HC

1. The ICH Q5E Document
Anthony Ridgway, Ph.D.
Biologics & Genetic Therapies Directorate
Health Canada
Presentation to CAPRA
March, 2004

2. Presentation Outline
 Some background (+ needs and challenges)
 Scope of the document
 Objectives, discussion points and principles
 Time frames and next steps

3. Comparability
Product of
Process
X
Product of
Process
Y
?
The Question

4. Comparability
 Characterization
 Specifications
 Validation
–changes to materials or process
Key Elements

5. Characterization
Purity/Impurity Profile
 Desired product (microheterogeneity)
 Product-related substances
 Product-related impurities
 Process-related impurities
 Contaminants
Drug substance = Multiple entities

6. Comparability
Extent of Studies
 Stage/extent of changes
 Impact on the product
 Analytical capability
 Link between quality criteria and
safety and efficacy

7. Comparability
Additional Testing
 Tests specifically directed at fully evaluating
the impact of the change on the product
 In-process assays at the manufacturing
steps which are most likely affected by the
manufacturing change

8. Comparable
“A conclusion that products are highly similar before
and after manufacturing process changes and that
no adverse impact on the quality, safety, or efficacy
of the drug product occurred. This conclusion can
be based on an analysis of product quality attributes.
In some cases, non-clinical or clinical data might be
indicated.”

9.  Expanding inventory of biotechnology products
 More new facilities, facility changes
 More additions to multi-use facilities
 More scale-ups (new indications, wider
acceptance, earlier use/combination)
Challenges to Industry
Increasing Numbers of Manufacturing
Process and Facility Changes

10.  Understanding national/regional requirements
 Preparing dissimilar submission types and
information packages
 Increased inventory of product(s) to prevent
shortages during changeovers
 Acceptable product may lose significant portion of
dating period due to regulatory delays
 Delays to implementation waiting for all approvals
Challenges to Industry
Direct and Delay-Related Costs of Making
Manufacturing Changes in a Global Marketplace

11.  Patients may wait longer for wider availability,
improved quality, or less expensive products
 Manufacturers are discouraged from
implementing improvements to the process
Challenges to Us All
Wider Consequences of Delays to
Implementation of Manufacturing Changes

12. New ICH Guideline
Concept Paper for Q5E
 Draft Title: "Comparability of Biotechnological/Biological
Products Subject to Changes in their Manufacturing
Process"
 To address industry costs and delays associated with
meeting region-specific requirements
 Proposes harmonization of the data packages to support
manufacturing changes/variations
 Focused on ("within-product") changes to manufacturing of
products defined within the scope of ICH Q6B

13. The Delicate Balance
 Less Detail
 consensus easier
 less useful
 more flexible
 greater differences in
interpretation
(inter-regional, inter-reviewer)
 More Detail
 consensus harder
 greater practicality
 less flexible
 fewer differences in interpretation
 prescriptive interpretation (?)
ICH Guidance

14. Historical Context
Q5E is built on earlier guidelines
Q5A- Viral Safety Evaluation of Biotechnological/Biological
Products Derived from Cell Lines of Human or Animal Origin
Q5B- Analysis of the Expression Construct in Cells Used for
Production of r-DNA Derived Protein Products
Q5C- Stability Testing of Biotechnological/Biological Products
Q5D- Derivation and Characterisation of Cell Substrates Used
for Production of Biotechnological/Biological Products
Q6B- Specifications: Test Procedures and Acceptance Criteria
for Biotechnological/Biological Products

15. "Recombinant" Production Process
and ICH Quality Guidance(s)
Cell Banks Formulation
Purification
Fermentation
Q5B Genetic
Stability
Q5D Cell Substrates
Q5A Viral Safety
Q6B Specifications
Q5C Stability
Drug Substance
Drug Product

16. Presentation Outline
 Some background (+ needs and challenges)
 Scope of the document
 Objectives, discussion points and principles
 Time frames and next steps

17. Elements of the Scope
• What types of scientific studies ?
• What product types ?
• What stages of manufacturing?
• What stages of development ?
• What can be compared ?

18. Elements of the Scope
Types of scientific studies
• Quality
– Physicochemical, biological, immunological, etc.
• Nonclinical (animal)
• Clinical
Product types
• Restricted to scope ICH Q6B

19. Q6B Scope
• Proteins and polypeptides, their derivatives, and
products of which they are components (e.g.
conjugates). These proteins and polypeptides
are produced from recombinant or non-
recombinant cell-culture expression systems
and can be highly purified and characterized
using an appropriate set of analytical
procedures.
• The principles may also apply to other types of
products such as proteins and polypeptides
isolated from tissues and body fluids.

20. Elements of the Scope
Stages of manufacturing
• All stages of the manufacturing process are
covered by the guideline
Stages of Development
• Main focus is on manufacturing changes
introduced post-approval, however, the
document contains a section specifically
addressing comparability during development

21. Elements of the Scope
Product comparisons following:
• change in equipment/raw material
• change in process steps
• change in manufacturing site
• change in manufacturer

22. Comparability
Consensus Position
Exclude “biogenerics“ (subsequent-entry; biosimilar; follow-on)
inclusion risks complicating the guideline and prolonging
the harmonization process
urgent need to address the impact that regional
requirements have on introduction of changes
(timing, cost, product availability)
vast majority of events/decisions pertain to "within-
product" changes
primary concept of change at discrete steps (usually
flanked by unchanged steps)
individual regions can choose to allow broader
application of guideline

23. Q5E Scope
• Products where changes are made by a single manufacturer
who can directly compare results from the analysis of pre-
change and post-change products
• All manufacturing operations executed by the authorised
manufacturer or other parties (e.g., contract manufacturer(s))
under contract with the manufacturer to produce the
product(s)
• Products where process changes are made in development or
for which a marketing authorization has been granted
• Product-type scope is same as Q6B

24. Presentation Outline
 Some background (+ needs and challenges)
 Scope of the document
 Objectives, discussion points, and principles
 Time frames and next steps

25. Objectives of the Guideline
(1)
The objective of this document is to provide
principles for assessing the comparability of
biotechnological/biological products before and
after changes are made in the manufacturing
process for the drug substance or drug product.

26. Objectives of the Guideline
(2)
This guideline is intended to assist in the design
and conduct of studies used to collect the
technical information to establish the
comparability of pre-change and post-change
products and, thereby, confirm that the
manufacturing process changes did not have an
adverse impact on the quality, safety or efficacy
of the drug product.

27. Discussion Points (1)
• Different interpretations for the scope
• Strategy for conducting the comparability
exercise
• Categories of outcomes from comparability
exercises
• Product and process aspects
• Characterisation & analytical procedure
capabilities

28. Discussion Points (2)
• Demonstration of drug product
comparability
• Description of the manufacturing process
& considerations
• Demonstration of comparability during
development
• Non-clinical and clinical studies

29. Life cycle of a product
Process A
Process B
Process C
Phase I
Phase II
Phase III
MARKETING AUTHORIZATION
TIME LINE
Variation I
Variation II
…

30. Example of changes to a
manufacturing process
Need to adapt the expression system
 retrospectively
SERUM FREE PROCESS

Change in cell growth and productivity

Adaptation Purification process
• Expression system
• Fermentation/culture process
• Purification process
• Formulation and filling
• DRUG PRODUCT
• DRUG SUBSTANCE

31. • One change… a cascade of changes…
• Necessity to reconsider downstream steps
… and upstream steps, as appropriate
• Planning activities: to be revised and
updated as needed
Manufacturing process
considerations

32. Table Of Contents (1)
1.0 Introduction
1.1 Objectives of the Guideline
1.2 Background
1.3 Scope
1.4 General Principles

33. Table Of Contents (2)
2.0 Guidelines
2.1 Considerations for the Comparability
Exercise
2.2 Quality Considerations
2.2.1 Analytical Techniques
2.2.2 Characterisation
2.2.3 Specifications
2.2.4 Stability

34. Table Of Contents (3)
2.3 Manufacturing Process
Considerations
2.4 Demonstration of Comparability
during Development
3.0 Nonclinical and Clinical
Considerations
4.0 Glossary
5.0 References

35. General Principles (1)
The goal of the comparability exercise is to
ensure the quality, safety and efficacy of the
drug product produced by a changed
manufacturing process through collection and
evaluation of the relevant data to determine
whether there is any adverse impact on the
drug product due to the manufacturing process
changes.

36. General Principles (2)
The demonstration of comparability does not
necessarily mean that the quality attributes of the
pre-change and post-change products are
identical; but that they are highly similar and that
the existing knowledge is sufficiently predictive to
ensure that any differences in quality attributes
have no adverse impact upon safety or efficacy of
the drug product.

37. General Principles (3)
A determination of comparability can be based on
a combination of analytical testing, biological
assays, and, in some cases, non-clinical and
clinical data.
If a manufacturer can provide assurance of
comparability through analytical studies alone,
non-clinical or clinical studies with the post-change
product might not be warranted.

38. General Principles (4)
However, where the relationship between specific
quality attributes and safety and efficacy has not
been established, and differences between quality
attributes of the pre- and post-change products are
observed, it might be appropriate to include a
combination of quality, non-clinical, and/or clinical
studies in the comparability exercise.

39. Presentation Outline
 Some background (+ needs and challenges)
 Scope of the document
 Objectives, discussion points and principles
 Time frames and next steps

40. EWG Meetings (1)
• Unofficial discussion group meeting :
February 4-5, 2002, Brussels (Concept paper)
• Unofficial discussion group meeting : Draft 0
September 10-12, 2002, Washington (Informal
workshop)

41. EWG Meetings (2)
• First discussion session of EWG : Draft 1
February 3-5, 2003, Tokyo
• Second discussion session of EWG : Draft 2
July 14-18, 2003, Brussels
• Interim EWG meeting : Draft 3
September 23-26, 2003 Washington
• Fourth discussion session of EWG : Draft 4
November 8-13, 2003, Osaka (Step2, Quality)

42. Input from Safety and Efficacy groups
• Step 2 (Quality) is released for comment
• Non-clinical and clinical experts will develop
input.
• Integrated Step 2 (Quality, Safety and
Efficacy) will be released for comment
• Reviewed by the Quality Biotech EWG prior
to Step 4

43. Comparability
Clinical Considerations
 Indication
mode of action
outcome measures
 Dosing and Patient Response
units of activity
route of administration
narrow therapeutic index
 Safety Versus Efficacy
immunogenicity
active ingredient vs impurities

44. Q5E Topic Leads
• Tony Lubiniecki (PhRMA) (Co-rapporteur)
• Shigeru Matsuki (JPMA) (Co-rapporteur)
• Pierrette Zorzi (EU)
• Ralf Gleixner (EFPIA)
• Toru Kawanishi (MHLW)
• Barry Cherney (FDA)
• Anthony Ridgway (Health Canada)
Q5E on Health Canada website:
www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/q5e_step2_notice_e.html
(Or once at the website, use the search window…enter ICH)
Comments accepted until April 30, 2004