Performance Based Regulation Industry Perspective & Proposal to Improve Regulatory Assessments

Transcription

1 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

2 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 riskand 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

3 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 IMPACT ON LIFECYCLE Effective communication throughout development & during NDA review Clinically relevant specifications Risk-based Dissolution Strategy LDKIT 2

4 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

5 Improving Confidence in Quality Means Focusing on Control - Robust Control is Predicated on Understanding Risk Regulatory Commitments CTD Pharmaceutical Quality System Management Management = Confidence in Quality Lifecycle 5 4

6 Control 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, 1 st principles, etc. Every CPP represents a Regulatory Commitment 5

7 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. Provide incentives for industry transparency rather than punitive admonishments *Conversations with Mary Oates, June

8 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. 7

9 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

10 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 Storage Handling Opaque PE Bottles Opaque ACLAR/Foil Blisters Ambient Conditions Protect from Light Keep unused tablets in closed container Easy to open Protective packaging 9

11 Example: Quality Target Product Profile QTTP ATTRIBUTE DRUG PRODUCT CQA CONTROL Purity Impurity/Degradation Control CQA 2 Contamination Control PQS DP Dissolution CQA 1 Quality DP Physical Characteristics CQA 3 Patient Compliance - Taste CQA 4 Identity Confirmation CQA 6 Potency Content Uniformity CQA 5 API Assay CQA 7 10

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14 QTPP ATTRIBUTE DRUG PRODUCT CQA FUNCTIONAL RELATIONSHIPS CONTROLS CPP 1 DP Release & Stability Specification Limit Purity Impurity Degradation Control = f (CPP 1 CPP 2 CPP 3 ) CPP 1 = f (CPP 23 CPP 24 ) CPP 3 = f (CPP 11 CPP 17 ) CPP 23 CPP 24 CPP 2 CPP 3 (CMA) Opaque ACLAR Specification Criteria Package Sealing Temperature (CMA) API Chromatography & Specification Limit (CMA) API Specification Limit CPP 11 Step 2 Temperature IPC Limit CPP 17 Step 2 Addition Rate Contamination N/A PQS Adherence to cgmp DP Dissolution = f (CPP 4 CPP 6 ) CPP 4 = f (CPP 18 ) CPP 4 CPP 18 CPP 6 Disintegration Specification Limit (CMA) Disintegrant Particle Size distribution Limits (CMA) API Particle Size Distribution Limits = f (CPP 5 CPP 6 ) CPP 23 API Crystallization Solvent Proportions Quality (Biorelevance) DP Physical Characteristics CPP 5 = f (CPP 7 ) CPP 6 = f (CPP 23 ) CPP 7 = f (CPP 13 CPP 14 CPP 19 ) CPP 5 CPP 7 CPP 13 CPP 14 DP Dissolution Specification Criteria IPC Drug Product Particle Size Distribution Lubricant Quantity Tablet Compression Force CPP 19 Blend Time Patient Compliance-Taste = f (CPP 10 ) CPP 10 = f (CPP 20 ) CPP 10 CPP 20 Flavor/Sweetener Quantity (CMA) Flavor/Sweetener Specification Criteria Identity Confirmation = f (CPP 8 ) CPP 8 API ID Specification Criteria, cgmp Potency Content Uniformity = f (CPP 9 ) CPP 9 = f (CPP 12 CPP 15 CPP 16 ) CPP 9 CPP 12 CPP 15 CPP 16 DP Stratified Sampling Criteria Blend Time Agitator Speed Component Feed Rate API Assay = f (CPP 21 ) CPP 21 = f (CPP 22 ) CPP 21 (CMA) API Specification Limits CPP API Mother Liquor Impurity Levels IPC 13

15 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. 14

16 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. 15

17 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 Summary of Comprehensive Control Strategy 4. Pharmaceutical Development 5. Post-Approval Change Management Plan Regulatory Commitments Reference to PQS Change Management 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 Description of Regulatory Obligations for Post- Approval Changes S.2.1 S.2.2 S.2.3 S.2.4 S.4.1 S.4.2 S.6 S.7.2 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.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 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 R A.2 3, 4, 5, 6, 7, 8, 9, 10, 11,16, 17,19, 21, 24 A.1 A.3 1, 2, 7, 12, 13,14, 15,16, 17,18, 20,22, 23 1, 5, 8, 17, 18, 22, 23, 24, 25, 28, 29, 30, 33, 35, 36, 37, 38 2, 3, 4, 6, 7, 9, 10, 11, 12, 13, 14, 15, 16, 19, 20, 21, 26, 27, 30, 31, 32, 34, 36, 37 16

18 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 riskbased 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. 17

19 Ultimate Objective Improve the regulatory process by ensuring confidence in quality through a product s lifecycle without increasing regulatory burden. Let s not constrain ourselves! 18

20 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 19