ISPE Breakfast Seminar: Expectations vs. Realities

ISPE Breakfast Seminar
January 2008
THE GMP CORE LAB

EXPECTATIONS VS. REALITIES
The GMP Core Lab Expectations vs. Realities
ISPE Breakfast Seminar January 2008
01
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Introduction
GMP & regulatory parameters
Case studies - analysis
Case studies - comparison
Lesson learned
Q&A
Presenters
Alan Orton
Principal, NFOE/NXL Architects
Paul Jeanson
Project manager/Compliance Specialist
SNC-Lavalin Pharma
Presentation structure
Setting the table outlining Good
Manufacturing Practice expectations
& regulatory criteria to be addressed
Looking at four current or recent GMP
laboratories and how they are dealing
with these issues
Identifying the principal challenges in
planning, designing and constructing,
and operating these facilities
Lessons learned
Case studies
Cell Therapy Centre of Excellence (CETC),
Maisonneuve-Rosemont Hospital, Montreal
Experimental Tissue Engineering Laboratory
(LOEX), Tissue Engineering & Regenerative
Medicine Centre, CHAUQ / Enfant-Jsus
Hospital, Quebec City
Veterinary & Food Biotechnology Institute
(LBVA), Faculty of Veterinary Medicine
University of Montreal, St. Hyacinthe
Connell OReilly Cell Manipulation Core
Facility (CMCF), Dana-Farber Cancer
Institute, Boston, Massachusetts
Why a GMP core lab?

Upgrading current core lab from
fundamental R&D to GMP safety level
(health risk management)
Participation in clinical trials institutional

recognition nationally & internationally
Absence of alternatives for scale-up or
manufacture of innovative products
Product commercialization
Allure of benchtop to bedside.
.invention to innovation
Cultural shift
Moving from the discovery make
as many errors as fast as you can,
try new methods - mode of
research.
To the delivery - error free,

repeatable, traceable, and highly
documented mode of product
development & manufacturing
Changing the way people work

going from flexible & adaptable.
to fixed & restricted.

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Introduction
Lesson learned
Q&A
GMP Means.
GMP: Good Manufacturing Practices (worldwide)
Regulations which have the force of law in most countries
Applies to establishments that fabricate, package, label, distribute,
import, wholesale, or test medication. (drugs, blood products &
biologicals). Part of quality assurance which ensure that products,
are consistently produced and controlled to the quality standards
appropriates to their intended use as required by the product
specifications.
Ensure that products are safe, pure, and effective

Ensure that drug manufacturing is carried out in safe and
quality processes, to avoid contamination and ensure
repeatability
10
Others GxP
QSR: Quality System Regulation (Medical Devices FDA).
MDR: Medical device regulations (HC) and ISO Certification, CE
mark /European Medicines Agency (EMEA)
GCP: Good Clinical Practices (ICH).
Standard for design, conduct, performance, monitoring, recording,
analyses, and reporting of clinical trials. Provides assurance that the data
and reported results are credible and accurate, and that the rights,
integrity, and confidentiality of trial subjects are protected.
GAMP: Good Automated Manufacturing Practices (guidelines)
11
Dedicated regulations to core lab compliance

GTP: Good Tissue Practices (FDA)
Based on GMP principles applicable to human cells &tissues & cellular &
tissue-based products (HCT/Ps). 21CFR 1270 and 1271.
To prevent the introduction, transmission, or spread of

communicable disease through the use of human cells, tissues,
and cellular and tissues based-products (HCT/Ps).
CTO: Cells, Tissues and Organs (HC)

Technical requirements to address the safety of Human Cells,
Tissues and Organs for transplantation (Directive and Guidance).
Laboratory Biosafety Guidelines (PHAC)

Quality and safety standard for human tissues and cells
(European Parliament and of the Council on ATMPs)
Guide to safety and quality assurance for organs, tissues and

cells (European Parliament and of the Council on ATMPs)
12
Why apply GxP/GMP to an institutional core lab?

Only guidelines applicable to all human cells &tissues &
cellular & tissues-based products (HCT/Ps), medications
(drugs, blood products & biologicals), medical devices
Lack of applicable hospital safety regulations
Only way to have recognized clinical trials and to be part
of international activities
Unique way to ensure safety of HCT/Ps treated patients
Provides a method to standardize treatments
Best way to achieve product quality (safety, purity,
strength, identity, reliability)
To ensure the health and safety of patients

13
GTP means (as GMP)
Components
Process
Equipment
Validation
Routine Monitoring
QA/QC
Environment
GTP
Personnel
Raw materials
14
Validation: What does it mean?

A methodology for demonstrating compliance with GXP
requirements
Testing of 100% of finished product is not feasible (to assure
product quality, representative sample testing is done)
Validation
Establishing documented evidence which provides a high
degree of assurance that a specific procedure, process,
equipment, material, activity, or system will consistently
produce a product meeting predetermined specifications
and quality attributes.
15
Validation: What does it mean for GTP?

Slightly different from GMP Validation expectations
Raw materials are constantly changing (Organs, tissues
infectious profiles, quantities)
Final products are constantly changing
Where the results of processing cannot be fully
verified by subsequent inspection and tests, you must
validate and approve the process according to
established procedures.
Validation activities and results must be documented,
including the date and signature of the individual(s)
approving the validation.
16
Validation: What does it mean?

Validation documentation:
Validation Master Plan
Pre-approved protocols for qualification of installation
(IQ), operation (OQ), performance (PQ) of equipment
Standard Operating Procedures for all critical aspects
of operations from raw material receipt to release of
final product
Execution of those protocols
Reporting of gathered data and results
Key component of global Quality Control / Quality
Assurance program
17
Documentation Lifecycle
Business Plan
Systems:
SOPs, Training, Operations,
Maintenance, Change Control
Engineering
Documents
Process
Definition
Conceptual
Design
Construction
Documents
Purchasing
Document
Commissioning
Documents
Field Tests
Vendor
Documents
Start-up
P&IDs
FAT
Specification
Drawing
Operation
Documents
Installation
Documents
Validation
Master Plan
Regulatory
Documents
Validation Protocols
IQ OQ PQ
Execute
Validation
Validation
Reports
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Benefits of Validations..
Compliance with applicable
regulations
Deliver systems that are fit for purpose
Decrease downtime
Reduction in rejections and reworks
Reduced testing for In-process and
finished goods
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01
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Introduction
Lesson learned
Q&A
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Case Study
Cell Therapy Centre of Excellence

(Centre dExcellence en Thrapie Cellulaire CETC),
Maisonneuve-Rosemont Hospital, Montreal

Core Lab Analysis Case Study 1
Project Description - CETC

Overview
A new core lab to be a Centre of Excellence for
cell therapy treatments in Qubec
Existing laboratory already a leader in autologous
(re-transplant of treated cells to same patient) &
allogeneic (transplants from a different donor) cell
therapy treatments, serving the Quebec health
care network
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Project Description - CETC

Potential products:
Autologous & allogeneic cell manipulations
for oncology and hematology treatments
Cartilage cell cultures for autologous
transplants (orthopedic reconstructions)
Cell treatments for ocular repairs (retinas,
corneas)
23
Facility plan - CETC
GMP cell
manipulation
lab suite
GMP cell
manipulation
lab suite
(CL-2)
Lab support
services
24
Facility characteristics - CETC

Net area: 6,530 sq. ft.; gross departmental area:
8,875 sq. ft. (1.36 factor)
Estimated construction cost (fit-out): $7.2M,

including GST, PST; excluding scientific equipment,
consultancy fees, etc.
Unit area construction cost : $1,100 / NSF

Estimated total consultancy fees: 25% of
construction cost (URS/FTP: $80K, A,M&E: $650K, V:
$1,050K)
Total project cost: n/a
25
Key considerations - CETC

GMP compliance is not a requirement
for present operations decision to
validate or not
Participation in multi-centric clinical
trials will be the primary drivers for
eventual GMP compliance
Justification of high initial capital and
start-up costs
26
Key challenges - CETC

Higher than average validation and
compliance costs, due to the relative
small size of the facility, multiplicity of
small instruments (lab type, not GMP purpose
built), & preparation of protocols & SOPs
Staff cost burden during 4-6 month
start-up & validation period
Training of hospital support staff to
meet continuous monitoring &
compliance requirements
Securing long term operational funding
support, with a projected staff of 25
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Case Study
Experimental Tissue Engineering Laboratory

(Laboratoire dOrganognse Exprimental - LOEX),
Tissue Engineering & Regenerative Medicine Centre,

CHAUQ - Enfant-Jesus Hospital, Qubec City
Project Description - LOEX

Overview
A new core lab for the GMP compliant generation of
reconstructive tissue products (tissue-like structures
incorporating living cells for in-vivo or ex-vivo uses)
Existing laboratory already unique in Canada for tissue
engineering, serving principally the Quebec health care
network
Core lab component of an academic research centre
(LOEX) within the CHA/Laval University structure
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Project Description - LOEX

Potential products (in vitro cell culture methods):
Mucosal & skin equivalents (Cutaneous
system)
Blood vessels (Vascular system)
Ligaments (Orthopaedic system)
Bronchial equivalents (Respiratory system)
Corneal equivalents (Cornea System)
Current products are primarily skin

equivalents intended for autologous
transplantation of reconstructed
epidermis into extensively burned
patients
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GMP Facility plan - LOEX
Support services: storage,

washing & sterilization
GMP lab
suite
GMP prep &

support
services
31
GMP Facility characteristics LOEX

Net area: 1,860 sq. ft.; excludes support services
area; gross departmental area: 2,480 sq. ft. (1.28 factor)
Estimated construction cost (fit-out): $1.0M,

including taxes; excluding scientific equipment,
consultancy fees, etc.
Unit area construction cost: $535 / NSF

Estimated consultancy fees: 11.3% of
construction cost ( Architectural/Mechanical/
Electrical only; no process engineering or validation fees

incurred or projected to date)
Total project cost: not available

32
Key considerations - LOEX

GMP compliance is not a requirement
for present operations
Participation in international multicentric clinical trails is the primary
driver for eventual compliance
Not-for-profit facility; fee for service
within Quebec health care network
High initial capital & start-up costs;
ongoing operating costs to be partly
mitigated by using Hospital services
33
Case Study
Veterinary & Food Biotechnology Laboratory

(Laboratoire de Biotechnologie Vtrinaire et Alimentaire (LBVA),
University of Montreal, St. Hyacinthe

Project description - LBVA

Overview
A new core laboratory intended for
the development & production of
innovative veterinary &human
biotherapeutic products
Core lab facility was integrated into
a new research annex constructed
on the U of Montreals Faculty of
Veterinary Medicine campus in St.
Hyacinthe, Quebec
35
Laboratory objectives - LBVA

Development, scale-up and pilot
production of innovative viral and
bacterial vaccines
Validated, compliant GMP facility for
production of clinical materials, licensing
batches, and small scale commercial runs
Research & development on new
molecular transport technologies
(adjuvants for diverse products)
Proprietary product development as well

as projects in partnership with the private
sector
36
Facility plan - LBVA
Support services: storage, dispensing,

solution, prep, washing & sterilization
Decon
services
(CL-2LS)
Cell culture
suite
Formulation
& filling
QC lab
Bacterial
fermentation
suite (CL-2LS)
Viral culture
suite (CL-2LS)
37
Facility characteristics - LBVA

Net area: 5,385 sq. ft.; Gross departmental area:
6,975 sq. ft. (1.3 factor)
Construction cost: $6.1M including GST, PST;
including a prorated portion of base building costs (~15%);

excluding scientific equipment, consultancy fees, etc.
Unit area cost : $1,125 / NSF

Global consultancy fees: 30% of
construction cost (PM: $200K, URS&FTP: $85K;
Process Engineering: $250K, A,M&E: $530K, V: $560K)
Total global project cost: $13.7M (taxes incl.)

38
Project timeline - LBVA

Initial planning &
funding request
1999 2000
Facility programming &

design
Q4-2001 Q2-2002
Construction
Q3-2002 Q3-2004
Operations team
engaged
Q4-2004
Business development
staff engaged
Q2-2006
Validation
Q1-2005 Q1-2007
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Critical process systems - LBVA

10 - 100 litre bioreactors
10 - 100 litre fermenters
Lyophilizer
Roller deck incubators
Tangential flow filtration system
Homogeniser
Chromatography system
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Key challenges - LBVA

Business case justification limited to initial
capital investment
Changes in Faculty management
during project development
Changes to processes & information
shortfall prior to validation start-up
Securing funding to complete validation
& achieve operational readiness
Sustaining initial interest from outside
partners during validation effort
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Lessons learned - LBVA

Expectations of U of M & projects
promoters differed for profit, GMP
operations not a core university activity
Lab status & operational authority limits
were not clear
Operations / validation staff were
engaged late in the project
Insufficient funds were available to
complete GMP compliance effort
Facility mission is now under review
42
Case Study
Connell OReilly Cell Manipulation Core

Facility (CMCF) ,
Dana Farber Cancer Institute (DFCI), Boston
Project Description - CMCF

Overview
DFCI core lab since 1996; Harvard Cancer Centre core
facility since 2000
1996 laboratory activities were procedurally compliant
with regulatory expectations; facility operations were too
small and not to GMP standard
CMCF provides not-for-profit autologous and allogeneic
cell therapy treatments to patients within the Harvard
Medical Centre and Boston area health care networks
44
Project Description - CMCF

Manufactures cellular products for clinical
use:
Stem cells
Tumour vaccines
Immune cells
CMCF currently supports over 30

clinical trials and process approximately
800 stem cell and immunotherapy
products annually for patients at MGH,
BWH, DFCI and BCH.
45
Regulatory parameters - CMCF

Design reviews held with the FDA and
with NIH (key funding support)
Class 10,000 established for both cell
production units following design reviews
Compliance with US FDA regulations
FDA Establishment registration obtained
FACT accredited cell processing lab for
adult stem cell transplantation program
at DFCI/BWH & pediatric stem cell
transplant program at BCH /DFCI
46
Overall facility plans
GMP Cell Manufacturing,

Gene Therapy
& support labs
Offices
R&D
Cyropreservation
47
Facility characteristics - CMCF

Net laboratory area: 3,990 sq. ft.;
Construction cost (fit-out): $3.3M USD;
excluding scientific equipment, consultancy fees,
etc.
Unit area construction cost: $827 USD

/ NSF
Estimated consultancy fees: 31% of
construction cost ( Architectural /Engineering
/Validation)
Total project cost: $5.0M USD
48
Project timeline - CMCF

Initial funding request Q1 - 2000
Funding approval
Q3 - 2000
Facility programming
& design*
Q3-2000 Q4-2002
Construction
Q1-2003 Q1-2005
Validation
Q1-2005 Q2-2005
* Includes time required to find & renovate space for previous

occupants to be relocated; the costs associated with these
moves are not included in this projects budget
49
Key challenges - CMCF

Finding & fitting into space was primary
challenge in moving the project forward
Defining regulatory standards to be met;
integrating FDA & NIH recommendations
during design
Staffing recruitment of qualified
manufacturing staff, plus a substantial
increase in training requirements
Dealing with continuing space shortfall;
limited space for expansion
50
Keys to success - CMCF

Primary objective for GMP compliance was improved patient
safety facilitated buy-in from DFCI/HCC management
Operations are supported by both clinical activities &
research funding (~50/50)
51
Keys to success - CMCF

Raising the profile of the CMCF
Part of the Centre for Human Cell Therapy
assists PIs in translating novel cell therapies
from animal models to human applications
Affiliated with the Harvard Stem Cell Institute
Collaborates with the Translational Cell
Therapy Laboratory
Developing projects with investigators from
Brigham & Womens, Mass General, Boston
Childrens hospitals
Identifying potential new users of the

laboratory developing a pipeline of projects
52
Lessons learned - CMCF

Project took longer to complete & cost
more than initially anticipated
A global vision of activities is essential;
beyond initial financing & start-up
Feedback from FDA & NIH was crucial
QC/QA effort & documentation
burden underestimated
Commitment necessary to build &
grow lab operations raising profile &
building networks
53
01
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05
06
Introduction
Lesson learned
Q&A
54
Comparison Laboratory structure & objectives

CETC
LOEX
LBVA
CMCF
Independent entity
No
No
No
No
For profit
No
No
Yes
No
Fee-for-service
Yes
Yes
Yes
Yes
Clinical trials /
external contracts
Maybe
Maybe
Yes
Yes
Capital investment
plan
Yes
Yes
Yes
Yes
Ongoing facility
marketing
Planned
No
Yes initiated
Yes
Formal long term

business plan
No
No
No
No
55
Comparison Project status
CETC
LOEX
LBVA
CMCF
Programming
complete
Yes
Yes
Yes
Yes
Design complete
Feasibility
Study
Preliminary
design
Yes
Yes
Construction
complete
No
No
Yes
Yes
Validation
intended
Maybe
Maybe
Yes
Yes
Validation
complete
n/a
n/a
60%
complete
Yes
GMP compliant
operations
(to be
determined)
(to be
determined)
No
Yes
56
Comparison Facility characteristics

CETC
LOEX
LBVA
CMCF
Net Area - NSF
6,530
2,360
5,385
3,990
Construction cost
$7.2M est.
$1.0M est.
$6.1M*
$3.3M USD
% M&E cost
70%
68%
59%*
n/a
Unit cost $ / NSF
$1,100
$535
$1,125
$827 USD
Consultancy fees %
25%
11%
29%
31%
Total project cost
n/a
n/a
$13.7M
$5.0M USD
Net to building
gross area ratio
0.467
0.542
0.49
n/a
NSF to Building GSF

gross-up factor
2.14
1.85
2.05
n/a
* Includes ~15% allowance for base building costs; % M&E based on global cost
57
Comparison Technical characteristics building systems

CETC
LOEX
LBVA
CMCF
Environmental
classifications
ISO 8 & 7
ISO 8 & 7
ISO 8 & 7
(ISO 5 Filling)
ISO 7(Class
10,000)
Biosafety
containment level
CL-2
none
CL-2LS
CL-2
Independent
HVAC
Yes
Yes
Yes
Yes
Air change rate

per hour
30-35
30
30 (60 in ISO
5 area)
30
Air circulation
strategy
30-100% nonrecirculated
30% nonrecirculated
15% min.
fresh air
100% nonrecirculated
Air filtration
strategy
Terminal
HEPA filters
Terminal
HEPA filters
Terminal
HEPA filters
Terminal
HEPA filters
Independent BAS
Yes
No-module
of main BAS
No-module
of main BAS
Yes
58
Comparison Technical characteristics - utilities

CETC
LOEX
LBVA
USP water
WFI water
Clean compressed air
CMCF
x
x
Clean steam
Laboratory vacuum
CO distribution
Liquid nitrogen distribution
x
x
CIP / SIP systems
Sterilization autoclave
Decontamination autoclave
x
x
59
Comparison Regulatory approach

CETC
LOEX
LBVA
CMCF
URS / Technical
program
Yes
Yes
Yes
Yes
Process flow
diagrams
Yes
No
Yes
Outside validation
consultants
To be
determined
No
Yes
Yes
Validation Master
Plan
To be
determined
To be
determined
Yes
Yes
New SOPs
prepared
Yes - Existing
modified
SOPs (Standard
Operating Procedures)
Existing to be
Existing to
modified
be modified
Yes (existing
updated)
Facility validation
To be
determined
To be
determined
Yes - 90%
complete
Yes
Process validation
To be
determined
To be
determined
Yes 50%
complete
Yes
60
Comparison Operations
CETC
LOEX
LBVA
CMCF
Anticipated total
staff
25
10
15-30
25-26
Scientific director
Yes
Yes
Yes
Yes
Technical director
To be
determined
To be
determined
Yes
Yes
QC/QA staff
1 currently
1 currently
Housekeeping
Hospital
services
Hospital
services
In-house lab
staff (start-up)
Outsourced
Building systems
technical support
Hospital
services
Hospital
services
University
services
Institute
services
Metered rates
or by area
Not
charged
Energy costs
Not currently Not currently

charged
charged
61
01
02
03
04
05
06
Introduction
Lesson learned
Q&A
62
Lessons learned Challenges to aspiring institutions

1. Judging the need to be GMP compliant
- understanding the implications
2. Justifying higher initial costs
3. Managing the paradigm shift in work
moving from an innovative research to
routine production operations
4. Committing to raising the labs profile &
market its services
5. Securing long term funding to maintain
compliant operations
63
Why do these labs matter

1. Help address the invention to innovation
gap in Canada
2. Build bridges between academia and
industry
3. Provides another source to industry for
new products, for trained staff, for pilot
scale or small market production
4. Industry has specific experience &
expertise that academic core labs need
5. Cross fertilization of research activities
64
01
02
03
04
05
06
Introduction
Lesson learned
Q&A
65
Thank-you
2007 NFOE et associs architectes, NXL Architects & SNC-Lavalin Pharma

www.nfoe.com
www.nxl.ca
www.snclavalin.com
66

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ISPE Breakfast Seminar

THE GMP CORE LAB

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

ISPE Breakfast Seminar January 2008

ISPE Breakfast Seminar January 2008

Why a GMP core lab?

Participation in clinical trials institutional

ISPE Breakfast Seminar January 2008

To the delivery - error free,

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

Changing the way people work

to fixed & restricted.

ISPE Breakfast Seminar January 2008

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

Ensure that products are safe, pure, and effective

ISPE Breakfast Seminar January 2008

GAMP: Good Automated Manufacturing Practices (guidelines)

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

Dedicated regulations to core lab compliance

To prevent the introduction, transmission, or spread of

CTO: Cells, Tissues and Organs (HC)

Laboratory Biosafety Guidelines (PHAC)

Guide to safety and quality assurance for organs, tissues and

ISPE Breakfast Seminar January 2008

Why apply GxP/GMP to an institutional core lab?

To ensure the health and safety of patients

ISPE Breakfast Seminar January 2008

GTP means (as GMP)

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

Validation: What does it mean?

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

Validation: What does it mean for GTP?

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

Validation: What does it mean?

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008

Cell Therapy Centre of Excellence

Maisonneuve-Rosemont Hospital, Montreal

The GMP Core Lab Expectations vs. Realities

Project Description - CETC

The GMP Core Lab Expectations vs. Realities

ISPE Breakfast Seminar January 2008