1
2	Topics Background General Aspects and Utility of Comparability Protocols (C.P.s) Draft Guidances for Industry on C.P.s Public Comments on Draft Guidances Current Thinking and Preliminary Comments on C.P.s
3	Reporting Categories for Postapproval Changes Filing category Potential to affect product quality Prior Approval Supplement (PAS) Substantial Changes Being-Effected-in-30-Days Supplement (CBE-30) & Moderate Changes-Being-Effected Supplement (CBE) Annual Report (AR) Minimal
4	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.“ - 69 FR 18727 (April 8, 2004)
5	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
6	General Aspects of a Comparability Protocol Well-planned Scientifically and technically sound (based on understanding of drug, process and proposed change) Adequate and current to implement the change Drug-, manufacturing process-, controls- and change-specific
7	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 >>>
8	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
9	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
10	Highlights of Public Comments (cont.) Clarify what is meant by comparability protocols for changes of a repetitive nature Provide examples of reduction in reporting category from PAS to AR
11	Highlights of Public Comments (cont.) 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
12	Advantages/Disadvantages of C.P.s - To Industry Advantages: Reduced reporting category for post-approval changes, if justified Shortened time line for distribution of drug product Facilitate process improvement and/or optimization May alleviate supply disruptions and/or shortages May reduce overall number of supplements Disadvantage: Risk of adverse effect not eliminated
13	Advantages/Disadvantages of C.P.s - To FDA Advantages: FDA being proactive in finding ways to reduce pharmaceutical industry’s down time May reduce overall number of post-approval supplements Disadvantage: May increase FDA workload initially
14	Two Basic Kinds of C.P.s Single-use comparability protocol: For a specific, one-time CMC change Repetitive-use comparability Protocol: Used more than once to make a specific type of CMC change
15	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 Becomes obsolete upon implementation of the change Examples: Substantially different synthetic route or purification process for drug substance Other one-time changes
16	Repetitive-use C.P. Can be used more than once Specific 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: Changes to a unit operation (e.g., equipment, operating parameters, materials) Container and closure system changes
17	Changes Where a C.P. May Be Appropriate Appropriate: Lack of adverse effect can be definitively 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
18	Basis of a C.P. C.P. based on and provides evidence of scientific and technological understanding of: Drug, manufacturing process, controls Proposed change Potential effect of change on product quality Gained from: Pharmaceutical development, i.e., drug and manufacturing process Commercial-scale production experience Experience with similar drugs and/or changes Scientific and technical literature
19	Specific Aspects to Consider for the Basis and Development of a C.P. Complexity of drug substance Complexity of drug product Complexity of impurity profile Stability of drug Relevancy and adequacy of quality controls for the drug Complexity of manufacturing process Robustness of manufacturing process Manufacturing process capability Robustness of manufacturing process controls Relationship between product quality characteristics and safety and effectiveness
20	General Approach to Demonstrating No Adverse Effect Based on understanding of drug, manufacturing process, controls and change All potential effects of change identified, not just the obvious Pre- and postchange drugs compared for all changes Relevant and adequate 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
21	Demonstration of Lack of Adverse Effect 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 of change on process controllability
22	Reduction of the Reporting Category -General Approach The greater the degree of demonstrated understanding of the drug, process and potential effect of the proposed change on the product quality, the greater the reduction in reporting category that can be justified
23	Reduction of the Reporting Category -General Approach (cont.) PAS to AR Substantial understanding of proposed change >>> Use of protocol substantially reduces potential risk of adverse effect on product quality PAS to CBE / CBE-30 Adequate understanding of proposed change Use of protocol moderately reduces potential risk of adverse effect Depending on drug and change, CBE or CBE-30 designated CBE-30 or CBE to AR Adequate understanding of proposed change
24	Reduction from PAS to AR - General Approach Substantial understanding of drug, process, controls, proposed change and potential effects of change on product quality Application of such understanding to minimize risk Preliminary data to support a lack of adverse effect FDA will determine whether information provided is sufficient
25	Reduction from PAS to AR - Example Information with supporting data from pharmaceutical development relevant to proposed change included with C.P.: Identification of critical variables and interactions between these, and associated steps and controls (e.g., design of experiments) Data from pilot batch(es) Data from full-scale production batch(es), if available
26	Reduction from PAS to AR - Exceptions Change too complex to be well-understood and to predict its effect on product quality as it may relate to safety and effectiveness Change would warrant submission of a supplement specification change change in impurity profile labeling change
27	Modifications 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 reporting categories (PAS, CBE-30, CBE, AR)
28	Summary C.P.s can be useful to industry to shorten time line for distribution of drug products C.P.s may offer substantial reduction in regulatory oversight of post-approval changes for applicants that demonstrate substantial understanding of drug, process and potential effect of change on product quality