QS COE Update - PQRIpqri.org/wp-content/uploads/2015/09/05-Feely-Change...Implement source change under normal change control procedures: • Monitor routine production: ... Change

Change Management Liam C. Feely, Ph.D. Vice President, Manufacturing Science & Technology AbbVie

Change Management| August 2015 | Company Confidential © 2015 2

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Changes are extremely common in relation to the production and supply of a pharmaceutical product over its lifecycle. Example changes include: • Manufacturing process parameters and scale • Analytical methods • In-process controls • Suppliers of Active Pharmaceutical Ingredients (APIs) regulatory

starting materials, reagents, excipients and packaging materials • Specifications related to ingredients and packaging materials • Material and Product Shelf Life • Sites of intermediate, API & product manufacturing /packaging

Change Management, therefore, needs to be an integral and important part of any company’s Pharmaceutical Quality System

Context


Q10 on Change Management (1)

“3. Change Management System (3.2.3)

Innovation, continual improvement, the outputs of process performance and product quality monitoring, and CAPA drive change. To evaluate, approve, and implement these changes properly, a company should have an effective change management system. There is generally a difference in formality of change management processes prior to the initial regulatory submission and after submission, where changes to the regulatory filing might be required under regional requirements.

The change management system ensures continual improvement is undertaken in a timely and effective manner. It should provide a high degree of assurance there are no unintended consequences of the change.



The change management system should include the following, as appropriate for the stage of the lifecycle:

(a) Quality risk management should be utilized to evaluate proposed changes. The level of effort and formality of the evaluation should be commensurate with the level of risk.

(b) Proposed changes should be evaluated relative to the marketing authorization, including design space, where established, and/or current product and process understanding. There should be an assessment to determine whether a change to the regulatory filing is required under regional requirements. As stated in ICH Q8, working within the design space is not considered a change (from a regulatory filing perspective). However, from a pharmaceutical quality system standpoint, all changes should be evaluated by a company’s change management system.



The change management system should include the following, as appropriate for the stage of the lifecycle:

(c) Proposed changes should be evaluated by expert teams contributing the appropriate expertise and knowledge from relevant areas (e.g., Pharmaceutical Development, Manufacturing, Quality, Regulatory Affairs, and Medical) to ensure the change is technically justified. Prospective evaluation criteria for a proposed change should be set.

(d) After implementation, an evaluation of the change should be undertaken to confirm the change objectives were achieved and that there was no deleterious impact on product quality.”


Change Management Process

Stimuli for change

Impact assessments

Risk assessment & information/data need to support

the change

Confirm acceptability of outcome and

document

Gain Regulatory approval

Implement and conduct post

implementation verification


Stimuli For Change (not exhaustive)

Commercial Manufacturing Experience (Continual knowledge gain &

improvement)

Trending of CQA Data

Enhancement of Control Strategy

Change of Shelf Life

Desire to utilize new technologies

Elimination of Suppliers

Desire to increase batch size,

throughput, etc. for Assurance of Supply

Inspection Observations/

cGMPs

Desire to increase number of

manufacturing sites or suppliers for

Assurance of Supply

Additional development studies or knowledge gained from other products

Pharmacopeial Changes


Clear definition of scope • Relevance to other sites? • Relevance to other products?

Impact on other aspects of the manufacturing process or control strategy

Regulatory Impact • Within or beyond established conditions? • Relevant to an approved post approval change protocol?

Impact Assessment


Objective is to ensure no unintended consequences of implementing the change

Risk Identification, Analysis & Evaluation • Consider input from CMC Scientists, Manufacturing, QA,

Regulatory, Supply Chain, Medical Affairs, etc.

Identify additional experimentation/data needed (risk control/reduction)

• At what scale this should be conducted? • What existing knowledge informs the level of risk? • What outcomes would be considered acceptable?

Risk Assessment and data needed to support the change


If experimental criteria are not met, revert back to risk assessment and either do not implement change or conduct additional experimentation with additional controls to ensure no unintended consequences of change

Confirm acceptability of outcome and document

Experimental Criteria Achieved?

Do not implement

change

YES

NO

Conduct experiments with additional controls

Continue to implement change

• Update Risk Assessment

• Update Manufacturing documents and Control Strategy as needed.

• Update any mathematical model as needed

• Complete re-validation (PPQ) as appropriate


• Update Regulatory Dossier and submit to Regulatory Authorities

• Wait…

• Once Regulatory Approval received, proceed to implementation

Gain Regulatory Approval


• Formally approve commercial batches and release to market

• Conduct any defined post validation monitoring

• Ongoing trending of batch to batch CQA data to confirm no process drift

Implement and conduct post implementation verification


Example: Adding a new supplier for an excipient

Additional source of supply of lactose • Standard high-shear

wet-granulation process • Conventional lactose/

microcrystalline cellulose formulation


Risk Assessment

Literature and internal experience: Primary particle size a key variable in wet granulation

Development experience: Product dissolution sensitive to extent of granulation

Production Experience: Dissolution not sensitive to normal variation in lactose particle size

0

2

4

6

8

10

12

0.1 1.0 10.0 100.0 Particle size, um

Volu

me

%

New Source Original Source

Particle size distribution of new source is outside of development and production experience

Potential product impact Source comparability


Risk Mitigation

Conduct small-scale study: • Head-to-head process comparison at 2L scale showed no difference

between original and new source

Verify: • Extended dissolution testing (profiles) of full scale demonstration batch

showed F2 comparability

Implement source change under normal change control procedures: • Monitor routine production:

• Trending of dissolution results reinforces no impact of change


Trend Monitoring: Apply Common Sense

3100

88

3100

83

3100

76

3100

67

3100

62

3100

57

3100

21

3100

16

3100

11

RD-0

8-000

6

RD-0

7-001

0

110

105

100

95

90

Tab Batch Number

Indi

vidu

al V

alue

_X=100.63+3 Std Dev

Prior to Validation Validation and Launch Build1 2

Lower Limit

Upper Limit1 2

-3 Std Dev

FLI -Assay

Not all statistical variations require action and adjustment: Resources should focus on patient impact


Changes relevant to Suppliers and Third Parties • Additional oversight provided through:

• Quality/Technical Agreements • Trending of data from Certificates of Analysis • Audits

Control of supply chain when approvals come through gradually over a number of years

• Don’t implement until final approval received or • Implement as approvals come in and make some of version A and

some of version B • Issue becomes even more complicated if a second change is

needed before all approvals received for first change

Additional Complications


Questions to Consider

Is there a need to standardize best practices? – Understand stimuli for change? – Understand scope of change and its implications for other

aspects of the process/control strategy? – Perform a science and risk-based assessment of the change?

What would need to be articulated in Q12 to encourage best practices implementation?

How would these practices be assessed by regulators during an inspection?

How would changes involving third parties, with different quality systems, be handled?

Are there specific types of changes that shouldn’t be done under a ‘Do and Tell’ and how might ICH Q12 address this?


Changes to the manufacture and supply of pharmaceutical products is common over the product lifecycle

Change Management is and integral part of a company’s Pharmaceutical Quality System

The scientific rigor used to confirm that a change will not adversely affect product performance is risk based and should be exclusive of whether a prior regulatory authority approval is needed or not

The variability in timing of regulatory approvals worldwide complicate the supply chain in relation to making changes in production

Trend monitoring is a valuable tool to ensure product manufacturing remains in control and also to confirm implemented changes have no adverse effect on overall product safety and efficacy

The opportunity for ICH Q12 is to enable more changes to be handled purely within within a company’s PQS rather than additionally requiring regulatory approval prior to implementation

Concluding Remarks

QS COE Update - PQRIpqri.org/wp-content/uploads/2015/09/05-Feely-Change...Implement source change under normal change control procedures: • Monitor routine production: ... Change

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