Application of Phase-Appropriate
CGMP and d Quality
Q lit Systems
S t to
t the
th
Development of Protein Bulk Drug
Substance (or API)
PDA Task Force
Presenter: Amnon Eylath
Di
Director Q
Quality,
li ARIAD Ph
Pharmaceuticals
i l
1
Current Task Force Members
• Amnon Eylath, ARIAD Pharmaceuticals (Chair)
• Vince Mathews, Eli Lilly and Company (Co-Chair)
• Kurt Brorson, FDA/CDER
• Robert Darius, GlaxoSmithKline
• V lk E
Volker Eck,
k PDA E
Europe
• Teresa Feeser, Bristol Myers Squibb
• Andrew Gunn III,
III Emergent BioSolutions
• Patricia Hughes, FDA/CDER
• Renita Johnson-Leva,
Johnson Leva Advanced BioScience Laboratories
• Matt Karpen, Amgen
• Bryan Silvey
Silvey, Baxter BioScience
• Kirsten Vadheim, BioCompliance Laboratories 2
Additional Contributors and
R i
Reviewers
• Monica Caphart
Caphart. FDA/ORA
• Britt Christensen, CMC Biologics
• Brenda Uratani, FDA/ORA
• Anders Vinther, Genentech
• Hannelore Willkommen, RBS Consulting
3
Acknowledgements:
• Thanks to Iris Rice of the PDA for continuous
and excellent administrative and
organizational support from the very
beginning
beg g of
o the
t e task
tas force
o ce
• Thanks to Jim Lyda, Richard Levy and Bob
Dana of the PDA for their support,
pp , advice
and insight
• Personal thanks to Daniel Bollag, Sr. VP RA
& Quality at ARIAD Pharmaceuticals for his
continued support and encouragement
4
Task Force Strategy
• To bring together subject matter experts
representing:
– Industry: Small and Large Companies
– Consultants: Experts in their field
– Regulatory Agencies
• Get input and comments from US, EU and
Japan
• Get input and comments from academic
facilities involved in GMP activities
5
Overview
• The Technical report’s goal is to propose a
basic science-based and compliant
basic,
approach towards the development of
Protein Bulk Drugg Substance (API)
( )
• Its scope covers the development path from
R&D, through preclinical studies, through PD
and scale up to commercialization
• It describes the minimum activities and
systems considered appropriate that should
support effective GxP (GRP, GLP, GMP, etc.)
6
TECHNICAL REPORT TABLE OF CONTENTS
1.0 INTRODUCTION
11S
1.1 Scope
1.2 Purpose
1.3 The Product Development Life Cycle
1.4 Product Quality and the Relationship between GMPs and CMC Requirements and
E
Expectations
t ti
1.5 A Graded, Phase-Appropriate Approach
1.6 Cell Banks
1.7 GMPs across Different Types of Biopharmaceutical Development Organizations
2.0 GLOSSARY OF TERMS
3.0 APPLICATION OF QUALITY PRACTICES BY PHASE OF DEVELOPMENT
3.1 General Requirements for Documentation
3.2 Process Development Areas
3.3 Toxicology Phase
pp y Material Manufacturing
3.4 Clinical Supply g Phase
4.0 CGMP REQUIREMENTS BY PHASE OF DEVELOPMENT
5.0
5 0 REFERENCES
APPENDIX 1- QUALITY SYSTEMS AS APPLICABLE TO CELL CULTURE DEVELOPMENT
APPENDIX 2- REFERENCES FOR RECOMMENDED TESTING OF MAMMALIAN AND E COLI 7
CELLS
Scope
• The scope of this technical report covers phase-
appropriate Current Good Manufacturing Practices
(CGMP) during therapeutic bulk protein drug substance
manufacturing from the R&D stage through completion
of phase 3 clinical trials
• The scope also includes implementation of a
pharmaceutical quality system that ensures the safety
and quality of products intended for use in clinical trials
trials.
• This report will focus on current best practices and the
appropriate regulatory framework.
• Chemistry and Manufacturing Controls (CMC)
submission/dossier requirements for therapeutic proteins
at the pre-marketing phase are not within the scope of
this document
8
Purpose
• To define CGMP principles important for manufacturing pre-
marketing therapeutic bulk protein, providing examples of
approaches towards CGMP compliance during clinical studies
• The examples provide an overview of the expectations across
regulatory authorities as products proceed from R&D to completion
of phase 3 clinical trials
• The report illustrates a phase-appropriate approach to the
implementation of CGMP, enabling supply of safe clinical materials
while maintaining manufacturing flexibility at non-commercial
non commercial scales
& during scale up & process transfer
• The report also describes a basic framework for clinical trial
manufacturing
a u actu g for o ssites
tes where
e e commercial
co e c a manufacturing
a u actu g is s not
ot tthe
e
organizational goal (e.g. university clinical investigators, start-up
biotech firms).
• This report
p is not intended to serve as a regulatory
g ygguidance.
9
The Bulk Drug Substance Development Life Cycle
Process Development Completed Technical Transfer
Post-
Marketing
Testing
Safety &
Efficacy
Testing
es
iti
it v
Ac
P
GM
&
C
CM
to
ch
roa
p
Ap
te
p ria
ro
App
-
e
as
Ph
Safety &
Safety Dosing
Testing Testing
One or Several Lots Multiple Lots Market
Animal / Cell
Testing more Lots Supplies
Pre-Clinical
Pre Clinical Product
R&D Phase I Phase II Phase III Commercial
(Tox assessment) Discontinuation
Phases of Development
*Size of study is often dependant 10
on disease state, e.g. oncology vs. endocrine
Quality and Compliance expectations increase
along the Drug Development timeline
• R&D / Phase I / Phase II / Phase III / Pre - Commercialization
• Q lit / GMP expectations
Quality t ti ffor Bi
Biotech
t h Bulk
B lk Drug
D Substance
S b t
applied by Phase of development
• Good Research and Documentation Practices
• GLPs Pre-Clinical (Tox assessment)
• Early Phase cGMP expectations
• Bioburden and endotoxin control
• Calibrated equipment / Qualified equipment
• Qualified Methods / Validated Methods
• Process validation
• Pre-Commercialization cGMP expectations
• Process Understanding increasing - QbD
• Risk-Based/Science-Based Approach to compliance decisions
ICH Q8/Q9/Q10 11
A Risk-based approach:
12
Product Quality and the relationship between
GMP and
GMPs d CMC requirements/expectations
i t / t ti
• The regulatory
g y strategy
gy used to ensure
biopharmaceutical product quality involves both CMC
and CGMP oversight.
• CMC requirements
i t sett the
th criteria
it i andd controls
t l ffor
manufacturing and testing, as described in the
submission or dossier.
• CGMP requirements are derived from the regulations
and guidelines pertaining to the implementation of
practices and standards in a manufacturing facility that
allows for the consistent production of a quality product
with the intended purity, safety and potency
characteristics
13
Example of table from the Technical Report
14
Example of table from the Technical Report (2)
15
Overlap
p Between GMPs and CMC
• Because theyy are both critical p
pillars of p
product q
quality,
y,
there are often areas of overlap between CMC
considerations and GMPs.
• Examples
E l off areas off overlap
l include:
i l d
– process development
– Validation
– continuous process improvement.
• Resolution of the overlap can be achieved by viewing
CMC d development
l t as a ““process, criteria
it i and
d controls
t l
setting activity” and GMPs as an “implementation
y
activity”
16
The Synergy of CGMP and CMC
Product Quality ICH Q8-10
CMC CGMP
Focus: Submission/dossier Facility/Manufacturing/Testing
Industry Setting manufacturing Implementing manufacturing and testing
and quality criteria and controls practices designed to meet manufacturing
Role: and quality standards
Guidance: ICH Q1-6 ICH Q7
g
Agencyy Assessment and Verification of conformance to
approval of manufacturing CGMP and to regulatory
Role: and quality standards and submission/dossier
controls standards through facility
inspections; evaluation of quality system
Note: For Biotechnological products, process validation summary data is included in the regulatory
application. Validation data and conformance to the commitments and standards described in the
Marketing Application are verified on site inspection.
17
Progress Status
• Comments incorporated from PDA membership
and the Biotechnology
gy Advisor Board in mid -
2010
p
• Draft version completed November 2010
• Sent out for comment by EMA and CBER
representatives
• Next Steps:
– Comment by academic/”small” GMP manufacturers
– Review by PDA Japan
– Review and Approval by PDA Biotechnology Advisory
Board.
Board
18
QUESTIONS?
19
