1. 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

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

3. 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)

4. 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

5. 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 (//
ICH CTD
Pharmaceutical Development (P.2)

6. P.2 Pharmaceutical Development
P.2.1 Components of the Drug Product
P Drug Substance
P Excipients
P.2.2 Drug Product
P Formulation Development
P Overages
P Physicochemical and Biological Properties

7. 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

8. 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.

9. 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)

10. 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 “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?)

11. 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 can be used to justify DS specification (S.4.1 & S.4.5)
Summary of bioequivalence testing in P.2.1.1

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

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

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

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

16. 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 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?

17. 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 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?

18. 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.”

19. 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

20. 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

21. 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

22. 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

23. 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.”

24. 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.”

25. 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?

26. 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

27. 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?

28. 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