International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use

CASSS Q11 – An Industry Perspective

Brian WithersAbbott Laboratories

Disclaimer :

The information within this presentation is based on the presenter's expertise and experience, and represents the views of the presenter for the purposes of a training workshop.

Agenda

ICH ProcessConcept PaperStatusIndustry Highlights from guidelineThoughts for the future

ICH

April 08 accepted as an ICH topic

Six Party Consensus

Public Consultation

Final Adoption

Implementation

EWG Consensus Building

5

4

3

2

1 EWG meetings - including writing drafts/ reviewing/ written comments/ revisions until agreed

Steps of the ICH Process

Concept Paper Q11Goals of Guideline

Harmonise submissionsOutline science based concepts Recommend approaches to demonstrating process and product understandingAddress complexity of processes/productsAccommodate different development approachesAddress enhanced and systematic approaches to drug development.

Timetable of Q11October 2006. Identified as a topic by ICH –Q strategy for evaluation

Drug substance guidance addressing chemical and biotech (similarities & differences), traditional and ‘best scientific practices’ for S2 of CTD

October 2007. ICH Quality Round Table AgreementsPrinciples of Q8, Q9, Q10 are applicable to chemical and biotech drug substances and drug productsLack of guidance on drug substance still a remaining gap

March 2008Concept paper approved by ICH Steering Committee

June 2008 EWG established Total of 6 meetings

Step 2 Nearly there!!!Step 4 Based on Public Consultation schedule.

M4Q Structure

3.2.S.2.2 Description of Manufacturing Process and Process Controls3.2.S.2.3 Control of Materials3.2.S.2.4 Controls of Critical Steps and Intermediates 3.2.S.2.5 Process Validation and/or Evaluation3.2.S.2.6 Manufacturing Process Development

Outline of Q111. Introduction2. Scope3. Manufacturing Process Development4. Description of Manufacturing Process5. Selection of Starting Material6. Control Strategy7. Process Validation/Evaluation8. Submission in CTD Format9. Lifecycle Management10. Examples11. Glossary GENERAL PRINCIPLES

WHAT TO SUBMIT

1 Introduction“A company can choose”Traditional Approach

Defined set points and operating ranges for process parameters

Drug substance control strategy typically based onDemonstration of process reproducibilityTesting to meet established acceptance criteria

Enhanced ApproachRisk management and more extensive knowledge used to select process parameters and unit operations that impact CQA’sEvaluation in studies to establish design space and control strategies applicable over the lifecycle of the drug substance

2 ScopeDrug substances as defined in

Q6A chemical entitiesQ6B

Biotechnological and biological

Preparation and organisation of contents of S2.2-S2.6 of Module 3 of CTDMight be appropriate for types of products outside Q6A and Q6BDoes not apply to contents of submissions during clinical researchDoes not address GMP guidance (Q7)

3 Manufacturing Process DevelopmentConfirms the principles of Q8r applicable for DS Drug substance CQA’s

Maintained at the level of drug substance linked to drug product

There is a commitment, as part of the control strategy, to identify and control the material attributes and process parameters found to be important for DS quality

Includes Platform Manufacturing as a specific class of prior knowledge

Platform Manufacturing

The approach of developing a production strategy for a new drug starting from manufacturing processes similar to those used by the same applicant to manufacture other drugs of the same type (e.g., as in the production of monoclonal antibodies using predefined host cell, cell culture, and purification processes, for which there already exists considerable experience)

4 Description of Manufacturing ProcessOne item of potential controversy for industry

To facilitate the approval of a design space for a complex product, such as a biotechnological/biological product, an applicant can choose to provide information on how movements within the design space will be managed post approval. This could help the reviewer understand how residual risk will be managed.

6 Control Strategy

General PrinciplesDefined in Q10A planned set of controls, derived from current product and process understanding, that assures process performance and product qualityEvery drug substance manufacturing process whether developed through traditional or enhanced (or combination of both) has an associated control strategy

6 Control StrategyDS Control Strategy can include:

Controls on input material attributes (including raw materials, starting materials, intermediates, reagents, primary packaging materials for DS, etc)Controls implicit in the design of the mfg processIn-process controls (including in-process tests and process parameters)Controls on drug substance (e.g., release testing)

6 Control Strategy

Set points and operating ranges set tightly to ensure consistencyTesting of DS greater contributor to evaluation of quality

• Systematic evaluation of sources of variability

• More meaningful controls• Iterative process as knowledge increases

• May include Design Space• Can provide for manufacturing flexibility

Traditional

Enhanced

7 Process ValidationPV section is less than 2 pages of a 30 page guidelineTraditional’ and Continuous process verification (CPV) coveredThe validation approach is not pre-determined by the development approach

Biotech section “Usually contains both commercial-scale and small-scale”Requirements of Q5 series maintained

Cell substrates/’Genetic stability’/Virus safetyImpurity ClearanceLifetime of columns

Small scale models Confirmed during commercial-scale production

Biotech and small scale modelsQ11 PV section acknowledges the contribution that small-scale model data can make to the overall validation packageRequires that data from small-scale models must be scientifically justified

Focus on scientific justification of the models rather than ‘validation’ or ‘qualification’ of the model

Demonstrating models are scalable “can allow manufacturers to propose process validation with reduced dependence on testing of commercial –scale batches”

Validation and PlatformMention of platform manufacturing made

Specific subset of prior knowledge(not explicit but data need to be proprietary to be platform) and applicant must have generated and understand a product-specific control strategyNeed demonstration of appropriate control strategyProcess validation “..should include data derived from the final manufacturing process and site….”

PV needs to explain relationship of PV runs to batch definition section

8 Submission in CTD FormatCTD format was established prior to concept of enhanced development approachQ11 provides suggestions for where information could be submitted in CTD formatApplicant should indicate where information is located

9 Lifecycle ManagementConcepts of Q10 apply to drug substanceUse of science and risk based approaches at each lifecycle stage promotes continual improvementKnowledge managementContinual improvement / change

Proposal for how changes may be managedEvaluate the impact of the change on the drug substanceMovement within Design Space does not require regulatory approval

Examples

Extension of ranges would normally initiate a regulatory post-approval change process

The applicant can include in the original submission a proposal for extension of ranges for moderate risk parameters

Extension of ranges is addressed primarily via the PQS (Q10)

Example 2: Use of QRM to Support Lifecycle management

Presentation of Design Space

Data Derived from Platform Manufacturing

Still Work Post Q11Level of Detail

Each cited study or risk assessment should be summarised with a level of detail sufficient to convey an understanding of the purpose of the study, the data collected, how it was analysed, the conclusions reached, and the impact of the study on the manufacturing process or further development of the manufacturing process. The risk assessment tools and study results on which a design space is based should be adequately described.

Use of Platform Manufacturing InformationValidation

Continuous Process VerificationDo we have the right forum for Scientific Dialogue

Concluding RemarksQ11 Does not:• Provide a template for development• Define Critical• Deal with Post-approval change• Use the term “Quality by Design”Q11 does:1. Confirms the applicability of enhanced approaches to DS2. Open the door to the future

PlatformsValidation approaches

Thank You