Quality (or CMC) Enablers for Efficient/Effective Drug Product Lifecycle … · 2016-11-16 ·...

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Quality (or CMC) Enablers for Efficient/Effective Drug Product Lifecycle Management – FDA’s Perspective Susan Rosencrance, Ph.D. Director, Office of Lifecycle Drug Products Office of Pharmaceutical Quality/CDER/FDA November 16, 2016 Symposium Session – AAPS 2016

Transcript of Quality (or CMC) Enablers for Efficient/Effective Drug Product Lifecycle … · 2016-11-16 ·...

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Quality (or CMC) Enablers for Efficient/Effective Drug Product Lifecycle Management –

FDA’s Perspective

Susan Rosencrance, Ph.D.Director, Office of Lifecycle Drug ProductsOffice of Pharmaceutical Quality/CDER/FDA

November 16, 2016

Symposium Session – AAPS 2016

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Drug Product Lifecycle Management –

OPQ’s Role

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OPQ – Focused on Drug Product Quality

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Strategically organized to streamline regulatory processes and focus on

product quality

Integrates functional areas for more informed

decision making

Emphasizes a lifecycle approach to drug

quality using knowledge management

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OPQ

Office of Testing and ResearchDirector:Lucinda Buhse

Office of SurveillanceActing Director:Sarah Pope Miksinski

Office of Process and Facilities Director:Robert Iser

Office of Program and Regulatory OperationsDirector: Giuseppe Randazzo

Office of Lifecycle Drug ProductsDirector:Susan Rosencrance

Immediate OfficeDirector: Michael KopchaDeputy Director: Lawrence Yu

Office of Policy for Pharmaceutical QualityDirector:Ashley Boam

Office of New Drug ProductsDirector:Sarah Pope Miksinski

Office of Biotech ProductsDirector:Steven Kozlowski

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OPQ’s Lifecycle Management Approach

• The Office of Lifecycle Drug Products (OLDP) generally leads the quality assessment of post-approval changes for generic and brand products and serves as the centralized home office*; inter-office collaborations occur where appropriate

• The Office of Process and Facilities (OPF) plays a key role in evaluating the need for inspection of manufacturing sites and makes the final site recommendation; performs a quality assessment of microbiological aspects; provides a quality assessment when complex manufacturing technologies/processes are involved.

* After the NDA transitions from the Office of New Drug Products (ONDP).

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• Centralizing the long-term lifecycle management function within a single OPQ sub-office has a number of benefits:

– Provides a uniform, consistent approach to post-approval changes (ANDA success story); promotes parity in the regulatory oversight of brand and generic drug products

– Provides a home-office that makes it easily manageable for all stakeholders (note: transition period for NDA supplements)

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Why OLDP?

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– OPQ’s major stakeholders (e.g., Office of New Drugs, Office of Generic Drugs, Industry) know who to contact when questions arise

– Agency receives approximately 5,000 supplements annually; need a system that can handle high-throughput efficiently; a centralized home office provides the right environment

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Why OLDP (cont.)?

Reference: Susan M. Rosencrance and Geoffrey K. Wu, Advancing pharmaceutical quality oversight during the lifecycle of generic drug products, Journal of Generic Medicines, Oct. 2015

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CMC Enablers or Tools for

Drug Product Lifecycle Management

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CMC Enablers or Tools for Drug Product Lifecycle Management

www.fda.gov

The Post-Marketing Phase

Supplements

I. Comparability Protocols

II. Post-Marketing Commitments/Requirements

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I. Comparability Protocols

www.fda.gov

• The regulations provide for protocols as an optional way to manage post-approval changes [21CFR 314.70(e) and 21 CFR 601.12(e)].

• A comparability protocol can be used to implement a CMC post-approval change.

A Comparability Protocol is a comprehensive, prospectively written plan for assessing the effect of a proposed CMC post-approval change(s) on the identity, strength, quality, purity, and potency of a drug product or a biological product (i.e., product), as these factors may relate to the safety or effectiveness of the product (i.e., product quality). = Agency definition in draft guidance published April 2016

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I. Comparability Protocols – Basic Facts

www.fda.gov

• Comparability Protocols can be submitted in original applications (NDAs, ANDAs, BLAs) and in supplements to these applications.

• Comparability Protocols allow the Agency to review and assess the:1. Description of one of more proposed post-approval

changes;

2. Supporting information including any analyses and risk assessment activities;

3. Plan for implementing the change; and

4. Proposed reduced reporting category for the change, if appropriate.

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I. Comparability Protocols – Basic Facts

www.fda.gov

• Agency approval of the submission containing the comparability protocol provides the applicant with an agreed-upon plan to implement the change.

• Comparability protocols facilitate post-approval changes and drug product lifecycle management because they enable a proactive approach to change implementation and product distribution, and promote continuous improvement.

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I. Comparability Protocols

www.fda.gov

Comparability Protocols -Chemistry, Manufacturing, and Controls

Information

Guidance for Industry

DRAFT GUIDANCE

U.S. Department of Health and Human ServicesFood and Drug Administration

Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

February 2003

Comparability Protocolsfor Human Drugs and

Biologics:Chemistry, Manufacturing, and Controls

Information

Guidance for Industry

DRAFT GUIDANCE

U.S. Department of Health and Human ServicesFood and Drug Administration

Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER)

April 2016

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I. The NDA Experience with Comparability Protocols

www.fda.gov

• The Agency has significant experience with comparability protocols in NDAs (original submissions and supplements)

• Survey of comparability protocols associated with NDAs since 2007

– Results show 106 comparability protocols submitted in 55 NDAs; all approved.

7672%

3028%

How submitted?

In an original NDA

As a PAS

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I. Comparability Protocols – NDA Experience

www.fda.gov

2443%

1018%

814%

611%

24%

12%

12%

12%

12%

12%

Dosage Form Distribution

IR Tablets/Capsules/ODT

Injections; Solutions/Powder

Inhalation; Powder/Solution

DR/ER Tablets/Capsules

Topical Cream/Ointment/Gel/Lotion

Ophthalmic

Oral Liquid

Oral Suspension

Suspension

Transdermal

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I. Comparability Protocols – NDA Experience

www.fda.gov

5350%

3230%

109%

66%

33%

22%

Manufacturing Site

Manufacturing Process

Container/Closure

Components/Composition

Specifications

Miscellaneous

Change Type Distribution

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I. Comparability Protocols – NDA Experience

www.fda.gov

Reporting Category Distributionwithout CP

LegendNA: CP contains comparability report or changes beyond CP scopeNot Specified: Proposed multi reporting categories or subject to regulation changes

Reduced Reporting Category Distribution with CP

6965%

1312%

55%

44%

1312%

22%

PAS

CBE 30

CBE 0

AR

Not Specified

NA

65%

5451%

1615%

2322%

66%

11%

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Case Study Example

• NDA x– Solid Oral Tablet

• S-x (PAS) – A comparability protocol for managing post-approval design space changes.

• Synopsis of Comparability Protocol: – Provided for specific design space changes resulting from equipment

changes or modifications.

– Used for changes to multiple design spaces at one time as long as the design spaces did not interact

– If any proposed change resulted in a change to a CQA (critical quality attribute) acceptance criteria, the proposed change was out of protocol scope.

– Defined the experiments, testing, acceptance criteria, and regulatory reporting strategy based on the specific proposed change

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Case Study Example (cont.)

• Synopsis of Comparability Protocol (cont.): – Defined the data to be included for the post-approval change

• Experimental Design and Results (e.g., conditions, in-process control results)

• Additional testing results from increased sampling plan

• Product CQA testing results for impacted CQAs

• Revised design space limits

• Changes to parameter criticality (if applicable)

• Stability results/Stability commitment

– Regulatory Filing Strategy:

• Design Space change for Critical Process Parameter (CPP) – CBE-30

• Design Space change for non-Critical Process Parameter – CBE-0

• Site addition as part of a change to the Design Space (with inspection history) – CBE-0

• S-x (PAS) - Approved August 2016

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I. The ANDA Experience with Comparability Protocols

www.fda.gov

• Limited experience with comparability protocols in ANDAs; just getting started with the issuance of the April 2016 draft guidance.

• Survey results show:

– 122 comparability protocols submitted in 44 ANDAs

– 2 comparability protocols submitted in 2 supplements

• All submitted comparability protocols are under evaluation and none have been approved yet.

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I. Comparability Protocols – ANDA Experience

www.fda.gov

23, 52%

6, 14%

5, 11%

3, 7%

2, 5%

2, 5%

1, 2% 1, 2% 1, 2% Dosage Form Distribution

IR Tablets/Capsules/ODT

ER/DR Tablets/Capsule

Injections ( solutions/powder)

Oral liquid

Inhalation

Sublingual Film

Transdermal

Ophthalmic

Vaginal Ring

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I. Comparability Protocols – ANDA Experience

www.fda.gov

27, 22%

11, 9%

20, 16%

19, 16%

17, 14%

17, 14%

6, 5%3, 2% 2, 2% Change Type Distribution

Container/Closure System (CCS)

CCS and Packaging site

Drug Substance Source

Manufacturing Site (drug product)

Manufacturing Site (drug substance)

Testing Facility

In-Process Test Removal

Manufacturing Process

Components and Composition

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I. Comparability Protocols – ANDA Experience

www.fda.gov

Reporting Category Distributionwithout CP

Reduced Reporting Category Distribution with CP

43, 35%

64, 52%

14, 12%

1, 1%

PAS

CBE 30

CBE 0

AR

0, 0%

34, 28%

24, 20%

64, 52%

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I. Comparability Protocols

www.fda.gov

Points to Consider when submitting a comparability protocol:

1. Firms are expected to employ:

– Effective use of knowledge and understanding of the product and manufacturing process

– A robust control strategy

– Risk management activities over a drug product’s lifecycle

– An effective pharmaceutical quality system

2. Protocols should contain application/product specific information(e.g., specifications, specific routine and non-routine tests) to demonstrate equivalency before and after the proposed change(s).

3. Typically one level downgrade for the reporting category is permitted.

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I. Comparability Protocols

www.fda.gov

4. Adding a new drug substance source (i.e., new DMF to the application) is inappropriate for comparability protocols.

5. Changes requiring new clinical or bioequivalence studies/data are inappropriate for comparability protocols.

6. Draft Guidance for Industry Comparability Protocols for Human Drugs and Biologics: CMC Information (April 2016) provides our current thinking.

Points to Consider when submitting a comparability protocol (cont.):

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NDAs ANDAs

Regardless of application type (NDA or ANDA), the science and associated risks are the same.

Same/similar rules apply (e.g., regulations, policies, guidance, guidelines, etc.)

Same documentation and supporting information should be provided,commensurate with the product complexity and associated risks.

Long historical practice; protocols have been submitted and reviewed since 2003

Little historical practice as applicants often asked to withdraw protocol; just

starting to review protocols

Generally the protocols contain good supporting information and are specific

Typically too general; lack of information to demonstrate product and process

understanding; lack of risk assessment

I. Comparability Protocols – NDAs vs ANDAs

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CMC Enablers or Tools for Drug Product Lifecycle Management

www.fda.gov

The Post-Marketing Phase

Supplements

I. Comparability Protocols

II. Post-Marketing Commitments/Requirements

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II. Post-Marketing Commitments/Requirements

www.fda.gov

• Under the regulations post-marketing requirements (PMRs) and post-marketing commitments (PMCs) refer to studies and clinical trials conducted after approval.

• They are agreed upon between the applicant and the Agency and are intended to further refine the safety, efficacy, or optimize use of the drug to ensure consistency and reliability of product quality.

• The regulations only apply to NDAs/BLAs, and not ANDAs

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II. PMCs vs PMRs – The Difference

PMCs

• Studies or clinical trials a sponsor has committedto conduct, but that are not required by a statute or regulation

PMRs

• Required studies and clinical trials under one or more statutes or regulations

www.fda.gov

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II. When a PMR is Involved

www.fda.gov

• The review issue, safety risk, and goal of the study/clinical trial is documented.

• A timetable for completion is established.

• There are periodic reports on the status of the study/clinical trial

• The PMR may occur at the time of approval or after approval if the Agency becomes aware of new safety information.

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Case Study Example

• PMR for Drug Product x

• Reason for PMR:

– The issue of foreign contamination was not permanently resolved at the time of BLA approval.

– A test/acceptance criteria for particulates was implemented to mitigate the risk for contamination of commercial batches, but alleviation via a specification was not considered a complete solution (i.e., no foreign contamination should be present).

– The applicant was required to perform a complete evaluation of foreign matter contamination for the intermediate and drug substance to prevent use in drug product manufacturing if contamination was present.

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Case Study Example (cont.)

• To fulfill the PMR the applicant submitted quarterly reports as required and provided a final summary with all required information on April 30, 2015

• On June 1, 2016 the Agency sent a PMR fulfillment letter to the applicant.

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The Importance of

Drug Product Lifecycle Management

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The Importance of Drug Product Lifecycle Management

• OPQ brings new opportunities through its emphasis on a lifecycle approach to drug product quality.

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The Importance of Drug Product Lifecycle Management

• The new paradigm in OPQ allows for:

– Clearer identification of product risks for more informed decision making

– Quickly addressing quality problems

– Overall efficiency improvements

– Greater parity in the regulatory oversight and quality assessment of brand and generic drugs

– Reduced regulatory oversight and increased operational flexibility in the commercial manufacturing phase

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Patients

Regulators

Industry

Good lifecycle management in the post-marketing phase results in a continuous

supply of quality drug products

Everyone Benefits!

The Importance of Drug Product Lifecycle Management

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Acknowledgments

• Geoffrey Wu

• Hasmukh Patel

• Hardikkumar Patel*

• Akshata Nevrekar*

• Xue Li*

* ORISE (Post-doctoral) Fellows

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