1. COMPARABILITY PROTOCOLS ACPS March 12-13, 2003 Stephen K. Moore, Ph.D. Chemistry Team Leader CDER/Office of New Drug Chemistry Co-Chair, Comparability Protocol Working Group

2. SPECIFICS ON THE USE OF COMPARABILITY PROTOCOLS l When might a comparability protocol be useful for a CMC change? l Product-specific and process-specific considerations l When might a comparability protocol be inappropriate? l Basic elements of a comparability protocol l Specific issues to be considered for comparability protocols for different types of changes

3. WHEN MIGHT A COMPARABILITY PROTOCOL BE USEFUL FOR A CMC CHANGE? l Comparability protocols are applicable to a wide variety of CMC changes l Comparability protocols cover many of the types of changes described in SUPAC, BACPAC and Changes to an Approved NDA and ANDA guidances l Comparability protocols can also cover many types of changes not described in other CMC guidances

4. WHEN MIGHT A COMPARABILITY PROTOCOL BE USEFUL FOR A CMC CHANGE (CONT.)? l Single change or multiple related changes with each change being discrete and specific l Changes of a repetitive nature are particularly useful l Specify a priori the tests, studies, analytical procedures, and acceptance criteria for demonstrating that the CMC changes will not adversely affect the product

5. PRODUCT-SPECIFIC AND PROCESS-SPECIFIC CONSIDERATIONS l Complexity of the product structure l Ability to characterize the chemical, physical, microbiological, and biological properties of the product (e.g., routine testing, stability studies, characterization studies) l Degree to which differences in product structure and physical properties can be detected l Degree of product heterogeneity, if present l The effect on safety of changes in the impurities

6. PRODUCT-SPECIFIC AND PROCESS-SPECIFIC CONSIDERATIONS (CONT.) l The robustness of the product l Rigorousness of the manufacturing process controls l Approved drug substance and/or drug product specifications expected to be met l Appropriate and sensitive analytical procedures established and validated or qualified to detect the effect of the change on the product

7. WHEN MIGHT A COMPARABILITY PROTOCOL BE INAPPROPRIATE? l Broad, nonspecific plans for CMC changes l A change whose adverse effect on the product cannot be definitively evaluated by prespecified tests, studies, analytical procedures, and acceptance criteria l Any CMC change that warrants the submission of an IND or new original application. l A CMC change that requires efficacy, safety (clinical or nonclinical), or PK/PD data to evaluate the effect of the change (e.g., certain formulation changes, clinical or nonclinical studies to qualify new impurities)

8. SPECIFIC EXAMPLES OF CHANGES THAT MAY BE DIFFICULT TO JUSTIFY UNDER A COMPARABILITY PROTOCOL l A change in the drug substance or drug product specifications l A change in the qualitative or quantitative formulation of the drug product l A change in the type of delivery system l A change from plant, animal, or multicellular source material to a different one

9. SPECIFIC EXAMPLES OF CHANGES THAT MAY BE DIFFICULT TO JUSTIFY UNDER A COMPARABILITY PROTOCOL (CONT.) l A change from synthesis-derived to naturally sourced material and vice versa l A change from solid phase to liquid phase peptide synthesis and vice versa l A move to a manufacturing site, facility, or area when a prior approval supplement is recommended because a CGMP inspection is warranted

10. BASIC ELEMENTS OF A COMPARABILITY PROTOCOL l Description of the planned changes l Specific tests and studies to be performed l Analytical procedures to be used l Acceptance criteria l Data to be reported under or included with the comparability protocol l Proposed reporting category l Action when equivalence not demonstrated using the approved comparability protocol l Commitment

11. SPECIFIC ISSUES TO BE CONSIDERED FOR COMPARABILITY PROTOCOLS FOR DIFFERENT TYPES OF CHANGES l Manufacturing process (e.g., effect on physical characteristics, impurity profile, downstream process, in-process controls) l Analytical procedures (e.g., effect on characteristics used in methods validation) l Manufacturing equipment (e.g., effect on manufacturing process) l Manufacturing facilities (e.g., CGMP Inspection status, scope of changes involved)

12. SPECIFIC ISSUES TO BE CONSIDERED FOR COMPARABILITY PROTOCOLS FOR DIFFERENT TYPES OF CHANGES (CONT.) l Container closure systems (e.g., repetitive changes particularly useful) l Process analytical technology (PAT) (e.g., early dialog with Agency encouraged) l Changes covered under a DMF or VMF (e.g., cross-reference to a comparability protocol)

13. SUMMARY l Comparability protocols allow FDA and industry to agree early on specified CMC changes, plan for assessing the effect of these changes and the reporting category l Savings in time of implementation and resources for many types of changes l A new regulatory mechanism, therefore, FDA and industry experiencing a learning curve l Guidance is hoped to stimulate interest in the use of comparability protocols