FDA/PQRI Conference on Evolving Product Quality Topic: Life Cycle Management and Postapproval

Changes (Current Practice-Future Direction)

“Regulatory Commitments”

Daniel Y. Peng, Ph.D. Office of Pharmaceutical Sciences (OPS)

Center for Drug Evaluation and Research (CDER) Food and Drug Administration (FDA)

Opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or policies of the FDA

1 September 17, 2014

The Bacon & Eggs Story

Commitment vs. Involvement

2

Industry & FDA have a common goal & shared responsibility:

“Availability of high quality medicine to the patient”

Definition of “Regulatory Commitment”

FDA has not given a definition yet…

Has been used to define which CMC portions/ elements of an application are subject to reporting (PAS, CBE, AR) if changed after approval

PhRMA White Paper- Regulatory Commitments and Post-approval Change Management – “A regulatory commitment (RC) is a specific description of

how a company intends to manufacture and control the drug product that is defined in the dossier, and that is subject to a regulatory action if changed after approval ”

– The definition is a good starting point, but the devil is in the details… 3

4

Current CMC Post-Approval Change - Law, Regulations and FDA Guidances Landscape

Food, Drug and Cosmetic Act – Manufacturing Changes

FD&C Act § 506A – Manufacturing Changes – Requires validation of all manufacturing changes before

distribution of product made with change – “Major manufacturing change”: requires preapproval before

distribution of product • Some formulation changes • Most changes in specification • Changes requiring clinical data to demonstrate equivalence • Allows for other types of major changes to be established

– “Other manufacturing change” • Changes requiring supplemental application • Changes not requiring supplemental application

– Submission of report- shall be submitted by such date as the secretary specifies

– Annual Report: allowed if the applicant makes more than one manufacturing change during a single year

5

Regulations Related to Change Management All changes must be assessed under the Pharmaceutical Quality

System (PQS) (21 CFR 211.22, 211.100, 211.110, 211.160, 211.180).

The applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application… 21 CFR 314.70 (a)

Prior Approval Supplements (PAS) – 21 CFR 314.70 (b) Changes… that has a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product…

Changes Being Effected (CBE/CBE-30) – 21 CFR 314.70 (c) Changes…. that has a moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency...

Annual Report (AR) - 21 CFR 314.70 (d) Changes … that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency … must be documented by the applicant in the next annual report…

Change Protocol- 21 CFR 314.70 (e) … may submit one or more protocols describing the specific tests and studies and acceptance criteria to be achieved to demonstrate the lack of adverse effect …..

6

FDA Guidances Related to Change Management

SUPAC Guidances (1995-1998) – Provide both change categories and method of

evaluation of the effects of the change – Specific to dosage form type

Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products (7/1/1997)

Changes to an Approved NDA or ANDA (4/1/2004) – Gives example listing of many changes and related

reporting categories

CMC Postapproval Manufacturing Changes Reportable in Annual Reports (3/14/ 2014)

7

Current FDA Regulatory Approaches-Limitations

Risk management concepts are applied, but often assumed that all products within a drug product category have same risk

Often overly conservative, occasionally overly liberal (e.g., narrow therapeutic index drugs; 10X scale up)

Insufficient flexibility to recognize well understood risks to product quality or process

Lack of clarity regarding “Condition established” and need for reporting could: – lead to unnecessary submission of post-approval supplements to FDA

for changes that could be managed solely by an applicant’s PQS – discourage continual improvement in drug manufacturing processes – or lead to citations for changes that should have been reported to FDA,

upon inspection.

8

Why do we need “RC”? Allow for more effective post-approval change

management – Focus on high risk areas of the product and process

– Reduce /or eliminate regulatory focus on well justified or demonstrated low risk areas

Promote knowledge rich submission Promote innovation and continual improvement Strengthen quality assurance and reliable supply of

product Provide the FDA pathways to better regulate post-

approval changes with more flexibility and in a risk-based fashion 9

PhRMA’s Definition of “Regulatory Commitment”

“a specific description of how a company intends to manufacture and control the drug product that is defined in the dossier, and that is subject to a regulatory action if changed after approval ”

10

“A Specific Description”

How much detail is enough? – Product and process specific high risk areas and

failure modes

Where to draw the line between the supportive information and commitments? – Does it mean “the supportive information” is not

important?

– Does “the supportive information” still need to be submitted to support if any RC change?

11

“Manufacture” What are the expectations for “Description of

drug substance/ product manufacture process”?

What process parameters and ranges should be included?

Is the master batch record one of the RC elements?

Should all changes to a batch record be reported to FDA?

12

“Control”

How does RC relate to control strategy? – A planned set of controls, derived from current product and

process understanding, that assures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10)

How does change in control strategy impact “RC”?

13

“Defined in the dossier”

Which CTD sections typically contain “RC”? – M4Q: The CTD-Quality

• Module 2 Quality Overall Summary (S.1-S.7 and P.1-P.8)

• Module 3 Body of Data (S.1-S.7 and P.1-P.8)

• Appendices

• Regional information

• Literature References

How to avoid the unintended consequence: imbedded “RC” elements in certain sections unintentionally or intentionally?

14

“…intended…if changed”

When and how often to update “RC”?

How do you communicate “RC” changes?

What supporting information is needed for the “RC” changes?

What documentation is needed for the changes made within the internal PQS?

15

“Subject to a regulatory action”

16

The DeLorean Time Machine

Scientific Considerations for “RC” Change Management

Assess how the change could affect the process/product or effectiveness of Control Strategy

– product-specific failure modes

Assess the potential severity of the effects of the change

Design and execute an evaluation plan to assess the effects of the change on the product and process, considering the risks

Formal risk assessment can be highly valuable in

assessing potential effects of changes and designing an

evaluation plan 17

PQS Considerations for “RC” Paradigm Shift – “Culture of Quality” Manufacturers take full responsibility for quality of their

products

– All manufacturing changes must be evaluated under the applicant’s Pharmaceutical Quality System (PQS)

– Focus on meeting patients’ expectations

– Regulators’ expectations considered minimal approach

Strive for continual improvement

Management and organizational commitment to prioritizing quality

Each person in organization understands and embraces their role in quality 18

Regulatory Considerations for “RC” “RC” and risk categories are likely to be proposed by

the applicant and subject to regulatory assessment.

Science and risk-based approach desired for establishing “RC”

– Product and process understanding

– High risk parameters identified and controlled?

– Low risk parameters justified or demonstrated?

– Control strategy justified and supported ?

Where does it go? Format? Summary or Hyperlinks?

19

Potential Strategies to Reduce the Filing Category of “RC” Changes

Comparability protocol

Testing and/or sampling beyond standard release testing and/or compendial standards

Use modern technologies which significantly increase the detectability of failure modes (e.g. LC/MS for new drug substance supplier, PAT for adaptive process control, IVIVC for dissolution testing, …)

Demonstrate the process is in a state of statistical control and capable (for example Cpk lower 95% confidence bound >1)

….. 20

Additional Questions for Discussion

Would all new application include “RC”?

How could RC be applied to legacy product?

– Can the applicant without “RC” continue to utilize “traditional” approaches to reporting changes?

Can the applicant with an approved “RC” continue to utilize “traditional” approaches to reporting changes?

21

Closing Remarks

“Regulatory Commitment” is a great concept, even though official terminology/definition is not available yet

FDA scientists are discussing and working on it

Guidance on pharmaceutical product lifecycle management is under consideration in ICH

Stay tuned….

22

Acknowledgments CDER: Donald Beers, Ashley Boam, Sharmista Chatterjee, Tara Gooen, Bob Iser, Nam Kim, Steven Kozlowski, Emanuela Lacana, Bernetta Lane, Jennifer Maguire, Christine Moore, Dupeh Palmer, Peter Qiu; Mahesh Ramanadham, Audrey Thomas, Ayse Yeaton,

Susan Rosencrance, Lawrence Yu

CBER: John Bishop, John Eltermann, Mahmood Farshid; Marion Gruber, Christopher Joneckis, Michael Kennedy, Nancy Kirschbaum, Ingrid Markovic; Laurie Norwood, Steve Rubin, Keith Wonnacott

CVM: Marea Harmon, Laura Huffman

23