Dr. Jean-Louis ROBERTChair CHMP/CVMP QWP

Luxembourg

Evolution règlementaire de l’approche qualité

opportunité et challenge

Plan de gestion du cycle de vie d’un

médicament (ICH Q12)

Aperçu

• Cycle de vie d’un médicament et changement

post-autorisation (variation)

– Acquis, situation actuelle

– Comment améliorer le futur?

2

Medicines and Regulation

• Highly regulated area

• Lifecycle of a medicine

– Development incl. technological transfer

– Application for a marketing authorisation

– Commercialisation

• Knowledge gain on process and product

• Continuous improvement

• Post approval changes

– Discontinuation

3

Pharmaceutical Quality: New Paradigm

• Described in ICH Q8, 9, 10 and 11

• Depending on the level of development (scientificunderstanding) achieved and an adapted quality systemin place, opportunities exist to develop more flexibleregulatory approaches, for example, to facilitate

• Risk-based regulatory decisions (reviews andinspections);

• Manufacturing process improvements, within theapproved design space described in the dossier,without further regulatory review

• Reduction of post-approval submissions;• Real-time release testing, leading to a reduction of

end-product release testing

4

Change Management

• Definition “Change Management” (ICH Q10)A systematic approach to proposing, evaluating,approving, implementing and reviewing changes

• Types– GMP related (well implemented in manufacturing

site)– Assessment related or regulatory changes

• Variation Regulation• Post Approval Change Management Protocol

(PACMP)• Verification Protocol (e.g. for design space not fully

established at commercial scale) mix possibilities

5

Regulatory Change Management

Situation in EU

• Mainly based on EU Variation Regulation

• The revised variation guideline is based on risk

• Q8, 9, 10 and 11 concepts have been taken into

account

• It should also provide a flexible and risk based

system for managing changes post approval

6

Reminder - Types of Changes/Variations

Changes not requiring

any prior approval

Changes requiring

prior approval

Do and tell

Variations

Immediate

notification

Annual

report

Evaluation Procedure adapted to the level of risk

Type IA Type IB Type II Extensionwithin a Design space

7

8

Reminder - Guideline Content – General principles

• Changes are classified as:

– Type IA variations (IA and IAIN) with conditions and documentation

requirements

– Type II (specific scopes, No conditions or documentation requirements)

– Examples of Type IB with documentation requirements

Post Approval Change Management

Protocol (PACMP)

• A PACMP describes specific changes (upfront) that the MAH would like to implement during the lifecycle of the product and how these would be prepared and verified

• This procedure (or tool) allows a faster and more predictable implementation of the change.

Concept introduced in EU through The Variations Classification Guideline that supports Variations Regulation EC (1234/2008)Further guidance Q&A

• Not to confuse with GMP change management!

9

+

Strategy

• Planned

studies

• Acceptance

criteria

• Methods

Results +

Strategy

• Planned

studies

• Acceptance

criteria

• Methods

Results

Traditional

Evaluation of a proposed

variation as a ‘whole’

(Strategy + Results)

Early Step 1:

Submission of aChange

Management Protocol

Fast Step 2:

Reporting of implementation of a change in accordance

with an approved protocol

Principle of PACMP

Type II Variation

Type IA or IB Variation10

Content of a PACMP: Amount of data

• Such a protocol would include for instance

– Justification for the need of a specific change

– A detailed description of the proposed change

– Risk assessment of the impact of the change on product quality.

– Adequacy of the approved control strategy to identify and manage these risks

– Description of additional controls which might be needed

– Description of the studies to be carried out and the acceptance criteria based on which the effect of the proposed change will be evaluated

– Commitment to update the approved protocol if needed

– Justification for submission of multiple changes

11

PACMP

• Advantage: Downgrade of type of variations:– Type II Type 1B– Type IB Type 1A

• Examples:– Change of API SM suppliers– Change of manufacturing site (biologicals)

• Experience so far: – Not very much used by Industry (bio more than chem)– Too product specific

• Full benefit achieved?

12

New Paradigm: next step

• LifeCycle Management (LCM): ICH Q12

Will solve all our problems?

• ICH guidelines on LCM

– Q10: Pharmaceutical Quality System

– Q11: Development/Manufacturing APIs

– Q3D: Residual elements

– M7: Genotoxic impurities

13

Scope Life Cycle Management (ICH Q12)

• “….to facilitate the management of post approvalchanges in CMC in a more predictable and efficientmanner across the product lifecycle”

• Optimization of resources for assessment and inspection

• Confidence and trust in the firm’s pharmaceutical qualitysystem (PQS)

• Scientific basis: Q8, Q9, Q10 and Q11

Address mainly early stages of product lifecycle(development)

• LM will focus on commercial phase

• Ultimate goal: better use of:

From “Tell and Do” to “Do and Tell”

14

LCM: Identified Key Elements

• Regulatory dossier/commitment

• Knowledge management

– How to share with Regulators

• Change management and Quality System

• Tools for LCM:

– Post Approval Change Management Protocols

– Comparability protocol

– Others………….?

15

Knowledge Management (KM): Key issue

• Implementation of changes to rely on company’s

product/process understanding

• How to manage KM (general sharing, communicating…)

• Knowledge

– At time of submission

– During commercialisation

• How to transfer KM

– Industry Regulators

– Regulators Industry?

• Inspectable?

16

Conclusion

Q12 discussion at a very early step

• How to keep track of the regulatory dossier?

• Information on site and/or in the dossier?

• Need for change in legislation?

• Eligibility for Q12:

– PQS

– How to manage knowledge

– Control strategy in place

– ………….

17