comparability protocolupdate advisory committee for pharmaceutical science manufacturing...

COMPARABILITY PROTOCOLUPDATEUPDATE

ADVISORY COMMITTEE FOR ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCEPHARMACEUTICAL SCIENCE

Manufacturing SubcommitteeManufacturing SubcommitteeJuly 20-21, 2004July 20-21, 2004

Stephen Moore, Ph.D.Stephen Moore, Ph.D.Chemistry Team LeaderChemistry Team Leader

Office of New Drug ChemistryOffice of New Drug ChemistryCenter for Drug Evaluation and ResearchCenter for Drug Evaluation and Research

Food and Drug AdministrationFood and Drug Administration

Topics

Definition and General Aspects Regulations Pertaining to Comparability

Protocols Draft Guidances for Industry on C.P.s Public Comments on Draft Guidances Current Thinking and Preliminary

Comments on C.P.s

Definition of a Comparability Protocol

A comprehensive, detailed plan that describes the specific type of proposed change tests and studies to be performed analytical procedures that will be utilized acceptance criteria to be achieved

to demonstrate lack of an adverse effect on the product quality as it may relate to the safety and effectiveness of the drug product

General Aspects of a Comparability Protocol

Well-planned in advance Scientifically and technically sound (based on

knowledge and understanding) Adequate and current to implement the change Drug, process, controls and change specific

Regulations Pertaining to Comparability Protocols

21CFR 314.70(e) and 601.12(e)

"Protocols. An applicant 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 for specified types of manufacturing changes on the identity, strength, quality, purity, and potency of the drug product as these factors may relate to the safety or effectiveness of the drug product. Any such protocols, if not included in the approved application, or changes to an approved protocol, must be submitted as a supplement requiring approval from FDA prior to distribution of a drug product produced with the manufacturing change. The supplement, if approved, may subsequently justify a reduced reporting category for the particular change because the use of the protocol for that type of change reduces the potential risk of an adverse effect."

Draft Guidances for Industry on Comparability Protocols

Guidance for Industry, Comparability Protocols —Chemistry, Manufacturing, and Controls Information (draft issued Feb., 2003). (Applies to chemical entities and synthetic peptides)

Guidance for Industry, Comparability Protocols — Protein Drug Products and Biological Products —Chemistry, Manufacturing, and Controls Information (draft issued Sept., 2003)

Public comments under review for final publication of guidances >>>

Highlights of Public Comments on Draft Guidances on C.P.s

(Excerpted and Paraphrased) Efficient use of comparability protocols should

provide regulatory relief by expediting review and approval of postapproval changes

Many changes are not anticipated at time of filing a marketing application

Highlights of Public Comments (cont.)

Level of specificity requested may define the protocol so narrowly as to diminish its future usefulness

Key to use of comparability protocols is the availability of sufficient manufacturing science data to demonstrate adequate understanding of the product and critical process controls


Clarify what is meant by comparability protocols for changes of a repetitive nature

Provide examples of reduction in reporting category from PAS to AR


Modifications to a comparability protocol in categories lower than PAS should be permitted (e.g., CBE-30, CBE)

CGMP aspects of postapproval changes should be addressed

We applaud the FDA for its efforts

Current Thinking on Comparability Protocols:Two Basic Kinds

Single-use comparability protocol:

For a specific, one-time CMC change

Repetitive-use Comparability Protocol:

Used more than once to make a specified type of CMC change

Current Thinking on Comparability Protocols:Single-use C.P.

For a single change or multiple related changes For multiple related changes:– Assessment of each of the individual changes– Combined effects of all of the changes on the product

quality

Examples: Drug substance or drug product manufacturing process

changes Changes in scale and related changes

Current Thinking on Comparability Protocols:

Repetitive-Use C.P.

Specific (specified) type of change narrowly defined

Boundaries established for extent of changes In general, multiple related changes comprised

only of subcategories of specified type of change

Examples: Container and closure system change Changes to a unit operation

Current Thinking on Comparability Protocols: Advantages/Disadvantages

To Industry

Advantages: Shortened time line for distribution of

drug product Reduced filing burden for commonly

made changes

Disadvantage: Risk of adverse effect not eliminated

Current Thinking on Comparability Protocols: Advantages/Disadvantages

To FDA

Advantages: FDA being responsive in finding ways to

reduce manufacturer’s down time May reduce overall number of post-

approval supplements

Disadvantage: May increase FDA workload initially

Current Thinking on Comparability Protocols: Appropriateness of a C.P.

Appropriate: Lack of adverse effect can be demonstrated

by analysis of product quality characteristics

Not considered appropriate: Nonspecific plans for CMC changes Nonclinical safety, nonclincal

pharmacology, PK/PD, clinical safety and/or effectiveness studies required

Current Thinking on Comparability Protocols:Principles and Recommendations

C.P. based on and provides evidence of scientific and technological knowledge and understanding of:– Drug, manufacturing process, controls– Proposed change– Potential effect of change on product quality

Gained from:– Pharmaceutical development information (drug and

manufacturing process)– Commercial scale production experience– Scientific and technical literature

Current Thinking on Comparability Protocols: Principles and Recommendations (cont.)

All potential effects of a change identified, not just the obvious

Pre- and postchange drugs compared for all changes Combination of routine quality controls testing and

characterization studies Analytical procedures sufficiently discriminatory to detect

potential differences Integrated analysis of all available data prior to

concluding lack of adverse effect

Current Thinking on Comparability Protocols: Demonstration of Lack of Adverse Effect

Based on knowledge and understanding Product quality characteristics of pre- and postchange

drugs:– Conform to specifications– Conform to acceptance criteria for characterization studies– Comparable: mean and standard deviation / qualitatively

Manufacturing process and process controls considerations:– Process controls met– Effect on process and process controls as they relate to the product

quality

Current Thinking on Comparability Protocols: Reduced Reporting Category

Factors to Consider: Degree of demonstrated knowledge and understanding Normal reporting category for change Drug-, process- controls- and change- specific

considerations (e.g., complexity) Validity of C.P. (e.g., scientifically and technically sound)

Current Thinking on Comparability Protocols: Reduced Reporting Category

PAS to AR– Substantial knowledge and understanding >>>– Use of protocol substantially reduces potential of adverse

effect on product quality

PAS to CBE / CBE-30– Adequate knowledge and understanding – Use of protocol moderately reduces potential of adverse

effect– Depending on drug and change, CBE or CBE-30

designated

CBE-30 or CBE to AR– Adequate knowledge and understanding

Preliminary Comments onReduction PAS to AR under C.P.

Approach

Substantial knowledge and understanding of drug, process, controls, proposed change and potential effects of change on product quality

Relevance and adequacy of tests, studies, analytical procedures and acceptance criteria to assess effects of change

Preliminary data to support a lack of adverse effect FDA will determine whether information provided is

sufficient


Examples Data from pharmaceutical development studies

relevant to proposed change included with C.P.:– Definition of change– Identification of critical process steps, parameters,

variables and/or controls pertinent to the change and interactions

– Data from pilot batch(es) – Data from full-scale production batch(es), if available


Examples (cont.)

Previously approved similar change to same drug referenced in C.P.

Previously approved same change to similar drug referenced in C.P.

Subsequent change of same specified type under approved repetitive-use C.P., if justified– First time: CBE or CBE-30– Second and subsequent times: AR


Exceptions

Change too complex Impurity profile changed for drug

substance or drug product Manufacturing change that requires

specification change

Preliminary Comments onModifications to an Approved

Comparability Protocol

Examples where modification of C.P. may be useful:

Modify change so acceptance criteria achieved Modify change to increase assurance of product

quality Update C.P. to keep it current and valid FDA identifying examples of modifications to

C.P. in all FDAMA reporting categories (PAS, CBE-30, CBE, AR)

Summary

Comparability protocols can be useful for industry to shorten time line for distribution of drug products

FDA exploring ways to make protocols more flexible and useful

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