performance based regulation industry perspective
TRANSCRIPT
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.
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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
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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
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Improving Confidence in Quality Means
Focusing on Control - Robust Control is
Predicated on Understanding Risk
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Control
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• 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
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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
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12
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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
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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
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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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