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 1
01 Introduction
02 GMP & regulatory parameters
03 Case studies - analysis
04 Case studies - comparison
05 Lesson learned
06 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.

01 Introduction
05 Lesson learned
06 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
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)
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)
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
GTP means (as GMP)
Components
Process
Equipment Validation
QA/QC
Routine Monitoring
Environment
GTP
Personnel
Raw materials
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.
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.
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
Documentation Lifecycle
Systems:
Business Plan SOPs, Training, Operations,
Engineering Maintenance, Change Control
Documents
Construction
Process Documents
Definition Commissioning
Purchasing Documents
Document
Field Tests
Conceptual
Design
Vendor
Documents
Start-up
P&IDs
FAT
Specification Operation
Documents
Installation
Drawing Documents
Validation Validation Protocols Execute

Master Plan IQ OQ PQ Validation
Validation
Regulatory
Reports
Documents
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
01 Introduction
05 Lesson learned
06 Q&A
Case Study
Cell Therapy Centre of Excellence

(Centre dExcellence en Thrapie Cellulaire CETC),
Maisonneuve-Rosemont Hospital, Montreal
Core Lab Analysis Case Study 1
The GMP Core Lab Expectations vs. Realities

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
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)
Facility plan - CETC
GMP cell
GMP cell
manipulation
manipulation
lab suite
lab suite
(CL-2)
Lab support
services
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
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
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
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
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
GMP Facility plan - LOEX
Support services: storage,

GMP lab washing & sterilization
suite
GMP prep &

support
services
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
Key considerations - LOEX
GMP compliance is not a requirement

for present operations
Participation in international multi-

centric 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
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
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
Facility plan - LBVA
Support services: storage, dispensing, Formulation QC lab

solution, prep, washing & sterilization & filling
Decon
services Bacterial
(CL-2LS) fermentation
suite (CL-2LS)
Cell culture Viral culture

suite suite (CL-2LS)
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.)
Project timeline - LBVA
Initial planning & 1999 2000

funding request
Facility programming & Q4-2001 Q2-2002

design
Construction Q3-2002 Q3-2004
Operations team Q4-2004

engaged
Business development Q2-2006

staff engaged
Validation Q1-2005 Q1-2007
Critical process systems - LBVA
10 - 100 litre bioreactors
10 - 100 litre fermenters
Lyophilizer
Roller deck incubators
Tangential flow filtration system
Homogeniser
Chromatography system
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
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
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
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.
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
Overall facility plans
GMP Cell Manufacturing,

Gene Therapy Offices
& support labs
R&D
Cyropreservation
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
Project timeline - CMCF
Initial funding request Q1 - 2000
Funding approval Q3 - 2000
Facility programming Q3-2000 Q4-2002

& design*
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
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
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)
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
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
01 Introduction
05 Lesson learned
06 Q&A
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 /
Maybe Maybe Yes Yes
external contracts
Capital investment
plan
Yes Yes Yes Yes
Ongoing facility Yes -
Planned No Yes
marketing initiated
Formal long term
No No No No
business plan
Comparison Project status
CETC LOEX LBVA CMCF
Programming
complete
Yes Yes Yes Yes
Feasibility Preliminary
Design complete Yes Yes
Study design
Construction
No No Yes Yes
complete
Validation
Maybe Maybe Yes Yes
intended
Validation 60%
complete
n/a n/a Yes
complete
GMP compliant (to be (to be
No Yes
operations determined) determined)
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

2.14 1.85 2.05 n/a
gross-up factor
* Includes ~15% allowance for base building costs; % M&E based on global cost
Comparison Technical characteristics building systems
CETC LOEX LBVA CMCF
Environmental ISO 8 & 7 ISO 7(Class

ISO 8 & 7 ISO 8 & 7
classifications (ISO 5 Filling) 10,000)
Biosafety
CL-2 none CL-2LS CL-2
containment level
Independent
Yes Yes Yes Yes
HVAC
Air change rate 30 (60 in ISO
30-35 30 30
per hour 5 area)
Air circulation 30-100% non- 30% non- 15% min. 100% non-
strategy recirculated recirculated fresh air recirculated
Air filtration Terminal Terminal Terminal Terminal
strategy HEPA filters HEPA filters HEPA filters HEPA filters
No-module No-module
Independent BAS Yes Yes
of main BAS of main BAS
Comparison Technical characteristics - utilities
CETC LOEX LBVA CMCF
USP water x
WFI water x
Clean compressed air x x
Clean steam x
Laboratory vacuum x
CO distribution x x x
Liquid nitrogen distribution x x x
CIP / SIP systems x
Sterilization autoclave x x
Decontamination autoclave x x
Comparison Regulatory approach
CETC LOEX LBVA CMCF
URS / Technical
Yes Yes Yes Yes
program
Process flow Yes (existing
Yes No Yes
diagrams updated)
Outside validation To be
No Yes Yes
consultants determined
Validation Master To be To be
Yes Yes
Plan determined determined
SOPs (Standard Existing to be Existing to New SOPs Yes - Existing

Operating Procedures) modified be modified prepared modified
To be To be Yes - 90%
Facility validation Yes
determined determined complete
To be To be Yes 50%
Process validation Yes
determined determined complete
Comparison Operations
CETC LOEX LBVA CMCF
Anticipated total
25 10 15-30 25-26
staff
Scientific director Yes Yes Yes Yes
To be To be
Technical director Yes Yes
determined determined
QC/QA staff 1 currently 1 currently 3 3
Hospital Hospital In-house lab Out-

Housekeeping
services services staff (start-up) sourced
Building systems Hospital Hospital University Institute
technical support services services services services
Not currently Not currently Metered rates Not
Energy costs
charged charged or by area charged
01 Introduction
05 Lesson learned
06 Q&A
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
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
01 Introduction
05 Lesson learned
06 Q&A
Thank-you
2007 NFOE et associs architectes, NXL Architects & SNC-Lavalin Pharma
www.nfoe.com www.nxl.ca www.snclavalin.com

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ISPE Breakfast Seminar

THE GMP CORE LAB

02 GMP & regulatory parameters

03 Case studies - analysis

04 Case studies - comparison

Setting the table outlining Good

Looking at four current or recent GMP

Identifying the principal challenges in

Cell Therapy Centre of Excellence (CETC),

Experimental Tissue Engineering Laboratory

Veterinary & Food Biotechnology Institute

Connell OReilly Cell Manipulation Core

Upgrading current core lab from

Participation in clinical trials institutional

Absence of alternatives for scale-up or

Allure of benchtop to bedside.

Moving from the discovery make

To the delivery - error free,

to fixed & restricted.

02 GMP & regulatory parameters

03 Case studies - analysis

04 Case studies - comparison

GMP: Good Manufacturing Practices (worldwide)

Regulations which have the force of law in most countries

Applies to establishments that fabricate, package, label, distribute,

Ensure that products are safe, pure, and effective

QSR: Quality System Regulation (Medical Devices FDA).

MDR: Medical device regulations (HC) and ISO Certification, CE

GCP: Good Clinical Practices (ICH).

GAMP: Good Automated Manufacturing Practices (guidelines)

GTP: Good Tissue Practices (FDA)

CTO: Cells, Tissues and Organs (HC)

Laboratory Biosafety Guidelines (PHAC)

Guide to safety and quality assurance for organs, tissues and

Only guidelines applicable to all human cells &tissues &

To ensure the health and safety of patients

A methodology for demonstrating compliance with GXP

Testing of 100% of finished product is not feasible (to assure

Establishing documented evidence which provides a high

Slightly different from GMP Validation expectations

Raw materials are constantly changing (Organs, tissues

Final products are constantly changing

Where the results of processing cannot be fully

Validation activities and results must be documented,

Validation Master Plan

Key component of global Quality Control / Quality

Validation Validation Protocols Execute

Compliance with applicable

Deliver systems that are fit for purpose

Reduction in rejections and reworks

Reduced testing for In-process and

02 GMP & regulatory parameters

03 Case studies - analysis

04 Case studies - comparison

Cell Therapy Centre of Excellence

Core Lab Analysis Case Study 1

The GMP Core Lab Expectations vs. Realities

A new core lab to be a Centre of Excellence for

Existing laboratory already a leader in autologous

Autologous & allogeneic cell manipulations

Cartilage cell cultures for autologous

Cell treatments for ocular repairs (retinas,

Net area: 6,530 sq. ft.; gross departmental area: