05 Feely Change Management ISPE Oct 15 v4

8/16/2019 05 Feely Change Management ISPE Oct 15 v4

1/21

Change Management

Liam C. Feely, Ph.D.Vice President,Manufacturing Science & TechnologyAbbVie


2/21

Change Management| August 2015 | Company Confidential © 2015 2

Disclosures

The views and opinions expressed in the following PowerPoint

slides are those of the individual presenter and should not be

attributed to the organization with which the presenter is

employed or affiliated.

These PowerPoint slides are the intellectual property of the

individual presenter and are protected under the copyright laws of

the United States of America and other countries. Used by

permission. All rights reserved


3/21


Changes are extremely common in relation to the production andsupply of a pharmaceutical product over its lifecycle. Example changesinclude:

• Manufacturing process parameters and scale

• Analytical methods

• In-process controls

• Suppliers of Active Pharmaceutical Ingredients (APIs) regulatorystarting 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 andimportant part of any company’s Pharmaceutical Quality System

Context


4/21


Q10 on Change Management (1)

“3. Change Management System (3.2.3)

Innovation, continual improvement, the outputs of processperformance and product quality monitoring, and CAPA drive change.To evaluate, approve, and implement these changes properly, acompany should have an effective change management system. Thereis generally a difference in formality of change management processes

prior to the initial regulatory submission and after submission, wherechanges to the regulatory filing might be required under regionalrequirements.

The change management system ensures continual improvement isundertaken in a timely and effective manner. It should provide a highdegree of assurance there are no unintended consequences of thechange.


5/21



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

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

(b) Proposed changes should be evaluated relative to the marketingauthorization, including design space, where established, and/orcurrent product and process understanding. There should be anassessment to determine whether a change to the regulatory filingis 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 pharmaceuticalquality system standpoint, all changes should be evaluated by acompany’s change management system.


6/21



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

(c) Proposed changes should be evaluated by expert teamscontributing the appropriate expertise and knowledge fromrelevant areas (e.g., Pharmaceutical Development, Manufacturing,Quality, Regulatory Affairs, and Medical) to ensure the change is

technically justified. Prospective evaluation criteria for a proposedchange should be set.

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


7/21Change Management| August 2015 | Company Confidential © 2015 7

Change Management Process

Stimuli forchange

Impactassessments

Risk assessment &information/dataneed to support

the change

Confirmacceptability ofoutcome and

document

GainRegulatoryapproval

Implement and

conduct postimplementation

verification



Stimuli For Change (not exhaustive)

Commercial Manufacturing Experience

(Continual knowledge gain &improvement)

Trending of CQAData

Enhancement ofControl Strategy

Change ofShelf Life

Desire to utilizenew technologies

Eliminationof Suppliers

Desire to increasebatch size,

throughput, etc. forAssurance of Supply

InspectionObservations/

cGMPs

Desire to increasenumber of

manufacturing sitesor suppliers for

Assurance of Supply

Additionaldevelopment studiesor knowledge gainedfrom other products

PharmacopeialChanges



Clear definition of scope• Relevance to other sites?

• Relevance to other products?

Impact on other aspects of the manufacturing process or controlstrategy

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 withadditional controls to ensure no unintended consequences of change

Confirm acceptability of outcome and document

ExperimentalCriteria Achieved?

Do notimplement

change

YES

NO

Conduct experiments withadditional controls

Continue to implementchange

•

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 Dossierand submit to RegulatoryAuthorities

• Wait…

• Once Regulatory Approval

received, proceed toimplementation

Gain Regulatory Approval



• Formally approve commercialbatches and release to market

• Conduct any defined postvalidation monitoring

• Ongoing trending of batch to

batch CQA data to confirm noprocess 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 internalexperience:

Primary particle size a key variable

in wet granulation

Development experience:

Product dissolution sensitive toextent of granulation

Production Experience:

Dissolution not sensitive to normalvariation in lactose particle size

0

2

4

6

8

10

12

0.1 1.0 10.0 100.0 Particle size, um

V o l u m e

%

New Source

Original Source

Particle size distribution of newsource is outside of developmentand production experience

Potential product impactSource comparability



Risk Mitigation

Conduct small-scale study:

• Head-to-head process comparison at 2L scale showed no differencebetween original and new source

Verify:

• Extended dissolution testing (profiles) of full scale demonstration batchshowed F2 comparability

Implement source change under normal change controlprocedures:

•

Monitor routine production:• Trending of dissolution results reinforces no impact of change


17/21


Trend Monitoring: Apply Common Sense

3 1 0 0

8 8

3 1 0 0 8 3

3 1 0 0

7 6

3 1 0 0

6 7

3 1 0 0

6 2

3 1 0 0

5 7

3 1 0 0

2 1

3 1 0 0

1 6

3 1 0 0 1 1

R

D - 0 8

- 0 0 0

6

R

D - 0 7

- 0 0 1

0

110

105

100

95

90

Tab Batch Number

I n d i v i d u a l V a l u e

_ X=100.63

+3 Std Dev

Prior to Validation Validation and Launch Build1 2

Lower Limit

Upper Limit

1 2

-3 Std Dev

FLI -Assay

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


18/21


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 graduallyover 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


19/21


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 practicesimplementation?

How would these practices be assessed by regulators during aninspection?

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

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


20/21


Changes to the manufacture and supply of pharmaceutical products is

common over the product lifecycleChange Management is and integral part of a company’s PharmaceuticalQuality System

The scientific rigor used to confirm that a change will not adversely affectproduct 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 thesupply chain in relation to making changes in production

Trend monitoring is a valuable tool to ensure product manufacturing remainsin 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 purelywithin within a company’s PQS rather than additionally requiring regulatoryapproval prior to implementation

Concluding Remarks


21/21

05 Feely Change Management ISPE Oct 15 v4

Documents

Transcript of 05 Feely Change Management ISPE Oct 15 v4