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Setting Specifications How and Where to Control Karin Sewerin on behalf of EBE MedImmune September 9, 2011 Specifications Presentation outline Monitoring of Critical Quality Attributes (CQAs) Testing Types of testing Types of

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SLIDE 1

Setting Specifications

How and Where to Control

Karin Sewerin

  • n behalf of EBE

MedImmune

September 9, 2011

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SLIDE 2

Specifications – Presentation outline

  • Monitoring of Critical Quality Attributes (CQAs)
  • Testing
  • Types of testing
  • Types of acceptance criteria
  • Handling of CQAs and non-CQAs

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SLIDE 3

Rationale for Setting Specifications

Specifications Specifications

Impurities Impurities Molecular structure Molecular structure Methods validation Methods validation Stability of product Stability of product Regulatory requirements Regulatory requirements Batch to batch variation Batch to batch variation Manufacturing process and control Manufacturing process and control Process evaluation Process evaluation 3

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SLIDE 4

Attribute Test Identity Suitable method Potency Relative activity Content A280 Purity Endotoxins Safety Sterility

Drug Product Specifications

Starting point - for setting specifications

  • The ideal case
  • No Critical Quality Attributes have been identified
  • Stable and robust process has been established
  • The real case
  • Add each CQA identified
  • Select a suitable method

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SLIDE 5

Risk Assessment - for control of CQAs

Severity Define CQAs – impact on S&E Severity Define CQAs – impact on S&E Detectability

  • capability of

analytical methods Detectability

  • capability of

analytical methods Probability

  • relationship of

product knowledge and process capability Probability

  • relationship of

product knowledge and process capability

Design of Control Strategy

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SLIDE 6

Procedural controls Procedural controls Routine Monitoring

I nput Control Output Control

Examples:

  • RM Spec
  • IPC on eluate

from previous step

  • IP test

Examples:

  • IPC on eluate

from this step

  • IP test
  • DS/ DP Specs

Process step

Control Strategy – for each step and the process

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SLIDE 7

Testing - for routine monitoring of QAs

  • 1. In Process Controls (IPC)
  • Confirm QAs on each batch
  • Control input for next step
  • Real Time Release Testing (RTRT)
  • 2. End Product Testing
  • Drug Substance and Drug Product
  • Skip lot testing
  • 3. Life cycle management
  • Real time stability monitoring
  • Accelerated stability testing
  • Comparability testing

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SLIDE 8

Example – Real Time Release Testing

  • Mab – Oligosacharide profile
  • Criticality assessment
  • Impact on: Biological activity / Immunogenicity / Clearance?
  • No - attribute is NOT a CQA – no routine monitoring required
  • Yes - attribute is a CQA - should be monitored
  • Prior knowledge
  • Glycosylation is formed during cell culture production and doesn’t change

during down stream processing or storage

  • In-Process testing in lieu of End Product testing
  • CQA testing is performed on the harvested bulk
  • Report result
  • In process Control in Batch records
  • On Certificate of Analysis with reference place of testing

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End Product Testing – DS vs DP

  • Drug Substance vs Drug Product testing
  • No DS release testing required
  • Direct filling of Purified DS
  • DP Certificate of Analysis includes testing of all CQAs
  • DS release is required if
  • Storage of DS before fill
  • Pooling – release testing to confirm product quality before mixing
  • f several batches

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Life cycle management – testing strategy

Specification Testing

  • Stability testing
  • Shelf life specifications
  • Routine monitoring on a periodic basis
  • Comparability testing
  • Assessment of impact after process changes

Investigational Testing

  • Forced degradation study / Accelerated stability
  • Initial assessment of the molecular capability and

understand the degradation pathway

  • Selection of stability indicating methods
  • Identify critical condition in the process
  • Formulation development

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SLIDE 11

Types of Acceptance Criteria

  • Quantitative
  • Range

< X <

  • “Open ended”

Not More Than Not Less Than

  • Qualitative
  • Compare to reference material

Protein Concentration: 10 ± 1 mg/mL Protein Concentration: 10 ± 1 mg/mL Host Cell Protein: < 10 ppm Host Cell Protein: < 10 ppm Identity: Profile comparable to Reference Material* Identity: Profile comparable to Reference Material*

* To a well characterized Reference Material

Examples

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SLIDE 12

Target / Set point Out of trend Out of trend

Quantitative Acceptance Criteria

Alert Lim its

for monitoring

  • f

process performance

Regulatory Acceptance Lim it

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Target / Set point

Action

Acceptance Acceptance

Out of trend Out of trend An action - to confirm that the quality of the product An action - to confirm that the quality of the product

--

Quantitative Acceptance Criteria

Action Lim its Alert Lim its

Examples:

  • Corrective action
  • Additional testing
  • End product testing

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Target / Set point Out of trend Out of trend An action to confirm the quality of the product An action to confirm the quality of the product

--

Quantitative Acceptance Criteria

Action Lim its Acceptance Lim its Alert Lim its

Acceptance / Rejection

Out Of Specifications Out Of Specifications

OOS investigation 14

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Example

  • alert limits

Acceptance limits

x x x x x x x x x x x x x x x x x x 15

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SLIDE 16

Example

  • alert limits

Acceptance limits

x x x x x x x x x x x x x x x x x x

Alert Limits

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SLIDE 17

Example

  • action limits

Affinity Affinity IEX IEX DS Bulk

End Product Testing < 10 ppm Process Validation > 500 000 ppm 5 – 10 000 ppm 1-200 ppm 5-8 ppm

< 1 0 ppm

IEX IEX

In Process Control < 10 000 ppm Action if > 10 000ppm

Control of HCP

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Process vs Clinical Experience

  • Experience vary between companies

What are the right specifications?

Process Process Clinical Experience Clinical Experience Example 2 Clinical experience is broader than Consistency batches

  • r

Consistency batches are broader than clinical experience Design space different Example 1 One company has a more consistent process than another company Process Process Design Space Design Space 18

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SLIDE 19

Acceptance limits

Batch # Registration

Internal limits for trending

Handling of QA:s - monitoring

  • 1. Consistency for Non-Critical QAs
  • Process performance – internal monitoring
  • 2. Clinical limits for Critical QAs
  • Within regulatory limits

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Summary

  • A strategy was presented for selection critical quality attributes

(CQA) and for selection of type of test to use for a specific attribute (IPC or end product testing)

  • Acceptance criteria for regulatory specifications should be based
  • n clinical experience and process capability
  • The process for performance should be monitored using internal

limits without regulatory commitment

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Acknowledgements

  • Mark Schenerman, MedImmune
  • Alistair Kippen, MedImmune
  • Ronald Imhoff, Janssen

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