Assessing Quality-by-Design A CMC Review Perspective Norman R. Schmuff, Ph.D. CMC Team Leader, ONDC Manufacturing Subcommittee of the Advisory Committee for Pharmaceutical Science September 17, 2003

Outline Current model Development Reports CTD’s P.2 “Pharmaceutical Development” Proposed contents for P.2 Future model

Assessing Quality-by-Design The Current Model IND Safety – major emphasis Product consistency & quality – minor emphasis CMC amendments usually brief NDA (1987) Original submission “Investigational Formulations” “In-process Controls” Supplements Annual Reports (1994)

Quality-by-Design Currently Available Information Not much Traditionally not shared – Why? Regulatory concerns Increased resources & size of submissions BUT, if available provides an opportunity to down-regulate post-approval changes

Development Reports ICH CTD EU Pre-CTD “Notice to Applicants” (//pharmacos.eudra.org/F2/eudralex/vol-2/home.htm) Development Chemistry Development Pharmaceutics FDA Product Development Report “Guide to Inspections of Oral Solid Dosage Forms Pre/Post-Approval Issues For Development And Validation” Jan 1994 (//www.fda.gov/ora/inspect_ref/igs/solid.html) ICH CTD Pharmaceutical Development (P.2)

P.2 Pharmaceutical Development P.2.1 Components of the Drug Product P.2.1.1 Drug Substance P.2.1.2 Excipients P.2.2 Drug Product P.2.2.1 Formulation Development P.2.2.2 Overages P.2.2.3 Physicochemical and Biological Properties

P.2 Pharmaceutical Development P.2.3 Manufacturing Process Development P.2.4 Container Closure System P.2.5 Microbiological Attributes P.2.6 Compatibility

P.2.1.1 Drug Substance CTD-Q says: The compatibility of the drug substance with excipients listed in P.1 should be discussed. Additionally, key physicochemical characteristics (e.g., water content, solubility, particle size distribution, polymorphic or solid state form) of the drug substance that can influence the performance of the drug product should be discussed. For combination products, the compatibility of drug substances with each other should be discussed.

Three Key Topics for P.2.1.1 “Discussion” of the compatibility of the DS with excipients “Discussion” of the physicochemical characteristics of the DS that can influence the performance of the DP “Discussion” of the compatibility of drug substances with each other (if combination product)

DS Physicochemical Characteristics What data and/or discussion goes where? How does this section differ from other related/similar sections of the CTD-Q? P.2.2.3 “Physicochemical and Biological Properties” (mentions polymorphism) S.3.1 “Elucidation of Structure and other Characteristics” (mentions polymorphs) S.4.5 “Justification of Specification” (justification for control of polymorphs?)

DS Physicochemical Characteristics (cont’d) One proposal: Data (parallel to ICH Q6A decision tree 4) Testing on DS - S.3.1 Testing of DP (e.g., dissolution) - P.2.1.1 Testing of polymorph ratios in DP - P.2.2.3 Discussion Summary of DS characterization in S.3.1 Data in P.2.1.1 can be used to justify DS specification (S.4.1 & S.4.5) Summary of bioequivalence testing in P.2.1.1

Q6A DS Particle Size Decision Tree P.2 Pharmaceutical Development Q6A DS Particle Size Decision Tree

DS Physicochemical Characteristics (cont’d) (Drug Substance Testing) S.3.1 Elucidation of Structure and Other Characteristics

DS Physicochemical Characteristics (cont’d) S.4.5 Justification of Specification (Drug Product Testing) P.2.1.1 Drug Substance S.4.1 Specification S.4.5 Justification of Spec

DS Physicochemical Characteristics (cont’d) (More Drug Product Testing) P.2.2.3 Physicochemical and Biological Properties

DS Physicochemical Characteristics (cont’d) Alternative proposal: Any kind of once-only testing should be in P.2 Polymorph screening on DS should be in P.2.1.1 instead of S.3.1 because it’s part of “pharmaceutical development”? Discussion and data? Only discussion (data goes in S.3.1)? All stress testing (a form of once-only testing)? Except maybe DS accelerated stability and stress testing performed as part of methods validation? Includes DS photostability?

Compatibility: DS w/ Excipients What data/discussion should we expect? Expect to see compatibility testing always, or only when interaction is likely? Who decides whether it is likely? Would it be acceptable to test all excipients at once, or should they be tested individually? What’s the difference between compatibility testing in P.2.1.1 and drug product stress testing performed as part of the method validation for DP degradation products? Assuming DP stress testing is performed—should it be?

P 2.1.2 Excipients (Pharmaceutical Development) CTD says: “The choice of excipients listed in 3.2.P.1, their concentration, and the characteristics that can influence the drug product performance should be discussed relative to their respective functions.”

P 2.1.2 Excipients (Pharmaceutical Development) Draft Drug Product Guidance adds: Excipient range justification Functional excipient performance Novel excipient* information Suitability/safety for excipients: Used at higher levels than approved products With inherent pharmacological activity Tracer information * defined as one used for the first time in the US or by a new route of administration

Other Excipient Sections P.4 Control of Excipients P 4.1 Specifications P 4.2 Analytical Procedures P 4.3 Validation of Analytical Procedures P 4.4 Justification of Specifications P 4.5 Excipients of Human or Animal Origin P 4.6 Novel excipients Appendix A3: Novel Excipients

P.2.2 Drug Product P.2.2.1 Formulation Development CTD says: Development history considering: Route of administration Usage Differences in clinical vs. to-be-marketed product Component & composition Manufacturing Dissolution Bioequivalence

P.2.2.1 Formulation Development Draft Drug Product Guidance adds: Scored-tablet data Appropriateness to labeled dosing Content uniformity Dissolution Overfill Amount Supportive studies [Polymorph decision tree (Q6A) — DP studies]? Diluent selection

P.2.3 Manufacturing Process Development CTD Says: “The selection and optimization of the manufacturing process described in P3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.” “Differences between the manufacturing process(es) used to produce pivotal clinical batches and the process described in P3.3 that can influence the performance of the product should be discussed.”

P.2.3 Manufacturing Process Development CTD Says: “The selection and optimization of the manufacturing process described in P3.3, in particular its critical aspects, should be explained. Where relevant, the method of sterilization should be explained and justified.” “Differences between the manufacturing process(es) used to produce pivotal clinical batches and the process described in P3.3 that can influence the performance of the product should be discussed.”

P.2.3 Manufacturing Process Development Describe MP and in-process controls Describe changes to process during clinical trials Explain selection & optimization of MP Critical aspects of MP Explain & justify sterilization process Explain differences between MP and pivotal clinical batch process What influence on product performance?

Development Data Identification of critical steps and variables Science-based specification and controls allow focus on high risk Lack adequate development data suggests Possibility of unidentified critical steps Higher risk in post-approval changes When “best practices” are employed Risk of poor product quality is minimized Lower risk in post-approval changes will allow down-regulation of reporting category

Quality-by-Design in the Future P.2 Pharmaceutical Development Further refined in Drug Product Guidance Second concept paper to be presented to ICH Steering Committee November in Osaka Closer co-operation between ORA and Center Review Chemists P.2 parts in post-approval submissions? Portions of the GMP “Product Development Report” included in P.2?

Quality-by-Design in the Future XML-based document management, and the eCTD will promote information reuse Information from “Annual Product Review” submitted in NDA “Annual Report”? Number of batches manufactured Observed trends