industry.

ISPE Korea Affiliate in • As an additional resource on the topic of C&Q, there was
Development a live Webinar 5 May 2009 on Implementing the ASTM
Standard for Verification (C&Q).
The Korea Affliate, the newest affiliate to join ISPE’s family,
There were also seminars devoted to GAMP and facility reno-
is well under way in its development. The Korea Affiliate will
vation, as well as two-day training courses. They are:
be located in South Korea, officially the Republic of Korea and
often referred to as Korea.
• GAMP® Good Practice Guides: Validation of Process Control
Systems (VPCS), and Calibration Management, A Risk-
Based Approach

• Extreme Facility Makeover: Successful Path to Facility

Renovation and Retrofit

• Training – Basic Principles of Computerized Systems

Compliance

• Training – Applying the GMPs

For upcoming ISPE Education and Training information,

visit www.ISPE.org or call ISPE Members Services at tel:
+1-813-960-2105.

60 PHARMACEUTICAL ENGINEERING May/June 2009

ISPE
Annual Meeting

Thriving In A Survival Environment

8 - 11 November • Manchester Grand Hyatt San Diego • San Diego • California, USA

Eleven Session Tracks:

• Product development • Supply chain management • Quality systems • Suppliers
• Facilities and equipment • Production systems • Project management • Survival-focused
• Information systems • Regulatory compliance • Investigational products

Wa t c h f o r d e t a i l s a n d o n l i n e r e g i s t r a t i o n a t w w w. I S P E . o r g / a n n u a l m e e t i n g .
 ISPE Update

INTERPHEX Keynote Message: Industry Needs to

Reinvent Itself
by Rochelle Runas, ISPE Technical Writer

E
xpiring patents. An economic facing stricter regulatory oversight; in a world of blockbusterology and we’re
slump. New technologies. Regula- the need to prove drug safety and going to live in a world of more targeted,
tory agencies becoming increas- comparative effectiveness (this third personalized medicines.”
ingly risk averse. A new administration standard will begin to emerge); generic Burrill said he envisions a consumer
in Washington. biopharmaceuticals, biosimilars; an driven healthcare world that includes
In a world today that faces these increase in stem cell funding; and an concepts such as genetic screening, web-
and other uncertainties, one thing’s increase in healthcare IT funding. based diagnostics, patient-centric self
for sure: The pharmaceutical industry So, in 2020, what will the healthcare care, and Wal-Mart-like health centers
needs to reinvent itself, whether it likes delivery system look like? Burrill said in operated by nurse practitioners. Medical
it or not. the last 2000 years, the pharmaceutical tourism will become more popular. For
That was a main message of this industry has not really changed; people example, it is becoming cheaper to send
year’s Keynote at Interphex NY, deliv- got diseases and they were treated. But, a patient in need of a hip replacement on
ered Tuesday, 17 March at the Jacob this is not going to be true in the next a plane to India and put them up in the
Javits Convention Center in New York, five to 10 years. Four Seasons, than getting the procedure
New York. The keynote included a pre- We are changing the nature of the done in local hospital, Burrill said.
sentation by G. Steven Burrill, CEO, healthcare equation, moving away from What does this kind of world mean
Burrill & Co., who shared his vision of a treatment-based system with a one size to the pharmaceutical industry? Accord-
the future of healthcare and overriding fits all mentality toward late stage detec- ing to Burrill, big pharma will disinte-
trends affecting the global industry. tion and intervention, and a prevention- grate, a trend already demonstrated
Burrill said the industry will be and wellness-based system. “We’ve lived by big company mergers. Low margin

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Pharm-halfpage.indd 1 6/30/2008 10:17:50 AM

62 PHARMACEUTICAL ENGINEERING May/June 2009
 ISPE Update
INTERPHEX Keynote Message
Continued from page 62.

ethical drugs will predominate (China, PhD, Senior Vice President, Biotech balancing the amount of inventory to
India, and other low cost manufacturing Operating Unit, Technical Operations carry vs. patient need.”
sites will have an edge). International and Product Supply, Wyeth Pharma- Ramakrishnan said his company
regulatory agencies will collaborate. ceuticals. The panel discussed how they greatly emphasizes six sigma programs
Big pharma today, which is verti- are handling today’s challenges. and efficiency.
cally integrated (R&D, manufacturing, “We try to balance cost and risk,” In the end, biology and technology
distribution, etc.) will disintegrate to be said Moore. “We put a lot of emphasis will be more important than concrete,
horizontally integrated. The “virtual on managing risk in our supply chain, said Kowolenko.
pharma company” will emerge, with
operations located at different sites.
Capital will go to where the best op-
portunities are and partnerships will
Sterile Clean Steam Sampling
continue, said Burrill. Also, diseases will
have no boundaries, so all companies big
and small will be global from day one.
The presentation was followed by a
panel discussion with Burrill; Timothy
Moore, Senior Vice President, Global
Supply Chain, Genentech; Divakar Ra-
makrishnan, PhD, Executive Director,
Manufacturing Science and Technology,
Eli Lilly & Co.; and Michael Kowolenko,

JPI Features Article on

PQLI Legacy Products

T he March 2009 issue of the Journal

of Pharmaceutical Innovation, avail-
able online to Members only, features
the following articles:

• PQLI®: Current Status and Future

Plans
by John C. Berridge
GEMÜ BioStar® Steam Sampler, the innovative automated
• PQLI Application of Science- and
Risk-based Approaches (ICH Q8, sampling system for the monitoring of pure steam quality
Q9, and Q10) to Existing Products
by Chris Potter ■ Sterile from the steam pipe to the laboratory
Sterilization prior to sampling, sterilized sample container, sterile sample transport
• Investigation of the Statistical Power
of the Content Uniformity Tests Us- ■ Automated, programmable and safe
ing Simulation Studies Hands-off auto sampling method eliminates potential contamination of the sample
and minimizes risk of injury to operating personnel
by Phillip D. Lunney and Carl A.
Anderson ■ Consistent, reliable and time saving
• Aqueous Solubility Enhancement Automation of the activity provides consistency and repeatability while reducing
the time required to complete the sampling by plant personnel
Through Engineering of Binary
Solid Composites: Pharmaceutical ■ Easy to install - easy to operate
Applications Simplified connections, easy plug and start, air-cooled, mobile or fixed installation,
repeatable and programmed process
by Michael D. Moore and Peter L. D.
EMA
Wildfong ACH. May 2009 52
5 M
11.-1 ooth K48-
,B
Hall 8
ISPE Members can access JPI by visit-
GEMÜ Gebr. Müller Apparatebau GmbH & Co. KG · Fritz-Müller-Str. 6-8 · D-74653 Ingelfingen
ing www.ISPE.org/JPI. Phone 07940/123-0 · Telefax 07940/123-224 · info@gemue.de · www.gemue.de

May/June 2009 PHARMACEUTICAL ENGINEERING 63

 Advertiser's Index ISPE Update
ACTIVE CHEMICAL............................ 65

AES CLEAN TECHNOLOGY................. 27

ISPE Brussels Conference
BUDZAR INDUSTRIES......................... 39 Highlights
CAL-CHEM CORP............................... 37

COMMISSIONING AGENTS................. 25

CRB CONSULTING ENGINEERS..............3

T he ISPE Brussels Conference welcomed more than 180 delegates to update their
knowledge and to network at Sheraton Brussels Hotel in Brussels, Belgium
on 30 March to 2 April 2009. This year’s conference offered a variety of new and
enhanced opportunities for attendees to take advantage of. Some of the highlights
JIM CRUMPLEY & ASSOCIATES.......... 64 from the conference were:
ELETTRACQUA.................................. 13
• Live webinar presentation from Nick Haycocks in California, USA on the HVAC
EMERSON PROCESS MANAGEMENT......9 Good Practice Guide and Good Engineering Practice, as well as the Environ-
mental Cleanliness Classification Quiz that generated lots of discussion at the
ENDRESS + HAUSER......................... 67 seminar Heating, Ventilation and Air Conditioning (HVAC): Good Practice and
Innovations.
FOOD AND DRUG
ADMINISTRATION/CDER.................... 65
• Regulatory aspects of continuous processing were presented by Dr. Moheb Nasr,
FARR AIR POLLUTION CONTROL...........2 Director, Office of New Drug Quality Assessment and Joe Famulare, Deputy
Director, Office of Compliance, FDA at the seminar Continuous Processing and
FESTO.............................................. 45 Process Intensification for APIs, BPCs and Excipients. Part of the program was
developed in conjunction with the International Pharmaceutical Excipients
FIKE CORP........................................ 29
Council (IPEC) since, for the first time, the seminar considered not only APIs/
GEA PROCESS ENGINEERING.............. 47 BPCs, but excipients, as well. Delegates were also introduced to the forthcoming
ISPE white paper on regulatory issues for continuous processing.
GEA WESTFALIA SEPARATOR............ 55
• In a change from the normal format, a one-day interactive Project Management
GEMU GMBH..................................... 63
Workshop was held on developing lean, agile project plans. Delegates were work-
GLATT GMBH.................................... 17 ing on a detailed project plan over the course of three exercises and received
templates as part of the conference documentation allowing them to put them
HACH COMPANY............................... 43 into practice back at the job.

HOWORTH AIR TECHNOLOGY............ 19

• Andrew Cochrane, UK regulator from MHRA, provided a very useful overview
HURST CORP.................................... 57 of the current status of the revision of Annex 11 during the seminar GAMP® 5:
Part 11, Annex 11 and Industry Hot Topics. The seminar included an interactive
IMA ACTIVE...................................... 53 workshop on Maintaining Control of Operation, as well as Quality Risk Manage-
ment in Process Automation, where the links between ICH Q9 and the GAMP® 5
IMA LIFE........................................... 35 QRM approach were explored. Two new groups were formed during the seminar:
INTELLIGEN....................................... 23
a GAMP SIG on outsourcing/offshoring topic, as well as a local GAMP Benelux
group with an interactive day of workshops coming up.
INTERPHEX365................................. 49
• A live webinar presentation was given by Cameron Sipe in the US on the up-
MECO .............................................. 11 date to the ISPE Water and Steam Baseline® Guide during the Critical Utilities
seminar.
NNE PHARMAPLAN............................ 68

OPTIMA MACHINERY......................... 31 The Brussels Conference also hosted a sold-out exhibition with a showcase of the
latest new tools and solutions.
PARSONS...........................................5
The next ISPE events in Europe include Madrid Training from 18 to 21 May;
PHARMACEUTICAL ONLINE................ 62
Strasbourg Conference held from 28 September to 1 October; and Dublin Training
PLASCORE........................................ 15 held from 19 to 22 October 2009.

QPHARMA..........................................7

TELSTAR.......................................... 41

WILDEN PUMP & ENGINEERING........... 51

66 PHARMACEUTICAL ENGINEERING May/June 2009

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for the Office of New Drug Quality Assessment (ONDQA), Office
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quality standards to assure safety and efficacy, and facilitate
new drug development. Strong organizational and executive
leadership skills are very desirable. The Division Director is

Division Director Position responsible for providing scientific direction and for planning,
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is desired. Candidates for Civil Service must be U.S. citizens.
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Graduates of foreign colleges/universities must provide proof of
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IS AN EQUAL OPPORTUNITY EMPLOYER AND HAS A SMOKE FREE ENVIRONMENT

May/June 2009 PHARMACEUTICAL ENGINEERING 65

 Advertiser's Index ISPE Update
ACTIVE CHEMICAL............................ 65

AES CLEAN TECHNOLOGY................. 27

ISPE Brussels Conference
BUDZAR INDUSTRIES......................... 39 Highlights
CAL-CHEM CORP............................... 37

COMMISSIONING AGENTS................. 25

CRB CONSULTING ENGINEERS..............3

T he ISPE Brussels Conference welcomed more than 180 delegates to update their
knowledge and to network at Sheraton Brussels Hotel in Brussels, Belgium
on 30 March to 2 April 2009. This year’s conference offered a variety of new and
enhanced opportunities for attendees to take advantage of. Some of the highlights
JIM CRUMPLEY & ASSOCIATES.......... 64 from the conference were:
ELETTRACQUA.................................. 13
• Live webinar presentation from Nick Haycocks in California, USA on the HVAC
EMERSON PROCESS MANAGEMENT......9 Good Practice Guide and Good Engineering Practice, as well as the Environ-
mental Cleanliness Classification Quiz that generated lots of discussion at the
ENDRESS + HAUSER......................... 67 seminar Heating, Ventilation and Air Conditioning (HVAC): Good Practice and
Innovations.
FOOD AND DRUG
ADMINISTRATION/CDER.................... 65
• Regulatory aspects of continuous processing were presented by Dr. Moheb Nasr,
FARR AIR POLLUTION CONTROL...........2 Director, Office of New Drug Quality Assessment and Joe Famulare, Deputy
Director, Office of Compliance, FDA at the seminar Continuous Processing and
FESTO.............................................. 45 Process Intensification for APIs, BPCs and Excipients. Part of the program was
developed in conjunction with the International Pharmaceutical Excipients
FIKE CORP........................................ 29
Council (IPEC) since, for the first time, the seminar considered not only APIs/
GEA PROCESS ENGINEERING.............. 47 BPCs, but excipients, as well. Delegates were also introduced to the forthcoming
ISPE white paper on regulatory issues for continuous processing.
GEA WESTFALIA SEPARATOR............ 55
• In a change from the normal format, a one-day interactive Project Management
GEMU GMBH..................................... 63
Workshop was held on developing lean, agile project plans. Delegates were work-
GLATT GMBH.................................... 17 ing on a detailed project plan over the course of three exercises and received
templates as part of the conference documentation allowing them to put them
HACH COMPANY............................... 43 into practice back at the job.

HOWORTH AIR TECHNOLOGY............ 19

• Andrew Cochrane, UK regulator from MHRA, provided a very useful overview
HURST CORP.................................... 57 of the current status of the revision of Annex 11 during the seminar GAMP® 5:
Part 11, Annex 11 and Industry Hot Topics. The seminar included an interactive
IMA ACTIVE...................................... 53 workshop on Maintaining Control of Operation, as well as Quality Risk Manage-
ment in Process Automation, where the links between ICH Q9 and the GAMP® 5
IMA LIFE........................................... 35 QRM approach were explored. Two new groups were formed during the seminar:
INTELLIGEN....................................... 23
a GAMP SIG on outsourcing/offshoring topic, as well as a local GAMP Benelux
group with an interactive day of workshops coming up.
INTERPHEX365................................. 49
• A live webinar presentation was given by Cameron Sipe in the US on the up-
MECO .............................................. 11 date to the ISPE Water and Steam Baseline® Guide during the Critical Utilities
seminar.
NNE PHARMAPLAN............................ 68

OPTIMA MACHINERY......................... 31 The Brussels Conference also hosted a sold-out exhibition with a showcase of the
latest new tools and solutions.
PARSONS...........................................5
The next ISPE events in Europe include Madrid Training from 18 to 21 May;
PHARMACEUTICAL ONLINE................ 62
Strasbourg Conference held from 28 September to 1 October; and Dublin Training
PLASCORE........................................ 15 held from 19 to 22 October 2009.

QPHARMA..........................................7

TELSTAR.......................................... 41

WILDEN PUMP & ENGINEERING........... 51

66 PHARMACEUTICAL ENGINEERING May/June 2009

 On-Line Exclusive Article
PHARMACEUTICAL ENGINEERING®
The Official Magazine of ISPE China SFDA Overview
May/June 2009, Vol. 29 No. 3

This article
presents the China State Food and Drug
responsibilities,
structure, Administration (SFDA) –
and affiliated
organizations for Responsibilities, Internal Structure,
the China State
Food and Drug
Administration
and Affiliated Organizations
(SFDA).
by Jason Tang

Introduction

R
The Agency develops good practices for drugs
egulatory responsibilities in Greater and medical devices in the areas of research,
China are split between a number of manufacturing, distribution, and use and
organizations on the mainland and supervises their implementation. The Agency
other regions. These include the State also develops good practices for food safety in
Food and Drug Administration (SFDA), the the consumer contact sector and supervises its
Ministry of Agriculture, the pharmaceutical implementation.
service of the Department of Health of the The Agency monitors food safety in the
Hong Kong Special Administrative Region, consumer contact sector and conducts inves-
and the Macau Health Authority with the tigations. The Agency releases information
Departamento dos Assuntos Farmacêuticos or related to the supervision of food safety in the
Pharmaceutical Affairs Department. Taiwan consumer contact sector. The Agency is in charge
Regulatory Affairs are controlled by the Taiwan of hygiene licensing and safety supervision of
Department of Health. food in the consumer contact sector, as well as
This article provides an overview of the cosmetic hygiene licensing, hygiene supervi-
responsibilities and structure of the SFDA. sion, and relevant review and approval work
of cosmetics.
Main Responsibilities The SFDA is in charge of the administrative
The responsibility for regulating drugs has and technical supervision and registration of
undergone significant changes in the past drugs and medical devices. It develops relevant
decade in China. national standards and supervises their imple-
Originally part of the domain of the Ministry mentation.
of Health until 1998, the State Drug Administra- The Agency conducts ADR monitoring and
tion (SDA) was formed as a separate bureau in adverse event monitoring of medical devices;
1999. This Agency’s name was changed in 2003 is responsible for drug and medical device re-
to the State Food and Drug Administration evaluation and withdrawal; engages in develop-
(SFDA) and remained separate. In July 2007, ing the national essential medicine list, assist-
irregularities within the organization called ing relevant authorities to adopt the national
China’s drug manufacturing practices into essential medicine system; and organizes the
question. In March 2008, the SFDA was amal- implementation of the classification system for
gamated back into the Ministry of Health. prescription drugs and OTC drugs.
©Copyright ISPE 2009

The SFDA develops policies and plans for The Agency is in charge of developing
the supervision of drugs, medical devices, cos- regulations for Traditional Chinese Medicines
metics, and food safety in the consumer contact (TCMs) and ethno-medicines, supervising their
sector and supervises their implementation. It implementation. The Agency develops quality
participates in drafting relevant laws, regula- standards of TCMs and ethno-medicines, Good
tions, and normative documents. Agricultural Practices for Chinese crude drugs

www.ISPE.org/PE May/June 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 1

 China SFDA Overview
and Preparation Standards for Chinese crude drugs, supervis- The Internal Structure of SFDA
ing their implementation, and enforces the protection system General Office (Department of Financial
for certain traditional Chinese medicines. Planning)
The SFDA supervises the quality and safety of drugs and The department of Financial Planning is responsible for the
medical devices, regulating radioactive pharmaceuticals, nar- daily government affairs operations, including documents
cotics, toxics, and psychotropics. The Agency releases quality and telegrams, meetings affairs, confidential affairs, and
and safety information for drugs and medical devices, and is archive management. The Department manages security
responsible for investigating and punishing illegal activities and secrecy work, openness of government affairs, dealing
in food safety in the consumer contact sector and in use of with complaint letters and visits, statistics management, etc.
drugs, medical devices, and cosmetics in the areas of research, The department develops and implements the planning and
manufacturing, and distribution. finance management system of headquarters and affiliated
The Agency directs local food and drug authorities on organizations. It is also responsible for managing adminis-
supervision, administration, emergency response, inspection, trative charges and instructing information construction in
and information construction. the regulatory system.
Developing and improving the qualification system for There are eight divisions under this Department:
licensed pharmacists is the responsibility of the Agency in
addition to supervising and directing the registration of 1. Division of General Affairs (Office of Complaint Letters
licensed pharmacists. and Visits)
The SFDA conducts international exchanges and coop- 2. Division of Secretaries I
eration related to food and drug regulation, in addition to 3. Division of Secretaries II
overseeing other work assigned by the State Council and the 4. Division of Emergency Management
Ministry of Health. 5. Division of Archives
6. Division of Development and Planning
7. Division of Budget Management
8. Division of Government Financial Affairs

Department of Policy and Regulations

The Department of Policy and Regulations engages in the
development of laws, regulations, and provisions related
to the Food and Drug Administration. It supervises the ad-
ministrative law-enforcement and oversees administrative
reconsideration, pleading, and hearing, etc. The Department
also provides news briefings.
There are four divisions under this Department:

1. Division of General Affairs (Office of Administrative Re-

consideration)
2. Division of Regulations
3. Division of Policy Research
4. Division of News (Office of News)

Department of Food License

The Department of Food License is responsible for managing
hygiene licenses for food and cosmetics; developing relevant
rules for the implementation of hygiene license for food and
cosmetics; developing hygiene standards and technical guide-
lines for cosmetics; examining and approving the law regarding
the use of new raw materials for cosmetics, manufacture of
domestic cosmetics for special use, and the first time import
of cosmetics, etc.
There are three divisions under this Department:
©Copyright ISPE 2009

1. Division of Food
2. Division of Health Food
3. Division of Cosmetics

Figure 1. Affiliated organizations.

2 PHARMACEUTICAL ENGINEERING On-Line Exclusive May/June 2009 www.ISPE.org/PE

 China SFDA Overview

Figure 2. SFDA structure.

Department of Food Safety and Inspection implementation; develops the list of OTC drugs; organizes the
The Department of Food Safety and Inspection oversees development of good practices for non-clinical and clinical drug
the safety supervision of food in the consumer contact sec- trials, supervising their implementation; and implements the
tor; develops good practices for food safety in the consumer protection system for traditional Chinese medicines.
contact sector and supervises its implementation; monitors There are five divisions under this Department:
food safety in the consumer contact sector and conducts in-
vestigations; releases information related to the supervision 1. Division of General Affairs
of food safety in the consumer contact sector; evaluates and 2. Division of TCMs and Ethno-Medicines
examines the safety of cosmetics by law; and supervises the 3. Division of Pharmaceuticals
hygiene of cosmetics. 4. Division of Biological Products
There are three divisions under this Department: 5. Division of Drug Research Supervision

1. Division of General Affairs Department of Medical Devices Inspection

2. Division of Food Supervision The Department of Medical Devices Inspection organizes
3. Division of Monitoring and Evaluation the development of national medical device standards and
supervises their implementation; develops the list of classified
Department of Drug Registration (Department of medical devices; is in charge of registration and regulation
TCMs and Ethno-Medicines Supervision) of medical devices; develops good practices for clinical trials,
The Department of Drug Registration organizes the develop- manufacturing, and distribution of medical devices, supervis-
©Copyright ISPE 2009

ment of national drug standards, product list of immediate ing their implementation; supervises the licensing of medical
packaging materials and containers to drugs, the requirements devices manufacturing and distribution; and organizes the
and standards for their medical use, and is responsible for adverse events monitoring, reevaluation, and elimination of
their registration; develops preparation standards for the medical devices.
prepared slices of Chinese crude drugs and supervise their There are five divisions under this Department:

www.ISPE.org/PE May/June 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 3

 China SFDA Overview
1. Division of General Affairs Department of International Cooperation (Office
2. Division of Registration I for Hong Kong, Macao, and Taiwan Affairs)
3. Division of Registration II The Department of International Cooperation organizes and
4. Division of Manufacturing and Distribution Inspection conducts international exchanges and cooperation in food and
5. Division of Research and Reevaluation drug regulation; and is responsible for managing exchanges
and cooperation with Hong Kong, Macao, and Taiwan affairs
Department of Drug Safety and Inspection in food and drug regulation.
The Department of Drug Safety and Inspection develops good There are three divisions under this Department:
practices for Chinese crude drug production, drug manufactur-
ing and distribution, and preparations produced by medical 1. Division of International Organization
institutions, supervising their implementation; engages in 2. Division of European, Asian, and African Affairs
developing the national essential medicines list; organizes 3. Division of American and Oceanian Affairs
the implementation of the drug classification system; controls
radio-active drugs, narcotics, toxics and psychotropics, and Summary
precursor chemicals; supervises the licensing of drug manu- The SFDA was formed on the basis of the State Drug Adminis-
facturing, drug distribution, and pharmaceutical preparations tration and is directly under the State Council of the People’s
in medical institutions; and organizes the adverse reaction Republic of China, which is responsible for the comprehensive
monitoring, reevaluation, and elimination of drugs. supervision of the safety management of food, health food,
There are five divisions under this Department: and cosmetics. The SFDA is the competent authority of drug
regulation in mainland China; however, it is not responsible
1. Division of General Affairs for regulating pharmaceutical ingredients manufactured and
2. Division of Drug Manufacturing Inspection exported by chemical companies.
3. Division of Drug Distribution Inspection
4. Division of Pharmacovigilance and Reevaluation
5. Division of Controlled Drugs Inspection

Bureau of Investigation
The Bureau of Investigation develops and implements the
investigation system for the regulation of food safety in the
sections of consumption, drugs, medical devices, and cosmetics;
oversees the market inspection of Chinese crude drugs; guides
and supervises relevant local departments in investigation
and enforcement, emergency management, advertisement
examination and approval, product recall, case investigat-
ing, and prosecuting; and organizes the investigation and
prosecution of illegal activities.
There are five divisions under this Department:

1. Division of General Affairs

2. Division of Inspection I
3. Division of Inspection II
4. Division of Inspection III
5. Division of Inspection IV

Department of Personnel
The Department of Personnel is in charge of personnel affairs
for headquarters staff and affiliated institutions; develops
and improves the qualification system for licensed phar-
macists; and supervises and guides registration of licensed
pharmacists.
There are four divisions under this Department:
©Copyright ISPE 2009

1. Division of General Affairs

2. Division of Carder
3. Division of Training
4. Division of Salary

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 On-Line Exclusive Article
PHARMACEUTICAL ENGINEERING®
The Official Magazine of ISPE Global Regulatory News
May/June 2009, Vol. 29 No. 3

Europe Danish Medicines Agency now seeking to extend the contractual

Czech Republic Monitors Compliance with API obligation to these two parties. The
GMP for Manufacture of Rules3 pharmaceutical industry views the
Medicinal Substances1 The Danish Medicines Agency has revision and compulsory supply of
The SIDC has issued Provision VYR-26 launched a project to monitor how wholesalers as an encroachment on its
Version 1: Instructions for Good Manu- companies comply with rules govern- commercial freedom.
facturing Practice in the Manufacture ing manufacture and handling of It has been noted that these changes
of Medicinal Substances, 12 March active pharmaceutical ingredients.1 would lead to less red tape and greater
2009 to determine the requirements The main purpose of the project is to harmonisation, both of which would
for good manufacturing practices in improve the possibilities for achieving facilitate work for internationally act-
the Czech Republic. efficient control of APIs via co-operation ing companies. For example, applicants
between pharmaceutical companies would be able to file their entire dossier
Denmark and the agency. in English, apart from product infor-
Danish Agency Updates In Denmark, as in other European mation, such as the label, summary of
“Qualified Person” Guidelines2 Union countries, APIs used in marketed product characteristics, and package
The Danish Medicines Agency has medicines must be manufactured in ac- leaflet.
published updated guidelines explain- cordance with EU good manufacturing
ing its requirements and expectations practice. The DMA will conduct spot United Kingdom
concerning the pharmaceutical com- checks to ensure compliance with the GMP1
pany “qualified person.” 1 Although rules. In 2009, it plans to inspect 15 API The MHRA have released guidelines
classified as guidelines, the list is manufacturers and carry out laboratory part of the MHRA Good Manufacturing
based on the requirements of the main analyses of APIs from 50 manufactur- Practice Risk-Based Inspection Process.
European Union directives on medi- ers selected by its Medicines Control The new guidelines are intended for
cines for human and veterinary use Division. Before inspecting the API sites holding or named on a United
(Directives 2001/83/EC and 2001/82/ manufacturers, the agency will inspect Kingdom manufacturing license in
EC respectively). Danish manufacturers of finished order to help them to complete the
Under the aforementioned Direc- products that use products from one compliance report form.
tives manufacturing authorization of the 15 API manufacturers. It says The compliance report must be com-
holders in the EU are required to have that it will be possible during these pleted in advance of an inspection and
at least one qualified person always at short inspections to discuss challenges aims at informing the inspector of the
their disposal. The role of the qualified and possible special risk areas relating changes on site. This compliance report
person is critical; his or her main respon- to API manufacturers. Relevant audit is part of the MHRA Good Manufac-
sibility in pharmaceutical production reports also will be discussed. turing Practice Risk-Based Inspection
is to certify that each batch of finished Process and will be coming into force
product that is released for sale or Germany on 1 April 2009.
supply in the EU/European Economic German Industry Criticizes
Area has been produced and tested in Proposed Revisions to International
accordance with the relevant EU direc- Pharmaceutical Act – Update4 China
tives, good manufacturing practices, The German pharmaceutical industry Advice on Quality Testing of
and the provision of the marketing has criticized some of the government’s Re-Packing of Import Drug1
authorization. proposed amendments to the Pharma- A notification has been issued that
The qualified person must have ceutical Act, which would oblige them requests that product imported into
experience in the areas of production, to supply wholesalers.1,2 The aim of the China and repacked should be up to
quality assurance, or quality control. health ministry is to guarantee the the quality specifications for import
The relationship between the qualified provision of medicines to the public as product approved by SFDA. The foreign
person and the company must be “of quickly as possible via wholesalers and manufacturer must take responsibility
significance” and requires a notice of pharmaceutical manufacturers. for product repacked on import.
permanent or contractual employment. In its draft amendment proposals
This means that the individual must published in December 2008,3 the min- Egypt
spend a minimum of 10 hours per week istry noted that within the distribution Strict Rules for Wholesalers
in the company. However, if the firm in chain, only pharmacies were subject to and Warehouses5
©Copyright ISPE 2009

question is small or only produces in a contractual obligation to supply the The Egyptian minister of health has
limited operations, this time limit may public. However, in order to guarantee issued a decree that aims to combat
be amended. The qualified person must the provision of medicines, pharmacies counterfeit drugs, control price manipu-
have sufficient knowledge of the quality had to themselves be adequately sup- lations, and tighten up the licensing
system in place in the company and must plied by wholesalers and manufactur- rules for pharmaceutical wholesale
furthermore be a resident of the EEA. ers, it reasoned. Hence, the ministry is distribution companies and phar-

www.ISPE.org/PE May/June 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 1

 Global Regulatory News
maceutical warehouses.1 The decree, maceutical Affairs; the Bureau of Food have drafted a guide on good importer
which entered into force on 19 January, and Drug Analysis; and the National practices to help ensure that health
updates the existing pharmaceutical Bureau of Controlled Drugs. The pro- products finding their way into the
law (127/1955) and replaces decree cess to establish the TFDA gathered US meet required standards.1-3 The
151/2006 on wholesaler/warehouse momentum in September 2008 after guidance is designed to help importers
licensing. melamine-contaminated milk powder detect and prevent potential problems
Under the decree, wholesale medi- made its way into Taiwan from China. at critical points along the life cycle of
cines are only allowed to be handled a product.
by licensed pharmaceutical wholesale United States The FDA notes that hazards can be
distribution companies or pharma- US FDA opens offices in India, introduced at any point in a product’s
ceutical warehouses (companies/ware- Latin America, and Europe7 lifecycle – such as designing, manufac-
houses). In addition, such companies/ As part of its efforts to better guarantee turing, processing, packing, receiving,
warehouses are now subject to inspec- the quality of food, drug, and medical storing, transporting, importing, and
tions by the Central Administration of device imports, the US Food and Drug distributing – that may put consumers
Pharmaceutical Affairs (CAPA) before Administration has opened offices in at risk. The guidance is designed to help
being granted a license. India, Latin America (Costa Rica), and importers anticipate potential sources
The decree explicitly states how a Europe (Belgium).1,2 The agency had al- of product hazards and offer preventive
warehouse should be set up, for ex- ready opened offices in China and there controls.
ample, it must have an area of at least are plans to set up offices elsewhere in In general, the guidance recommends
500 square meters, as well as a separate Latin America and also in the Middle that importers should know the producer
entrance and appropriate storage facili- East.3 Deployment of FDA personnel of the foreign products they purchase
ties (warehouses licensed prior to 19 at these overseas offices will allow the and any other manufacturers with which
January will have until 30 June 2010 agency to carry out frequent inspec- they do business, such as consolidators,
to comply with the area requirement). tions of manufacturing units exporting trading companies, and distributors; un-
They also must have computerized products to the US market. derstand the products that they import
electronic data storage systems that India is the fourth-largest exporter and the vulnerabilities associated with
keep records of inventory, purchases, by volume of drugs and biologics, espe- these products; understand the hazards
and sales. Companies/warehouses must cially generic pharmaceuticals to the that may arise during the product life
obtain only registered medicines from US. The FDA’s Indian office will provide cycle; and ensure proper control and
licensed pharmaceutical manufactur- technical advice, conduct inspections monitoring of these hazards.
ing companies or licensed importing of facilities that export to the US, and
offices with which they have distribu- “work with Indian government agen- United States Pharmacopeial
tion contracts. CAPA inspectors have cies and the private sector to develop (USP) Looks to Closer
the right to see these contracts and it is certification programs to allow the Collaboration with FDA9
forbidden to handle or store any prod- efficient flow of safe... FDA-regulated The USP joins other consumer and
ucts not covered by these contracts. goods between the US and India.” healthcare organizations that have
Latin American countries are key urged President Obama’s administra-
Taiwan trade partners for the US and the tion to work with Congress to increase
Taiwan’s Plan to Create New FDA’s presence in the region will begin funding for the FDA. “Failure to give
Regulatory Body6 capacity-building in the regulation of the FDA these resources jeopardizes
Two Taiwanese legislative committees drugs, medical devices, and food. The the Obama Administration’s ability to
have jointly approved a draft bill put agency also plans to set up offices in achieve its broad healthcare quality
forth by the country’s executive branch Mexico and South America later in the goals,” warns the USP.
(the Executive Yuan) to establish a year. In strengthening the science base
new Food and Drug Administration The FDA’s European office, in Brus- of the FDA’s decision-making, agency
office that would bring a number of key sels, will spearhead regulatory collabo- managers must have greater access to
regulatory and product safety activities ration with the European Commission. scientific expertise, recommends the
under one roof.1,2 For the Taiwan FDA Its remit will be to build on the existing USP. This could include making better
(TFDA) to become functional, the bill robust relationships with the European use of the National Academy of Sciences
now has to be cleared by the Legisla- Medicines Agency, the European Food and the USP, which already collaborate
tive Yuan. Safety Authority, the European Com- with the agency in the development
©Copyright ISPE 2009

The TFDA Organic Law envisages mission, and the individual member of standards. A stronger focus on the
merging four departments that are state authorities. risk assessment of new drugs is also
presently under the control of the suggested.
Department of Health into one single Import Safety8 Standards are regarded as critical
entity to form the TFDA: the Bureau The Food and Drug Administration and to the FDA’s regulatory role. Greater
of Food Safety; the Bureau of Phar- several other US government agencies emphasis on the role of public standards

2 PHARMACEUTICAL ENGINEERING On-Line Exclusive May/June 2009 www.ISPE.org/PE

 Global Regulatory News
and associated technical aids in drug Genetically Engineered (GE) animals small population. As part of its review
and food quality would enhance qual- issued by the US Food and Drug Ad- of the GE goats used to produce the
ity assurance, the USP believes. Closer ministration’s Center for Veterinary drug, the CVM assessed the safety
collaboration between the FDA and Medicine recommends a rigorous of the rDNA construct to the animal,
standard-setting organizations could and transparent review process for including a full review of the construct
help fill gaps in existing standards medicines and other therapeutic goods and its stability in the genome of the
and increase recognition of standards, derived from such animals (also called goats over seven generations. The CVM
potentially bringing national unifor- biopharm or transgenic animals) be- also reviewed and concurred with the
mity to all drugs and food ingredients, fore they are approved.1 GE animals sponsor’s plan to continue to monitor
while conserving FDA resources. Col- can produce pharmaceutical proteins the construct and its expression for the
laborative efforts also could include and replacement tissues in their milk, lifetime of the approved product.
third-party verification and the USP’s eggs, and blood, which can be used in The drug is already approved for use
nascent verification programs might the treatment of human disease. They in Europe1 and was accorded a prior-
prove a useful model for ensuring the also can be used for developing animal ity review by the FDA in September
safety of imports. models for human diseases. 2008.
On the subject of follow-on bio- Among other things, the CVM, which
logicals (known also as biogenerics or is responsible for the oversight of GE South Africa
biosimilars), the USP believes that it animals, sets out the requirements GMP
has the authority to develop or revise for investigational use of GE animals The Medicine Control Council from
monographs for these products if a and for submitting new animal drug South Africa released the new version
regulatory pathway is established applications (NADAs); explains the 4 of the Guide to Good Manufacturing
through amendments to the Public process for completing preapproval Practice for Medicines amending Radio-
Health Service Act. assessments for GE animals; outlines pharmaceuticals (Annex 3) and Herbal
Finally, the USP believes that the postapproval responsibilities (e.g., Medicinal Products (Annex 7). The
FDA should enhance its activities in the recordkeeping, submission of annual standards in this guide apply to medi-
international community to promote reports); and addresses environmental cines and similar products intended
the competitiveness and standing of considerations. The CVM encourages for human and veterinary use and are
the US in the world. Among initiatives developers of such animals to contact to maintain high standards of quality
put forward are that the commissioner the centre early in the development assurance in the development and to
should assess the effectiveness of the process. facilitate manufacture and control of
International Conference on Harmoni- The guidance is based on the Fed- medicinal products.
sation and enhance work with other eral Food, Drug, and Cosmetic Act’s
countries’ drug control laboratories. framework for new animal drugs and References
Separately, the USP Convention has only pertains to GE animals containing 1. www.idrac.com
announced new standards for heparin heritable recombinant DNA constructs 2. RAJ issue: Vol 20 No 0409: Guide-
and glycerin, both of which have been (i.e., intended to affect the structure or lines from the Danish Medicines
involved in recent episodes of adul- function of the body of the GE animal, Agency on its expectations of a
terated products resulting in patient regardless of the intended use of prod- qualified person in a pharmaceutical
deaths. ucts that may be produced by those company, 17 February 2009, www.
Revisions to the monographs for animals). The CVM says that although dkma.dk/1024/visUKLSArtikel.
heparin sodium and heparin sodium many of the recommendations in the asp?artikelID=14732.
injection are available for public review document may be relevant to animals 3. RAJ issue: Vol 20 No 0409: DMA
and comment until 15 May 2009 and bearing non-heritable rDNA constructs press release, 12 March 2009, www.
are due to become official in August (e.g., intended for use in gene therapy), dkma.dk/1024/visUKLSArtikel.
2009.3,4 it may issue separate guidance on the asp?artikelID=14850.
A revised standard for glycerin that regulation of those animals. 4. RAJ issue: Vol 20 No 0309:
provides a new test for manufacturers to On a separate note, the FDA has 1. VFA press release, 19 January
use in preventing glycerin diluted with granted its first-ever approval of a bio- 2009, www.vfa.de/de/inline/nach-
diethylene glycol (DEG) from entering logical drug produced by a GE animal; richten/pm-005-2009-warum-
the US drug supply also has been issued the product is derived from the milk of keine-wettbwerbliche-loesung.
for public comment and became official a GE animal for treating people with html.
©Copyright ISPE 2009

on 1 May 2009.6 hereditary antithrombin deficiency, a 2. BPI press release, 19 January

rare clotting disorder associated with 2009, www.bpi.de/Default.aspx?
FDA Explains Strict Rules for severe complications.3,4 The drug, GTC tabindex=1&tabid=491&p=1&t
Approving Drugs from GE Biotherapeutics’ ATryn, has been given p_id=335&name=pmNews&con
Animals10 an orphan designation because heredi- trol=ipopup.
Final guidance on the regulation of tary antithrombin deficiency occurs in a 3. Proposed amendments to Phar-

www.ISPE.org/PE May/June 2009 PHARMACEUTICAL ENGINEERING On-Line Exclusive 3

 Global Regulatory News
maceutical Act, 22 December 9. RAJ issue: Vol 20 No 0309:
2008, www.bmg.bund.de/cln_117/ 3. Pharmacopeial Forum, Mar-Apr
nn_1168248/SharedDocs/Down- 2009, Vol. 35(2), 1-10, www.usp.
loads/DE/GV/GT/Entwuerfe/ org/pdf/EN/hottopics/heparinSo-
publizierte-Entwuerfe/Refer- diumMonograph.pdf.
entenentwurf__15.AMG__Nov 4. Pharmacopeial Forum, Mar-Apr
elle,templateId=raw,property= 2009, Vol. 35(2), 1-3, www.usp.
publicationFile.pdf/Referente- org/pdf/EN/hottopics/heparinSo-
nentwurf_15.pdf. diumInjectionMonograph.pdf
5. RAJ issue: Vol 20 No 0309: 6. USP, Revision Bulletin, 4 Febru-
1. MoHP Decree No 25, 18 January ary 2009, www.usp.org/USPNF/
2009. notices/glycerinMonographAn-
2. MoHP workshop on Intellec- nouncement.html.
tual Property Enforcement and 10. RAJ issue: Vol 20 No 0309:
Combating Trade in Counterfeit 1. FDA, Guidance for Industry: Reg-
Medicines and Medical Devices, ulation of Genetically Engineered
12-19 January 2009. Animals Containing Heritable
6. RAJ issue: Vol 20 No 2 February Recombinant DNA Constructs
2009: [#187], 15 January 2009, www.
1. Taiwan Central News Agency, fda.gov/cvm/Guidance/fguide187.
First review of draft FDA Act pdf.
approved by legislative Commit- 3. FDA press release 6 February
tees, 18 December 2008, www. 2009, www.fda.gov/bbs/topics/
cnanews.gov.tw/cnaeng. NEWS/2009/NEW01952.html.
2. Scrip World Pharmaceutical 4. GTC Biotherapeutics press re-
News online, 21 June 2007. lease, 9 January 2009, www.gtc-
7. RAJ issue: Vol 20 No 2 February bio.com/pressreleases/pr010909.
2009: html.
1. HHS press release, 15 Janu- 5. The Regulatory Affairs Journal
ary 2009, www.hhs.gov/news/ – Pharma, 2006, 17(7), 456-457.
press/2009pres/01/20090115a.
html. This information was provided by Frank
2. HHS press release, 7 Janu- Sayala and Rohini Chari, Pharmaceuti-
ary 2009, www.hhs.gov/news/ cal Research Associates (UK).
press/2009pres/01/20090107a.
html.
3. The Regulatory Affairs Journal –
Pharma, 2008, 19(11), 797-798.
8. RAJ issue: Vol 20 No 2 February
2009:
1. Federal Register, 13 January
2009, 74(8), 1692-1693, http://
edocket.access.gpo.gov/2009/pdf/
E9-453.pdf.
2. FDA press release, 12 January
2009, www.fda.gov/bbs/topics/
NEWS/2009/NEW01941.html.
3. FDA, Good Importer Practices
Draft Guidance, 12 January
2009, www.fda.gov/oc/guidance/
goodimportpractice.html.
©Copyright ISPE 2009

4 PHARMACEUTICAL ENGINEERING On-Line Exclusive May/June 2009 www.ISPE.org/PE

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 Table of Contents
The Global Information Source for Pharmaceutical Science and Manufacturing Professionals

The Official
Magazine of
ISPE

May/June 2009 Volume 29, Number 3

Cover Design
Articles
Lynda Goldbach, ISPE
Publications Manager 8
The FDA’s Draft Process 40Global Regulatory Framework
Validation Guidance – Overview: US FDA, EMEA, PIC/S,
Current Issue/Theme A Perspective from Industry and ICH
May/June 2009 by Nuala Calnan, Alice Redmond, and by Dr. Kate McCormick
Regulatory - PQLI Stan O’Neill
50Barrier Isolation History and
Next Issue/Theme 18 The Draft Process Validation Trends – 2008 Final Data C

July/August 2009
Guidance – A Perspective from by Jack Lysfjord and Michael Porter M

Utilities the FDA

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May/June 2009 PHARMACEUTICAL ENGINEERING 7
 Process Validation Guidance
This article
provides an The FDA’s Draft Process Validation
overview of the
draft guidance, Guidance – A Perspective from
the key changes
in relation to the Industry
1987 guidance,
and reviews
its potential by Nuala Calnan, Alice Redmond, and Stan O’Neill
impact on the
current industry
approaches to
science- and
risk-based
design and Abstract

T
validation. It sets out the approaches that the
qualification he long anticipated draft of the FDA’s FDA consider to be appropriate elements of
Guidance for Industry on Process Valida- process validation for the manufacture of human
activities tion should be welcomed for the clarity and veterinary drugs, including biologicals and
which support of its integrated three stage lifecycle APIs. No specific mention is made within the
the process process, its emphasis on the need for effective scope to investigational medicinal products or
validation scientific knowledge led programs, and the medical devices, for which CDRH has published
elimination of the “Three Golden Batches” its own guidance through the Global Harmoni-
program. concept. zation Task Force.
This article provides an overview of the
Introduction draft guidance, the key changes in relation to
In November 2008, the FDA published the long the 1987 guidance, and reviews its potential
anticipated draft of its Guidance for Industry impact on the current industry approaches to
on “Process Validation: General Principles and science- and risk-based design and qualification
Practices.” This draft, which has just completed activities which support the process validation
its public comment period, will replace the FDA’s program.
1987 “Guideline on General Principles of Process
Validation” when finalized and represents the The Lifecycle Approach
FDA’s current thinking in regard to process The guidance states at the outset that it has
been written to promote “modern
manufacturing principles, process
Basic Principles of Quality Assurance improvement, innovation, and sound
science” and is significantly aligned
Effective Process Validation contributes significantly
with the Product Lifecycle Ap-
to assuring drug quality.
proach described in the ICH Guid-
The basic principle of Quality Assurance is that a
ance Q8 (R1), Q9, and Q101 and the
drug should be produced that is fit for its intended use;
Quality by Design (QbD) initiative.
this principle incorporates the understanding that the
This lifecycle approach emphasizes
following conditions exist:
the importance of the links between
• Quality, safety, and efficacy are designed or built the following:
into the product.
• Quality cannot be adequately assured merely by in- 1. product and process design and
process and finished-product inspection or testing. development
• Each step of a manufacturing process is controlled 2. qualification of the commercial
to assure that the finished product meets all design manufacturing equipment and
characteristics and quality attributes including speci- process
fications. 3. maintenance of the process in a
Ref: Guidance for Industry Process Validation: General Prin- state of control during routine
ciples and Practices (Nov 2008). commercial production

Continued on page 10.

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 Process Validation Guidance
tion is then used to develop the approach to process vali-
Three Stages of Process Validation dation, and the scientific knowledge is verified by testing
(in-process, release, characterization) of each significant
Process validation involves a series of activities taking
step of the commercial manufacture process.
place over the lifecycle of the product and process.
• The significant emphasis in the lifecycle is on maintaining
Stage 1 – Process Design: The commercial process is the process in a state of control over the life of the process,
defined during this stage based on knowledge gained which will require ongoing data analysis of both intra-batch
through development and scale-up activities. and inter-batch variability, and appropriate provisions to
Stage 2 – Process Qualification: During this stage, address deviations and nonconforming data.
the process design is confirmed as being capable of • It emphasizes the importance of both QA professionals and
reproducible commercial manufacturing. line operators in providing feedback for continued process
Stage 3 – Continued Process Verification: Ongoing verification.
assurance is gained during routine production that the • Not surprisingly, the guidance focuses on the importance
process remains in a state of control. of demonstrating, documenting, and utilizing process un-
derstanding in designing effective validation programs. It
Ref: Guidance for Industry Process Validation: General
Principles and Practices (Nov 2008). provides a strong lead in acknowledging that qualification
programs devoid of process understanding will not guar-
antee the assurance of quality required.
One of the key messages from this draft is that validation of
the process is not a “one off ” event, but represents an ongoing Significant Recommendations
continuum of scientific knowledge development and ongoing The main body of the guidance is provided under section IV
assurance. There is a real emphasis throughout the draft on Recommendations, where very useful general considerations
the importance of acquiring this knowledge about the process on the three stages of process validation and their associated
from the early process design stage right throughout com- activities are outlined.
mercial manufacture, which is a significant departure from This is where we see the most significant alignment with
the convention of (essentially) testing the process outputs. current industry thinking for implementation of science- and
Success relies on the establishment of a comprehensive risk-based lifecycle approaches and where the most signifi-
science-based process design, which focuses on understanding cant departures from the prescriptive approaches of the 1987
the sources of variability in achieving process understanding guidance are noted.
and recognizes that more knowledge will be gained during Under “General Considerations for Process Valida-
product commercialization. The draft emphasizes that the tion,” it emphasizes the importance of making the entire
key to this success will lie in an organizations proficiency “in process validation program more effective and efficient through
the collection and evaluation of information and data about the following:
the performance of the process,” and outlines specific guid-
ance relating to the use of quantitative statistical methods • good project management
to enhance understanding of process performance. • robust scientific knowledge collection, management, and
From this, the guidance defines Process Validation activi- archiving
ties in three stages identified in Figure 1. • uniform collection and assessment of information meth-
Key tenets of the lifecycle approach outlined are: ods
• reducing the burden of redundant information gathering
• A manufacturer should have gained a high degree of as- • use of an integrated team approach
surance in the performance of the manufacturing process
before any batch from the process is commercially distrib-
uted for use by consumers.
• This assurance should be obtained from objective informa-
tion and data from laboratory, pilot, and/or commercial­
scale studies – this implies a need for greater scrutiny of
process performance during the early stages of commercial
manufacture.
• A successful validation program depends upon the skilled
interpretation of the information and knowledge gained
from product and process development regarding sources
of variation, its impacts, and the associated risks.
• This knowledge and understanding is cited as the basis
for establishing the appropriate control strategy for the
manufacturing process.
Figure 1. Process validation lifecycle activities shown in three
• The product and process design and development informa- stages.
Continued on page 12.
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 Process Validation Guidance
conditions so that the process output remains constant and
Key Definition: Process Validation (PV) reproducible. However, it does indicate that in the case of PAT,
the approach to process qualification will be different from
“The collection and evaluation of data, from the process
that for other process designs by focusing on the qualification
design stage throughout production, which establishes
of the measurement system and control loop.
scientific evidence that a process is capable of consis-
Significantly, by grouping the recommendations for product
tently delivering quality products”
and process design together in this stage, it further endorses
Ref: Guidance for Industry Process Validation: General an integrated approach. Within this integrated approach,
Principles and Practices (Nov 2008). while it acknowledges that the full spectrum of input vari-
ability typical of the commercial production is not generally
known at this stage, it directly recommends that the team
• appropriately documented Project Plans responsible for process design take early consideration of the
• the support of senior management functionality and limitations of commercial manufacturing
• statistical assessment of data equipment by utilizing their knowledge about measurement
systems in a production setting, contributions to process
The draft recommends the “integrated team approach” as variability from different raw materials or component lots,
presented in the FDA’s 2006 guidance entitled, “Quality production operators or environmental conditions. This ethos
Systems Approach to Pharmaceutical Current Manufacturing will no doubt be welcomed by many involved in the start up
Principles,” involving expertise from a variety of disciplines, of regulated commercial manufacturing facilities who have
including process engineering, industrial pharmacy, analytical dealt with the challenges posed when this early integration
chemistry, microbiology, statistics, manufacturing, and quality of commercial production and process design has not been
assurance. Furthermore, both here and throughout the docu- successful.
ment, it emphasizes the need for effective and efficient pro-
grams and supports the move away from overly bureaucratic Stage 2: Process Qualification
traditional qualification practices and in doing so provides This stage of the process validation lifecycle is undoubtedly
good alignment with the key principles of the recent ASTM going to generate the most comment and perhaps lead to some
standard E2500-07.2 initial confusion, due to its use and definition of terminology
In “Specific Stages and Activities of Process Validation in relating to Process and Performance qualification.
the Product Lifecycle,” the guidance gives specific direction The stated goal of this key stage is that “the process design
on each of the three stages of process validation. is confirmed as being capable of reproducible commercial
manufacture.” The guidance further divides this stage into
Stage 1: Process Design the following two elements:
The stated goal of this stage is to “design a process suitable
for routine commercial manufacturing that can consistently 1. design of the facility and qualification of the equipment
deliver a product that meets its Critical Quality Attributes and utilities
(CQAs).” The guidance again makes reference to ICH Q10, 2. Performance Qualification (PQ)
Pharmaceutical Quality Systems, and draws some distinctions
around the varying levels of controls required related to the Stage 2-1: Design of the Facility and
product development lifecycle activities. Qualification of Utilities and Equipment
The focus of this stage is on developing methods and com- This section of the guidance opens with a welcome reference
petencies for building and capturing process knowledge and to the essential role that proper facility design and commis-
understanding and in using this scientific knowledge as the sioning play in the start-up of a facility and cites them as
basis for establishing an approach to effective process control. prerequisites to the commencement of PQ.
It states that the “Design of Experiment (DOE) studies can help Most significantly, the guidance gives a key definition for
develop process knowledge by revealing relationships, including qualification as shown below:
multi-factorial interactions, between the variable inputs (e.g., The draft guidance states that qualification of utilities and
component characteristics or processing parameters) and the equipment generally includes the following activities:
resulting outputs (e.g., in-process material, intermediates, or
the final product).” Risk analysis tools can be used to minimize
the total number of experiments conducted while maximiz- Key Definition: Qualification
ing knowledge gained. The results of the DOE studies should “Activities undertaken to demonstrate that utilities and
be used to establish ranges of incoming component quality, pieces of equipment are suitable for their intended use
equipment parameters, and in­ process material quality at- and perform properly is referred to in this guidance as
tributes. qualification”
The draft draws attention to the recent advances with Pro-
Ref: Guidance for Industry Process Validation: General
cess Analytical Technology (PAT), which may be used for real
Principles and Practices (Nov 2008).
time analysis, facilitating control loops to adjust the processing
Continued on page 14.
12 PHARMACEUTICAL ENGINEERING May/June 2009
 Process Validation Guidance
• selecting utilities and equipment based on whether they • The manufacturing conditions set for the PQ are established
are appropriate for their specific use based on the cumulative data from all relevant studies (e.g.,
• verifying that the utility system and equipment are built/ designed experiments; laboratory, pilot, and commercial
installed in compliance with the design specifications and batches).
operate in accordance with the process requirements in • Objective measures (e.g., statistical metrics) are used to
all anticipated operating ranges for routine production evaluate the outputs and justify that adequate assurance
• challenging the equipment or system functions while has been achieved.
under loads comparable to that expected during routine • Greater scrutiny of process performance is undertaken
production during PQ through the use of enhanced levels of sampling
• performance of interventions, stoppage, and start-up as is and testing. This enhanced level of monitoring and testing
expected during routine production should be capable of confirming uniform product quality
is achieved throughout the batch during processing.
The guidance requires that these qualification activities
are covered either under an individual plan or as part of an It will be important to understand and assess the impact of
overall project plan. In line with the ICH Q9, Quality Risk these expectations relating to PQ early in the overall lifecycle
Management guidance, the plan should consider the use of as they may affect process development activities, system
risk management to prioritize certain activities and to identify design, equipment selection, or team selection considerations
the appropriate level of effort for both the performance and and will certainly influence the development of methods and
the documentation of these qualification activities. procedures.
Finally, it confirms the requirement for the qualification In relation to the number of PQ batches required, to date
activities to be documented in a report with conclusions product PQ was typically followed by the traditional “three
that specifically address the criteria set out in the plan. It PV batches.” Now no fixed number of new PQ batches are
is important to note this draft’s expectation that the quality prescribed and manufacturers must provide justification
control unit must review and approve both the qualification for any rationale used in asserting that assurance has been
plan and the report. There is divergence here with the recently achieved. However, it is noted that the words “commercial
published ASTM E2500-072 standard, which seeks Quality batches” are used, which would suggest the use of more than
Unit preapproval of the qualification acceptance criteria rather one batch.
than the plan, but concurs on the Quality Unit post approval Furthermore, it is important to note the expectation that
of the qualification report. the greater scrutiny accompanied by the enhanced level of
sampling undertaken during the PQ batches should continue
Stage 2-2: Performance Qualification (PQ) initially into the continued process verification stage.
Performance Qualification (PQ) is the phrase used to described Of particular note in the document is the recommendation
the second element of the overall process qualification and that the PQ lots should be manufactured under normal con-
combines the actual qualified facility, utilities, and com- ditions. Thus, a matrix approach with extremes of operating
mercial manufacturing process equipment with the trained conditions is not expected for this phase of validation.
personnel using cGMP compliant control procedures (SOPs), The guidance provides specific recommendations on the
and all raw materials and components necessary to produce format and content of the PQ protocol and the report includ-
commercial batches. ing as follows:
The use of the phrase Performance Qualification (PQ) in
the context of producing commercial batches may present • manufacturing conditions, such as operating parameters,
divergence from what is widely understood to be within the process limits, and raw materials inputs are document-
scope of a “traditional” PQ, which currently focuses on equip- ed
ment and process performance for clean utilities, cleaning, and • details of the data to be collected, including when and how
sterilization processes. In the 1987 guide, this was described it is evaluated
as Process Performance Qualification and was distinguished • details of the in-process, release, and characterization tests
from that which was referred to as Product Performance to be performed, as well as the acceptance criteria for each
Qualification. This draft combines the two efforts within significant step
this stage in order to achieve the stated goal of overall Per- • the sampling plan, including sampling points, the number
formance Qualification (PQ) which is to “confirm the process of samples, and the frequency of sampling for each unit
design and demonstrate that the commercial manufacturing operation, based on statistical confidence incorporating
process performs as expected.” risk analysis
Success at this stage is cited as an important milestone • criteria showing the processes consistently produce quality
in the product lifecycle and must be completed before a batches, including a description of the statistical methods
manufacturer commences commercial distribution of the drug used to define both intra-batch and inter-batch variability,
product. and provisions to address deviations and nonconforming
The draft requires that the design of the PQ study should data
ensure that: • design of facilities and qualification of utilities and equip-

14 PHARMACEUTICAL ENGINEERING May/June 2009

 Process Validation Guidance
1987 PV Guidance 2008 Draft
Defines validation as “establishing documented evidence” Defines validation in terms of “establishing scientific evidence”
Principles of quality assurance wording revision from “cannot be inspected or to “cannot be adequately assured merely by in-process and finished product
tested into the finished product” inspection or testing”
Principles of quality assurance wording revision from “designed and built into the to “is designed or built”
product”
Wording revision from “maximize the probability that” to “is controlled to assure”
Introduction of “integrated team approach”
Introduction of “product lifecycle” concept
exclusion of “revalidation” and “retrospective process validation”
Introduction of Process Analytical Technology (PAT) concepts for PV
Introduction of “root cause” (e.g., review of customer complaints and impact on
process)
Removes validation information for medical devices
Emphasizes Science Based Knowledge development
Emphasizes the use of qualitative statistical methods to monitor, evaluate and
justify assurance of process performance
Table A. Key changes between 1987 PV Guidance and 2008 Draft.

ment, training, and verification of source materials port their relaxation.

• validation status of analytical methods used to measure It is noted that data gathered during this stage may identify
the process, materials, and product ways to improve and/or optimize the process and appropriate
• review and approval by the appropriate department and procedures to control and manage these changes must be in
the quality unit
Concludes on page 16.

Finally, the draft elaborates on the opportunities presented

for manufacturers utilizing PAT systems to support activities
undertaken in the next stage.

Stage 3: Continued Process Verification

The stated goal of the third process validation stage is to “con-
tinually assure that the process remains in a state of control
(the validated state) during commercial manufacture.” This
will require robust systems for detecting unplanned depar-
tures (drift) from the designed process, and there is a strong
emphasis on the use of statistically trended data, which is
reviewed in a timely manner by trained personnel, such as
statisticians or persons with adequate training in statistical
process control techniques.
The development of a Data Collection Plan is recommend
ensuring that the information collected can verify that the
critical quality attributes are being controlled throughout the
process.
This production data also should evaluate process stability
and capability and the scrutiny should include both intra-
batch as well as inter-batch variation. The quality unit should
evaluate this data, discuss possible trends or drifts in the
process, and coordinate any correction or follow-up actions
with production personnel.
As referred to previously, the draft recommends that the
enhanced monitoring and/or sampling initially established
during the process qualification stage continue until sufficient
data is available to generate significant variability estimates
and justification, using statistical metrics, is available to sup-

May/June 2009 PHARMACEUTICAL ENGINEERING 15

 Process Validation Guidance
place. It highlights that maintenance of the facility, utilities, and Verification of Pharmaceutical and Biopharmaceutical
and equipment is another important aspect of ensuring that Manufacturing Systems and Equipment, July 2007.
a process remains in control. While the document discusses 3. Notes for Guidance on Process Validation; CPMP/
the use of continued process verification to identify variability QWP/848/96, EMEA/CVMP/598/99 September 2001.
and improve the process, no mention is made to the possible
implications on already commercialized batches. About the Authors
Finally, it states a fundamental tenet that following the Nuala Calnan is a Principal Consultant
scientific based approach requires that information transpar- with PM Group, Ireland and has more than
ency and accessibility are essential so that organizational units 17 years of experience in the pharmaceuti-
responsible for the process can make informed, science-based cal industry. Currently, she is a member of
decisions that ultimately support the ongoing commercial the ISPE International Board of Directors
release of a product. and was a member of the Author Task Team
which produced the recent ASTM E2500-07
Conclusion International Standard. Calnan also is a
It is the opinion of the authors that this guide will be welcomed member of the document development task team currently
for many reasons, primarily for the clarity and simplicity of writing the ISPE Baseline Guide: Science and Risk-Based Ap-
the integrated three stage lifecycle process, but also for the proach for the Delivery of Facilities, Systems, and Equipment.
emphasis on the need for effective and efficient science-based She graduated in 1991 with a BSc in engineering (BSc Eng)
programs, which seek to reduce unnecessary duplication in and achieved her MBA in 2002. She is a regular contributor
activities through the application of product and process at ISPE conferences. She can be reached by telephone: 353-
knowledge throughout the lifecycle. 14040700 or by email: nuala.calnan@pmg.ie.
From a facility, utility, and equipment qualification per- PM Group, Kilakee House, Belgard Square, Tallaght, Dublin
spective the welcomed avoidance of traditional, prescriptive 24, Ireland.
terminology such as DQ, IQ, and OQ offer teams real opportu-
nities to look behind the prepared templates and design and Alice Redmond is CQ Technical Director
execute qualification and validation programs which are not with PM Group, has more than 20 years
only valid, but valuable to the ongoing operation and continu- of experience in the R&D, pharmaceutical
ous improvement. There is only one minor exception to this (API, formulation fill, solid dosage), and
relating to an external cross reference in the introduction to biotechnology industry. She graduated with
the very prescriptive validation approach for APIs found in a BSc in biotechnology in 1987, a PhD in
the ICH Q7A guidance. This is likely to add confusion rather biotechnology in 1991 and a MBs in 2001.
than clarity and which hopefully will be dealt with through Current responsibilities include oversight of
the public comment phase. regulatory compliance, GEP, quality, commissioning, qualifi-
Upon first review, this draft in itself does not appear to cation and validation strategies on a corporate level for PM
have any new implications for the preparation and submis- Group. Redmond is an active member of ISPE and PDA. She
sion of regulatory filings. co-chaired and presented at the ISPE GEP ICQ Conference in
However, for many organizations, aligning this FDA pro- Copenhagen in 2006, and the Singapore ISPE Conference in
cess validation guidance with the current EMEA legislative July 2008. She can be contacted by telephone: 353-214358922
requirements and recommendations for process validation or by email: alice.redmond@pmg.ie.
would be very beneficial.3 PM Limited, Loughmahon Technology Park, Blackrock,
Finally, from an ISPE Technical Documents perspective, Cork, Ireland.
due to the revised use of terminology and the welcome step
back from prescriptive qualification practices, final publica- Stan O’Neill is the Managing Director of
tion of this guidance will provide an opportunity to review the Compliance Group. After qualifying as
several current ISPE Guidance documents for alignment. This a pharmacist, he spent more than five years
will impact both the Baseline® Pharmaceutical Engineering working in the pharmaceutical industry in
Guides series and Good Practices Guide series, many of which Regulatory Affairs, marketing, and Quality
are already under revision for alignment with recent ICH Assurance (QP), and then joined the Irish
guidance. Medicines Board (IMB) for a period of 10
years. In his capacity as a Senior Inspec-
References tor, he performed GMP inspections throughout the world,
1. See the FDA/International Conference on Harmonisation represented Ireland at European level for the negotiation of
(ICH) guidance for industry: standards of inspection for medicinal products, and trained
a. Q8 Pharmaceutical Development Inspectors at Irish, European, and International levels. He
b. Q9 Quality Risk Management can be contacted by telephone: 353-866032297 or by email:
c. Q10 Pharmaceutical Quality Systems stanoneill@compliancegroup.eu
2. ASTM E2500-07: Standard Guide for Specification, Design, The Compliance Group, 22 Earlsfort Terrace, Dublin 2,
Ireland.
16 PHARMACEUTICAL ENGINEERING May/June 2009
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 Process Validation Q&A
This article
presents the The Draft Process Validation
questions and
answers from Guidance – A Perspective from the
a recent ISPE
Webinar focused FDA
on the FDA’s
draft process
validation
guidance.

Introduction
In January 2009 Grace McNally of the US FDA
provided a first time public view and under-
A Yes, Q7A has a very prescriptive specific sec-
tion about validation. That is the standard
for APIs. If there appears to be any conflict
standing on the new draft Guidance for Industry between that and this guidance, I would cer-
– Process Validation in a live ISPE Webinar. tainly ask that you submit those comments to
Paul D’Eramo, Executive Director, Johnson & us and we will consider them as we revise the
Johnson, hosted a question and answer session guidance for final.
which gave attendees the chance to submit their
questions and have them directly answered by
McNally. The following is a transcript of some
of the highlights of that Q&A session:
Q When you implement this, is there a plan for
how you will be training the FDA investiga-
tors to make sure everybody’s consistent?

Q Do we have any idea on when it might get

finalized? A Yes, that’s a very good question. We haven’t
done that in a formal comprehensive way.
We have the basic drug school or courses geared

A Once we get the comments in we’ll have

to empanel a group of experts to evaluate
them, make some decisions, write responses, and
toward our pharmaceutical inspectorate. Myself
and others involved in this working group have
given talks about this new guidance – it wasn’t
adopt suggestions if appropriate or not. I can’t published because we weren’t distributing it at
tell you exactly how long that process will take that point – and the concepts in it, discussing
but it’s certainly our intention to get that done the principles and how they should be thinking
and get a final published this year, 2009. about process validation, which isn’t terribly
different than the thinking we had under the

Q Did you discuss this draft with other regula-

tory bodies such as in Europe, to see what
their reaction might be in regards to harmoniz-
1987 guidelines. A careful reading of the 1987
guidelines is very revealing. It is not fundamen-
tally different in its basic principles.
ing some of their documents? But yes, the investigative staff will need to be
trained and we will be developing a formal train-

A No, this was an FDA effort only and it did not

involve other regulatory agencies. Certainly,
it’s available to them. I’ve been to conferences
ing program. Certainly this is just a draft and
there may be revisions, so we are not prepared
to do that quite yet until we have the final. As
where representatives from other regulatory far as the implementation phase, it’s important
bodies have asked about it, so they are aware to remember that this is a guidance, it’s not a
that it was in draft. Of course, it’s on the Web regulation. These are recommendations. This
and it’s available for everybody to take a look is the current thinking about what we believe
at and comment on. are useful practices for process validation in
this day and time. So an implementation phase

Q It’s clear in the document you’ve referenced

Q8, Q9, and Q10. It’s not as clear as how
doesn’t really apply to this guidance.

this relates to Q7, especially because there are

sections in Q7 that discuss validation. So should
we defer to that?
Q How does this guide relate to the aseptic
processing guide? Does that processing guide
take precedent for sterile products?
Continued on page 20.
18 PHARMACEUTICAL ENGINEERING May/June 2009
 Process Validation Q&A

A Yes, that’s a good point. The aseptic

processing guide is as direct and
prescriptive for that activity and that
that is performing well, and there’s no
indication, there’s no quality indicator
data that suggests to you something is
A While it’s true that references to
statistical criteria and procedures
are prominently featured in this guid-
manufacturing operation. So if there is amiss, I’m not suggesting that you run ance, I will say that that’s not new …
a guidance out there that specifically out and begin R&D all over for each of It’s a topic that we need to shine light
addresses a type of manufacturing these product and process lines. on and put on the table. It is my belief
activity, that is what you want to look It would make sense to me that as that it has been somewhat ignored as
at. This guidance is not intended to part of your overall quality system, of late. Certainly it has to be wrestled
conflict with the aseptic processing and certainly as part of the periodic with. It raises a lot of questions about
guide or any of the guidances out there. evaluation of all product lines, that how to do this.
I know in the biological realm there are whatever your procedures dictate that But I would say it really is not new.
specific guidances for viral clearance or you consider each of these products I’m looking at the old guidance, second
other technical manufacturing aspects and processes as part of your periodic to last section. It’s talking about testing,
and those should be your primary evaluation procedures. You can cer- test data, and ...process monitoring.
reference. tainly take for example, you may want It says, “specific results on the other
to consider some sort of risk analysis hand can be statistically analyzed and

Q Can you explain the major differ-

ences between the old guide and
the new as it relates to existing (or
of each of your product lines and pro-
cesses and see what can and should be
done to improve them if that appears
a determination can be made of what
variance and data can be accepted.”
So those ideas have been around for a
legacy) products? For example, if we necessary, based our your data and long time. In Stage 3, you can use Six
have to revalidate an existing product, evaluation. There’s no move afoot on Sigma. We’re not going to prescribe
should I use the new guideline or the our part to send investigative teams what statistical tools to use and really
old principles? out to go through a company’s product we’re just looking for a scientific basis
line, find the five year old process that and objective measures, and statistics

A Process validation is a lifecycle and

if you’re in a position of revalidating,
for whatever reason... I would direct
seems to be doing quite well and start
digging into R&D records … that’s not
the goal and it won’t be part of any ac-
are one of them.
In this day and age, I understand
from many people in industry that there
your attention to Stage 3. If you have tion on the field’s part. are a lot of good software packages out
an existing product in process and But I would say to you as the com- there and they can be very valuable. And
you’re revalidating it, I would assume pany to think about your processes and even in Stage 2, you have limited data
there’s been some trigger for that. It product lines. You do and are required at that point and so the power of those
would make sense to me that the trig- and certainly want to have in place analyses may not be as great because
ger for that is information you gath- these periodic evaluation procedures. you have much more accumulative data
ered during what we’re calling Stage So when an older and existing process in Stage 3, once you’re making a lot of
3, commercialization activities that comes up, my question then to you, is commercial batches … but they would
you do under 211.180 (e), part of your do you think you should apply these be very useful. We’re not going to dictate
periodic evaluation. (That information) new principles. And they’re really not which statistical tools to use, but you
brought to your attention something that new actually. I would recommend as a company should select what works
that needs to be changed or checked. that everybody who is concerned about for you and be able to defend why it’s
So it would make sense at that point to this new guidance being different than scientific and objective.
incorporate the principles in this new the old should sit down with the new
guidance. And remember they’re not
that different. If I was to go back, and
I do have the old guideline here in front
one and the old one and carefully read
them. Q Was a there a reason why risk
analysis was not discussed in the
document?
of me, it also calls for a maintenance of
a state of control.
So I would say good companies con-
Q Someone made the comment, it
seems our industry lags somewhat
in process monitoring/statistical pro- A Yes, we made a deliberate effort
to not explore topics that have
cerned about quality are going to use cess control. It is now clear that this is already been thoroughly covered in
revalidation for whatever the impetus an expectation. Another asks, can you other guidelines or guidances. Risk
was... to adopt a modern view. As a com- use Six Sigma concepts to rationalize management is thoroughly discussed
pany you also want to be philosophically process validation being in a state in ICH Q9 and we’ve referenced it. But
congruent. If companies are embracing of control. Can you elaborate on that to avoid retread on already established
an attitude of continuous improve- Continued Verification, Stage 3, the concepts – we mention it and there is
ment it seems to me that that would monitoring part, and how you foresee an expectation that risk analysis will
permeate their thinking for all their that? be used throughout the lifecycle and all
product lines. Now, having said that I’m of the stages – felt it was not necessary
not saying if you have an old process to go into detail. That is expected, and

20 PHARMACEUTICAL ENGINEERING May/June 2009

 Process Validation Q&A
Need
use the guidances available on it.
Q Is there value in executing PQ at
ranges versus a target or should
Knowledge?
Q Will a glossary be added? There are
terms such as process verification
and product performance. Criticality
this be carried out in the development
phase? No Budget for
Travel?
is not really defined anywhere. Do you
think you’ll go back and put some of
those terms into a glossary?
A That’s a great question and that
really speaks to the old guideline.
In the old guideline you certainly get
the impression that the boundary con-

A A few thoughts on criticality. We

actually in our earlier versions
used the word critical throughout the
ditions (worst case challenges, edge of
the operating parameters that have
been established, whatever you want
document. The definition of criticality to call it, edge of operating limits) in
has been greatly debated. We’ve seen the old guidance to me and my read-
many definitions, whether individual ing of it is that that’s something you’re
companies prefer a definition, whether going to do as your making commercial
a regulatory body has a certain slant batches, this performance qualification
on their definition. In the interest of stage or what we would call it, Stage 2.
getting this guidance done, we did not It seems to me that while that knowl-
put a glossary in because so many of edge should be pursued, it would make
the terms are debatable in terms of sense that that would be in the Stage 1
what they mean. Criticality, we took arena, or I should at least say, it’s not
out of there and went back to our source something you want to do when you’re
document which is the GMP and chose
to use the word “significant.” So you’ll
ultimately confirming your process
design and working with product you
No Problem.
see in those places that term instead intend to sell. I would agree with the
of criticality. inquiry statement that before you ready ISPE Online Learning
But the comment about the glossary what you think is commercial product
in general, there isn’t a glossary. But you’ve probably already explored that delivers critical
if the comments we get back strongly
suggest that that is indispensible or
and have some understanding of what
those limits are and what their impact
knowledge and
absolutely necessary in order to pre- is on the product quality and process. I training to you
vent confusion or make this guidance agree that you would want to explore
meaningful and useful then we’ll take that up front. anytime, anywhere,
that into consideration.
and at a price to fit
And I should just say as an aside,
there’s no magic to the terminology
that we chose to use for this guidance:
Q Please elaborate on the following –
“to have sufficient understanding of
the commercial process, the manufac-
your budget.
Stage 1, Stage 2, Stage 3. They’re just turer will need to consider the effects
terms we chose and then laid out what of scale; however, it is not typically nec-
they meant. That’s something each of essary to explore the entire operating
your individual companies probably range at commercial scale if assurance
do as well. Certainly there’s value in can be provided by other data.” Can you
everybody using and having the same clarify what is sufficient understanding
meaning but to expect that to happen, and what is the agency’s thinking there
I wouldn’t bet money on it. I think the and the same for scale? Does this need
key about terminology is, whenever you to be done at full scale batches?
get involved in a discussion with some-
body, whether it’s in an audit, or your
collaborating on something, as long as
that group understands what is meant
A ...as far as sufficient data, there
are certain words that the Agency
will use, such as “appropriate” or “suf-
Visit www.ISPE.org/
onlinelearning for a
by certain terms, then you can make ficient.” Because it’s going to differ from
complete list of Online Learning
progress and have a successful meeting company to company and product to
or inspection, or move forward. But the product… it’s a judgment call that the
opportunities or call ISPE
glossary issue, I would say we will look manufacturer must make and then be Member Services at tel:
at that in terms of the comments that able to explain why they feel this is +1-813-960-2105.
we get back from everybody. adequate from a science perspective...
Concludes on page 22.
May/June 2009 PHARMACEUTICAL ENGINEERING 21
 Process Validation Q&A
the key there, is people will talk in terms a procedure. I don’t want to say protocol some cogent, appropriate manner that
of how many commercial size batches because I don’t want to give people the I really think will differ from product
do I have to make. The more important idea that this is what you have to do. to product and process to process. The
question is, having made these batches, But doesn’t it make sense, if you’re go- agency isn’t going to dictate that. As
however many there are, what is it that ing to assess performance over time, to far as number ... there is this element
you’re looking (for). That’s the criteria. establish some criteria and some sort of of reproducibility, so right off the bat
That’s what you want to specify in your procedure and then execute it, gather you know you’ve got to have more than
protocol, your plan. The real question that data and do those analyses. And put one. And when I say one I don’t mean
is, but what about them, what are you numbers, I mean that’s mainly where one batch. I mean, I’d rather say data
doing with them, what is the data you’re we’re coming from, the statistics that you point, or for whatever the data points
looking at, what is the information? Is see in this new guidance are “objective that are important or for whatever the
it during processing, are you looking at measures,” I think it maybe only says attributes or parameters are important,
the controls and the process parameters, it once in there. But if you’re going to reproducibility is an element that needs
how tight they are or not. Are you looking assert that you have confidence in this to be demonstrated.
at attributes of the in-process material unit operation, this process overall, this
in the final product and what about it,
are you going to do some analysis of
that data. It’s not about the number of
particular attribute, can you put a num-
ber on it. I think more and more today
you can if you use the right tools.
Q Why doesn’t the guide talk about
revalidation?

batches, it’s what data are you gleaning

and how are you handling that data and
what are your expectations.
Confidence intervals, how sure am I
about this data point or this statistical
metric I just calculated. How confident
A We didn’t use “revalidation” because
really Stage 3, the output of those
monitoring activities, is going to give
am I. It’s going to depend on sample you the impetus to revisit potentially

Q Does the Continued Process Veri-

fication Program for a given drug
product require formal protocol, similar
size, it’s going to depend on a lot of
things. But you can put a label on how
confident you are on some of your data
design or revisit Stage 2. So revalidation
is really a function of what you find in
Stage 3. It’s covered in concept, we just
in fashion to Performance Qualifica- … I think this inquirer’s insight is a fine didn’t use the word. It’s something Stage
tion? Should this data be collected, one and makes sense. Again, Stage 3, 3 will dictate what you need to do.
analyzed, summarized (and approved) if you’re trying to maintain things in a
by the QA – Validation Department? state of control you want to be able to
measure what it’s doing, what is that Q Can you please comment on the
responsibilities of manufacturers

A That’s a very good question. I am

not saying it’s required but it makes
rational sense. If you have a new prod-
process doing over time. It’s really the
essence of that 211.180 (e), Periodic
Evaluation, when you say you’re doing
of record and contract manufacturers?
Who’s responsible for the validation?

uct or process for which you don’t have

a lot of history and you don’t have a
similar product or process from which
a Periodic Evaluation, what tools are
you employing to do that. So really what
the inquirer is getting at is what tools
A Ultimately the manufacturer or the
company’s name that’s on the label
is responsible. Having said that, it’s im-
you could leverage information; I think do we want to devise to do our Periodic possible for the contract manufacturer
that’s one of the holes in the way things Evaluation. I think it’s a great idea. not to be involved. I know that there
are operated right now. You have the are these quality agreements that the
pre-approval and post-approval and it
goes from getting approval and launch
to automatically, oversight is at routine
Q You purposely did not use the
number three in batches in the
document, but there are a few ques-
contract manufacturer and the actual
manufacturer of record will negotiate
and the responsibilities should be laid
levels. Well the routine levels may not tions asking if it would be appropriate out in these quality agreements. So
be appropriate immediately. to mention a minimum number? there are special considerations. And
To answer this person’s question, it’s that’s very prevalent. There are lots of
not required, but I think it’s an excel-
lent idea, sort of a transition; things
aren’t on and off, like flipping a light
A Here’s the key word you have to
think about. You have to demon-
strate reproducibility. As far as a mini-
contract manufacturers even within one
company so that has to be worked out
and transferred, whether to a site in
switch. And I suspect companies don’t mum number, again it’s not the number India or in the US... Both parties are go-
just say it’s a new process, and so now of batches, it’s what is the data. That’s ing to have some responsibility because
once it’s approved we’ll just treat it like the key criteria that you’re looking at, they will each be inspected on their own
the one that’s been running for three and how are you going to analyze that merit; they are registered drug compa-
years seamlessly. I think there is more data using what tools. You have two con- nies. If you’re responsible for transfer of
oversight and appropriately so. siderations, the product attributes, and a process to another location, that needs
So under Stage 3 I can envision and you have the process parameters and to be one of your primary concerns in
would certainly recommend that you the ability to control them. So any crite- getting those responsibilities laid out
would have formal protocols, or at least ria needs to account for both of those in and understood by all parties.

22 PHARMACEUTICAL ENGINEERING May/June 2009

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 Defining Regulatory Expectations
This article
provides a A Comparison of the FDA’s Draft
comparison of
the provisions Process Validation Guidance and
ASTM E2500
found in ASTM
E2500 versus
the expectations
for equipment
qualification by Robert E. Chew, PE
as enunciated
in the FDA’s
recent draft
process validation
guidance.
Introduction

T
management to focus on those aspects of the
he pharmaceutical/biotechnology in- facility, equipment, and automation that provide
dustry has shown great interest in the control of risk to the patient, or otherwise help
ASTM Standard E25001 for the Design, assure manufacture of a quality product.
Specification, and Verification of facili- The EU GMPs Annex 15 on Qualification
ties, equipment, and systems. Many companies and Validation, published in 2001, states that
are attempting to implement this standard. In “A risk assessment approach should be used to
quite a few instances, organizations responsible determine the scope and extent of validation.”
for compliance are concerned that this standard The document then prescribes use of Design
represents a significant change from how indus- Qualification (DQ), Installation Qualification
try has practiced qualification in the past. There (IQ), Operational Qualification (OQ), and Per-
is a further concern regarding terminology formance Qualification (PQ) as being precursors
(what certain documents need to be called) and to process validation. These terms are defined
the structure of documents with respect to EU and general content is specified. These terms
regulatory expectations. The FDA’s new draft and provisions are echoed in the more recent
process validation guidance includes expecta- ICH Q7A, GMPs for manufacture of active
tions for equipment qualification. How do the pharmaceutical ingredients, which has been
expectations in this new guidance compare with adopted by the US, EU, and Japanese regulators
the approach defined by ASTM E2500, and how as either regulation or official guidance.
can the EU expectations be reconciled with these In July 2007, ASTM E55 committee (which
documents? This article provides an analysis of is developing standards related to pharmaceuti-
these provisions and a recommended approach cal manufacturing) issued its Standard E2500
to equipment qualification. covering the design, specification, verification,
and acceptance of facilities, equipment, and as-
History sociated automation for use in pharmaceutical
ICH Q9, Quality Risk Management, was final- and biotechnology manufacturing. The purpose
ized at Step 4 in November 20052 and has been of this standard is to describe how to implement
adopted by the Japanese, EU, and US regulators the ICH Q9 principles of quality risk manage-
as either guidance or incorporated into regula- ment in a controlled and documented manner
tions. This document provides principles and ex- that meets regulations and demonstrates
amples of tools of quality risk management that manufacturing systems are suitable for their
can be applied to all aspects of pharmaceutical intended use.
quality, including development, manufacturing, In November 2008, the FDA issued its draft
distribution, and the inspection and submis- update to the 1987 Process Validation Guidance.
sion/review processes. One way (out of many) In January, the FDA delivered a webinar on this
that risk management can be used is to focus subject, hosted by ISPE. See related article on
the facility and equipment design and opera- page 8 in this issue for a full discussion of the
tion around risk to the patient. A qualification contents of this draft guidance. Industry has
approach also can make use of quality risk been provided with an opportunity to comment
Continued on page 26.
24 PHARMACEUTICAL ENGINEERING May/June 2009
 Defining Regulatory Expectations
on this draft guidance, and it remains to be seen the degree medical device and other industries: Verification is the act
to which comments and changes will be incorporated into the of confirming, through objective evidence, that a particular
final guidance. feature or specification has been met. This definition fits with
ISPE has under development a new Baseline® Guide Vol- the use of the term verification in ICH Q7A, in that DQ, IQ,
ume 12: Science and Risk-Based Approach for the Delivery of OQ, and PQ are defined in terms of “documented verification
Facilities, Systems, and Equipment, which will provide details that…”
on how to implement a program based on ASTM E2500. ISPE The third related term is Commissioning. The FDA draft
also is developing a Good Practice Guide that will provide guidance states, “It is essential that activities performed to
further options and approaches to qualification, including assure proper facility design and commissioning precede PQ.”
how to evolve practices based on the original Baseline® Guide Commissioning is widely used in many industries, particularly
Volume 5: Commissioning and Qualification, toward an ASTM the construction industry; therefore, it is a definition that is
E2500-based approach. readily understood by many parties and is of benefit to project
teams.
Terminology For purposes of this article, the following terminology will
For many years, a Qualified system meant that there existed be invoked. For additional discussion of this choice of defini-
a QA pre-approved, executed, and QA post-approved set of tions, please see related article in the July/August 2008 issue
documents consisting of an IQ and OQ (and in many cases a of Pharmaceutical Engineering.3
PQ) protocol. For computer systems, and later most systems, Verification – the act of confirming, through objective
this set of documents was expanded to include user require- evidence, that a particular specification has been met.
ments, functional requirements, traceability matrices, etc. The Commissioning – a well-planned, documented, and man-
content of these protocols more often than not was dictated by aged engineering approach to the start-up and turnover of
local procedures. It did not matter whether the protocol con- facilities, systems, and equipment to the end-user that results
tent actually corresponded to critical aspects of the system or in a safe and functional environment that meets established
whether the qualification process actually yielded equipment design requirements and stakeholder expectations.
that was fully functional and ready to manufacture quality Qualification – a state, or determination, that the equip-
product. What mattered was whether the local procedure ment has been found to be suitable for its intended use.
was followed to develop, execute, and approve each protocol.
Today, there are projects where money is being wasted and Basis for Qualification
time is being lost as decisions are made to address procedural What defines or what constitutes suitability for use? Neither
issues that are oblivious to good engineering and science and the FDA guidance, nor EU GMPs, address this question in
the impact on product quality. general terms, but instead merely provide examples of quali-
This is changing. The most important change is what it fication activities. See Content and Execution below. ICH Q7A
means to Qualify a manufacturing system. This change began has the general requirement to comply with the approved
with ISPE’s Baseline® Guide Volume 5: Commissioning and design and to operate and perform as intended.
Qualification. This Guide defined IQ, OQ, and PQ in terms The ASTM E2500 standard provides a much clearer defini-
of “aspects…that can affect product quality.” This is a more tion of what suitability for use is, and how it is assured. While
focused approach than the traditional approach of inspecting both the FDA draft guidance and the ASTM standard discuss
and testing against all engineering specifications (which can understanding the process science behind manufacturing, the
yield very thick protocols, a measure of success for some). ICH standard goes further to define critical aspects as “functions,
Q7A defines DQ as “verification that the proposed design… features, abilities, and performance characteristics necessary
is suitable for the intended purpose.” ASTM E2500 defines for the manufacturing process and systems to ensure consistent
verification as “a systematic approach to verify that manu- product quality and patient safety.” The standard requires the
facturing systems…are fit for intended use…” The FDA’s new definition of product and process requirements, and the use
draft Process Validation guidance states, “activities under- of risk assessments to identify appropriate controls through
taken to demonstrate that utilities and pieces of equipment design solutions and other means. Collectively, the process
are suitable for their intended use and perform properly is requirements and risk assessments can be used to derive the
referred to as Qualification.” The draft guidance also states, critical design and operating characteristics; these constitute
“Focusing on qualification efforts without understanding the “suitability for use.”
manufacturing process may not lead to adequate assurance The ASTM E2500 standard prescribes a lifecycle approach:
of quality.” In short, a Qualified system no longer means one “Assurance that manufacturing systems are fit for intended
with signed off protocols created and executed per a rigid use should not rely solely upon verification after installation,
procedure, but rather a system that has been shown to be but be achieved by a planned and structured approach applied
suitable for its intended use. throughout the system lifecycle.” The standard prescribes
This use of the term Qualification to mean a demonstra- a series of steps necessary to design, specify, and verify the
tion of suitability for use is equivalent to how ASTM E2500 manufacturing systems. The FDA guidance includes a brief
uses the term Verification. The author believes that the term mention of the need to assure proper facility design and com-
Verification has a more narrow and specific meaning in the missioning, but does not carry this idea to any greater detail.
Continued on page 28.
26 PHARMACEUTICAL ENGINEERING May/June 2009
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 Defining Regulatory Expectations
The determination, via the ASTM process requirements • Operate in accordance with process requirements in all
and risk assessment process, of what constitutes suitability anticipated operating ranges. This is further amplified
for use is a more robust and process-science driven approach to include challenges under load, performance of inter-
than the FDA guidance “examples.” While one cannot argue ventions, start and stoppage as expected during routine
with the general thrust of these examples, the potential is operations, and ability to hold operating ranges as long as
that industry will focus on these perceived requirements necessary during routine production operations.
to the detriment of good science and good test engineering
practices. The author feels the above attempts by regulators to engage
in the practice of defining the approach and scope of inspec-
Planning for Qualification tions and testing are overly prescriptive. For example, the
Both the ASTM E2500 standard and the FDA draft guidance last sentence regarding the ability to hold operating ranges
are remarkably similar with respect to planning, the only dif- as long as would be necessary during routine production
ference being use of Verification Plan (ASTM) vs. Qualification could lead a team to conclude they have to show the ability
Plan (FDA). The EU GMPs also contain similar requirements. to control bioreactor temperature, pH, dissolved oxygen,
Table A illustrates the respective requirements for “plans.” etc., over a time period equal to a normal cell culture batch,
which could be days or weeks. A test engineer would not as-
Content and Execution sess this as being necessary, but would instead understand
The EU GMPs are the most prescriptive, defining DQ, IQ, the science of the process and test those control loops under
OQ, and PQ. Neither the FDA draft guidance nor the ASTM expected worst case challenge conditions for heat transfer or
standard defines how the design review and inspection and test oxygen uptake, etc. Eventually, of course, such control is by
programs should be structured; during ISPE’s webinar with default demonstrated during development batches or process
FDA, the FDA presenter stated that there is no expectation for validation lots. However, teams may interpret the guidance
IQ/OQ/PQ per se. The EU GMPs prescribe content of IQ, OQ, regarding qualification of equipment preceding PQ lots as
and PQ with IQ having the most prescriptive detail. The FDA being a hard requirement and endeavor to execute such tests
draft guidance states, “Qualification of utilities and equipment in a non-optimal manner.
generally includes the following activities.” The examples are The ASTM standard prescribes that specific methods,
similar to the EU content examples and include: performance, and documentation of inspection and testing
activities are to be determined by subject matter experts. The
• selection of materials of construction (note the words are verification activities should be conducted using a systematic
selection, not verification!) approach and documented, the extent of which is scaled based
• operating principles and performance characteristics ap- on risk to patient, risk to product quality, and the complexity
propriate for their specific use and novelty of the equipment. This is a science and risk-based
• built and installed per design specifications – and it clari- engineering approach. The use of subject matter experts, as
fies this by stating “built as designed with proper materi- defined by the standard, is in complete agreement with 21
als, capacity, and functions, and properly connected and CFR 211.25, Personnel Qualifications.
calibrated.”

Plan Element ASTM FDA EU

Strategy/studies or tests to use/timing or sequence/scheduling X X X
Define acceptable documentation of detailed activities X X X
QA approval (for systems with critical aspects) X X Note 1
Acceptance criteria X X
Developed and approved by subject matter experts X
Responsibilities/organizational structure X X
Incorporate risk management to prioritize activities and adjust level of effort in both performance and documentation X X Note 2
thereof
Choice to use system-based planning or one overall project plan X X X
Managing change during the project Note 3 X X
Validation policy, and reference to existing documents X
Note 1: Common expectation is that the validation master plan be approved by QA.
Note 2: The Principle (preamble) states “A risk assessment approach should be used to determine the scope and extent of validation.” It is presumed that the scope
and extent are discussed in the validation plan.
Note 3: ASTM positions Change Management as a required supporting process to the project, but does not mention it in the context of the verification plan. It is likely
teams would choose to include such a subject in their verification plans.
Table A. Comparison of ASTM, FDA, and EU expectations for contents of a “Qualification Plan (FDA/EU)” or “Verification Plan (ASTM E2500).”

28 PHARMACEUTICAL ENGINEERING May/June 2009

 Defining Regulatory Expectations
Review, Approval, and Release Summary and Recommendations
ASTM E2500, the EU GMPs, and the FDA draft guidance Table B summarizes the similarities and differences between
document all require a summary report following the field the US FDA, EU GMPs, and ASTM E2500 with respect to
inspections and testing. This report is to summarize the demonstrating manufacturing systems are suitable for their
findings, highlight any deviations, and describe any changes intended use.
to the plan/protocol that may have occurred. The ASTM It is this author’s opinion that if a project team follows
standard describes a two-step process, Verification Review, the requirements of the ASTM E2500 standard, it will have
which is performed by an independent (second check) subject met the expectations of both US FDA and EU regulators for
matter expert, followed by an Acceptance and Release, which demonstrating manufacturing system suitability for use. While
includes the quality unit for systems with critical aspects. In project teams may choose to be sensitive as to what labels are
other words, technical experts review the technical results attached to what documents and to a few particulars of the
and make a determination as to suitability for use, while the regulations, overall the ASTM standard provides the most
quality unit provides a final approval of this determination robust, science- and risk-based methodology of any of the
and official release for manufacturing, at which point the documents discussed.
system is placed under QA pre-approved change control (vs. For those who feel more comfortable having documents
change management during the project). labeled “DQ, IQ, OQ, and PQ,” the following is suggested with
It should be noted that NONE of the three documents respect to documents typically produced during an ASTM
describe the typical onerous and formal deviation resolution E2500-based project.
process present in most projects today. Only the EU GMPs
and the ASTM standard mention deviations, and both discuss • The final risk assessment and identification of critical
them in terms of documentation via the final summary report. aspects/acceptance criteria and confirmation that the
While the FDA draft guidance does not specifically mention design includes all process requirements could be labeled
deviations, the subject can be inferred under the contents the DQ.
of the qualification plan: “the criteria appropriate to assess • A checklist of these critical aspects and their acceptance
outcomes [should include how to deal with deviations].” criteria could be used to review the verification/commission-
ing work to confirm all critical aspects have been checked.

Concludes on page 30.

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 Defining Regulatory Expectations
Qualification Expectation ASTM FDA EU
Focus on science-based process understanding and meeting process requirements X X
Equipment and facilities suitable for intended use X X
QA approves [qualification] [verification] plan X X
QA approves [qualification] [verification] report X X
QA approves protocols Note 1 Note 1 Note 2
Risk assessment to “scale” effort, documentation X X X
Flexibility on how effort is structured X X
Specific aspects to check are spelled out X X
Critical aspects derived from risk assessments and process requirements X
Use of project change management X X X
Use of subject matter experts: how to verify, adjudicate departures from specification X
Use of vendor documents X
Design and testing of facility, process, equipment based on process understanding X X X
Final report to summarize findings and deviations X X X
Note 1: The QA unit is to approve the acceptance criteria and other high level aspects of the qualification planning effort as discussed under Planning for Qualification.
Note 2: QA approval is inferred. EU Annex 15 requires approval of protocols, but does not state by whom.
Table B. Summary comparison of key expectations of ASTM E2500 program, FDA process validation guidance, and EU GMP Annex 15.

These checklists could be labeled “IQ/OQ” protocols. These References

checklists could actually be created or copied from the final 1. ASTM E2500-07: Standard Guide for Specification, Design,
risk assessment and list of critical aspects, eliminating a and Verification of Pharmaceutical and Biopharmaceutical
separate protocol pre-approval step – the approval of the Manufacturing Systems and Equipment, July 2007.
DQ also could serve as the approval of these checklists. 2. See the FDA/International Conference on Harmonisation
• A similar approach could be taken for PQ work or a more (ICH) guidance for industry:
traditional PQ protocol could be used that includes the a. Q8 Pharmaceutical Development
specific test cases and instructions for execution. b. Q9 Quality Risk Management
• These checklists that are labeled IQ/OQ protocols also could c. Q10 Pharmaceutical Quality Systems
be used as the final verification report and the approval 3. Adamson, R., Calnan, N., Chew, R., Wisniewski, S., “Com-
thereof would constitute the acceptance and release phase missioning, Qualification, and Verification: A Review
of ASTM standard. Solving the Terminology Conundrum,” Pharmaceutical
Engineering, July/August 2008, Vol. 28 No. 4.
As a cautionary note, it is the author’s experience that teams
attempting to implement ASTM E2500 with respect to risk About the Author
assessments and contents of protocols spend significant effort Robert E. Chew, PE is President and CEO
trying to understand and spell out the detailed mechanics of of Commissioning Agents, Inc. and has 20
documentation format, structures, what goes where, etc. It years of experience in the pharmaceutical
also is the author’s experience that teams tend to view risk industry. He was a member of the Author
assessments solely through the lens of focusing on the inspec- Task Team which produced the recent ASTM
tion and testing (verification/qualification) effort. That is not E2500-07 International Standard. Chew also
the intent of ICH Q9, Quality Risk Management. Instead, it is a member of the team currently writing the
is the author’s recommendation that teams approach risk ISPE Baseline Guide Volume 12: Science and
assessments with a holistic view – conduct risk assessments Risk-Based Approach for the Delivery of Facilities, Systems,
with the idea of identifying, assessing, and controlling risk and Equipment. He is a former member of ISPE’s Interna-
to the patient through a variety of means (engineering and tional Board of Directors, and has been a frequent speaker for
other quality system-related means). The risk assessments ISPE globally. He graduated in 1981 with a BS in chemical
should commence at a high level starting with conceptual engineering from Case Western Reserve University. He can be
design, continuing through more detail as the design devel- reached by telephone: +1-317-710-1530 or by email: Robert.
ops. It will then become apparent to teams as to how to use Chew@Cagents.com.
these results – to improve the design, to improve procedures, Commissioning Agents, Inc. P.O. Box 34320, Indianapolis,
to improve training, to improve other aspects of the quality Indiana 46234 USA.
system, not to mention providing a focus on the critical design
and operating aspects of the manufacturing systems.

30 PHARMACEUTICAL ENGINEERING May/June 2009

 Defining Regulatory Expectations
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06.03.2009 09:06:49 31
 Industry Interview
Jean-Louis
Robert talks
Pharmaceutical Engineering Interviews
candidly about
his role with the
Dr. Jean-Louis Robert, Head of Luxembourg’s
International
Conference on
Laboratoire National de Santé, Service du
Harmonization Contrôle des Medicaments
(ICH), the
continued
importance of by Dr. John C. Berridge
harmonizing
quality
standards both
within the ICH

T
regions and he following is a recent interview with System (Q10), and currently he is Rapporteur
beyond, and the Jean-Louis Robert, Head of Luxem- for the implementation of ICH Q8, Q9, Q10. At
bourg’s Laboratoire National de Santé, the European Pharmacopoeia, he is a member
need for global Service du Contrôle des Medicaments, of the Commission and of the group of experts
implementation conducted by ISPE’s European Regulatory Af- 10 B (synthetic products). Currently he chairs
of initiatives fairs Advisor, who was a European Industry the Steering Committee of the Certificate of
such as Quality Representative at the International Conference Suitability of the European Pharmacopoeia.
on Harmonisation (ICH) from its inception He also serves as a pharmaceutical expert at
by Design until 2007. WHO.
(QbD), design
space, and risk
management.
Dr. Jean-Louis Robert
studied chemistry at
Q Jean-Louis, today you contribute to a wide
variety of activities associated with public
health protection. For example, you are the
the University of Basle
quality representative to the EMEA’s Commit-
(CH) and obtained his
tee on Human Medicinal Products (CHMP) and
PhD from there in 1976.
the Chairman of the Quality Working Party
He had a post-doctoral
(QWP). For many years, you and I worked closely
training at the Pharma-
together as members of a variety of ICH Expert
ceutical Institute of the
Working Groups. Your latest ICH contribution
“Eidgenössische Technis-
has been the completion of the Annex to ICH
che Hochschule” (ETH) in
Q8 in November 2008. Congratulations! This
Zurich (CH). He spent one year with a pharma-
surely represents the conclusion of another very
ceutical company before joining the National
valuable ICH guideline.
Health Laboratory (LNS) in Luxembourg. In

A
his current position, he is Head of the Depart- Yes, thank you. I was very happy to take
ment of Control of Medicines, an Official Medi- over the completion of this guideline after
cines Control Laboratory (OMCL) at the LNS, you had led the Expert Working Group through
member of the European Directorate for the to Step 2 in the ICH process. While principles
Quality of Medicines OMCL (Council of Europe, of Quality by Design (QbD) were not totally
Strasbourg) network. He has been a member of new in Europe, it is extremely useful to have a
the Committee for Human Medicinal Products guideline such as Q8(R1) to explain an enhanced
(CHMP) since 1995 (co-opted since 2004) at the approach to pharmaceutical development and
European Medicines Agency (EMEA) in London all the opportunities linked to it.
and Chairman of the CHMP/CVMP Quality
Working Party since 1995. Within the Interna-
tional Conference on Harmonization (ICH), he is
Q Can you tell me more about your role and
responsibilities as Head of the Laboratoire
National de Santé, Service du Contrôle des
or was involved in following topics: Validation of
Medicaments in Luxembourg?
Analytical Procedures (Q2), Common Technical

A
Document-Quality, revision of the guidelines I am responsible for the laboratory which
on impurities (Q3A and Q3B), Pharmaceutical deals primarily in the quality control of the
Development (Q8), Pharmaceutical Quality medicines sold in Luxembourg. This monitoring

32 PHARMACEUTICAL ENGINEERING May/June 2009

 Industry Interview
is done in close collaboration with the
Division of Pharmacy and Medicines
(Luxembourg Inspectorate) at the na-
nominated to the CPMP, as it was then,
in January 1995 and became a co-opted
member of the CHMP in 2003. The har-
A Right now, our priorities can be
seen by reviewing the work pro-
grammed on our Web site. In the recent
tional level, and they are responsible monization of quality standards across past, we have significantly increased
for the review and approval of human Europe is the responsibility of the Qual- our collaboration with the Inspectors’
and veterinary dossiers in Europe. The ity Working Party (QWP). I have chaired working party where we are planning
laboratory is also involved in developing the QWP since March 1995. As an EU greater involvement of assessors with
methods to characterize the chemical expert, I support the activities of the inspectors as we review and approve
and physical properties of drugs at European Directorate for the Quality of new marketing authorization applica-
pharmacopoeial level. The laboratory is Medicines (EDQM) European Pharma- tions. We work very closely with the
a member of the European Official Medi- copoeia, OMCL network, and represent Biological Working Party and this has
cines Control Laboratories (OMCL) Europe in the International Conference been especially so with the development
network, coordinated by the European on Harmonisation (ICH). of the recent ICH guidelines. Looking
Directorate of Quality of Medicines further into the future, of course we will
(Council of Europe, Strasbourg). It is
also engaged in anti-counterfeiting
Q Tell us more about the role of the
QWP and why is it so important
to have an organization such as the
continue to adapt to new scientific prog-
ress and work across Europe to support
activities. the training of assessors, where there
QWP?
may be opportunities to work together

Q Please tell me more about the role

and responsibilities of an OMCL.
A As Europe continues to grow, it is
vitally important to have a coordi-
with organizations such as ISPE. We
do also have a very active PAT team,

A An OMCL is an official laboratory

that supports the regulatory au-
thorities and complements the inspec-
nating organization that oversees the
development, implementation, and
application of common standards and
addressing specific issues with regard
to PAT, Quality by Design, giving advice
to industry on product related issues.
tion services in controlling the quality quality systems across all the member This group chaired by Dr. Keith Pugh
of medicinal products on the market states. Where we see the need to develop from MHRA includes experts from QWP,
by independent testing. It is an inde- a guideline for industry regarding a qual- BWP, and GMDP IWP.
pendent laboratory responsible for the ity matter, we address it through a well-
quality control of medicines for human
and veterinary use in member states of
documented and rigorous procedure. We
actively seek input from industry and
Q Tell us more about your role in ICH.
I believe you are the longest serving
member of the Quality Expert Working
the Convention on the elaboration of other interested parties across the whole
Groups?
the European Pharmacopoeia and the of the community and are always willing
observer states. The Commission of the
European communities and the Council
of Europe set up the network in May
to hear comments and suggestions on
how we can improve quality standards
in Europe, and internationally, for the
A With your recent retirement, I
think I am now the longest serv-
ing member supporting the quality
1994 and the European Secretariat took benefit of patients. topics! Clearly, my primary role is to
on this new responsibility. The main pur- The QWP also represents a single represent the EU in this area. I have
pose of the European network of OMCLs source of scientific advice for indus- really enjoyed working for the past 15
is the mutual recognition of tests carried try. We hold regular meetings with years and still enjoy supporting the
out at the national level from countries companies who seek our input as they harmonization of quality standards
that belong to the European Union and progress their candidates through the both within the ICH regions and those
the sharing of expertise, standardiza- later stages of development. observer countries that adopt the ICH
tion, and international collaboration for In addition, the QWP provides a guidelines. One of the more demanding
the other countries. Among the many central point of contact and liaison roles is that of the rapport. Generally,
things the network does, it has set up a with other regulatory authorities. For industry acts as the rapport until a
coordinated European approach for the example, we recently collaborated with guideline reaches step two, after which
surveillance of marketed products. It Health Canada in the elaboration of a the regulatory authority from the same
is also responsible for the coordination guideline for inhaled products, and we region will take over the responsibility.
of the official batch release of vaccines, frequently welcome visitors from the Personally, I have led the development
for example. FDA or other agencies to our QWP meet- of the guidelines concerning analyti-
ings. For instance, Swissmedic and the cal validation, impurities (revision),

Q As an EU expert with the EMEA

and representative to the CHMP,
what are the main areas that you focus
European Pharmacopoeia participate
as observers to our meeting.
pharmaceutical development part of,
the quality aspects of the CTD-Q, and
currently Q8, Q9, and Q10 IWG.
on and contribute to?
Q What are your current key priorities
as Chairman of the QWP? How do
Q There are many different initiatives

A At the CHMP level, my main contri-

butions are for the pharmaceutical
quality aspects of submissions. I was
you see the role and priorities of QWP
changing or developing over the next
(FDA’s initiative on Pharmaceutical
Quality Systems for the 21st Century,
decade? ICH Guidelines, industry association
Concludes on page 34.
May/June 2009 PHARMACEUTICAL ENGINEERING 33
 Industry Interview
initiatives, etc.) that share the same arena, especially in global implementa- in industry at Merck in Darmstadt. I
concepts (some of which are not so tion of these many initiatives? then moved to the laboratory in Lux-
“new”), such as QbD, design space, risk embourg in 1978 and have been there
management, etc. What do you think is
the best way forward to facilitate global
A I think it is the combination of ex-
pertise and the global reach of orga-
nizations such as ISPE that facilitates
ever since. The most important is not so
much what somebody has studied, but
implementation of those concepts? to continuously improve one’s scientific
global implementation. ISPE, with its
knowledge and to be open minded.

A There are probably two ways which

we can facilitate the global imple-
mentation of these concepts. Starting
Communities of Practice (COPs), Edu-
cation Committees, Regional Affiliates,
and extensive guides and technology Q What has been your most fulfilling
role in your career?
with ICH Q8, we have been focusing based learning, bridges regulators and
more on creating a higher level of guid-
ance that is less prescriptive than was
industry, and is a powerful resource that
can assist everyone whatever region
A I have really enjoyed working in a
small agency because it provided
me with a diverse range of opportuni-
perhaps the case with earlier guidelines. they operate in.
ties, including the chance to review
This means that there then needs to be
agreement on interpretation. Since it
is industry, not regulatory authorities,
Q In your career, what are the most
significant issues or changes you
have seen in the global pharmaceuti-
dossiers (first in the BENELUX regis-
tration), to work as part of the OMCL
network, and to support the European
that develops new drugs, it is important
cal environment and what changes or Pharmacopoeia. I have really enjoyed
for industry to develop and share their
challenges do you anticipate in the next participating in the development of
understanding on the interpretation
few years? the EMEA, the establishment of the
and implementation of these guidelines.
CPMP/CHMP, and the OMCL network.
For example, there have been a number
of groups that have developed and pub-
lished case studies and other training
A There have been so many. What I am
really pleased to see is the move from
assuming quality can be controlled by
Of course working in the ICH also has
been very exciting. Just for the record, I
have not missed a single QWP meeting
materials that support the implementa- end product testing to the appreciation
since it was set up!
tion of these guidelines. The more we can of the importance of product and process
do that and the more that we can jointly
collaborate in their development and
elaboration, the greater will be the adop-
understanding, thereby supporting
continual improvement. The size of the
application file has increased though!
Q What kinds of activities do you enjoy
in your free time?

tion throughout the world. Secondly, we

just need to continue the dialogue. No
I’ve also seen a significant drift away
from localized European manufacture
A I love being with my family. While
I used to play football, jog, and play
squash, I spend more time now on my
guideline is ever 100% complete. There to globalized outsourcing, and I do
bicycle and I really enjoy the wild and
will always be questions. The recently have a concern as to whether industry
rugged scenery of our local Ardennes.
established Implementation Working will be able to maintain their quality
I relax by reading -- thrillers, history,
Group (IWG) has a role to document standards.
and political commentaries.
and answer these questions and thereby
provide a valuable resource to support
the global implementation of the ICH
Q For our readers who might want to
follow in your distinguished foot-
steps, what education and preparation
Q Are there any other comments/last
thoughts you would like to convey
quality guidelines. to our readers?
is needed for a career in a regulatory

Q What is your involvement with

ISPE?
agency, particularly as a pharmaceuti-
cal assessor? A Maybe I can finish this interview
with a message to my industry
friends and colleagues. I think industry

A I have enjoyed many years of involve-

ment with ISPE. In addition to con-
tributing to meetings and workshops in
A Of course there are many routes
that one can take to become a
pharmaceutical assessor. Studying
needs to be its greatest critic. It really
is important for you to do all you can
to achieve the greatest understanding
both Europe and the USA, I participate pharmacy is obviously a good route into
of each other and an understanding of
in the Regulatory Affairs Committee regulatory activities, but the scientific
the authorities that regulate you. Do
meetings and contribute to the Inter- degrees of chemistry or biology are also
what you can to build trust. We, the
national Leadership Forum, which is appropriate. These days, I would rec-
authorities, welcome open discussions
where senior regulators from around ommend that a period in industry to
and transparency, and are always will-
the world and Industry executives can gain a wide exposure to contemporary
ing to receive new ideas and suggestions
share issues relating to quality and pharmaceutical technology is valuable
from you. As you engage in more and
make proposals for their resolution. before considering entering a regulatory
more outsourcing, do pay attention to
agency. I started my career with a BSc

Q In what ways do you believe a global

organization such as ISPE can assist
regulators, pharmaceutical companies,
in chemistry and then did my PhD in
Basle. I stayed in Basle to do a post-Doc
the quality systems throughout the
whole of your supply chain to ensure
the robust quality and sustainability
at the ETH, and then took my first post
and individuals in the international of all your supplies.

34 PHARMACEUTICAL ENGINEERING May/June 2009

 Industry Interview
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 Product Quality Lifecycle Implementation (PQLI)
This article
presents the PQLI® – What is it?
current status
of ISPE’s PQLI
initiative. It by Dr. John C. Berridge
details how
PQLI will
provide the
global industry
with the tools
necessary to Current Status

I
include the provision of a technical framework
implement the SPE launched its Product Quality Lifecycle comprising, for example, explanatory docu-
ICH quality Implementation (PQLI®) initiative in June ments and illustrative examples, supporting
vision. 2007 to help industry find practical ap- the implementation of enhanced science- and
proaches to the global implementation of risk-based approaches to product realization,
recent ICH guidelines. Through PQLI, ISPE technology transfer, commercial manufacture,
is spearheading approaches to assist in the and its continual improvement in both research-
implementation of, in particular, ICH Q8(R1) and generic-based organizations. PQLI clearly
(Pharmaceutical Development), Q9 (Qual- recognizes that there is no one way to implement
ity Risk Management), Q10 (Pharmaceutical the ICH guidelines, rather there are many per-
Quality System) and imminent Q11, and to fectly satisfactory ways to address the concepts
support the work of the ICH Implementation that are described. PQLI is therefore developing
Working Group. ISPE is working with industry a variety of tools to communicate science and
and regulatory leaders worldwide to support risk-based processes, and a growing series of
pragmatic and practical implementation of the publications demonstrates the areas of current
guidelines based on sound scientific, engineer- activity (see References).
ing, and business principles. Key goals of PQLI PQLI encompasses the whole of the product

Figure 1. The strategic

themes, structure, and
status of PQLI.

36 PHARMACEUTICAL ENGINEERING May/June 2009

 Product Quality Lifecycle Implementation (PQLI)

“Within PQLI, ISPE has established multi-disciplinary, multi-national teams in support of

these strategic themes, addressing them from the perspectives of both small molecules
(chemically derived) and biotechnology.”

lifecycle and comprises three strategic themes - Figure 1. processes and examples which demonstrate this and show
how their application can result in significant business ben-
• Principles of Quality by Design efits. The paper provides three contrasting case studies which
• Pharmaceutical Quality System Elements indicate a wealth of opportunities to improve processes for
• Enablers existing products through the use of science- and risk-based
approaches, and the subsequent business benefits and regula-
These strategic themes represent the key components of tory opportunities that can accrue.
the ICH quality vision described at the July 2003 meeting The principles of QbD also are equally applicable to
in Brussels which supported the development of the recent biotechnology products. PQLI has an international team of
ICH quality guidelines: industry experts assembling technical guidance and examples
to support this sector of our industry.
“Develop a harmonised pharmaceutical quality system
applicable across the lifecycle of the product emphasiz- Pharmaceutical Quality System
ing an integrated approach to quality risk management As described in ICH Q10, the opportunities to change the
and science.” paradigm of development and manufacturing activities for full
utilisation of enhanced scientific approaches come only with an
Within PQLI, ISPE has established multi-disciplinary, multi- integrated and robust pharmaceutical quality system. At our
national teams in support of these strategic themes, addressing planned conferences in 2009 in Washington, Strasbourg, and
them from the perspectives of both small molecules (chemi- San Diego, PQLI is organizing presentations and workshops to
cally derived) and biotechnology. Ensuring alignment with
Continued on page 38.
the published ICH guidelines and supporting the future IWG
activities is a major focus of PQLI. The PQLI teams benefit
enormously though the presence of past and current mem-
bers of ICH Expert and Implementation working groups and
they have further benefitted from input and feedback from
members of the three ICH regulatory authorities.

Principles of Quality by Design

The principles of Quality by Design (QbD) are described in
ICH Q8(R1). Three multinational, multidisciplinary teams
were set up to address the priority topics of Criticality (Critical
Quality Attributes and Process Parameters), Design Space, and
Control Strategy. Through their deliberations a set of papers
was published in the Journal of Pharmaceutical Innovation
in June 2008. These papers were published with requests for
comments, and from the feedback received it is clear there is
a continuing need for PQLI to demonstrate how the concepts
of the ICH guidelines translate into practical application in
all areas of the product lifecycle. Industry continues to ask
to see the high level ICH concepts made simple, real, and
practical. A more comprehensive explanatory paper is in
preparation to show how the different elements of QbD fit
together. Case studies and worked examples are a helpful
way of exemplifying the principles and the PQLI teams are
actively developing such examples. These examples are all
aimed at providing clearer options that demonstrate there are
many ways of implementing an enhanced, Quality by Design
approach rather than suggesting there is just a single way.
The principles of QbD are applicable throughout the
lifecycle, and a publication in JPI (March 2009) describes

May/June 2009 PHARMACEUTICAL ENGINEERING 37

 Product Quality Lifecycle Implementation (PQLI)

Figure 2. PQLI process to generate technical implementation guidance.

explore the issues and potentially spawn further topic teams Conclusions
to develop the appropriate technical tools. The vision of the ISPE PQLI initiative is to make available
to our global industry the technical and scientific tools and
Enablers understanding that enable comprehensive implementation
The two enablers described in ICH Q10 are knowledge man- of the ICH quality vision. We are fortunate to have on our
agement and quality risk management. PQLI is addressing teams industry experts, current and past members of ICH
quality risk management primarily through the tools being Expert Working Groups, and to receive excellent feedback
developed to support QbD principles. Knowledge management from leading regulators across the ICH regions. Building on
is a vital enabler that has received little attention so far, but a foundation of the principles of QbD, PQLI is strengthen-
represents the key theme of ISPE’s Strasbourg Conference ing this work and now addressing the remaining elements
in September 2009 “Managing Knowledge through Science described in ICH Q10 to provide a unique and comprehensive
and Risk Assessment.” technical framework and set of guides.
ISPE welcomes all contributions, from both members and
Future Plans non-members, who have ideas and examples that describe the
PQLI will continue its efforts to assist in the adoption and practical application of the new ICH quality guidelines. ISPE
implementation of the ICH quality vision. The goal is to is keen to collaborate with colleagues and organizations who
provide a set of resources useful to small, medium, and large share the same objectives towards rapid and comprehensive
innovator companies working on chemical and biotechnology support of the implementation of the ICH quality vision.
active ingredients and products as well as generic companies. If you have any comments, or contributions you wish to
For established concepts, those that are already well-defined make to PQLI, please feel free to email PQLI@ispe.org.
by guidelines and the ICH implementation working group,
PQLI will continue to support and complement implementa- References
tion topics with practical case studies, training opportunities PQLI Publications
and extension of the understanding to global audiences. For 1. Garcia, T., Cook, G., and Nosal, R., PQLI Key Topics -
example, PQLI has in preparation a technical guide which will Criticality, Design Space, and Control Strategy, Journal
describe the continuum of development of a product through of Pharmaceutical Innovation (2008) 3:60–68.
to manufacturing and consideration of opportunities for con-
tinual improvement. Incorporating the feedback received on 2. Nosal, R., and Schultz, T., PQLI Definition of Criticality,
the June 2008 JPI papers, it pulls together the foundation Journal of Pharmaceutical Innovation, (2008) 3:69–78.
work on critical quality attributes and process parameters,
design space, and control strategy, linking to many case stud- 3. Lepore, J., and Spavins, J., PQLI Design Space, Journal
ies and examples illustrating implementation. of Pharmaceutical Innovation, (2008) 3:79–87.
For newer concepts, PQLI will support further debate and
discussion through papers, conference presentations, and 4. Davis, B., Lundsberg, L., and Cook, G., PQLI Control
workshops that involve both industry and regulators: this Strategy Model and Concepts, Journal of Pharmaceutical
well established process is illustrated in Figure 2 and is being Innovation, (2008) 3:95–104.
used to develop implementation guidance around strategic
themes 2 and 3. 5. Bolton, R., and Tyler, S., PQLI Engineering Controls and
Automation Strategy, Journal of Pharmaceutical Innova-
tion, (2008) 3:88–94.

38 PHARMACEUTICAL ENGINEERING May/June 2009

 Product Quality Lifecycle Implementation (PQLI)

6. Berridge, J.C., PQLI®: Current Status and Future Plans,

Journal of Pharmaceutical Innovation, (2009) 4:1–3.
Your Single Source Solution Provider
7. Potter, C., PQLI Application of Science- and Risk-based Director Series
Approaches (ICH Q8, Q9, and Q10) to Existing Products,
Journal of Pharmaceutical Innovation (2009), 4:4–23. Reactor Temperature
Control Module
Other Associated or Referring Publications
8. Ende, D., Bronk, K.S., Mustakis, J., O’Connor, G., Santa
Maria, C.L., Nosal, R., Watson, T. J. N., API Quality by
Design Example from the Torcetrapib Manufacturing
Process, Journal of Pharmaceutical Innovation, (2007)
2:71–86.

9. Somma, R., Development Knowledge Can Increase Manu-

facturing Capability and Facilitate Quality by Design,
Journal of Pharmaceutical Innovation, (2007) 2:87–92.

10. Drennen, J.K., III, Editorial: Introducing PQLI Innovations

from ISPE’s Product Quality Life Cycle Implementation
(PQLI) Initiative, Journal of Pharmaceutical Innovation,
(2008) 3:59.

11. JPI Interviews Moheb Nasr, PhD, Director, Office of New

Drug Quality Assessment (ONDQA), CDER, US FDA,
Journal of Pharmaceutical Innovation, (2007) 2:67–70.

About the Author Features Include:

Dr. John Berridge retired from Pfizer Global � Temperature Range from -80º to +285ºC
Research and Development at Sandwich in
January 2006 as Vice President of Pharmaceu- � Stainless Steel Construction
tical Sciences. He spent more than 31 years at � Sizes from 20 Liter to 500 Gallon Reactors
Pfizer, starting as an Analytical Chemist, and
more recently responsible for all aspects of � Jacket Delivery Pressure Control
chemistry, pharmacy, analytical, and regula- � Single Loop or Cascade Control
tory CMC in Europe. His research interests
have been directed toward high performance liquid chromatog- � General Duty or Explosion Proof
raphy with special emphasis on the use of chemometrics. This Classification
research was recognized by the award of the Chromatographic
� PLC Control, Data Logging & Trending
Society’s Jubilee medal in 1989. Berridge was involved in the
Software, Self Tuning for Accuracy ±1ºC
ICH processes from their inception until November 2007,
representing EFPIA in the Quality topics discussions. He has
contributed to guidelines on impurities in drug substances and Budzar Industries has specialized in process
their dosage forms, specifications, and the Common Technical fluid heat transfer systems since 1975 and has
Document (Quality): he was the Industry rapporteur for the earned a global reputation for quality and
pharmaceutical development guideline (Q8). In 1995, he was ingenuity in the design, engineering, and
presented with an FIP IPS award for his outstanding contri- manufacturing of temperature control systems.
bution to industrial pharmacy and in 1997, he was awarded Budzar Industries systems are found throughout
the Royal Pharmaceutical Society Chiroscience award for his the world, delivering accurate temperature
services to the pharmaceutical industry. Berridge now acts measurement and control to the production of
as an independent consultant and as European Regulatory pharmaceuticals, chemicals, petroleum, rubber,
Affairs Advisor and PQLI project manager to ISPE. He can power, steel, food, and plastics.
be contacted by email: pqli@ispe.org.
Budzar Industries
38241 Willoughby Parkway
Willoughby, Ohio 44094
440-918-0505 • www.Budzar.com

May/June 2009 PHARMACEUTICAL ENGINEERING 39

 Global Regulatory Framework Overview
This article
provides Global Regulatory Framework Overview:
a general
overview of the US FDA, EMEA, PIC/S, and ICH
organizational
structures of the
US FDA, EMEA, by Dr. Kate McCormick
PIC/S, and ICH
as they relate to
pharmaceutical
manufacturing
and regulation.
The content US FDA

T
relevance to the regulation of drugs and biologi-
in this article he Food and Drug Administration (FDA) cal products are discussed below.
is sectioned has responsibility for regulation of
into three drugs and biological products which are Office of Regulatory Affairs
manufactured and/or sold in the US. The The Office of Regulatory Affairs (ORA) is the
Knowledge FDA is part of the Health and Human Services lead office for all field activities of the FDA. The
Briefs, which Department of the US government. Its role is to duties and functions of ORA are divided between
are available guard the welfare of consumers. Full details of four main Offices: Resource Management,
online and the FDA can be found at: www.fda.gov. Regional Operations, Criminal Investigations,
The FDA’s authority is based upon various and Enforcement. ORA regions are the Pacific,
free to ISPE Southwest, Central, Southeast, and Northeast
laws and statutory documents, as shown in
Members. Figure 1. While drugs fall under the Food, Drug, regions of the US. Each region supports a number
and Cosmetic Act, biological products fall under of local FDA offices.
not only the Food, Drug, and Cosmetic Act, but
also the Public Health Service Act. Center for Biologics Evaluation and
While the statutes provide the legal basis Research
for the FDA’s authority, the regulations which The mission of the Center for Biologics Evalu-
they enforce are contained within the Code of ation and Research (CBER) is to protect and
Federal Regulations, Title 21. Of particular enhance public health through the regulation
importance in relation to manufacturing are of certain therapeutic biological products as
parts 210 and 211. These are generally written well as blood products, vaccines, and tissue and
as 21CFR 210 and 21CFR 211. gene therapy products.

Organizational Structure Center for Drug Evaluation and

As Figure 2 shows, the FDA is divided into seven Research
main divisions or Centers. Detailed organization The Center for Drug Evaluation and Research
charts can be found at: http://www.fda.gov/oc/ (CDER) is responsible for the regulation of
orgcharts/orgchart.html. chemically-derived and most therapeutic bio-
The Centers and Offices that have particular logical products, both new drugs and generics.

Figure 1. Statutory and

Regulatory Authorities.
Center for Devices and
Radiological Health
The Center for Devices and Radiologi-
cal Health (CDRH) is responsible for
the regulation of medical devices and
radiation emitting products.

Office of Combination
Products
The Office of Combination Products
(OCP) is an office within the FDA’s
Office of the Commissioner, which is
Continued on page 42.
40 PHARMACEUTICAL ENGINEERING May/June 2009
 Global Regulatory Framework Overview
In Phase II, which lasts 2 years, a
small number of patients are voluntarily
given the drug to determine its effective-
ness and to highlight any side effects.
In Phase III, a much larger popula-
tion of patients is given the drug to con-
firm its effectiveness and to identify any
adverse reactions over a longer period of
time. This phase lasts for between 3 and
3.5 years. Once these phases have been
Figure 2. Organizational structure of the FDA.
completed, the company files a New
responsible for general oversight of training in drug development, manu- Drug Application (NDA) or a Biological
the agency’s regulation of combination facturing, quality assurance, and risk Licensing Application (BLA) with the
products. The primary responsibilities management. These investigators, as FDA. The process of assessment and
for regulating specific combination well as other FDA drug investigators, approval by the FDA takes between
products remain in one of the product inspect all facilities that are regulated 1.5 and 2.5 years. Once the drug has
centers – CDER, CBER, or the CDRH. by CDER, including those manufactur- been approved and is marketed, there
The OCP is responsible for assigning an ing therapeutic biological products. The is a much larger potential population
FDA center to have primary jurisdiction Pharmaceutical Inspectorate is often for further testing. Additional post
(lead center) over a particular combina- assigned to inspect the higher risk drug approval testing related to a drug’s
tion product. The OCP also oversees manufacturing facilities. approved indication(s) intended to
multi-center reviews of combination optimize the safe and effective use of
products, ensures consistent and ap- Licensing/Approval Procedure the drug is called Phase IV testing.
propriate post-approval regulation of Figure 3 shows the approval or licens- It can be seen from the bottom of the
combination products, and resolves ing process for a New Chemical Entity figure that each approved drug arises
disputes relating to combination (NCE) by the FDA. The process, which from the evaluation of an average of
products. can take up to 15 years in total, may be 5,000 compounds.
divided into 8 phases. Firstly, there is
Team Biologics the pre-clinical stage, lasting between Pharmaceuticals in the 21st
The FDA Team Biologics was estab- 3.5 and 6.5 years. During this stage Century
lished in 1997 to assure the quality and in-vitro and in-vivo (animal) studies In August 2002, the FDA launched its
safety of biological products. It consists are carried out to assess safety and initiative “Pharmaceutical cGMPs for
of a core team of certified ORA investi- biological activity. At the conclusion of the 21st Century – A Risk-based Ap-
gators, CBER certified inspectors, and this stage, the company files an Inves- proach.” The launch document included
specially trained compliance officers tigational New Drug (IND) application. the following statement:
representing both ORA and CBER. In effect, this is a request for a permit
“FDA resources will be used most ef-
for the drug to be transported across
fectively and efficiently to address the
Pharmaceutical Inspectorate state boundaries for the purposes of
most significant health risks.”
FDA’s Pharmaceutical Inspectorate clinical trials.
was established under the agency’s Clinical trials are carried out on In other words, the agency does not
Pharmaceutical CGMP’s for the 21st humans. In Phase I, which lasts up to have sufficient resources to regularly
Century: A Risk-Based Approach. This 1.5 years, the drug is tested on healthy inspect all the sites around the world
is a group of certified FDA drug inves- volunteers to prove it is safe and to that are making drugs and biological
tigators who have received advanced identify the appropriate dosage. products for the US market. Hence, it
would use risk management to decide
the priorities for inspection.
At the same time, it said it required
from companies:

“The most up-to-date concepts of risk

management and quality systems ap-
proaches to be incorporated, while con-
tinuing to ensure product quality.”

The FDA wants companies to enhance

the scientific approach to GMP to
emphasize risk-based control point
Figure 3. The FDA approval or licensing process for a New Chemical Entity (NCE). analysis and decision-making. In other

42 PHARMACEUTICAL ENGINEERING May/June 2009

 Global Regulatory Framework Overview
words, for each situation, risks should Regulatory Documentation All these references are contained in
be assessed as a precursor to deciding In terms of regulation of manufacture of “The rules governing medicinal prod-
what action, and at what level, is ap- medicinal products, all member States ucts in the European Community.” They
propriate. are bound by a single set of legislation are available at: http://ec.europa.eu/
While this initiative was launched by (Directives) and regulations. In the EU, enterprise/pharmaceuticals/eudralex/
the FDA, it is in line with the philosophy regulation of medicinal products is the eudralex_en.htm.
of both the EU and Japanese regulators. same both for human and veterinary There are currently 10 volumes
It is the basis of recent activities within products. However, the legislation is covering different aspects of medicinal
ICH, culminating in the publication of covered by two Directives, both origi- products from development and regis-
three new guidelines: ICH Q8 (Pharma- nating from 2001: 2001/83/EC relates to tration through to marketing. Volumes
ceutical Development), ICH Q9 (Qual- products for human use and, 2001/82/ 1 and 5 contain all the legislation,
ity Risk Management), and ICH Q10 EC relates to veterinary products. including the directives mentioned
(Pharmaceutical Quality System). Over time, these Directives have previously. The remaining volumes
been amended; most recently, they contain the guidance documents.
EMEA have been expanded to include the Volume 4 is of specific interest as it
The European Medicines Agency manufacture of herbal medicines: concerns good manufacturing practices
(EMEA) (http://www.emea.europa.eu/) for medicines. It is divided into two
has overall responsibility for regulation • Directive 2004/27/EC (amending parts: Part I covers the requirements
of medicinal products within the Euro- Directive 2001/83/EC on human for the manufacture of finished products
pean Union (EU) (http://europa.eu/). medicines). or secondary manufacturing, as it is
The EU is an expanding group of • Directive 2004/28/EC (amending sometimes called, and Part II covers
countries in Europe that have commit- Directive 2001/82/EC on veterinary the requirements for the manufacture
ted to economic and political union. As medicines). of active substances, also known as Ac-
of 1 January 2009, there are 27 Member tive Pharmaceutical Ingredients (APIs)
States. The current members are shown The Directives are expanded and or sometimes as drug substances.
in Figure 4. explained via a series of guidance In addition to Parts I and II, there
documents. are a number of annexes. In some cases,
Continued on page 44.

May/June 2009 PHARMACEUTICAL ENGINEERING 43

Hach-PAT700-inuse-halfpg.indd 1 12/23/2008 11:13:18 AM

 Global Regulatory Framework Overview
• provides independent, science-based
recommendations on the quality,
safety, and efficacy of medicines
and on more general issues relevant
to public and animal health that
involve medicines.
• applies efficient and transparent
evaluation procedures to help bring
new medicines to the market by
means of a single, EU-wide market-
ing authorization granted by the
European Commission.
• implements measures for continu-
ously supervising the quality, safety,
and efficacy of authorized medicines
to ensure that their benefits out-
weigh their risks.
• provides scientific advice and incen-
tives to stimulate the development
and improve the availability of in-
novative new medicines.
• recommends safe limits for residues
of veterinary medicines used in food-
producing animals for the establish-
Figure 4. Member states of the European Union (EU) as of 1 January 2009.
ment of maximum residue limits by
the European Commission.
these represent the requirements relat- of Medicinal Products. It later became • involves representatives of patients,
ing to specific types of products, whereas known as the European Medicines healthcare professionals, and other
others expand on the requirements of Evaluation Agency (hence the acronym stakeholders in its work, to facilitate
Part I or deal with new concepts that EMEA), but has since changed its name dialogue on issues of common inter-
have developed since the main text was to the European Medicines Agency. est.
published. The EMEA is responsible for evalu- • publishes impartial and comprehen-
ation of the safety, efficacy, and quality sive information about medicines
The European Medicines Agency of products which are submitted for a and their use.
The EMEA was set up in 1995 as the marketing authorization within the EU. • develops best practice for medicines
European Agency for the Evaluation The EMEA: evaluation and supervision in Eu-
rope, and contributes alongside
Member States and the European
Commission to the harmonization
of regulatory standards at the in-
ternational level.

The EMEA is a scientific body that

advises individual Member States and
other bodies within the EU and uses a
network of scientists from across the
EU to facilitate the operation of the
evaluation system. It has responsibility
for the procedures to authorize phar-
maceuticals, monitor them once in the
marketplace and withdraw that autho-
rization if there is evidence of a problem.
The EMEA also operates information
sources and electronic communication
in order to enhance the safe use of
pharmaceuticals within the EU.
Figure 5. Organizational structure of the EMEA.

44 PHARMACEUTICAL ENGINEERING May/June 2009

 Global Regulatory Framework Overview
Organizational Structure required, but a full assessment will not application was made.
The EMEA is located in London. Its be carried out.
organizational structure is shown in National Authorizations
Figure 5. Decentralized Procedure It also is possible for a drug to be regis-
The EMEA is divided into five divi- Under the decentralized procedure, tered for sale in a single Member State
sions, three of which involve review which also is applicable for conventional only. This is particularly used for legacy
and approval responsibilities. One drugs, an application is made simulta- products that are imported from third
division focuses on pre-authorization neously to a number of Member States. countries (countries outside of the EU),
(assessment of drugs before they are One State is appointed as the Reference where the license was in place before
launched on the market place) while Member State to carry out the assess- the importing countries had access to
another deals with post-authorization ment. Authorization, if granted, will 26.03.2009
_Anz_Schaltschr190x115en.qxd the EU. 10:35 Uhr Seite 1
of medicines for human use (evaluation apply within the States to which the
Continued on page 46.
of drugs after they have been launched,
primarily through the pharmacovigi-
lance system).
The EMEA inspection section is
in the same division as veterinary
medicines. However, this is for organi-
zational reasons only; the inspections
section relates both to human and
veterinary medicines. Communications
and administration functions round out
the remaining two divisions.
It is important to note that while
the EMEA coordinates GMP inspection
activities across the Member States,
it does not have any inspectors in the
section. Each Member State has one or
more national inspection bodies respon-
sible for carrying out the inspections.
There is mutual recognition of these
inspections across all Member States.

Authorization Procedures
within the EU
There are a number of different ways in
which drugs can be authorized for sale

Ready to install!
in the EU, depending on the nature of
the drug and its supply chain:

Centralized Procedure
For some specific drug types, including
biotechnology products, orphan drugs, The ultimate in one-stop shopping.
and veterinary growth enhancers, it is Pre-assembled, customer-specific
mandatory to use the centralized proce-
dure. A single application is made to the control cabinets, completely equip-
EMEA and authorization, if granted,
applies across all Member States. ped to boost the reliability of your
systems. Designed for fast commis-
Mutual Recognition Procedure
For the majority of conventional drugs, sioning and harsh ambient conditions.
the mutual recognition procedure is
applicable. As the name suggests, an
authorization which has already been
granted by one Member State will be www.festo.com
recognized by other Member States.
In this case, a separate application is

May/June 2009 PHARMACEUTICAL ENGINEERING 45

 Global Regulatory Framework Overview
Summary • to pursue and strengthen the co- document apart from minor changes in
The role of regulatory authorities like operation established between the terminology and one annex.
the European Medicines Agency in the participating authorities in the field Other key guidelines include those
scientific evaluation and oversight of of inspection and related areas with relating to blood establishments and
medicines is critical in the assurance of a view to maintaining their mutual APIs. The guideline on Site Master Files
both public and animal health. To learn confidence and promoting quality includes a template that many compa-
more about the agency and its opera- assurance of inspections nies use to write their own SMF.
tions and purview, please visit their web • to provide the framework for all These and other publications are
site: http://www.emea.europa.eu/. necessary exchange of information available in downloadable PDF formats
and experience from the PIC/S web site.
PIC/S and ICH • to coordinate mutual training for in-
The evaluation and approval of medi- spectors and other technical experts Membership of PIC/S
cines for human use along with responsi- in related fields In order to become a member of PIC/S,
bilities for inspection and oversight of the • to continue common efforts toward the authority in question has to dem-
manufacturing and distribution of these the improvement and harmonization onstrate that it has the organizational
medicines occurs at numerous agencies of technical standards and proce- framework and procedures in place to
around the globe. Manufacturers of phar- dures regarding the inspection of the apply a GMP inspection system that is
maceutical products face substantial manufacture of medicinal products at least on a par with those of the other
challenges in assuring that their prod- and the testing of medicinal products members. This will include a formal
ucts and processes conform to the varied official control laboratories quality management system similar to
requirements of these agencies. These • to continue common efforts for the ISO 9000, although it does not need to
organizations are the Pharmaceutical development, harmonization, and be externally accredited. The author-
Inspection Co-operation Scheme (PIC/S), maintenance of Good Manufacturing ity also has to demonstrate that it has
which is primarily involved in mutual Practice (GMP) trained, competent inspectors who can
recognition of GMP inspection results • to extend the cooperation to other operate the system effectively.
between the regulatory authorities of its competent authorities having the As part of the accession process
members, and the International Confer- national arrangements necessary (and on an ongoing basis) inspectors
ence on Harmonisation (ICH), which to apply equivalent standards and take part in multinational inspection
is primarily involved in harmonized procedures with a view to contribut- teams which provides peer review on
drug regulatory requirements between ing to global harmonization their systems and practices.
Europe, the US, and Japan. There are currently 37 regulatory
The PIC/S Web site, www.picscheme. authorities, from 34 countries, that are
Establishment and Purpose of org, is a very useful reference site. full members of PIC/S, as shown below.
PIC/S (e.g., the Czech Republic and France
PIC was set up in 1970 under the aus- PIC/S Publications have 2 authorities, one dealing with
pices of the European Free Trade As- The documentation that is developed human medicines and the other with
sociation (EFTA). Its full title was “The and published by PIC/S is useful both veterinary products.) Twenty-two of
Convention for the Mutual Recognition for the inspectorates (for whom the the 27 member States of the EU are
of Inspections in Respect of the Manufac- references are primarily intended) and included in this number.
ture of Pharmaceutical Products.” also for industry (who can use the refer- At any time, there also will be other
PIC is a legally binding treaty ences to understand what inspectors regulatory authorities being assessed
between countries. However, under are going to look for). for membership or having expressed
EU law, it is not permissible for indi- The GMP guide PE009-7 was is- an interest in the workings of PIC/S.
vidual Member States to sign treaties sued in its latest form in May 2007. It Although all members of PIC/S have
with countries outside the EU. Only is virtually identical to the EU Part I to operate to an equivalent standard,
the European Commission can sign
such treaties. However, the European
PIC/S Full Members
Commission is not a member of PIC.
Argentina, Australia, Austria, Belgium, Canada, Cyprus, Czech Republic (x2),
If the work of PIC was not to be lost, a
Denmark, Estonia, Finland, France (x2), Germany (x2), Greece, Hungary,
compromise needed to be found.
Iceland, Ireland, Israel, Italy, Latvia, Liechtenstein, Malaysia, Malta, Nether-
The PIC Scheme (PIC/S) was set up
lands, Norway, Poland, Portugal, Romania, Singapore, Slovak Republic, South
in 1995. It differs from PIC in that it is
Africa, Spain, Sweden, Switzerland, United Kingdom
an informal agreement between regula-
tory authorities in Member States and
PIC/S Partners
is not legally binding. However, its goals
European Directorate for the Quality of Medicines and Healthcare (EDQM),
are an extension of those of PIC. The
European Medicines Agency (EMEA) and UNICEF.
purpose of the PIC scheme is:
Concludes on page 48.
46 PHARMACEUTICAL ENGINEERING May/June 2009
 Pharmaceutical
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 Global Regulatory Framework Overview
they are not all using the same refer- The ICH Web site can be found at: 1. Overview of FDA – http://www.
ence documents. For example, the 22 www.ich.org. ispe.org/cs/explore_by_topic/fda_re-
members that also are Member States sources
of the EU will be using Volume 4 Parts ICH Publications 2. What’s New at the FDA – http://
I and II. Unlike PIC/S, publications from ICH www.ispe.org/cs/resourcecenter
Other members, such as Canada and are for direct use in industry. Topics are 3. Recent FDA Slide Presentations –
Australia, will have their own national subdivided into four categories: http://www.ispe.org/cs/fda_section/
documentation. However, if these docu- recent_fda_slide_presentations
ments were examined in detail, it would • Quality topics, relating to chemical 4. What’s New at the EMEA – http://
be very difficult to identify significant and biotechnical active ingredients www.ispe.org/cs/resourcecenter
differences in the principles being ex- and to pharmaceutical products 5. Knowledge Briefs: http://www.ispe.
pressed. • Safety topics, relating to in vitro and org/cs/resource_library_section/
in vivo pre-clinical studies knowledge_briefs
Establishment and Purpose of • Efficacy topics, relating to clinical • “Quality by Design,” by John Ber-
ICH studies in human subjects ridge, KB-0001-Jun08.
The full title of ICH is “The Interna- • Multidisciplinary topics, where ex- • “Risk-Based Approaches to Cross
tional Conference on Harmonisation of perts from more than one discipline Contamination,” by Stephanie
Technical Requirements for Registra- collaborate in the development of Wilkins, KB-0004-Oct08.
tion of Pharmaceuticals for Human guidelines which do not uniquely 6. Product Quality Lifecycle Implemen-
Use.” ICH was set up in 1990 as a joint fit into one of the above categories tation: http://www.ispe.org/pqli
forum between regulatory authorities
and the pharmaceutical industry, with In the first category, Quality topics, a About the Author
a focus on harmonizing the procedures widening of scope has been seen. For ex- Dr. Kate McCor-
used to evaluate the safety, quality, and ample, it was via ICH that the guideline mick of Heathside
efficacy of medicines. At that time, com- for Active Pharmaceutical Ingredient Information Services
panies were experiencing difficulties in (API) manufacturing has been formal- Ltd, United Kingdom,
submitting dossiers for product licenses ized, with the publication of ICH Q7 is a manufacturing
in different countries and regions due to Good Manufacturing Practices for Phar- consultant with ex-
differing regulatory expectations. maceutical Ingredients. This has since tensive strategic and
The purpose of ICH was to identify been incorporated into the regulatory operational manage-
ways in which greater harmonization guidance of the EU, Japan, and the US. ment experience in the pharmaceutical
could be achieved in the interpretation More recently, a new ICH Quality Vision industry, both in the UK and inter-
and application of technical guidelines was developed which spawned guidelines nationally. She has 10 years of line
and requirements for product registra- in support of a greater emphasis on sci- management and 20 years of internal
tion. This would reduce the need for ence and risk-based approaches. and external consulting experience. She
duplicate testing during research and Three key documents have been has worked with multinationals, SMEs,
development of new medicines. produced to date: non-governmental organizations and
The objective was therefore more national regulatory authorities in more
economical use of resources, and elimina- • ICH Q8 (R1) Pharmaceutical Devel- than 50 countries. She is the author
tion of unnecessary delay in the develop- opment of Quality (a textbook within the But-
ment and availability of new medicines • ICH Q9 Quality Risk Management terworth Heinneman pharmaceutical
while maintaining safeguards on quality, • ICH Q10 Pharmaceutical Quality engineering series) and Manufacturing
safety and efficacy, and regulatory obli- System in the Global Pharmaceuticals Industry,
gations to protect public health. the editor of gmp Review and a regular
Since the emphasis was on products These publications have been the cata- speaker at international conferences.
containing new drugs, the scope of the lysts in creating a major transformation McCormick gained a degree in biochem-
activities was limited to registrations in the ways in which the industry will istry and a doctorate in microbiology,
in Western Europe, Japan, and the US, be developing, manufacturing, and over- both at London University. She also has
where the majority of new medicines seeing the quality of future medicines a Masters in Business Administration.
are currently developed. and related products. She is registered as a senior GMP expert
Work occurs within ICH by means of within the EU and is eligible as a QP
Expert Working Groups which are ap- For Further Information under the terms of the EU directive.
pointed to develop guidance on specific For more detailed and related informa- She is currently European Education
topics. In the past few years, the scope tion, the following ISPE resources are Advisor for ISPE. She can be contacted
of ICH discussions has widened to in- available: by telephone: 44-1626-854611 or by
clude not only R&D, but also activities email: kate@heathside.com.
relating to manufacturing.

48 PHARMACEUTICAL ENGINEERING May/June 2009

 Global Regulatory Framework Overview
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May/June 2009 PHARMACEUTICAL ENGINEERING 49

 Barrier Isolation History and Trends
This article
presents the Barrier Isolation History and Trends –
final data
from a survey 2008 Final Data
conducted
on the use of
barrier isolators by Jack Lysfjord and Michael Porter
for automated
fill/finish
operations.

A
s the journey in time of barrier isolation perfection with all data. Numbers are as good
technology went from prototypes in the as the data we get, and they are not absolute.
late 1980s and early 1990s to today, Trends are real and that is what should be used
there have been questions regarding for comparison.
the need for benchmarking the usage of bar- This is the sixth survey on the use of Barrier
rier isolator technology. Another way to say it Isolators for automated fill/finish operations
is; what is everyone else doing in regard to this that began in 1998. The surveys have been done
technology? This survey presents its history and only on the even years because of the energy
trends. We have attempted to gather as much content it requires by both the authors and the
information as possible to use as a database; users. Manual operations in a glovebox are not
however, we also know that we never achieve considered. It is evident that usage of barrier
isolator technology continues to
1998 2000 2002 2004 2006 2008 become much more common in the
84 172 199 256 304 391 industry.
In the advanced aseptic pro-
Table A. Filling barrier isolators (worldwide).
cessing arena a new relative has
evolved called a Restricted Access
1998 2000 2002 2004 2006 2008 Barrier System (RABS). Surveys for
11 19 30 42 50 59 this technology were done in 2005
Table B. Filling barrier isolators (Asia only). and 2007 with the 2007 data to be
presented in another article to be
1998 2000 2002 2004 2006 2008 published.
57 85 97 116 146 196 Table A shows 391 total isolators
worldwide for aseptic fill/finish ap-
Table C. Filling barrier isolators (Europe only). plications (that we know of) in 2008
as well as the progression of number
1998 2000 2002 2004 2006 2008 of units since 1998. Tables B to D
35 49 66 90 105 133 show the major pharmaceutical re-
gion breakouts for Asia, Europe, and
Table D. Filling barrier isolators (North America only).
North America. Figure 1 shows the
global deliveries by year. Figures 2
to 4 again show deliveries by year
for the three regions.
Some companies embrace tech-
nology while others wait. Figure 5
shows companies who have most
aggressively embraced the use of
isolators. Figures 6 to 8 show the
regional breakout information. Table
E displays the increasing number
of pharmaceutical companies using
Figure 1. Barrier isolator filling lines – deliveries by year. isolators (99).

50 PHARMACEUTICAL ENGINEERING May/June 2009

 ISPE
Presents:
Technical Documents
for the Pharmaceutical Manufacturing
and Biotechnology Industries

ISPE Good Practice Guide:

Maintenance

www.ISPE.org/publications
Item # IGPGMAINT
Member: $145 / €105
Nonmember: $215 / €155
- Published May 2009
The ISPE Good Practice Guide: Mainte-
nance provides practical solutions and
tools for ensuring quality and compliance
of maintenance operations in a regulated
industry. Covering current and established
practices, this guide helps achieve technical and regulatory accuracy and
cost-effective compliance in a new or an existing maintenance program
for effective strategy and efficiency. Offering maximum flexibility, this guide
clearly helps define roles and responsibilities across cross-functional areas
and recommends a systematic approach aimed at continuous improvement
of maintenance operations.

The Guide is focused on maintenance in cGMP areas and provides a

practical and consistent interpretation of the necessary elements of a
pharmaceutical maintenance program. The Guide seeks to enable
widespread adaptation and encourage innovation.

ISPE Good Practice Guide:

Good Engineering Practice
Item # IGPGGEP
Member: $145 / €105
Nonmember: $215 / €155
- Published December 2008
This first edition of the ISPE Good Prac-
tice Guide: Good Engineering Practice
covers the complete lifecycle of engineer-
ing from concept to retirement.

The Guide:
• aims to promote a common understanding of the concept and
principles of GEP
• defines and explains the term “Good Engineering Practice”
• describes the fundamental elements existing in pharmaceutical
and related industries
• identifies practices, demonstrating how GEP concepts may be ap-
plied in the pharmaceutical industry considering the entire range of
Bookmark: tear along the lines

pharmaceutical engineering activity

• identifies key attributes of GEP, including how GEP relates and
interfaces with GxP

www.ISPE.org/publications
 ISPE
Presents:
Technical Documents
for the Pharmaceutical Manufacturing
and Biotechnology Industries
GAMP® 5: A Risk-Based
Approach to Compliant GxP
Computerized Systems
titles and more!
on these great
Save
Offer valid at the ISPE 2009 Washington Seminars and Courses,1-4 June 2009. Discount applies to ISPE Members only.

Item # 5BOUNDUS/ 5BOUNDEU

Member Price: $250 / 185
Nonmember Price: $450 / 375
- Published February 2008
20%
Provides pragmatic and practical industry
guidance to achieve compliant computerized systems fit for intended
use in an efficient and effective manner. Describes a flexible risk-based
approach to compliant GxP regulated computerized systems, based on
scalable specification and verification. Points to the future of computer
systems compliance by centering on principles behind major industry
developments such as PQLI; ICH Q8, Q9, Q10; and ASTM E2500.

ISPE Good Practice Guide:

Development of Investigational
Therapeutic Biological Products
• GAMP® 5: A Risk-Based Approach to

• ISPE Good Practice Guide:

• ISPE Good Practice Guide:

Compliant GxP Computerized Systems

Good Engineering Practice

Maintenance

Item # IGPGBIOL
Member Price: $145 / 105
Nonmember Price: $215 / 155
- Published August 2007
Provides readers with an understanding of issues surrounding product
and process development, manufacturing, investigational product sup-
ply chain management, quality control/quality assurance, and global
regulatory requirements for biopharmaceuticals.

ISPE Baseline® Guide:

Active Pharmaceutical
• ISPE Baseline® Guide: Active

• GAMP Good Practice Guide:

• ISPE Good Practice Guide:

Therapeutic Biological Products
of Bulk Pharmaceutical Chemicals
Pharmaceutical Ingredients, a Revision

Electronic Data Archiving

Development of Investigational

Ingredients, a Revision of Bulk

Pharmaceutical Chemicals
Item # API0607
Member Price: $200 / 145
Nonmember Price: $400 / 335
- Published June 2007
Bookmark: tear along the lines

The first revision in the Baseline Guide series incorporates new regula-
tions and guidance, such as: ICH Q7, ICH Q9, GAMP® 4, 21 CFR Part
11, Guidance for Industry, Sterile Drug Products Produced by Aseptic
Processing – Current Good Manufacturing Practice (cGMP), FDA Draft
Guidance for Industry PAT – Framework for Innovative Pharmaceutical
Manufacturing and Quality Assurance, and much more.
 Barrier Isolation History and Trends
Container type is shown in Figures 9 to 12. It is interesting
to see how, for example, the usage of ampoules and syringes
in Asia and in Europe compare to in North America.

Figure 4. Barrier isolator filling lines – deliveries by year (North

America only).

Figure 2. Barrier isolator filling lines – deliveries by year (Asia only).

Figure 3. Barrier isolator filling lines – deliveries by year (Europe only). Figure 5. Barrier isolator filling lines – companies with highest usage.
Continued on page 52.

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May/June 2009 PHARMACEUTICAL ENGINEERING 51
 Barrier Isolation History and Trends
Maximum line speed is shown in the next four graphs 13 ISO 8 in operation with hydrogen peroxide vapor used in
to 16. It is interesting to note the majority of isolator usage in 87% of the reported applications for the biodecontamination
North America is for slow speed operation 1 to 100/minute. agent.
Since 1998, the isolators have been hard wall (stainless Gloves can be one of the most scrutinized areas by regula-
steel and glass). Soft wall applications were used when the tors. Type of glove used is a decision to be made by users of
technology started, but reliability, pressure change issues, the technology. Two piece gloves were preferred by 54% over
sterilant absorption, and outgassing pushed the manufactur- one piece gloves 46%. If gloves are two piece, smooth sleeves
ing to hard wall design. are preferred by 86% over pleated sleeves 14%.
Surrounding room classification is predominately (65%) Glove replacement period data is in Figure 17 with some

1998 2000 2002 2004 2006 2008

32 56 67 83 84 99
Table E. Number of companies using barrier isolation.

Figure 6. Barrier isolator filling lines – companies with highest usage

(Asia only).
Figure 9. Container type.

Figure 10. Container type (Asia only).

Figure 7. Barrier isolator filling lines – companies with highest usage

(Europe only).

Figure 11. Container type (Europe only).

Figure 8. Barrier isolator filling lines – companies with highest usage

(North America only). Figure 12. Container type (North America only).

52 PHARMACEUTICAL ENGINEERING May/June 2009

 Barrier Isolation History and Trends

Figure 13. Maximum speed. Figure 15. Maximum speed (Europe only).

Figure 16. Maximum speed (North America only).

Figure 14. Maximum speed (Asia only).

companies able to use gloves up to six months. Method of 89% of responses indicated usage of a second thin glove with
integrity testing gloves is shown to be predominantly by pres- the glove port (typically placed on the hand prior to entering
sure decay - Figure 18. Visual inspection also should be done. the glove port).

Continued on page 54.

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May/June 2009 PHARMACEUTICAL ENGINEERING 53
 Barrier Isolation History and Trends
Positive overpressure is typically used in these applica-
tions. The concept of “more is always better” does not apply to
systems with mouse holes at exits or depyrogenation tunnels
that are interfaced with the isolator. Too much overpressure
can “blow” the tunnel hot zone air into the washer and melt
many parts. Small vials can be blown out of mouse holes
destroying the product. Figure 19 indicates that the majority
of applications operate between 21 and 40 pascals or ~.1 to
.2 inches of water over pressure.
Tunnel sterilizable cool zone technology was used by 65% Figure 17. Glove replacement period.
of those responding.
Containment was a requirement on 42% of total responses
over the six surveys. The data with this question must be
looked at on a survey by survey basis to look at percent of
containment needed on these responses for a two year period.
Since 2006, 100% of 2008 responses indicated a containment
need.
Those that indicated that they campaigned product fills
within one isolator sterilization event made up 59% of re-
sponses. Figure 20 shows the length of campaign from the Figure 18. Method for integrity testing of gloves.
responses. The maximum campaign length is 28 days.
Finally, cumulative deliveries of isolators are shown in
Figure 21. We believe that isolator usage is increasing even
faster than shown at the time of writing this article based on
equipment manufacturers comments. Data was gathered in
first quarter 2008 and the 2009 increase will be much larger

www.ISPE.org/strasbourgconference
Figure 19. Pressure to washer rooms (12.5 Pascals = .05" Water).

than shown here. 2009 data counted was only for what was
ordered by first quarter 2008 for delivery in 2009. Many more
lines were ordered for 2009 after the data was collected. The
dotted line indicates a change in slope after 2004.
The Trends and Conclusions are:

• Worldwide increase in filling line isolators continues (391)

with significant increase in Europe (50) from 2006.
• Asia (9) and North America (28) showed growth in two
Managing Knowledge through years.
Science and Risk Assessment • Isolators are embraced by some companies and avoided
by others.
• Mergers and facility consolidation impact the number of
28 September - user companies.

1 October 2009
• Number of reported isolator lines in operation increased
(230 to 283) in two years.
Palais de Congrès • Vials continue to be the predominant container.
Holiday Inn Strasbourg City Centre • Hard wall isolators continue to be the preference.
• Smooth sleeve gloves are even stronger than in 2006
(86%).
• Slight preference for two piece gloves (54%).
Sponsorship and Table Top Exhibit • Use of a thin second glove is very strong (89%).
Opportunities Available • Use of depyrogenation tunnels with sterilizable cool zone
increased (65%).

54 PHARMACEUTICAL ENGINEERING May/June 2009

 Barrier Isolation History and Trends

Figure 20. Campaign products (longest run).

The Most Gentle Touch

in Biotechnology
Like a newborn baby, biologically derived products
require careful, precise and tender handling. Our
centrifuges provide this treatment and more:
Figure 21. Barrier isolator filling line – cumulative deliveries (2009 is
partial data). Hydrohermetic feed for gentle product treatment
Hydrostop for highest yields
• Containment need is increasing (42%) (100% in last two
years).
Hygenic design for cleaning-in-place (CIP) and
• Campaigning is increasing (59%). sterilization-in-place (SIP)
Scaled for 2 to 25,000 liter reactors
Benchmarking information for those companies investigat- GMP-compliant documentation
ing the use of isolators is shown below (strongest preferences
from survey): To learn more about GEA Westfalia Separator and
how we can assist you with your separation needs
• hard wall isolator; stainless steel and glass in developing and manufacturing breakthrough
• biodecontamination technology using hydrogen peroxide biotech products, please contact Sean Eicher at
vapor (201) 784-4318 or email Sean.Eicher@geagroup.com.
• ISO 8 in operation surrounding room classification
• gloves only, meaning minimize use of half-suits for inter-
ventions
• two piece gloves with smooth sleeves
• use of a thin second glove
New Patterson, CA full-service repair, parts
• doing glove integrity tests with pressure decay test (plus and training facility now open!
visual)

Capital equipment technology and the accompanying de-

preciation expense last a long time. Remember that today’s
decisions will impact the company for 15 to 25 years. Look at
what is in the pipeline for R&D to make a decision that will
cover future products. Many product candidates will have
the need of aseptic processing and containment in order to
protect both operators and product.

* The author may be contacted for questions or comments by GEA Westfalia Separator, Inc.
telephone: +1-952-546-2082 or by email: jlysfjord@Q.com. 100 Fairway Court · Northvale, NJ 07647
Phone: (201) 767-3900 · Fax: (201) 767-3416
1212H

Service: (800) 509-9299

www.wsus.com
May/June 2009 PHARMACEUTICAL ENGINEERING 55
 RABS History and Trends
This article
presents the Restricted Access Barrier System
2007 final data
of a survey (RABS) History and Trends – 2007
conducted on
the use of RABS Final Data
for automated
fill/finish
operations for by Jack Lysfjord and Michael Porter
aseptically filled
injectable drugs.

T
he authors have done surveys on the use conventional cleanroom situation using existing
of barrier isolator technology in 1998, process equipment. The solution was to create a
2000, 2002, 2004, and in 2006. These hard wall barrier with glove ports and transfer
surveys are an attempt to “benchmark” ports for stoppers to separate the operator from
the pharmaceutical industry on a global basis the critical zone or filling closing zone. This bar-
and to look at the historical data and the trends. rier sat in a cleanroom which was class 100 (ISO
The data is for automated fill/finish operations 5) in operation with full ceiling HEPA filters
for aseptically filled injectable drugs. Manual that generated unidirectional airflow on both
operations and hand filling and closing in a glove the outside and inside of the barrier. The top of
box are not considered. In 2004, a question was the barrier was approximately six inches below
asked if it would be possible to get the same type the HEPA filters and extended below the filling
of information for RABS since there seemed to stoppering machine table top with a three inch
be a great deal of interest in this technology. air gap to the table top for air to flow out of the
Due to the energy required to do each survey, barrier with no pressure differential. The doors
the best fit was on the alternate years 2005 and were physically locked to prevent any interven-
2007. The 2004 isolator and 2005 surveys were tions. The operator to product separation was by
presented in conferences, but not published. a hard wall barrier together with air flow with
The 2005 RABS data points are presented here no pressure differential – the first RABS.
along with the RABS data from 2007. Isolators provide separation between the
RABS is a spin off from isolators. Pfizer, Ka- operator and product with a hard wall barrier
lamazoo Michigan (previously Upjohn) in 1992 and pressure differential.
coined the term RABS for “Restricted Access The first RABS was a “Passive RABS.” There
Barrier System.” Their goal was to reduce the also is “Active RABS” and “Closed RABS” today.
contamination risk to a product when filled in a Figures 1 to 3 depict types of RABS.

Figure 1. Passive RABS. Figure 2. Active RABS. Figure 3. Closed RABS.

56 PHARMACEUTICAL ENGINEERING May/June 2009

 RABS History and Trends
The use of a RABS implies more than the enclosure since • a quality system
the following must be in place for the concept of separation • proper surrounding room design (ISO 7 minimum)
with air flow to be successful and reduce the contamination - ISO 5 annex for open door interventions
risk to the product: • proper gowning
• proper cGMP training
• properly designed equipment • initial high level disinfection with a sporicidal agent
• management oversight • proper SOP for rare allowed interventions
- disinfection (non sporicidal)
- line clearance
Year Asia Europe North America TOTAL
- documentation of the event
2005 12 40 23 75
2007 23 63 38 124
The S in RABS is for “SYSTEM” and without the systems and
Table A. Number of RABS units. procedures above, a simple enclosure is not a RABS and can
result in increasing the risk to the product.
In 2005, Stewart Davenport from Pfizer, Kalamazoo,
Michigan (part of the team that developed the first RABS)
and Joerg Zimmermann from Vetter, Ravensburg, Germany,
presented data on cumulative RABS lines media fills from
both companies. Each had media fill data that were over one
million media fills with no unexplainable positives. They both
use the philosophy of never opening the doors of their RABS
yielding data equivalent to media fill data of isolators. That
is impressive. Here is the survey of RABS history and trends
for 2007.
We found 124 RABS in the 2007 RABS survey. Table A
gives 2005 and 2007 data and the breakout between Asia,
Europe, and North America.
Continued on page 58.
Figure 4. Number of RABS units delivered by year.

DELABELING SOLUTIONS
for
• SYRINGES*
• CARTRIDGES
• GLASS VIALS
• PLASTIC VIALS
• METAL CANISTERS
*new 2009
Figure 5. Number of RABS units delivered by year (Asia only).
Information:
www.hurstcorp.com

Other HURST products:

Automatic vial TrayLoaders,
plastic vial trays and custom made
stainless steel products.

HURST CORPORATION 610-687-2404

Box 737 - Devon, Pennsylvania 19333 - USA
Figure 6. Number of RABS units delivered by year (Europe only).

May/June 2009 PHARMACEUTICAL ENGINEERING 57

 RABS History and Trends
The number of RABS delivered by year overall and the
three region breakout are shown in Figures 4 to 7. The types
of RABS, passive, active, and closed, are described in Table B.
RABS operating philosophy- never opened, limited open, and
frequent open responses are shown in Table C. The alarming
piece of data indicates many systems (17 companies) frequently
open the doors of their RABS.
A listing of the companies with the highest RABS usage
is shown in Table D. In 2005, 28 companies had RABS. In
2007, the number increased to 36. In 2005, 25 RABS lines
were reported in operation. 36 were in operation in 2007.
Table E shows the RABS lines and the container types that

Figure 8. Maximum line speed/minute.

Figure 7. Number of RABS units delivered by year (North America

only).

Figure 9. Maximum line speed/minute (Asia only).

Year Passive Active Closed TOTAL
2005 16 25 17 58
2007 35 52 39 126
Table B. Types of RABS.

Year Never Opened Limited Open Frequently Open TOTAL

2005 22 29 1 52
2007 31 48 17 96
Table C. Philosophy for using RABS.

2005 2007
# Company # of Rabs Company # of Rabs
1 Vetter Pharma 10 Vetter Pharma 10
Figure 10. Maximum line speed/minute (Europe only).
2 Pfizer 7 Pfizer 10
3 Aventis 5 GSK 7
4 GSK 4 Aventis 5
Table D. Top 4 companies with RABS.

2005 2007
Vial/Bottle 48 77
Ampoule 8 12
Syringe/Cartridge 18 29
Ophthalmic 2 5
IV 0 0
Other (including BFS) 0 2
TOTAL Responses 76 125
Table E. Types of containers processed in RABS. Figure 11. Maximum line speed/minute (North America only).

58 PHARMACEUTICAL ENGINEERING May/June 2009

 RABS History and Trends
Year Autoclave Sanitize in Place Other TOTAL
2005 16 11 4 31
2007 16 21 12 49
Table F. Method of sanitizing gloves.

Year Yes No TOTAL Respondents

2005 29 0 29
2007 31 7 38
Table G. Second inner glove used.

2005 2007
Each Cycle 4 3 Figure 12. Number of days line campaigned.
Every 5 Runs 1 1
Every 15 Cycles 10 10
Every 6 Weeks 1 1
Every 3 Months 4 4
Every 6 Months 0 1
As Needed 8 18
TOTAL Responses 28 38
Table H. Glove replacement time.

2005 2007
Pressure Decay 20 20
Visual 4 18
Other 2 2
None 1 1 Figure 13. RABS.
TOTAL Responses 27 41
Table I. Glove test method. they process. Figure 8, 9, 10, and 11 lists frequency of RABS
use by maximum line speed in total and then breakouts for
2005 2007 the three regions.
Active Oxygen Agent 10 Glove data is listed in Tables F, G, H, and I. The types of
Gas Formaldelhyde 10 sanitizing agents used are listed in Table J.
Spor Klenz 0 6 When RABS lines campaign product, the length of cam-
Chemical Agent and Formaldehyde Gas 5 5 paign in days and frequency are displayed in Figure 12. Six
Peracetic Acids 3 3 of the responses indicated a need for containment of potent
Chemica Agent and VHP Gas 2 2 product to protect the operator.
Decon Quat 100 2 2 Figure 13 displays the cumulative use of RABS and how
Germex B12, Apesin AP3, Apesin Rapid 2 2 the rate of delivery has jumped since 2003. Note that nine
IPA 2 responses did not indicate year of delivery to get total to 124
Rotating Disinfectant Regime 2 units. In summary:
2 Phenols + IPA 1 1
Bleach/Detergent 1 • RABS use is increasing globally.
Disinfectant Medium Level • Europe is ahead of North America-similar to isolator
Alkalidetergent High Level 1 data.
Hydrogen Peroxide 1 1 • Asia started later, but is increasing in use of RABS.
Hypochlorite 5% 2 1 • RABS is an option to consider to improve asepsis particu-
Liquid Disinfectant 1 1 larly with retrofits.
Same as Room Sanitizers, typical 1 • Frequent opening of doors on the barrier is a big caution
Vesphene, LPH 1 1 area since it will compromise asepsis. If this is the routine
VHP Gas 1 1 mode of operation, it is not a RABS.
Alcohol 70%, decon. clean 1
TOTAL Responses 28 38 * The author may be contacted for questions or comments by
telephone: +1-952-546-2082 or by email: jlysfjord@Q.com.
Table J. Types of sanitizing agents.

May/June 2009 PHARMACEUTICAL ENGINEERING 59

 ISPE Update

US FDA Speakers Figure Prominently at ISPE’s

2009 Washington Conference

N
umerous regulators from the US Food and Drug CDER), Elaine Morefield (Supervisory Chemist, CDER),
Administration (US FDA) were featured speakers at Grace McNally (Senior Compliance Officer, CDER) and
the ISPE 2009 Washington Conference – Engineering Patrick Swann (Deputy Director, Division of Monoclonal
Regulatory Compliance, that took place at the JW Marriott Antibody, CDER) of the US FDA were invited, as well.
in Washington, DC, USA, 1 to 4 June 2009.
Speaker information – along with seminar agendas and • Ilisa Bernstein (Sr. Advisor Pharmacist, CDER) and Steven
training course outlines – for the four-day event are available Silverman (Regulatory Counsel, CDER) were featured US
on the ISPE Web site and include the following listings: FDA speakers at the Global Supply Chain Integrity and
Anti-Counterfeiting seminar. A representative from the
• Richard Friedman (Director, Mfg. and Product Quality, FDA’s Office of Policy and Program Planning, CDER also
CDER), Tara Gooen (Chemical Engineer, CDER), Robert was invited to speak.
Sausville (Supervisory Consumer Safety Officer, CBER),
and Joyce Rockwell (Consumer Safety Officer, CBER) were • Barry Rothman, Consumer Safety Officer for the FDA’s
featured US FDA speakers at the 18th Annual Barrier Division of Manufacturing and Product Quality, CDER
Isolation Technology Forum: Innovation Updates and New was invited to speak at the Current and Future Packaging
Case Studies. Challenges for Investigational Products seminar.

• Helen Winkle (Director, Office of Pharmacy, CDER), Chris- • H. Gregg Claycamp, PhD, the Associate Director of Risk
tine Moore (Deputy Director, CDER), and Sharmista Chat- Analysis and Strategic Policy Assessment, CVM was the
terjee (Staff Fellow/Reviewer, CDER) were featured US FDA featured FDA speaker at the Applied Risk Management
speakers at the PQLI®: Science, Regulatory, Manufacturing, – Addressing Cross Industry Challenges seminar.
and Engineering Working Together for Global Realization
and Implementation of the ICH Quality Vision seminar. • Malcolm Oliver, GMP Inspector for the MHRA, was in-
Joseph Famulare (Deputy Director, Office of Compliance, vited to speak at the Commissioning and Qualification
CDER), Richard Friedman (Director, Mfg. and Product (C&Q): Practical Applications of Science and Risk-based
Quality, CDER), Vibhakar Shah (Consumer Safety Officer, Approaches to Validation seminar, along with several
confirmed leaders of the pharmaceutical manufacturing
industry.

ISPE Korea Affiliate in • As an additional resource on the topic of C&Q, there was
Development a live Webinar 5 May 2009 on Implementing the ASTM
Standard for Verification (C&Q).
The Korea Affliate, the newest affiliate to join ISPE’s family,
There were also seminars devoted to GAMP and facility reno-
is well under way in its development. The Korea Affiliate will
vation, as well as two-day training courses. They are:
be located in South Korea, officially the Republic of Korea and
often referred to as Korea.
• GAMP® Good Practice Guides: Validation of Process Control
Systems (VPCS), and Calibration Management, A Risk-
Based Approach

• Extreme Facility Makeover: Successful Path to Facility

Renovation and Retrofit

• Training – Basic Principles of Computerized Systems

Compliance

• Training – Applying the GMPs

For upcoming ISPE Education and Training information,

visit www.ISPE.org or call ISPE Members Services at tel:
+1-813-960-2105.

60 PHARMACEUTICAL ENGINEERING May/June 2009

ISPE
Annual Meeting

Thriving In A Survival Environment

8 - 11 November • Manchester Grand Hyatt San Diego • San Diego • California, USA

Eleven Session Tracks:

• Product development • Supply chain management • Quality systems • Suppliers
• Facilities and equipment • Production systems • Project management • Survival-focused
• Information systems • Regulatory compliance • Investigational products

Wa t c h f o r d e t a i l s a n d o n l i n e r e g i s t r a t i o n a t w w w. I S P E . o r g / a n n u a l m e e t i n g .
 ISPE Update

INTERPHEX Keynote Message: Industry Needs to

Reinvent Itself
by Rochelle Runas, ISPE Technical Writer

E
xpiring patents. An economic facing stricter regulatory oversight; in a world of blockbusterology and we’re
slump. New technologies. Regula- the need to prove drug safety and going to live in a world of more targeted,
tory agencies becoming increas- comparative effectiveness (this third personalized medicines.”
ingly risk averse. A new administration standard will begin to emerge); generic Burrill said he envisions a consumer
in Washington. biopharmaceuticals, biosimilars; an driven healthcare world that includes
In a world today that faces these increase in stem cell funding; and an concepts such as genetic screening, web-
and other uncertainties, one thing’s increase in healthcare IT funding. based diagnostics, patient-centric self
for sure: The pharmaceutical industry So, in 2020, what will the healthcare care, and Wal-Mart-like health centers
needs to reinvent itself, whether it likes delivery system look like? Burrill said in operated by nurse practitioners. Medical
it or not. the last 2000 years, the pharmaceutical tourism will become more popular. For
That was a main message of this industry has not really changed; people example, it is becoming cheaper to send
year’s Keynote at Interphex NY, deliv- got diseases and they were treated. But, a patient in need of a hip replacement on
ered Tuesday, 17 March at the Jacob this is not going to be true in the next a plane to India and put them up in the
Javits Convention Center in New York, five to 10 years. Four Seasons, than getting the procedure
New York. The keynote included a pre- We are changing the nature of the done in local hospital, Burrill said.
sentation by G. Steven Burrill, CEO, healthcare equation, moving away from What does this kind of world mean
Burrill & Co., who shared his vision of a treatment-based system with a one size to the pharmaceutical industry? Accord-
the future of healthcare and overriding fits all mentality toward late stage detec- ing to Burrill, big pharma will disinte-
trends affecting the global industry. tion and intervention, and a prevention- grate, a trend already demonstrated
Burrill said the industry will be and wellness-based system. “We’ve lived by big company mergers. Low margin

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62 PHARMACEUTICAL ENGINEERING May/June 2009
 ISPE Update
INTERPHEX Keynote Message
Continued from page 62.

ethical drugs will predominate (China, PhD, Senior Vice President, Biotech balancing the amount of inventory to
India, and other low cost manufacturing Operating Unit, Technical Operations carry vs. patient need.”
sites will have an edge). International and Product Supply, Wyeth Pharma- Ramakrishnan said his company
regulatory agencies will collaborate. ceuticals. The panel discussed how they greatly emphasizes six sigma programs
Big pharma today, which is verti- are handling today’s challenges. and efficiency.
cally integrated (R&D, manufacturing, “We try to balance cost and risk,” In the end, biology and technology
distribution, etc.) will disintegrate to be said Moore. “We put a lot of emphasis will be more important than concrete,
horizontally integrated. The “virtual on managing risk in our supply chain, said Kowolenko.
pharma company” will emerge, with
operations located at different sites.
Capital will go to where the best op-
portunities are and partnerships will
Sterile Clean Steam Sampling
continue, said Burrill. Also, diseases will
have no boundaries, so all companies big
and small will be global from day one.
The presentation was followed by a
panel discussion with Burrill; Timothy
Moore, Senior Vice President, Global
Supply Chain, Genentech; Divakar Ra-
makrishnan, PhD, Executive Director,
Manufacturing Science and Technology,
Eli Lilly & Co.; and Michael Kowolenko,

JPI Features Article on

PQLI Legacy Products

T he March 2009 issue of the Journal

of Pharmaceutical Innovation, avail-
able online to Members only, features
the following articles:

• PQLI®: Current Status and Future

Plans
by John C. Berridge
GEMÜ BioStar® Steam Sampler, the innovative automated
• PQLI Application of Science- and
Risk-based Approaches (ICH Q8, sampling system for the monitoring of pure steam quality
Q9, and Q10) to Existing Products
by Chris Potter ■ Sterile from the steam pipe to the laboratory
Sterilization prior to sampling, sterilized sample container, sterile sample transport
• Investigation of the Statistical Power
of the Content Uniformity Tests Us- ■ Automated, programmable and safe
ing Simulation Studies Hands-off auto sampling method eliminates potential contamination of the sample
and minimizes risk of injury to operating personnel
by Phillip D. Lunney and Carl A.
Anderson ■ Consistent, reliable and time saving
• Aqueous Solubility Enhancement Automation of the activity provides consistency and repeatability while reducing
the time required to complete the sampling by plant personnel
Through Engineering of Binary
Solid Composites: Pharmaceutical ■ Easy to install - easy to operate
Applications Simplified connections, easy plug and start, air-cooled, mobile or fixed installation,
repeatable and programmed process
by Michael D. Moore and Peter L. D.
EMA
Wildfong ACH. May 2009 52
5 M
11.-1 ooth K48-
,B
Hall 8
ISPE Members can access JPI by visit-
GEMÜ Gebr. Müller Apparatebau GmbH & Co. KG · Fritz-Müller-Str. 6-8 · D-74653 Ingelfingen
ing www.ISPE.org/JPI. Phone 07940/123-0 · Telefax 07940/123-224 · info@gemue.de · www.gemue.de

May/June 2009 PHARMACEUTICAL ENGINEERING 63

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May/June 2009 PHARMACEUTICAL ENGINEERING 65

 Advertiser's Index ISPE Update
ACTIVE CHEMICAL............................ 65

AES CLEAN TECHNOLOGY................. 27

ISPE Brussels Conference
BUDZAR INDUSTRIES......................... 39 Highlights
CAL-CHEM CORP............................... 37

COMMISSIONING AGENTS................. 25

CRB CONSULTING ENGINEERS..............3

T he ISPE Brussels Conference welcomed more than 180 delegates to update their
knowledge and to network at Sheraton Brussels Hotel in Brussels, Belgium
on 30 March to 2 April 2009. This year’s conference offered a variety of new and
enhanced opportunities for attendees to take advantage of. Some of the highlights
JIM CRUMPLEY & ASSOCIATES.......... 64 from the conference were:
ELETTRACQUA.................................. 13
• Live webinar presentation from Nick Haycocks in California, USA on the HVAC
EMERSON PROCESS MANAGEMENT......9 Good Practice Guide and Good Engineering Practice, as well as the Environ-
mental Cleanliness Classification Quiz that generated lots of discussion at the
ENDRESS + HAUSER......................... 67 seminar Heating, Ventilation and Air Conditioning (HVAC): Good Practice and
Innovations.
FOOD AND DRUG
ADMINISTRATION/CDER.................... 65
• Regulatory aspects of continuous processing were presented by Dr. Moheb Nasr,
FARR AIR POLLUTION CONTROL...........2 Director, Office of New Drug Quality Assessment and Joe Famulare, Deputy
Director, Office of Compliance, FDA at the seminar Continuous Processing and
FESTO.............................................. 45 Process Intensification for APIs, BPCs and Excipients. Part of the program was
developed in conjunction with the International Pharmaceutical Excipients
FIKE CORP........................................ 29
Council (IPEC) since, for the first time, the seminar considered not only APIs/
GEA PROCESS ENGINEERING.............. 47 BPCs, but excipients, as well. Delegates were also introduced to the forthcoming
ISPE white paper on regulatory issues for continuous processing.
GEA WESTFALIA SEPARATOR............ 55
• In a change from the normal format, a one-day interactive Project Management
GEMU GMBH..................................... 63
Workshop was held on developing lean, agile project plans. Delegates were work-
GLATT GMBH.................................... 17 ing on a detailed project plan over the course of three exercises and received
templates as part of the conference documentation allowing them to put them
HACH COMPANY............................... 43 into practice back at the job.

HOWORTH AIR TECHNOLOGY............ 19

• Andrew Cochrane, UK regulator from MHRA, provided a very useful overview
HURST CORP.................................... 57 of the current status of the revision of Annex 11 during the seminar GAMP® 5:
Part 11, Annex 11 and Industry Hot Topics. The seminar included an interactive
IMA ACTIVE...................................... 53 workshop on Maintaining Control of Operation, as well as Quality Risk Manage-
ment in Process Automation, where the links between ICH Q9 and the GAMP® 5
IMA LIFE........................................... 35 QRM approach were explored. Two new groups were formed during the seminar:
INTELLIGEN....................................... 23
a GAMP SIG on outsourcing/offshoring topic, as well as a local GAMP Benelux
group with an interactive day of workshops coming up.
INTERPHEX365................................. 49
• A live webinar presentation was given by Cameron Sipe in the US on the up-
MECO .............................................. 11 date to the ISPE Water and Steam Baseline® Guide during the Critical Utilities
seminar.
NNE PHARMAPLAN............................ 68

OPTIMA MACHINERY......................... 31 The Brussels Conference also hosted a sold-out exhibition with a showcase of the
latest new tools and solutions.
PARSONS...........................................5
The next ISPE events in Europe include Madrid Training from 18 to 21 May;
PHARMACEUTICAL ONLINE................ 62
Strasbourg Conference held from 28 September to 1 October; and Dublin Training
PLASCORE........................................ 15 held from 19 to 22 October 2009.

QPHARMA..........................................7

TELSTAR.......................................... 41

WILDEN PUMP & ENGINEERING........... 51

66 PHARMACEUTICAL ENGINEERING May/June 2009

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