Performance Based Regulation Industry Perspective ...

PERFORMANCE BASED QUALITY ASSESSMENT

Performance Based Regulation – Industry

Perspective & Proposal to Improve

Regulatory Assessments

FDA/PQRI Conference on Evolving Product Quality

17 Sep 2014

Bethesda, MD

roger nosal

Vice President & Head Pfizer Global Chemistry, Manufacturing & Controls

Groton, CT

Life Cycle Management & Post-Approval

Changes

(Current Practice – Future Direction)

Regulatory bodies across the world are placing unprecedented

emphasis on performance of the industry and life-cycle management

of drug products, especially in the post-approval phase. This session

will focus on these two interrelated aspects. Discussions will be

centered around the following topics:

1) How to better manage post-approval CMC changes following risk-

and science-based approaches;

2) How to integrate production data (e.g., batch data) into the

current regulatory framework (e.g., annual reports); and

3) How to assure product quality and prevent drug shortages utilizing

performance-based regulation.

1

IMPACT ON

LIFECYCLE

Risk-based Regulatory Review Topics

• Risk-based reviews

– Risk review criteria

– Risk assessments - tools to audit & validate risk assessments

– Benefit/risk, residual risk and risk mitigation

• Breakthrough Therapy products

• Regulatory Commitments

• Control Strategy

• QOS as the primary review document

• Effective communication throughout development & during

NDA review

• Clinically relevant specifications

• Risk-based Dissolution Strategy

LDKIT

2

Performance-based Expectations Through a

Product’s Lifecycle

• Confidence in Quality

– Depends on a robust Comprehensive Control Strategy

• Appropriately justified Regulatory Commitments

• Technically relevant post-approval changes

• Robust PQS - & Management

– Consistently demonstrated through a product’s lifecycle

• Performance Criteria

– Consistent demonstration of quality assurance

• How to convey product quality

• How to transparently share manufacturing experience & history

• Risk-based Regulatory Review

– Regulatory relevance

– Appropriate balance of benefit/risk 3

Regulatory

Commitments

Pharmaceutical

Quality System

Management Management

CTD Confidence

in Quality =

Lifecycle

4

Improving Confidence in Quality Means

Focusing on Control - Robust Control is

Predicated on Understanding Risk

5

Control

5

• A “control” is not achieved by an analytical

method

– A specification & accompanying analytical methods

demonstrate & confirm “control”

– Control of a Critical Process Parameter (&/or Critical

Material Attribute) is achieved by an understanding of

the relationship between input & output variables in a

manufacturing process:

• Material attributes

• In-Process Controls

• Process conditions, operating parameters, 1st principles, etc.

• Every CPP represents a Regulatory Commitment

“More Carrots/Less Stick”*

Aviation Safety Action Program ASAP encourages air carrier and repair station employees to voluntarily

report safety information that may be critical to identifying potential

precursors to accidents. Under ASAP, safety issues are resolved through

corrective action rather than through punishment or discipline. An ASAP is

based on a safety partnership that includes the FAA and the certificate

holder, and usually includes a third party, such as the employee's labor

organization. Today, 98 operators have 231 programs covering pilots,

mechanics, flight attendants, and dispatchers.

*Conversations with Mary Oates, June 2014 6

Provide incentives for industry transparency rather

than punitive admonishments

Example: Comprehensive QOS

• A summary of Module 3

– Includes hyperlinks to data and information in Module 3

• Provides a comprehensive control strategy for the

drug product based on the Target Product Profile,

– Identify risks to product quality, i.e., Drug Product CQA &

mitigation of those risks through clear justification of controls.

– Contains all Regulatory Commitments

– Summarizes results from risk assessments & experiments

w/hyperlinks to detailed data in Module 3 &/or

referenced to raw data residing in a firm’s PQS

– A summary of development of the product formulation,

API & DP manufacturing processes, product & process

understanding & data to substantiate the control

strategy (regulatory commitments) for the product.

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Example: Comprehensive QOS

• Tells a compelling story that conveys confidence

in quality.

• Satisfy criteria/questions described in FDA’s

Question based Review (QbR) approach.

• Could serve as the preliminary review document,

i.e., PMDA uses the QOS as their primary review

document with provisions for hyperlinks to Module

3 & X-reference to PQS information & systems

8

Example: Product Characteristics –

Target Product Profile

CRITERIA PRODUCT CHARACTERISTICS TARGET ATTRIBUTE

Therapeutic Indication Chronic Hypertension Immediate release

Patient Population Adult & Geriatric Easy to swallow

Markets Global Meet global regulatory

requirements

Route of Administration Oral BID Opportunity for lifecycle OD or

ER formulation

Treatment Duration Chronic

Dosage Form(s) 10, 20 & 50-mg Tablets Small & easy to differentiate

Co-Administration Fasted Taste tolerability

Pharmacokinetics Class BCS 2 (Low Solubility/High Permeability) IVIVR Considerations

Package Configurations • Opaque PE Bottles

• Opaque ACLAR/Foil Blisters

Easy to open

Storage • Ambient Conditions

• Protect from Light Protective packaging

Handling Keep unused tablets in closed container

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Example: Quality Target Product Profile

QTTP ATTRIBUTE DRUG PRODUCT CQA CONTROL

Purity Impurity/Degradation Control CQA2

Contamination Control PQS

Quality

DP Dissolution CQA1

DP Physical Characteristics CQA3

Patient Compliance - Taste CQA4

Identity Confirmation CQA6

Potency Content Uniformity CQA5

API Assay CQA7

10

12

11

12

QTPP ATTRIBUTE DRUG PRODUCT

CQA FUNCTIONAL RELATIONSHIPS CONTROLS

Purity

Impurity

Degradation

Control

= f (CPP1 CPP2 CPP3)

CPP1 = f (CPP23 CPP24)

CPP3 = f (CPP11 CPP17)

CPP1 DP Release & Stability Specification Limit

CPP23 (CMA) Opaque ACLAR Specification Criteria

CPP24 Package Sealing Temperature

CPP2 (CMA) API Chromatography & Specification Limit

CPP3 (CMA) API Specification Limit

CPP11 Step 2 Temperature IPC Limit

CPP17 Step 2 Addition Rate

Contamination N/A PQS Adherence to cGMP

Quality

(Biorelevance)

DP Dissolution

= f (CPP4 CPP6)

CPP4 = f (CPP18)

CPP4 Disintegration Specification Limit

CPP18 (CMA) Disintegrant Particle Size distribution Limits

DP Physical

Characteristics

= f (CPP5 CPP6)

CPP5 = f (CPP7)

CPP6 = f (CPP23)

CPP7 = f (CPP13 CPP14 CPP19)

CPP6 (CMA) API Particle Size Distribution Limits

CPP23 API Crystallization Solvent Proportions

CPP5 DP Dissolution Specification Criteria

CPP7 IPC Drug Product Particle Size Distribution

CPP13 Lubricant Quantity

CPP14 Tablet Compression Force

CPP19 Blend Time

Patient

Compliance-Taste

= f (CPP10)

CPP10= f (CPP20)

CPP10 Flavor/Sweetener Quantity

CPP20 (CMA) Flavor/Sweetener Specification Criteria

Identity Confirmation = f (CPP8) CPP8 API ID Specification Criteria, cGMP

Potency

Content

Uniformity

= f (CPP9)

CPP9 = f (CPP12 CPP15 CPP16)

CPP9 DP Stratified Sampling Criteria

CPP12 Blend Time

CPP15 Agitator Speed

CPP16 Component Feed Rate

API Assay = f (CPP21)

CPP21= f (CPP22)

CPP21 (CMA) API Specification Limits

CPP22 API Mother Liquor Impurity Levels IPC 13

Key Messages

• Industry & FDA agree that conveying enhanced QbD

approaches in regulatory applications can be improved

– FDA wants industry to improve confidence in product quality

– Industry wants FDA to adopt risk-based regulatory review approaches.

• Effectively conveying enhanced process understanding &

product knowledge in a regulatory application has been a

challenge for both FDA and industry

– FDA concerns:

• Lack of transparency in risk assessments,

• Absence of a coherent & complete description of a product control strategy,

• Understanding lifecycle Management.

– Industry concerns:

• Inconsistency in regulatory assessments,

• Lack of integration between inspections & assessments,

• Absence of incentives for flexible regulatory approaches for post-approval

changes.

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Key Messages

• Improving the quality of the regulatory application to

effectively convey a comprehensive control strategy

will benefit both FDA & industry.

• The structure of Module 3 in the ICH CTD is not

amenable to effectively conveying the narrative of a

comprehensive & integrated control strategy.

• Alternative use of the QOS in Module 2 provides an

opportunity to improve the ability to convey an

enhanced process understanding & product knowledge

in a regulatory application with hyperlinks to detailed

information in Module 3.

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Proposed Content of a Comprehensive

Quality Overall Summary

# CQOS SECTION DESCRIPTION OF CONTENTS

LINK TO CTD

MODULE 3.2

LINK TO QBR

(Q#)

S P A/R DS DP

1. TPP Description of Product Attributes

2. QTPP Description of Quality Attributes & Control Limits S.1 P.2.2

3. Summary of

Comprehensive

Control Strategy

• Regulatory Commitments

• Reference to PQS Change Management

S.2.1

S.2.2

S.2.3

S.2.4

S.4.1

S.4.2

S.6

S.7.2

P.3.1

P.3.2

P.3.3

P.3.4

P.4.1

P.4.2

P.5.1

P.5.2

P.7

P.8.2

A.2 3, 4,

5, 6,

7, 8,

9, 10,

11,16,

17,19,

21, 24

1, 5, 8,

17, 18,

22, 23,

24, 25,

28, 29,

30, 33,

35, 36,

37, 38

4. Pharmaceutical

Development

• Justification for Control Strategy

• Summary of Product Design & Development History

• Summary of Risk Assessment Approach & Results

• Summary of Results from Experiments

• Summary Justification for Product & Process Design

• Summary Justification for Analytics

• Summary of Batch Analyses

S.2.5

S.2.6

S.3

S.4.3

S.4.4

S.4.5

S.5

S.7.1

S.7.3

P.1

P.2

P.3.5

P.4.3

P.4.4

P.4.5

P.4.6

P.5.3

P.5.4

P.5.5

P.5.6

P.6

P.8.1

P.8.3

A.1

A.3

1, 2,

7, 12,

13,14,

15,16,

17,18,

20,22,

23

2, 3, 4,

6, 7, 9,

10, 11,

12, 13,

14, 15,

16, 19,

20, 21,

26, 27,

30, 31,

32, 34,

36, 37

5. Post-Approval Change

Management Plan

Description of Regulatory Obligations for Post-

Approval Changes

R

16

Key Messages

• Product Control Strategy = Regulatory Commitments

– Defines a fundamental construct to demonstrate and convey

assurance of quality.

– Provides a scaffold for substantiating how a science- and risk-

based approach delivers appropriate product quality.

– Establishes a standard for subsequent post-approval change

management.

– Simplifies post-approval change notification/prior approval

criteria.

– Aligns a regulatory application with a company’s PQS (change

management system) to assure appropriate quality through the

product’s lifecycle.

– Aligns with FDA QbR tool to simplify regulatory assessment.

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Ultimate Objective

18

Improve the regulatory

process by ensuring

confidence in quality

through a product’s

lifecycle without

increasing regulatory

burden.

Let’s not constrain ourselves!

LDKIT

Dan Bollinger Takeda John Lepore Merck

Xavier Castell Takeda Rick Lit Amgen

Andrew Chang Novonordisk Steve Mason Amgen

Graham Cook Pfizer Moheb Nasr GSK

Frank Diana endo Roger Nosal Pfizer

Jeff Ferguson Lilly Mark Rosolowsky BMS

Georges France Novartis Tom Schultz J & J

Betsy Fritschel J & J Steve Tyler abbvie

John Groskoph Pfizer Jim Webb BI

Nirdosh Jagota Roche-Genentech Diane Zezza Novartis

Bob Kelly Bayer

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