ECA Task Force CCS Guideline

How to Develop and Document a
Contamination Control Strategy

– ECA Task Force on Contamination Control Strategy –
An ECA Foundation Guidance Document

ECA Task Force on
Content
1. Background ................................................................................... 3
2. Introduction................................................................................... 3
3. Contamination Control Strategy (CCS) – the Elements listed in Annex
1 4
4. Development and Documentation of a Company's CCS ..................... 5
4.1. The "3-Stage-Approach" ................................................................................. 6
4.2. Stage 1: Develop the CCS ............................................................................... 7
4.2.1. The principles ............................................................................................... 7
4.2.2. Level A: Explicit Annex 1 Requirements – expressed in figures and numbers ... 9
4.2.3. Level B: Explicit Annex 1 Requirements – described in words ........................ 9
4.2.4. Level C: Implicit or vaguely defined requirements for a specific process,
situation, or condition ......................................................................................... 10
4.3. Stage 2: Compile the CCS Documentation ....................................................... 11
4.4. Stage 3: Evaluate the CCS ............................................................................ 11
5. Responsibilities/Ownership ........................................................... 12
6. Future challenges in the holistic evaluation of the CCS performance12
Attachment 1: Example of a gap assessment (non-exhaustive) .............. 14
Attachment 2: Example of a CCS Table of content ................................ 16
Attachment 3: Template for the Contamination Control Strategy Document
(example)............................................................................................ 18
Attachment 4: Relevant/Helpful Guidelines and Documents: ................... 45
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How to Develop and Document a Contamination Control Strategy

Date
Authors January 2022
Arjan Langen (GE Healthcare) – Global Sterility Assurance Director

Axel Schroeder (Concept Heidelberg) – Operations Director
Dr. Christine Arbesser-Rastburg (Consultant) – Senior Consultant
Dr. Ingrid Walther (Pharma Consulting Walther) – GMP-compliance
consultant
Isabelle Hoenen (Lilly) – Associate Senior Consultant for Sterility assurance
Luigi Scaffidi (Boehringer-Ingelheim) – Manager Qualification/Validation
(Aseptic Quality Assurance)
Robert Schwarz (Edu.fh) – University Lecturer and Consultant
Stephan Loew (CSL Behring) – Senior Manager Technical Support
Laboratories
Dr. Ulrich Kissel (KisselPharmaConsulting GmbH) – Founder and CEO of
KisselPharmaConsulting GmbH
Vimal Sachdeva (World Health Organization) – Senior GxP Inspector
Walid El Azab (STERIS) – Senior Manager Technical Services
Technical Review January 2022
ECA Foundation
Approval
ECA Foundation
Disclaimer
This document has been issued to support and guide the reader when preparing a Contamination Control Strategy
(CCS) and the required documentation. The authors have compiled the content to the best of their knowledge and
belief based on their own experience. This document does not constitute a binding guideline and does not release
the user from the responsibility to adapt the contents to his processes and circumstances. It also does not guarantee
the fulfilment of regulatory expectations and acceptance of the respective CCS by the competent authorities.
The attached documents may serve to facilitate the preparation (Attachment 3), as non-binding examples
(Attachment 1 and 2), or as supplementary information (Attachment 4). They do not claim to be complete or
generally applicable.
PLEASE NOTE: Text quoted from the Annex 1 is written in italics!

For the ease of reading, "sterile manufacturing" in this document and its attachments also cover "low-bioburden
manufacturing" and "bioburden-controlled manufacturing." In cases where "sterility" shall be achieved, this is
indicated in the context.
The term "risk assessment" or "risk analysis" is used interchangeably — specific definitions differentiating the words
to be defined by the pharmaceutical manufacturers.
The term "Key Performance Indicator (KPI)" and "Quality Performance Parameters (QPP)" can be used
interchangeably.
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1. Background
For pharmaceutical manufacturers and their suppliers, contamination of any kind that leads to product or
production losses represents a significant risk. As recent events in the past, such as foreign particulate
contamination (https://www.fiercepharma.com/pharma/contaminant-moderna-covid-19-vaccine-vials-
found-japan-was-metallic-particles-report), have shown, this can lead to supply bottlenecks for individual
medicinal products or groups of medicinal products.
Manufacturers should design their production facilities, equipment, and processes and implement Quality
Risk Management (QRM) to ensure appropriate contamination control to minimize or detect
contamination. Since measures affect different stages of a manufacturing process and often fall under the
responsibility of other departments (e.g., quality control, quality assurance, or manufacturing), it may not
always ensure that the data obtained in the process, e.g., from the original qualifications and validations,
process controls and ongoing environmental monitoring, are linked with each other. This also applies to
corrective and preventive actions that are often taken as a result of deviations and trend analyses but are
neither integrated into a strategy for a holistic view nor is there a linkage of all critical control points and
the evaluation of the effectiveness of all controls (design, procedures, technology, and organization).
However, a holistic view is proposed in the draft revision of Annex 1 version 12 (2020) for particulates,
microbial, and pyrogen contamination.
2. Introduction
Annex 1 draft version 12 (2020) "Manufacture of Sterile Products" deals with the demanding challenge of
controlling contamination in a wide range of sterile product types:
 Finished dosage forms, Finished products, or Drug Products
 Active Substance, Active Ingredients, or Drug Substances
 Excipients
 Primary packaging materials
Any time Annex 1 is referenced in this document, it refers to Annex 1 draft version 12 (2020).
Slightly different from the impression conveyed by the title, Annex 1 not only targets the status of
"sterile" products. It also gives guidance to products that are not intended to be sterile:
"However, some of the principles and guidance, such as contamination control strategy, design of
premises, cleanroom classification, qualification, monitoring and personnel gowning, may be used to
support the manufacture of other products that are not intended to be sterile such as certain liquids,
creams, ointments, and low bioburden biological intermediates but where the control and reduction of
microbial, particulate and pyrogen contamination is considered important."
In general, Annex 1 strongly relies on the principles of Quality Risk Management but contains specific and
explicit requirements on the other hand (refer to Section 4.2).
The intent of Annex 1 can be understood to ensure "Contamination Control", the approach and the level
of details should be commensurate with the type of process and product. Depending on the process and
product type, the intent of Annex 1 can be understood as the adequate approach to ensure
 Sterility Assurance
 Bioburden control / low bioburden
 Pyrogen / endotoxin control
 Control of foreign particulate matter
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In summary, the entirety of measures to achieve the intent of Annex 1 can be summarized as the
as defined in Annex 1:
"Contamination Control Strategy (CCS) – A planned set of controls for microorganisms, pyrogens and
particulates, derived from current product and process understanding that assures process performance
and product quality. The controls can include parameters and attributes related to active substance,
excipient and drug product materials and components, facility and equipment operating conditions, in-
process controls, finished product specifications, and the associated methods and frequency of
monitoring and control."
Additional elements of potential contamination source (e.g., virus, cross-contamination) being identified
should be included in the CCS as applicable (refer to attachment 2 or 3).
3. Contamination Control Strategy (CCS) – the Elements listed

in Annex 1
Like a Site Master File (SMF), which provides an overview of the facility, the CCS document provides an
overview of the totality of contamination control measures and their linkage to an overall strategy, the
CCS.
The proposed elements to be considered for the CCS are listed in Annex 1:
"2.5 The development of the CCS requires thorough technical and process knowledge. Potential sources
of contamination are attributable to microbial and cellular debris (e.g., pyrogen, endotoxins) as well as
particulate matter (e.g., glass and other visible and sub-visible particulates).
Elements to be considered within a documented CCS should include (but are not limited to):
i. Design of both the plant and processes.

ii. Premises and equipment.
iii. Number does not appear in the listing
iv. Personnel.
v. Utilities.
vi. Raw material controls – including in-process controls.
vii. Product containers and closures.
viii. Vendor approval – such as key component suppliers, sterilization of components and single use
systems (SUS), and services.
ix. For outsourced services, such as sterilization, sufficient evidence should be provided to the
contract giver to ensure the process is operating correctly.
x. Process risk assessment.
xi. Process validation.
xii. Preventative maintenance – maintaining equipment, utilities and premises (planned and
unplanned maintenance) to a standard that will not add significant risk of contamination.
xiii. Cleaning and disinfection.
xiv. Monitoring systems – including an assessment of the feasibility of the introduction of scientifically
sound, modern methods that optimize the detection of environmental contamination.
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xv. Prevention – trending, investigation, corrective and preventive actions (CAPA), root cause
determination and the need for more comprehensive investigational tools.
xvi. Continuous improvement based on information derived from the above. "
Acknowledging that this listing provides headers and keywords, it is not exhaustive. Therefore, deeper
consideration has to be given to the elements, sub-structures should be implemented, and even new
elements may need to be introduced, depending on the specific contamination control requirements for
individual products and processes. Following are four examples of additional elements that could play a
role depending on the manufacturing or product conditions:
xvii. Pest Control

xviii. Virus Safety
xix. Deviation Management/CAPA
xx. Aseptic Process Simulation
The document's structure is not predetermined and can be based, for example, on the table of contents
of Annex 1, on the order of enumeration according to Chapter 2.5 (V12, 2020), or even be designed
individually.
4. Development and Documentation of a Company's CCS

Consultation with industry partners has shown that there are different statuses of "CCS-readiness."
However, the consultation also revealed that the interpretation of the term "strategy" is not the same
among all involved partners. On the one hand, "strategy" is understood as "The way to implement CCS,"
and on the other hand, it is understood as "the approach to demonstrate that the CCS is in place." Also,
some companies use the term Contamination Control Program as a synonym to the CCS.
Figure 1: Contamination Control Strategy Implementation Process
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4.1. The "3-Stage-Approach"

Thus, the ECA came to the 3-stage-approach to achieve "CCS-readiness."
- Stage 1: Development (or review and refinement/improvement) of the CCS

- State 2: Compilation of the CCS documents
- Stage 3: Evaluation of the CCS
This document is intended to provide guidance for two possible cases:
1. For a new plant, new equipment, e.g., for:

o Mapping of the manufacturing processes to identify possible sources of contamination.
o Carry out a risk assessment to evaluate the risk of contamination.
o Establish preventive measures and their controls in a holistic system (including the
definition of responsibilities).
o Assess and manage the residual risk of contamination.
2. For an existing facility that has already carried out a risk assessment, e.g., for:
o Evaluation of existing contamination control measures
o Analysis and overview of possible gaps
o Risk assessment and, if necessary, the addition of further measures and integration into
the overall system (including determination of responsibilities)
o Manage the residual risk of contamination.
The table below supports the user to assess the status of "CCS-readiness implementation" and indicates
the required activities:
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Stage 1 Stage 2 Stage 3

Company Develop the CCS Compile the CCS-Document Evaluate the
CCS
is new in sterile - Identify what needs to
manufacturing has be done to ensure
little experience contamination control
- Apply the principles of
QRM*
- Prepare the
documentation
is in a matured Review the existing
state contamination control
measures based on the
principles of QRM*:
- Critically review Compile the documentation in
existing concepts an easily accessible/readable Refer to
- Gap assessment and structured way; in section 4.4
missing elements. Attachment 2 or 3.
(Refer to attachment
1) Refer to Section 4.3.
- Prepare the
documentation,
rationale, etc.
has broad and CCS is fully implemented: - -
proven experience re-assess the existing gap
assessment to confirm
compliance:
- Confirmed go to
Stage 2!
- Not confirmed cover
the missing elements
(apply QRM principles).
* Refer to Section 4.2
4.2. Stage 1: Develop the CCS
4.2.1. The principles
Developing a CCS must be based on an in-depth understanding of the specific processes and products,
fundamental and scientific know-how in sterile manufacturing, QRM, and contamination control.
Fundamental requirements are laid down in numerous guidelines, regulations, codes and standards, and
technical reports, which outline state-of-the-art approaches. A list of these reference documents is
provided as Attachment 4, "Guiding documents,"; which does not claim to be exhaustive.
The term "the element" refers to the elements No. i. – xvi. (Refer to Section 3) and additional elements
of relevance in connection with contamination control. The steps mentioned in the enumeration above
(bullet points) provide the underlying principle for the CCS.
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The following sections provide some suggestions for the CCS development based on the three different
stages (further elaborated under items 4.2.2. – 4.2.4), keeping in mind that the fundamental principle is
QRM, the steps of which may be summarized as follows:
1. Understand the impact of a change in elements of the CCS

2. Identify what could present a risk for product and/or patient safety
3. Develop measures to eliminate the risks or reduce them to an acceptable level (residual risks) or
to provide evidence that the risks are under control
4. Perform and/or implement the measures and ensure the resulting tasks and procedures are
reliably implemented
5. Document the evidence of the actions taken
6. Evaluate the effectiveness of the measures (e.g., controls, procedural, structural, etc.) in place
and identify improvements to be implemented where needed
Please note: These steps 1-6 are not an explicit part of any guideline. However, they are derived from
the general idea of QRM and can be deduced from, e.g., ICH Q9 Quality Risk Management.
Steps 1 to 3 are about preparing and documenting the risk assessments.
The measures may be one-time, periodic, or permanent activities. Typical measures performed in step 4
are:
 Qualification of related systems

 Validation of manufacturing processes, cleaning, decontamination, sterilization processes, etc.
 Monitoring
 Preparation and implementation of Standard Operating Procedures (SOPs)
 Definition, implementation of the controls (e.g., In-Process-Control "IPC", QC release testing)
 Training of personnel
Step 5 documents the historical results of the measures identified in step 4. Finally, step 6 is about
trending and analysing the historical results of the measures to identify the remedial action/improvement
needed in the process.
Note: To make this CCS holistic document clear and the ideas applicable for a broad spectrum of
readers, the ECA has renounced identifying and describing situations where the general approaches may
not be applicable; furthermore, the document is not focused on processes with idiosyncrasies. It is – as in
any case – the pharmaceutical manufacturer's responsibility to select and apply the correct approach for
its products and processes. The included case studies are to illustrate the general approaches.
4.2.1.1 Degree of detail
The requirements in Annex 1 are divided into different levels of details, and three different levels may be
identified:
Level A: Explicit requirements: expressed in figures and numbers; refer to section 4.2.2.
Level B: Explicit requirements: described in words; refer to section 4.2.3.
Level C: Implicit or unclearly defined requirements for a specific process, situation, or condition;
refer to section 4.2.4.
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4.2.2. Level A: Explicit Annex 1 Requirements – expressed in figures and numbers
The level A objective is to list the different Annex 1 requirements, compared to the processes,
procedures, and the surrounding manufacturing environment. Explicit Annex 1 requirements may not
always be fully applicable depending on the topic, yet QRM can be applied to ascertain compliance.
Identified requirements need to be documented and justified in a company's Pharmaceutical Quality
Systems (PQS). At the end of level A, the manufacturer should have gap-assessed processes against the
Annex 1 requirements and should have identified remediation measures to put in place.
Example: Table 1: Maximum permitted airborne particulate concentration during classification.
4.2.3. Level B: Explicit Annex 1 Requirements – described in words
The majority of requirements in Annex 1 are described in the text; some are clear or unambiguous,
whereas others require interpretation and adaptation to specific situations.
Thus, in many cases, QRM has to be applied for the implementation of these requirements. The QRM
approach has to be used for each element No. i. – xvi. and other elements of relevance in connection
with Contamination Control.
Examples:
Example 1
"A suitable sampling schedule should be in place to ensure that representative pure steam is obtained for
analysis on a regular basis. Other aspects of the quality of pure steam used for sterilisation should be
assessed periodically against validated parameters. These parameters should include the following
(unless otherwise justified): non-condensable gases, dryness value (dryness fraction) and superheat."
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Example 2
"4.11 The transfer of materials, equipment, and components into an aseptic processing area should be
carried out via a unidirectional process. Where possible, items should be sterilized and passed into the
area through double-ended sterilizers (e.g., through a double-door autoclave or depyrogenation
oven/tunnel) sealed into the wall. Where sterilization on transfer of the items is not possible, a procedure
which achieves the same objective of not introducing contaminant should be validated and implemented,
(e.g., using an effective transfer disinfection, rapid transfer systems for isolators or, for gaseous or liquid
materials, a bacteria-retentive filter)."
For the requirements outlined in 4.11, the intention of the requirements has to be understood and
interpreted for the specific processes, and for this QRM has to be applied. Annex 1 can only describe a
general set of measures (minimum requirement), which needs to be supplemented and specified by the
manufacturer based on QRM on the real processes, installations, and conditions.
Some examples for questions, which may result from 4.11:
- Is the installed (planned) unidirectional flow an appropriate risk mitigation measure?

- Can the material be sterilized at that stage as needed for mitigation?
- Is the installed (planned) double-ended sterilizer appropriately mitigating the risk?
- Can depyrogenation or sterility be proven where needed?
Questions as provided above as examples need to be considered, and risks and risk mitigation,
respectively reduction needs to be addressed and documented following the QRM procedure.
For the explicit requirements, Annex 1 allows to use of alternative approaches and support them with
rationales:
"Where alternative approaches are used, these should be supported by appropriate rationales and risk
assessment and should meet the intent of this Annex."
The rationales may be developed and documented in risk assessments.
4.2.4. Level C: Implicit or vaguely defined requirements for a specific process, situation,
or condition
Where requirements are implicit, it is mandatory to apply the QRM principles stringently; Steps 1-6 have
been presented in Section 4.2.1.
QRM process and the respective results are required to be documented.
For example:
"9.31 Microorganisms detected in Grade A zone and Grade B area should be identified to species level
and the potential impact of such microorganisms on product quality (for each batch implicated) and
overall state of control should be evaluated. Consideration should also be given to the identification of
microorganisms detected in Grade C and D areas (for example where action limits or alert levels are
exceeded or where atypical or potentially objectionable microorganisms are recovered). The approach to
organism identification and investigation should be documented."
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4.3. Stage 2: Compile the CCS Documentation

When having the CCS with all its elements in place, the next challenge is to compile the CCS document,
i.e., compile the individual documents to have them readily accessible during routine operations and
inspections.
As there may be many documents, the questions are: How to compile them in one document to have
good documentation, verification, and easy access to them?
The CCS document has to compile or mostly reference documents providing evidence that the CCS with
its elements and correlation are reliably implemented. Such documents are mainly:
- Risk Assessments / Risk Analyses

- Qualification and Validation reports
- Maintenance programs (including calibration programs)
- Monitoring and controls plans (e.g., IPC, QC release instructions)
- SOPs / policies / working instructions, etc.
- Master batch records, product specifications (e.g., QTPP document), and release specifications
- Raw or starting material specifications
- General QA documents
- Approved documents, rationales, strategies, etc.
- Monitoring results
- Trending results and reports (e.g., historical EM, Continuous Process Verification "CPV," etc.)
- Complaint management and complaints related to potential contamination during manufacturing,
e.g., foreign particulates
For this purpose, the ECA has prepared templates to compile CCS documents; attachment 2 and
attachment 3. The attachments show what this document can look like. However, no experience is
available regarding regulatory inspections, as the corresponding revision of Annex 1 has not yet been
finalized and set effective.
The CCS Document template (Attachment 3) follows the structure of the elements No. i. – xvi. It has the
main chapter for each element and numerous sub-chapters for more details. Furthermore, it allows
adding more chapters as considered necessary, depending on the individual products, processes, and
conditions.
In its chapters and sub-chapters, the document mentions relevant elements to be considered for the CCS.
Thus, it is the "backbone," providing the platform to briefly summarize the main ideas for the respective
section and add references to the respective documents.
4.4. Stage 3: Evaluate the CCS

The intent of the CCS is not only to document all the measures and controls in a holistic document. It
also allows manufacturers to have a holistic view of their contamination control measures and how well it
prevents contamination.
As explicitly suggested by Annex 1: "2.6 The CCS should consider all aspects of contamination control
and its life cycle with ongoing and periodic review resulting in updates within the quality system as
appropriate."
Manufacturers have to review/analyse data gathered by controls to define if:
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1. The measures are working in preventing contamination.

2. The residual risk of contamination is still acceptable based on defined regulatory and process limits
and parameters.
3. The CCS should be reviewed and improvements implemented as applicable.
The frequency of a periodic CCS review depends on several variables that the manufacturers have to
identify, for example:
 Change in the process; the change control should trigger the review of the existing risk
assessments where necessary.
 Deviations that may conclude that the contamination program in place is lacking and trigger the
review of existing risk assessments where necessary.
 Introduction of new equipment, a new product that would lead to the creation or review of
existing risk assessments
 Results from routine data trending and analysis that indicate a potential gap in the CCS
Any defined frequency could be modified on a risk-based approach (e.g., absence of trends, deviations)
5. Responsibilities/Ownership
Related responsibilities and required resources within an organization need to be clarified to bring a
strategy to life and translate it into daily operations. As defined in Chapters 1 and 2 of the EU GMP part 1
and also in EU GMP part 2, the general responsibility for quality lies with the senior management.
However, responsibility for individual sub-areas may be delegated to qualified staff, depending on their
expertise, qualifications, training, and responsibilities as listed in their respective job descriptions.
Accordingly, the responsibilities for the ongoing review and updating of a CCS should also be defined and
documented, i.e., an "oversight" position that receives any change notifications or changes control
information from the sub-areas (of the different elements) and initiates discussion on potential
adjustments CCS. For this, an option could be to integrate into any change control an assessment of
whether or not the intended change could impact Contamination Control.
6. Future challenges in the holistic evaluation of the CCS

performance
Our industry tends to use a one-level or two-level model to analyze the data and trend them (e.g., EM
data, bioburden data, release, or stability data vs. time). This type of model analysis only allows to view
in a silo and rely on an expert to confirm a correlation between the data. Still, this may lead to
subconscious bias in the conclusion made by the expert. Consequently, using a multi-level model data
analysis is suggested to have a holistic view. Using a multi-model data analysis would allow confirming
the interlink between KPIs if any.
One of the challenges that manufacturers may encounter is a holistic view of big quantities of data
gathered by the control systems in place.
Annex 1 stipulates that manufacturers have approaches to use such data and do not purely rely on
product testing.
"2.7 The manufacturer should take all steps and precautions necessary to assure the sterility of the
products manufactured within its facilities. Sole reliance for sterility or other quality aspects should not be
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placed on any terminal process or finished product test." Consequently, manufacturer can not only rely
on the sterility or other quality aspects (release testing) to ensure product is safe of contaminant".
Some manufacturers may turn to big data analytics that allows analysing KPIs at multi-model rather than
a one model analysis. Big data analytics tends to offer its user the possibility to capture, store, analyze,
share, transfer, visualize and query.
The goal is to identify and collect the data/information needed to present a holistic view and help make
decisions. The question to ask is what data can help the manufacturers to evaluate the CCS?
When evaluating the performance, the CCS cross-functional team may want to involve a statistician or a
data scientist to help analyze the data.
In the future, the goal may be to confirm that the data analysed helps to look ahead (proactive) rather
than behind (reactive).
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Attachment 1: Example of a gap assessment (non-exhaustive)

Key supporting Site Strategies,
Key Site Procedures
Identified potential gaps (or documentation Rationales, Risk assessments
Annex 1 rev12 draft
Key Areas Key Elements Detailed CCS Elements improvement need)
reference Include Reference, title and
versus Annex 1 draft expectations Include Reference, title and if
hyperlink to the document
possible hyperlink to the
Facilities Design Facility design requirements (plant layout, air 4.1, 4.2, 4.3, 4.5, 4.6, 4.7, 4.1 explain how controls and monitoring are "scientifically
filtration, material of construction, cleanability, 4.8, 4.9 justified and capable of evaluating the state of environmental
airlock design, logical and chronological 4.10, 4.11, 4.12, 4.13, 4.17 conditions for cleanrooms, airlocks and pass-throughs used for
activities flows ) 6.6 material and equipment transfer "
6.21
4.3 Barriers should be considered in the CCS." Any alternative
approaches to the use of RABS and Isolators should be justified "
To be filled out accordingly To be filled out accordingly
Develop the current material transfer and airlocks sections using

wording of 4.10, 4.11, 4.12, 4.13
HVAC system design requirements (Air 4.13, 4.14, 4.15, 4.16 Develop an adequate section to cover 4.16 "Setpoints and the
Filtration/HEPA Filters, Pressure cascades, 4.35 criticality of pressure differentials should be documented within
Temperature, RH, locations of air inlets & the CCS " / "where alarm delays are set, these should be To be filled out accordingly To be filled out accordingly
outlets, ducts cleanability, air exchanges rates, assessed and justified within the CCS "
alarms settings and controls ..)
Area Classification / Grade cascading 4.1, 4.4, 4.12, 4.13, 4.20 No gap identified
8.14
Physical segregation of activities (dedicated 4.2, 4.3, 4.4 4.3 Use of barriers should be considered in the CCS : any
facility/area, use of closed systems, other 4.18, 4.19, 4.20, 4.21, 4.22, alternative approaches to the use of RABS or isolators should be
containment systems, ... ..) / Barriers 4.23 justified To be filled out accordingly To be filled out accordingly
8.10, 8.14, 8.15, 8.16
Facilities, equipment, Utilities Localized Unidirectional Air Flow 4.2, 4.25 No gap identified
and Infrastructure Design, application/protection, dust control systems 4.6
Facilities
Qualification, Maintenance and
Control Classification & Qualification of Qualification Program and control (AFPT, Air 4.15, 4.21, 4.26, 4.27, 4.28, 4.30 & 4.33 develop the current section to explain how current
Facilities / Barriers velocity…) 4.29, 4.30, 4.31, 4.32, 4.33, strategy fulfills the requirement for the sampling locations and
4.34 their positioning during classification " critical processing
locations should be based on a documented risks assessment
and knowledge of the process and operations " and during
qualification "the number of sampling locations s hould be based
on a documented risk assessment, including the results of the To be filled out accordingly To be filled out accordingly
classification, air visualization and knowledge of the process
and operations "
Facility Cleaning and Disinfection Cleaning Programs (agents selection, frequency, 4.22, 4.36, 4.37 No gap identified
materials…) / Practices
Sanitization agents validation (including 4.24, 4.37, 4.38 No gap identified
verification against local flora)
Pest Control Pest control Program / Traps location maps Identified as additional risk No gap identified
beyond Annex 1 To be filled out accordingly To be filled out accordingly
requirements
Maintenance Program for facilities (including Fit and Finish 5.3, 5.6 No gap identified
program)
Periodic HEPA filters integrity testing 4.34 No gap identified To be filled out accordingly To be filled out accordingly
Maintenance practices for product protection 5.6 No gap identified To be filled out accordingly To be filled out accordingly
Return to service after maintenance 5.6, 5.7 No gap identified To be filled out accordingly To be filled out accordingly
Waste Management Waste flow and segregation No gap identified To be filled out accordingly To be filled out accordingly+B2:H17
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Key supporting Site Strategies,

Key Site Procedures
Identified potential gaps (or documentation Rationales, Risk assessments
Annex 1 rev12 draft
Key Areas Key Elements Detailed CCS Elements improvement need)
reference Include Reference, title and
versus Annex 1 draft expectations Include Reference, title and if
hyperlink to the document
possible hyperlink to the
Equipment Design Equipment design requirements /capability / 5.1, 5.2, 5.3, 5.8 5.9 Include in the CCS the more precise requirement for particles
cleanability 5.9 counters maximum tubing length and minimum bend radius To be filled out accordingly To be filled out accordingly
8.34
Operational practices (out of place or in place 5.6 No gap identified
cleaning of pieces of equipment, draining, To be filled out accordingly To be filled out accordingly
drying, steaming, sterilization,…)
Equipment integrity and storage conditions 4.11 No gap identified
after cleaning and sterilization (system integrity 8.45, 8.46, 8.47, 8.48
Equipment To be filled out accordingly To be filled out accordingly
, storage under positive pressure prior to use…)
Preventive and Corrective Maintenance Program for equipment 5.6 No gap identified To be filled out accordingly To be filled out accordingly
Maintenance Maintenance practices for product protection 5.6 No gap identified To be filled out accordingly To be filled out accordingly
Return to service after maintenance 5.6, 5.7 No gap identified To be filled out accordingly To be filled out accordingly
Qualification and Validation of Cleaning / Sterilization of all Equipment (e.g. 5.4, 5.5 5.5 "Indirect Contact parts should be sterilized "
Facilities, equipment, Utilities
Equipment tanks, filtration systems, filler parts, isolator To be filled out accordingly To be filled out accordingly
and Infrastructure Design,
decontamination etc) - Validation Program
Qualification, Maintenance and
Utilities Design (Water systems, Utilities generation and distribution systems 6.1, 6.2, 6.3, 6.4, 6.5, 6.6 6.19 add to existing chapter for gases that "any transfer
Control
Clean steam, Compressed gases) design (materials of construction, loops, 6.7, 6.8, 6.9, 6.10, 6.11 pipework or tubing that is located after the final sterilizing
recirculation conditions, heat exchangers 6.16, 6.17 filter " is sterilized
design, process control limits, on-line control 6.18, 6.19
systems, sanitization capabilities, …), Quality
levels and applications
Sanitization Sanitization Program (method, frequency…) 6.10, 6.12 No gap identified To be filled out accordingly To be filled out accordingly
Utilities Preventive and Corrective Maintenance Program for utilities 6.11 No gap identified To be filled out accordingly To be filled out accordingly
Maintenance Maintenance practices for product protection 6.12, 6.20 6.22, 6.23 Create adequate section to document the
6.22, 6.23 contamination control of heating, cooling and hydraulic systems
Return to service after maintenance 6.12 No gap identified To be filled out accordingly To be filled out accordingly
Qualification and Validation of Utilities Qualification Strategy and control 6.13 6.13 iii explain how current risk based strategy (including the
Utilities 6.15 frequency) fulfills the requirement "a sample from the point at
the end of the distribution loop each day that the water is used "
Process Design To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Aseptic Intervention Management To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Process Design, Validation and Glove Control Strategy (RABS, Isolator) To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Process
Control
Sterilization Validation To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Sterilization Validation To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Sterilizing Filtration Validation and integrity To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
testing strategy To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Sterile hold times validation To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Process Validation incl. Product hold times To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Product properties, CQAs To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Selection of Material and Components
(native, RTU, RTS)
Material / Component Flow and Storage To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Materials and Components Supplier Management To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Product, Container Closures
Design, validation and Control
Qualification of Material and Components To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Lab Equipment and Methods To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Selection of Container / Closure System To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Container / Closure systems
Qualification of Container / Closure System To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly To be filled out accordingly
Page 15 of 47
ECA Task Force on Contamination Control Strategy
Attachment 2: Example of a CCS Table of content
1. Purpose and scope of the document

2. Definitions and abbreviations
3. List of the GMP sites
4. Brief description of the plants and facilities (refer to SMF)
5. Brief description of product currently manufactured
6. CCS and site's objective
7. CCS cross-functional team
8. Roles and responsibilities
9. CCS communication and decision-making process
10. QRM scope in regard to the CCS requirements
a. Reference to gap assessment vs. the CCS requirements
11. Elements to consider for the CCS
a. Facility layout
i. Cleanroom classification
ii. Cleanroom Pressure, temperature, humidity, etc.
iii. HVAC layout
iv. Maintenance program
v. Control access to the defined area
b. Intermediate, product, material & Personnel Flow
c. Utilities
i. Water
1. QRM and controls
2. Preventive maintenance program
3. Qualification (reference) and routine monitoring
ii. Compressed gas
1. QRM and controls
iii. Steam
1. QRM and controls
iv. Equipment
1. Process equipment cleaning validation
2. Qualification (reference)
3. QRM and controls
v. Premises
Page 16 of 47
1. Cleanroom qualification
2. Cleaning and disinfection
3. Maintenance program
4. Material transfer and disinfection
d. Process contamination risk assessment
i. Product A
1. List of the QRM
2. List of the routine sampling and controls
ii. Product B
e. Aseptic manipulation and intervention risk assessment
f. Visual inspection
g. Single Use Systems
i. Particulate monitoring
ii. Integrity monitoring
h. Third party management
I. Personnel Training and qualification
12. CCS Evaluation
a. Overview of the critical controls
b. Contamination residual risk threshold
c. List of the QRM part of the CCS (See Annex C)
d. Routine KPI and target (see Annex B)
e. Periodic review of the CCS
f. Elements that trigger the CCS review
13. Continuous improvement and governance decision (see annex A)
14. Conclusion
15. References
16. Document history
17. Annexes
a. List/link of QRM related to CCS
b. List/link of the procedures/policies related to CCS
c. List/Link to the rationale, strategy/position paper, etc.
d. Link to gap analysis
e. Summary of the improvement to implement
f. Summary of the KPI to follow in routine. Including e.g., EM data, etc.
Page 17 of 47
Attachment 3: Template for the Contamination Control Strategy Document
(example)
About this CCS-document template and how to use and understand it

This template is meant to support the documentation of the CCS strategy. It is not an instruction
on developing and implementing the CCS strategy, although – implicitly – essential steps for
implementing a CCS can be deduced from this document.
Experience shows that although a well-elaborated CCS may be implemented, it can be
challenging to find/identify the document where the specific information is laid down, stated, or
defined! The compilation of the CCS elements in this document should be holistic and overview.
Note: For larger companies, e.g., with an extensive product portfolio, it may be advisable
to create appendices instead of listing all information in the CCS document.
Like a Site Master File, this CCS document needs to be kept current but not updated with, e.g., a
new version of an SOP quoted in the document.
Although not explicitly required in Annex 1, the CCS document should be controlled. Thus,
approval is required. The template has a signature section on the front page.
The CCS document guides the reader to the respective Risk Assessments / Risk Analyses (RAs),
reports, SOPs, and other relevant documents and should cover the main purpose of these
documents, but – to avoid mismatches and conflicting statements – not repeat or summarize in
detail the contents of the underlying documents.
For Sections 1 – 16, it is suggested to use tables wherever possible; this document indicates a
format in each section. Sub-sections have been added to provide room for further details: e.g.,
Section 5 "Utilities" has been sub-sections for "water," "steam," "gases" – if other sections are
required, they may be added. If less sub-sections are needed for your specific situation, delete
them!
Some guiding hints regarding color coding and fonts:

Text in blue in this template is explanatory provides tips and suggestions. This text is not meant
to remain in the company's CCS-Document.
Text quoted from Annex 1 is written in Times New Roman fonts.
Text in black may be regarded as "suggested text," which can be adopted, adapted, modified,
amended – as adequate.
Page 18 of 47
Document Approval
Name Function Responsible for Section(s) Date / Signature
QA Approval of the CCS-

document
Different functions may be responsible for different sections of the document
Page 19 of 47
Table of Contents
0. Introduction……………………………………………………………………………….22
0.1. Objective .................................................................................................................. 22
0.2. Definitions and Abbreviations ................................................................................. 23
1. Design of both, the plant and processes…………………………………………………24
1.1. The Processes ........................................................................................................... 24
1.1.1. Terminally Sterilized Products ........................................................................ 24
1.1.2. Aseptic Manufacturing..................................................................................... 25
1.1.3. Low Bioburden Processes / Bioburden-Controlled Processes ......................... 25
1.2. The Plant .................................................................................................................. 26
1.2.1. General ............................................................................................................. 26
1.2.2. Terminally Sterilized Products ........................................................................ 26
1.2.3. Aseptically Manufactured Products ................................................................. 26
1.2.4. Low Bioburden Processes / Bioburden-Controlled Processes ......................... 27
2. Premises and Equipment…………………………………………………………………27
2.1. Premises ................................................................................................................... 27
2.2. Equipment ................................................................................................................ 27
For major equipment, consider making reference to the SMF – or copy from SMF…………27
3. No. 3 is empty – left out - in Annex 1 Draft……………………………………………..27
4. Personnel………………………………………………………………………………….28
4.1. General ..................................................................................................................... 28
4.2. Gowning Requirements ........................................................................................... 28
4.3. Clean Room Clothing .............................................................................................. 28
4.4. Personnel Monitoring............................................................................................... 29
5. Utilities……………………………………………………………………………………29
5.1. Water ........................................................................................................................ 29
5.1.1. Purified Water .................................................................................................. 29
5.1.2. WFI .................................................................................................................. 29
5.2. Steam........................................................................................................................ 30
5.3. Gases ........................................................................................................................ 30
5.3.1. Product-contact-compressed air (direct or indirect product contact) ............... 30
5.3.2. N2 ..................................................................................................................... 30
5.3.3. CO2................................................................................................................... 31
5.3.4. O2 ..................................................................................................................... 31
5.3.5. Further Gases ................................................................................................... 31
6. Raw Material Controls – including in-process controls……………………………….31
6.1. Raw Material (Starting Material) Controls .............................................................. 32
6.2. In-Process Controls .................................................................................................. 32
Page 20 of 47
7. Product Containers and Closures………………………………………………………..32
8. Vendor approval – such as key component suppliers, sterilization of components and
single use systems (SUS), and services………………………………………………………….33
8.1. General processes..................................................................................................... 33
8.2. Detailed information regarding vendors .................................................................. 33
9. For outsourced services, such as sterilization, sufficient evidence should be provided to
the contract giver to ensure the process is operating correctly…………………………………34
9.1. General processes..................................................................................................... 34
9.2. Detailed information regarding suppliers ................................................................ 34
10. Process Risk Assessment…………………………………………………………………35
11. Process Validation………………………………………………………………………..37
12. Preventative maintenance – maintaining equipment, utilities, and premises (planned and
unplanned maintenance) to a standard that will not add the significant risk of contamination
…………………………………………………………………………………………….38
13. Cleaning and Disinfection (Decontamination and Sterilization)………………………39
13.1. Equipment ............................................................................................................ 39
13.2. Clean Rooms / Clean Areas ................................................................................. 40
13.3. Clean Room Clothing .......................................................................................... 40
14. Monitoring Systems - including an assessment of the feasibility of the introduction of
scientifically sound, modern methods that optimize the detection of environmental contamination
…………………………………………………………………………………………….40
14.1. General Procedures .............................................................................................. 41
14.2. Monitoring of Systems ......................................................................................... 41
14.2.1. Water and Steam .............................................................................................. 41
14.2.2. Clean Rooms .................................................................................................... 42
14.2.3. Gases ................................................................................................................ 42
14.3. Personnel .............................................................................................................. 43
15. Prevention – trending, investigation, corrective and preventive actions (CAPA), root
cause determination, and the need for more comprehensive investigational tools 43
16. Continuous improvement based on information derived from the above…………….44
17. Further relevant aspects – e.g. about viral safety………………………………………44
Page 21 of 47
0. Introduction
0.1. Objective
This document is based on Annex 1, which requires to develop of a Contamination Control
Strategy based on the following principles (quoted from Annex 1):
"The development of the CCS requires thorough technical and process knowledge. Potential
sources of contamination are attributable to microbial and cellular debris (e.g., pyrogen,
endotoxins) as well as particulate matter (e.g., glass and other visible and sub-visible
particulates)."
The elements to be considered are listed in Annex 1:
i. Design of both the plant and processes.

ii. Premises and equipment.
iii. Nothing mentioned under this number
iv. Personnel.
v. Utilities.
vi. Raw material controls – including in-process controls.
vii. Product containers and closures.
viii. Vendor approval includes key component suppliers, sterilization of components and
single-use systems (SUS), and services.
ix. For outsourced services, such as sterilization, sufficient evidence should be provided to
the contract giver to ensure the process is operating correctly.
x. Process risk assessment.
xi. Process validation.
xii. Preventative maintenance – maintaining equipment, utilities, and premises (planned and
unplanned maintenance) to a standard that will not add the significant risk of
contamination.
xiii. Cleaning and disinfection.
xiv. Monitoring systems – including an assessment of the feasibility of introducing
scientifically sound, modern methods that optimize the detection of environmental
contamination.
xv. Prevention – trending, investigation, corrective and preventive actions (CAPA), root
cause determination and the need for more comprehensive investigational tools.
xvi. Continuous improvement based on information derived from the above.
xvii. Add more elements that are applicable!
This CCS-Document summarizes how our company approached each of the elements and how
we maintain the standard to ensure an adequate level of contamination control. This document
considers quality risk assessment and the overall approach to managing microbiological,
particulate, and cross-contamination of products manufactured in the sites. It makes to relevant
Page 22 of 47
documents, where details are defined and documented to avoid mismatches; this CCS document
does not repeat details provided in other documents.
To facilitate reading and understanding of the document, the document follows some rules:
 To maintain apparent reference to the Elements mentioned in Annex 1, the numbers of
Sections 1 – 16 refer precisely to the numbers of the elements. As relevant, sub-sections
may need to be added.
 If text is quoted from Annex 1, it is written in Times New Roman fonts.
 Whenever clear guidance is provided in regulatory documents, design, processes, and
procedures are based on this guidance (e.g., clean room grades and related particle and
microbiological requirements). Thus, such details are not repeated.
 The principles of Quality Risk Management have been applied.
 Reference to documents (reports, instructing documents, SOPs, etc.) is provided in each
section.
Approval of the CCS document with ongoing review and update is recommended, and it is
therefore appropriate to include this document as part of the Site Master File. The document
should be included in the project documentation for a facility under construction or major facility
revamping or development.
0.2. Definitions and Abbreviations
Term / Abbreviation Definition / Long Version

CCS Contamination Control Strategy:
A planned set of controls for microorganisms, pyrogens and
particulates, derived from current product and process
understanding that assures process performance and product
quality. The controls can include parameters and attributes
related to the active substance, excipient and drug product
materials and components, facility and equipment operating
conditions, in-process controls, finished product specifications,
and the associated methods and frequency of monitoring and
control.
CCS-document This document compiles references to all documents related to
the CCS as well as conclusions on how to ascertain and maintain
contamination control.
The Elements The elements mentioned in Annex 1 under i. – xvi., which refer
to Sections 1 – 16 of this document.
PV Process Validation
QRM Quality Risk Management
RA Risk Assessment / Risk Analysis
Page 23 of 47
Term / Abbreviation Definition / Long Version
SMF Site Master File
Add further Definitions and Abbreviations as required
1. Design of both the plant and processes
Provide the name of the products and associated manufacturing facilities. Provide some
information of the:
- product presentation (e.g., syringes, vials, cartridge)
- formulation or product-specific variants (e.g., volumes, strength)
1.1. The Processes

Describe the different processes, list the sequential stages, and detail the associated controls –
terminally sterilized products, aseptic manufacturing, low bioburden, bioburden controlled – a
brief description to evaluate if the CCS is adequate.
Add information about the type of microbial contamination that the product would support
growth. Describe any stage of the manufacturing process that could decrease or deactivate
contamination. Explain if the product could support the proliferation of microbial during the
shelf-life. Add some information on the closure system integrity and controls in place. Refer to
any document that determines the risk of contamination.
State some information around the measures in place to ensure the security of the aseptic process
and the sterility assurance level of terminally sterilized products:
= initial and ongoing validation (media fill)
= equipment and process qualification and requalification
= process validation and ongoing verification
= personnel qualification and requalification and disqualification
= describe the samples taken from each batch for microbial and particle control or sterility
assurance.
= refer product microbial and particulate contamination assessment
1.1.1. Terminally Sterilized Products

Describe specific information about sterilization methods / processes.
Page 24 of 47
Mention / list the products / types of products manufactured as terminally sterilized products
Product Name Product Type Container

Volume Material
1.1.2. Aseptic Manufacturing

Mention / list the products / types of product manufactured under aseptic conditions

Volume Material
1.1.3. Low Bioburden Processes / Bioburden-Controlled Processes

Mention / list the products / types of product manufactured as low bioburden / bioburden
controlled products

Volume Material
Page 25 of 47
1.2. The Plant
1.2.1. General
The plant is designed to ensure the process steps are performed in the clean room Grades are
required according to Annex 1.
Access to the clean room grades is via separate air-locks for personnel and material.
Layouts of the different areas may be inserted to show hygienic zones, personnel, and material
flow. Reference to SMF may be helpful.
Provide details of the type of contamination control systems are in place, such as RABS, Isolator,
etc., describe or provide the drawing of the facility HVAC systems.
Describe the utilities being used for the process (e.g., Oxygen, nitrogen) and refer to the specific
section for the contamination control
Provide some general cleanroom information such as cleanroom finishes, air supplied quality,
the material of construction, access to cleanroom, presence of interlock, etc.
Provide information on the cleanroom contamination control such as viable and non-viable
contamination control measures, type of systems to prevent airborne contamination during the
process (e.g., unidirectional flow), pressure differential, maintenance of the cleanroom and
HVAC systems/filters, temperature, relative humidity, etc.
1.2.2. Terminally Sterilized Products

Process Step Clean room grade
1.2.3. Aseptically Manufactured Products

Page 26 of 47
1.2.4. Low Bioburden Processes / Bioburden-Controlled Processes

Process Step Clean Room Grade
2. Premises and Equipment
Although not part of the elements listed in Annex 1, reference to Qualification (SOPs, Master
Plan etc.) may be made here.
2.1. Premises
Concerning Premises, refer to Section 1.2
2.2. Equipment
For major equipment, consider making reference to the SMF – or copy

from SMF.
3. No. 3 is empty – left out - in Annex 1 Draft
Page 27 of 47
4. Personnel
4.1. General
Personnel is trained in all areas of their responsibilities. More details about the areas and the
applicable procedures are provided:
Type of Training Reference Document

Title No.
Induction training
General GMP-training
Hygienic behavior
Personnel Qualification
4.2. Gowning Requirements
Description Reference Document

Title No.
Gowning requirements for the different
clean room grades are defined.
4.3. Clean Room Clothing

Title No.
Material, quality, and design of clean
room clothing is adequate for the
respective clean room Grade
Changing and replacement of clean room
clothing
Cleaning of clean room clothing
Sterilization of clean room clothing
Validation of the sterilization process
Page 28 of 47
4.4. Personnel Monitoring

Note: Section 14 in Annex 1 is about monitoring, thus, in this template, Personnel Monitoring is
mentioned in Section 14.3. Personnel Monitoring may either be mentioned under Section 4
"Personnel" or in Section 14 – a matter of taste. But: cross-reference should be made.
Summarize the personnel contamination control methods in place and the gowning. States if any
of these activities are qualified and describe the qualification process and periodic qualification

Title No.
RAs, SOPs, evaluation Refer to section 14
5. Utilities
Consider making reference to SMF!

Briefly describe the method of preparation / distribution – refer to the monitoring Section.
5.1. Water
5.1.1. Purified Water
Title No.
Specification
Preparation
Distribution
Monitoring refer to Section 14.2.1
5.1.2. WFI
Title No.
Specification
Page 29 of 47
Title No.
Preparation
Distribution
5.2. Steam

Title No.
Specification
Preparation
Distribution
5.3. Gases
5.3.1. Product-contact-compressed air (direct or indirect product contact)
Title No.
Specification
Preparation
Distribution
5.3.2. N2
Title No.
Specification
Storage
Distribution
Page 30 of 47
5.3.3. CO2
Title No.
Specification
Storage
Distribution
5.3.4. O2
Title No.
Specification
Storage
Distribution
5.3.5. Further Gases

Title No.
Specification
Storage
Distribution
6. Raw Material Controls – including in-process controls
Relevant aspects
Page 31 of 47
 how starting materials are sampled and tested
 microbiological requirements and endotoxin limits are part of the specification.
6.1. Raw Material (Starting Material) Controls

Title No.
Test specifications for each starting
material are prepared and approved;
specifications follow the Marketing
Authorization
Incoming goods' testing
Sampling
QC-Testing
Starting Material release procedure
6.2. In-Process Controls

Relevant aspects
 the stages for contamination-control-related IPC-testing
 the limits

Title No.
Stages at which IPC-tests are performed
Bioburden limits for the respective stages
7. Product Containers and Closures
Relevant aspects
 different products, their container and closures
 CCI tests
Page 32 of 47
 Routine process for testing container closure integrity
Title No.
Container Type - Specification
Closure Type - Specification
Container System Qualification
Container Closure Integrity Testing
Routine tests for container closure
integrity
8. Vendor approval – such as key component suppliers, sterilization of

components and single-use systems (SUS), and services
8.1. General processes
Relevant aspects:
 SOP for vendor qualification (presumably the same SOP as for supplier qualification,
which is relevant in Section 9) – consider combining Sections 8 and 9 or make cross-
references!
 Routine vendor evaluation / auditing
 List critical vendors such as primary packaging component or raw material, critical
consumable, or SUS,
Title No.
Vendor / supplier qualification process
Vendor / supplier evaluation
Vendor / supplier auditing
8.2. Detailed information regarding vendors
Component Vendor Reference Document
Page 33 of 47
Title No.
Contract
Qualification
document
Audit Report
Annual evaluation
Contract
Qualification
document
Audit Report
Annual evaluation
Contract
Qualification
document
Audit Report
Annual evaluation
9. For outsourced services, such as sterilization, sufficient evidence should

be provided to the contract giver to ensure the process is operating
correctly
Note: This Section is quite similar to section 8
Provide a detail or refer to SMF of the outsourced activity such as microbial or release testing
performed by an external laboratory
9.1. General processes

Refer to Section 8.1
9.2. Detailed information regarding suppliers
Service Contract acceptor Reference Document

Title No.
Page 34 of 47
Service Contract acceptor Reference Document
Title No.
Contract
Qualification
document
Audit Report
Annual evaluation
Process Validation
Contract
Qualification
document
Audit Report
Annual evaluation
Process Validation
Contract
Qualification
document
Audit Report
Annual evaluation
Process Validation
10. Process Risk Assessment

The title "process risk assessment" is somehow narrowing the scope of the general requirement
to base decisions on Quality Risk Management – suggestion to broaden the scope (but still keep
the title for clear reference to Annex 1)
Relevant aspects:
 SOP(s)
 Registers
 Overview of existing RAs for manufacturing / cleaning / decontamination / sterilization

Title No.
Page 35 of 47
Title No.
The concept of QRM is implemented
throughout the organization (SOP)
A register of RAs is maintained by QA
RAs for manufacturing processes:
RAs for aseptic manufacturing processes:
RAs for cleaning processes:
RAs for decontamination processes:
RAs for sterilization processes:
Page 36 of 47
11. Process Validation

Following the GMP-requirements, all manufacturing processes have been validated and re-
validation takes place on a regular basis / processes are under continuous verification Processes
are re-validated after Changes that require re-validation.
Process Validation is based on a QRM approach and the underlying RAs mentioned in
Section 10.
Note: The CCS does not refer to general cleaning validation but should focus on microbiological
aspects.
Relevant aspects:
 Process Validation SOP
 PV-reports reports
Title No.
The concept of PV is described in SOP
The concept of continuous process
verification is described in SOP
Aseptic process simulation is performed
according to SOP
PV-reports for manufacturing processes:
Aseptic process simulation reports

(media fill reports)
PV-reports for cleaning processes:
Page 37 of 47
Title No.
PV-reports for decontamination

processes:
PV-reports for sterilization processes:
12. Preventative maintenance – maintaining equipment, utilities, and

premises (planned and unplanned maintenance) to a standard that will
not add significant risk of contamination
Relevant aspects – presumably covered in SOP(s):
 The way to define maintenance requirements (e.g., vendor involvement, in-house-
experience, involvement of external companies)
 QA involvement
 How are maintenance plans developed (servicing / inspection / replacement actions and
for the system) - Are log-book-entries considered
 The basis for the development of the maintenance program (frequency for performing
maintenance actions)
 Calibration
 Responsibility for system approval after maintenance
 Refer to the document that lists the planned maintenance activities to ensure systems,
plan, and equipment is operational to prevent contamination.
 Refer to the existing maintenance program document, refer to all formal assessments and
confirm that the contamination control is optimal.
 Describe the procedure when recurring or critical maintenance schedule is exceeded and
how the implication on product quality is investigated.
Page 38 of 47
13. Cleaning and Disinfection (Decontamination and Sterilization)

Procedures are in place for cleaning and disinfection, decontamination, and sterilization.
Note: "decontamination and sterilization" are not mentioned in the enumeration in Annex 1;
however, it appears feasible to cover these important aspects in this section.
List the procedures and make reference to the SOP numbers and – as applicable – validation
reports (cross-references to Section 0 should be considered)
Also, summarize the contamination control treatments to minimize surface and personnel
contaminations.
Consider listing and detailing the contamination control product or system used and their
purpose.
13.1. Equipment
Equipment Type Activity Reference Document

Title No.
Cleaning
Disinfection
Cleaning
Disinfection
Cleaning
Disinfection
Cleaning
Disinfection
Cleaning
Disinfection
Cleaning
Disinfection
Page 39 of 47
Equipment Type Activity Reference Document
Title No.
13.2. Clean Rooms / Clean Areas
Room No. / Area Grade Activity Reference Document

Title No.
A Cleaning
Disinfection
B Cleaning
Disinfection
C Cleaning
Disinfection
D Cleaning
Disinfection
13.3. Clean Room Clothing

Refer to Section 4.3
14. Monitoring Systems - including an assessment of the feasibility of the

introduction of scientifically sound, modern methods that optimize the
detection of environmental contamination
Relevant aspects:
 Reference to Risk Assessments, which lead to the sampling points
 SOPs
Page 40 of 47
 Reference the summary reports and how the description of how trending is done (SOP!)
and conclusions are drawn.
14.1. General Procedures

Title No.
Instruction on how to develop sampling
points / frequency / warning and action
limits
Instruction for the preparation of reports
SOP on how to perform trending
14.2. Monitoring of Systems

14.2.1. Environment
Summarize and cross-reference with the relevant section of this document to describe the viable
and non-viable monitoring and testing methods associated. Describe if the sampling is performed
by internal or external personnel and the overall oversight by the quality department.
Describe the frequency, location, and type of sampling, including the definition of the alert and
action limits. State the frequency of the historical EM data review and analysis.
Refer to the section discussing the filter integrity, the velocity of air supplied, smoke studies,
pressure differential, temperature, relative humidity, etc.
Refer to the microbial media and incubation program used, air exposure of the media (e.g., settle
plate) validated, etc.
14.2.2. Water and Steam

Type Activity Reference Document
Title No.
City Water optional! RA
Monitoring SOP
Summary Report
Purified Water RA
Monitoring SOP
Summary Report
Clean Steam RA
Page 41 of 47
Title No.
Monitoring SOP
Summary Report
14.2.3. Clean Rooms

Consider further differentiation into different areas and / or clean room grades

Title No.
viable monitoring RA
Monitoring SOP
Summary Report
Non-viable monitoring RA
Monitoring SOP
Summary Report
14.2.4. Gases
Title No.
Product-contact- RA
compressed air
Monitoring SOP
Summary Report
N2 RA
Monitoring SOP
Summary Report
CO2 RA
Monitoring SOP
Summary Report
O2 RA
Monitoring SOP
Page 42 of 47
Title No.
Summary Report
Further RA
Monitoring SOP
Summary Report
14.3. Personnel
Note: see remark in Section 4.4
Area Grade Activity Reference Document

Title No.
Grade B RA
Monitoring SOP
Summary Report
Grade C RA
Monitoring SOP
Summary Report
Grade D RA
Monitoring SOP
Summary Report
15. Prevention – trending, investigation, corrective and preventive actions

(CAPA), root cause determination and the need for more comprehensive
investigational tools
Refer to the document that describe the requirement for an effective investigation, quality
management systems, and the document that describes the deviations process and CAPA
including document that track and trend reoccurrence and CAPA effectiveness.
State the procedure in place to address reoccurring deviation to ensure proper contamination
control states.
Page 43 of 47
Title No.
Incidents and deviations are managed via:
Investigation of incidents and deviations
(Root causes analyses) is described in
SOP:
Corrective and preventive actions
(CAPAs) are managed according to:
16. Continuous improvement based on information derived from the

above
Summarize processes and procedures for continuous improvement and include the document
subject to periodic updates
 preparation of reports (frequency!), e.g., management reports or PQRs
 evaluation of incidents and deviations and related CAPAs
 trending analysis of EM, product quality review, etc.
 internal communication/escalation via regular or extraordinary meetings with defined
participants.
 KPIs and their evaluation
In this section also provide some information about the trigger that would lead to improvement
derived from data reviewing (e.g., visual inspection defect characterization).
17. Further relevant aspects – e.g., with regard to viral safety
18. References:
List the regulatory, literature, or industrial references used if needed.
19. Attachments
Page 44 of 47
Attachment 4: Relevant/Helpful Guidelines and Documents:
Regulatory:
i) European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Chapter 3: Premises and Equipment, (2014)
ii) European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Chapter 5: Production, (2014)
iii) European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Part II: Basic Requirements for Active Substances used as Starting Materials,
(2014)
iv) European Union, Guidelines of 19 March 2015 on the formalized risk assessment for
ascertaining the appropriate good manufacturing practice for excipients of medicinal
products for human use, Official Journal of the European Union, (2015/C 95/02), (2015)
v) European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Annex 2: Manufacture of Biological active substances and Medicinal
Products for Human Use, (2018)
vi) European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Annex 3 Manufacture of Radiopharmaceuticals, (2008)
vii) European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Annex 14 Manufacture of Medicinal Products Derived from Human Blood or
Plasma, (2011)
viii) European Commission, EudraLex - Volume 4 - Good Manufacturing Practice (GMP)
guidelines, Guidelines on Good Manufacturing Practice specific to Advanced Therapy
Medicinal Products, (2017)
ix) European Union, Guidelines of 5 November 2013 on Good Distribution Practice of
medicinal products for human use, Official Journal of the European Union, (2013/C
343/01), (2013),
x) European Union, Guidelines of 19 March 2015 on principles of Good Distribution
Practice of active substances for medicinal products for human use, Official Journal of
the European Union, (2015/C 95/01), (2015)
xi) EMA Guideline on setting health-based exposure limits for use in risk identification in
the manufacture of different medicinal products in shared facilities (20 November 2014)
xii) U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current
good manufacturing practice for finished pharmaceuticals, subpart C = Building and
Facilities, sec. 211.42 Design and construction features (b), (c)
xiii) U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current
good manufacturing practice for finished pharmaceuticals, Subpart F - Production and
Process Controls, sec. 211.113 Control of microbial contamination (a), (b)
xiv) U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current
good manufacturing practice for finished pharmaceuticals, Subpart B - Organization and
Personnel, sec.211.28 Personnel responsibilities (a)
xv) U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current
good manufacturing practice for finished pharmaceuticals, Subpart E - Control of
Page 45 of 47
Components and Drug Product Containers and Closures, sec. 211.80 General
requirements. (b)
xvi) U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current
good manufacturing practice for finished pharmaceuticals, Subpart E - Control of
Components and Drug Product Containers and Closures, sec. 211.84 Testing and
approval or rejection of components, drug product containers, and closures (d)
xvii) U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current
good manufacturing practice for finished pharmaceuticals, Subpart D - Equipment, sec.
211.67 Equipment cleaning and maintenance (a)
xviii) U.S. Food & Drug Administration, Code of Federal Regulation Title 21, part 211 current
good manufacturing practice for finished pharmaceuticals, Subpart C - Buildings and
Facilities, sec. 211.56 Sanitation (c)
xix) U.S. Department of Health and Human Services Food and Drug Administration,
Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current
Good Manufacturing Practice, (2004)
xx) U.S. Department of Health and Human Services Food and Drug Administration,
Guidance for Industry - Good Manufacturing Practice Considerations for Responding to
COVID-19 Infection in Employees in Drug and Biological Products Manufacturing,
(2020)
xxi) U.S. Department of Health and Human Services Food and Drug Administration,
Guidance for Industry - Guidance for Industry Non-Penicillin Beta-Lactam Drugs: A
CGMP Framework for Preventing Cross Contamination, (2013)
xxii) U.S. Department of Health and Human Services Food and Drug Administration,
Guidance for Industry Current Good Manufacturing Practice—Guidance for Human
Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act, Draft
Guidance. https://www.fda.gov/media/88905/download (accessed Jan 6, 2021)
xxiii) pharmaceutical inspection co-operation scheme gmp guide, 2nd targeted consultation
document on revision of annex 1
xxiv) pharmaceutical inspection co-operation scheme gmp guide, ps inf 25 2019 (rev. 1) draft,
manufacture of advanced therapy medicinal products for human use
xxv) pharmaceutical inspection co-operation scheme gmp guide, ps inf 26 2019 (rev. 1) draft,
manufacture of biological medicinal substances and products for human use
xxvi) pharmaceutical inspection co-operation scheme gmp guide, pe 009-15 (part i), guide to
good manufacturing practice for medicinal products part i
xxvii) pharmaceutical inspection co-operation scheme gmp guide, pe 009-15 (part ii), guide to
good manufacturing practice for medicinal products part ii
xxviii) pharmaceutical inspection co-operation scheme gmp guide, pe 009-15 (annexes), guide
to good manufacturing practice for medicinal products annexes
xxix) world health organisation, good manufacturing practices for pharmaceutical products:
main principles, annex 2, who technical report series 986, 2014,
xxx) world health organisation, who good manufacturing practices for active pharmaceutical
ingredients (bulk drug substances), annex 2, who technical report series 957, 2010
Page 46 of 47
xxxi) world health organisation, points to consider for manufacturers and inspectors:
environmental aspects of manufacturing for the prevention of antimicrobial resistance
annex 6, who technical report series 1025, 2020
xxxii) world health organisation, who good manufacturing practices for sterile pharmaceutical
products, annex 6, who technical report series 961, 2011
xxxiii) world health organisation, who good manufacturing practices for biological products,
xxxiv) who good manufacturing practices for the manufacture of investigational pharmaceutical
products for clinical trials in humans, annex 7, who technical report series 863, 1996
xxxv) who good manufacturing practices for radiopharmaceutical products
xxxvi) WHO GMP for Pharmaceutical Products containing Hazardous Substances, TRS 957,
Annex-3 (2010)
xxxvii) International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human use, Quality Risk Management, Q8 (R2), Pharmaceutical
Development, August 2009.
https://database.ich.org/sites/default/files/Q8%28R2%29%20Guideline.pdf (Accessed
Nov 29, 2021)
xxxviii) International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human use, Quality Risk Management Q9, November.
https://database.ich.org/sites/default/files/Q9%20Guideline.pdf (accessed Nov 29, 2021).
xxxix) International Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human use, pharmaceutical quality system Q10.
https://database.ich.org/sites/default/files/Q10%20Guideline.pdf (accessed Nov 29,
2021).
Industry:
I. ECA Guidelines for the Evaluation and Investigation of Microbiological Deviations
- Chapter 1 - Deviation Handling of Microbiological Environmental Monitoring
Excursions in Non-Sterile Pharmaceutical Manufacturing
- Chapter 2 - Lab Investigations – Endotoxin Out of Specification (OOS)/ Out of Trend
(OOT)/ Atypical Results Investigations
- Chapter 3 - Guidance for Sterility Test Failures
II. ECA Standard Operating Procedure (SOP): Laboratory Data Management - Out of
Specification (OOS) Results
III. ECA Laboratory Data Management Guidance: Out of Expectation (OOE) and Out of
Trend (OOT) Results
IV. ECA Good Practice Guide on Validation
V. ECA Good Practice Guide "Visual Inspection of Medicinal Products for Parenteral Use -
Version 3.2"
VI. Container Closure Integrity Testing of Medicinal Products for Parenteral Use - Position
Paper - Version 2.0
VII. USP general chapter discussing contamination control: <1116>; <1072>; <1231>;
<1229>; etc.
Page 47 of 47

ECA Task Force CCS Guideline

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How to Develop and Document a

Contamination Control Strategy

An ECA Foundation Guidance Document

How to Develop and Document a Contamination Control Strategy

Authors January 2022

Arjan Langen (GE Healthcare) – Global Sterility Assurance Director

Technical Review January 2022

PLEASE NOTE: Text quoted from the Annex 1 is written in italics!

3. Contamination Control Strategy (CCS) – the Elements listed

i. Design of both the plant and processes.

xvii. Pest Control

4. Development and Documentation of a Company's CCS

Figure 1: Contamination Control Strategy Implementation Process

4.1. The "3-Stage-Approach"

- Stage 1: Development (or review and refinement/improvement) of the CCS

This document is intended to provide guidance for two possible cases:

1. For a new plant, new equipment, e.g., for:

Stage 1 Stage 2 Stage 3

4.2. Stage 1: Develop the CCS

4.2.1. The principles

1. Understand the impact of a change in elements of the CCS

 Qualification of related systems

4.2.1.1 Degree of detail

Level B: Explicit requirements: described in words; refer to section 4.2.3.

4.2.2. Level A: Explicit Annex 1 Requirements – expressed in figures and numbers

4.2.3. Level B: Explicit Annex 1 Requirements – described in words

- Is the installed (planned) unidirectional flow an appropriate risk mitigation measure?

The rationales may be developed and documented in risk assessments.

4.3. Stage 2: Compile the CCS Documentation

- Risk Assessments / Risk Analyses

4.4. Stage 3: Evaluate the CCS

1. The measures are working in preventing contamination.

6. Future challenges in the holistic evaluation of the CCS

Attachment 1: Example of a gap assessment (non-exhaustive)

Develop the current material transfer and airlocks sections using

Key supporting Site Strategies,

Attachment 2: Example of a CCS Table of content

1. Purpose and scope of the document

About this CCS-document template and how to use and understand it

Some guiding hints regarding color coding and fonts:

Contamination Control Strategy

Name Function Responsible for Section(s) Date / Signature

QA Approval of the CCS-

Different functions may be responsible for different sections of the document

The elements to be considered are listed in Annex 1:

i. Design of both the plant and processes.

0.2. Definitions and Abbreviations

Term / Abbreviation Definition / Long Version

Add further Definitions and Abbreviations as required

1. Design of both the plant and processes

1.1. The Processes

1.1.1. Terminally Sterilized Products

Product Name Product Type Container

1.1.2. Aseptic Manufacturing

Product Name Product Type Container

1.1.3. Low Bioburden Processes / Bioburden-Controlled Processes

Product Name Product Type Container

1.2.2. Terminally Sterilized Products

1.2.3. Aseptically Manufactured Products