Topic 1. Challenges and Considerations for Implementation of ICH ...

Topic 1. Challenges and
Considerations for
Implementation of ICH Q11
Overview
(Topic Owner: Betsy Fritschel)
CMC Focus Group Meeting
May 11 th 2012

� New ICH Guidelines
Why Q11?
� Q8 Pharmaceutical Development
� Q9 Quality Risk Management
� Q10 Pharmaceutical Quality System
� Concepts of these guidelines apply to Drug Substance
as well as Drug Product
� Process for manufacture of Drug Substance is very
different from Drug Product – e.g. purification
� Need Q11 to clarify principles of Q8, Q9, and Q10 as
they relate to Drug Substance and provide examples

Current Status Q11
� Step 1 EWG Consensus April 2008 – April 2011
� Step 2 – Signatures May 2011
� Step 3
- Stage 1 Public comment June – Sept 2011
- Stage 2 Resolve comments 1 st Quarter 2012
� Step 4 Publication of final version
� Step 5 Implementation
Target May 2012

1. Introduction
2. Scope
Outline of Q11
3. Manufacturing Process Development
4. Description of Manufacturing Process
5. Selection of Starting Materials & Source Materials
6. Control Strategy
7. Process Validation/Evaluation
8. Submission in CTD Format
9. Lifecycle Management
10. Illustrative Examples
11. Glossary

Wrap Up
CMC Focus Group Meeting
May 11, 2012

Breakout Session Overview
Example 1: Linking Material Attributes and
Process Parameters to Drug Substance CQA’s
� Design space and manufacturing flexibility
� Traditional and Enhanced Approach in determination
of ranges for parameters
� Development of a Design Space using prior
knowledge and chemistry first principles. (not just
DoE)
� Using an enhanced approach to achieve
manufacturing flexibility
� Using set parameters in multivariate analysis

Breakout Session Overview
Example 2: Use of Quality Risk Management
� Possible communication tool for presenting a risk
ranking for parameters evaluated during development
of a design space
� Summarizes a proposal for how specific future
changes will be managed and communicated during
the product lifecycle

Breakout Session Overview
Example 3: Presentation of A Design Space for
A Biotechnological Product Unit Operation
� Analogous to ICH Q8R2, example 2 where a two
parameter design space consists of the overlap
region for two CQAs
� Q11 example 3 shows the common region of
successful operating ranges for three CQAs
� In addition, the successful operating range for one
CQA (residual DNA) was derived from prior
knowledge (platform manufacturing)

Breakout Session Overview
Example 4: Selecting an Appropriate Starting
Material
� Illustrates general principles
� Importance of considering all general principles
described when selecting an appropriate starting
material, rather than applying each general principle
in isolation.

Breakout Session Overview
Example 5: Summary of Control Elements for
Select CQA’s
� Illustrates how part of a drug substance control
strategy might be summarized in tabular form.
� Illustrates examples of upstream control, CQA and
specifications (and/ or drug substance specification).

Q11 Output General Comments
� Regional interpretation and regulation remains a concern for QBD
acceptance and uptake
� Regulatory flexibility – does it exist, should it exist?
� Most contentious points in discussion leading to Q11 became examples to
illustrate concepts.
� ICH Q11 gives examples and and is not a template

Output Example 1-Linking Material attributes and
process parameters to DS CQAs- development of
Design Space
� Submissions tend to be hybrid and there is a clear acceptance that this is not
bad
� There is conflict over meaning of QBD terms within organizations
� General agreement that organizations are not comfortable using term design
space in files
� Design space is submitted and approved by definition
� Statistics are not the only way to define a design space
� DS allows that changes within DS are allowed.
� Design space is useful for managing deviations outside the batch sheet and
allows change due to human and mechanical variability as long as it is filed!
� Use of the term PAR is contentious for some.
� Piecing together unit operations into a holistic CS across operations is more
difficult than defining a design space for a unit operation.
� Statistical analysis not always necessary but it add greater understanding of
variation
� How do we file and present DS

Output Example 2- Using QRM to Support Lifecycle
Management of PP
� Not all parameters are created equal
� Recognizes a continuum of risk
� Hard to define a critical process parameter
� Helps put into perspective what is critical vs non-critical it is based on
risk and clearly articulated
� Management of risk can change over the lifecycle of product
� How do we best report the change in risk due to new knowledge during
lifecycle?

� Not discussed
Output Example 3

Output Example 4-Starting Materials
� Strong agreement with document approach
� Science based approach is welcome
� Not a check box mentality
� Puts the onus on the manufacturer to control the integrity of supply chain
� The fewer steps you register the more control you need.

Output Example 5- Summary of Control Elements-
Control Strategy
� Specification of API is just a part of control strategy.
� Not all CQA’s need to be included in spec or tested in API
� Upstream control along with purging allows for higher levels of impurities than those defined
in spec.
� Certificate of Analysis vs specification- does this cause confusion?
� CS table is presented in S4.5 (Justification of Spec)