http://www.fda.gov/cder/guidance/6672dft.pdf

1. http://www.fda.gov/cder/guidance/6672dft.pdf

2. Objectives

3. Describe the common vision • Product quality and performance achieved and assured by design of effective and efficient manufacturing processes • Product specifications based on mechanistic understanding of how formulation and process factors impact product performance • An ability to effect continuous improvement and continuous "real time" assurance of quality

4. Understanding the vision • In the US, pharmaceutical product and process development information is generally not shared in regulatory submissions and/or not utilized in (regulatory) decisions on quality • How does (lack of) information/knowledge about “….design of effective and efficient manufacturing processes…” impact on • Regulatory specification setting? • Continuous improvement? • Efficiency and cost?

5. Understanding the vision A Warning Letter • Was the process design adequate for the intended use? • How was this process “controlled”? • What may have been the regulatory decision (e.g., in-process dissolution specification)? • Could appropriate product and process development information have helped? How? • How could this process be improved?

6. Understanding the vision • Specifications based on mechanistic understanding – “science and risk-based” • Can lead to more efficient approval decisions and regulatory flexibility for post approval continuous improvement (improving productivity and reducing variability) • Minimize knowledge uncertainty that drives the need for regulatory in-process specifications and specifications with unnecessarily tight acceptance criteria (e.g., based on process capability) • Process understanding as a means to minimize the need for additional “characterization”, need for prior approval and “re-validation” to qualify changes necessary for continuous improvements

7. Understanding the vision • An integrated systems approach for regulatory decisions and oversight • CMC Review and CGMP Inspection • R&D and Industrial Operations • Continuous improvement within a facility’s quality system • Knowledge transfer and feedback • Minimal standards and risk-based specifications • Opportunity for regulatory flexibility for only those who “understand” their product and process and communicate this understanding to regulators Hesitating to act because the whole vision might not be achieved, or because other do not yet share it, is an attitude that only hinders progress. Mahatma Gandhi

8. The Goal and Characteristics of Pharmaceutical Quality Decision System Goal • “The quality of drug substances and drug products is determined by their design, development, in-process controls, GMP controls, process validation, and by specifications applied to them throughout development and manufacture.” Life-cycle Characteristics ICH Q6A

9. ICH Q6A Decision Characteristics Specifications In process controls Development Design Process validation GMP Controls “…where the provision of greater understanding of pharmaceutical and manufacturing sciences can create a basis for flexible regulatory approaches.” What is the ICH Q8 Opportunity?

10. ICH Q8: Suggested contents for the 3.2.P.2 Pharmaceutical Development section of a regulatory submission in the ICH M4 Common Technical Document (CTD) format.

11. Knowledge based – assessment is not an “audit” function • Describe the knowledge that establishes • the type of dosage form selected and the formulation proposed • Include sufficient information to provide an understanding of the development of the drug product and its manufacturing process. • Summary tables and graphs are encouraged.

12. At a minimum…. • Describe those aspects of drug substances, excipients, and manufacturing processes that are critical and that present a significant risk to product quality, and therefore should be monitored or otherwise controlled • These critical formulation attributes and process parameters are generally identified through an assessment of the extent to which their variation can have impact on the quality of the drug product.

13. In addition…. • The applicant can choose to conduct other pharmaceutical development studies that can lead to an enhanced knowledge of product performance over a wider range of material attributes, processing options and process parameters. • Inclusion of this additional information provides an opportunity to demonstrate a higher degree of understanding of manufacturing processes and process controls. • This scientific understanding establishes the design space.

14. Design Space • The design space is the established range of process parameters that has been demonstrated to provide assurance of quality. In some cases design space can also be applicable to formulation attributes. • Working within the design space is not generally considered as a change of the approved ranges for process parameters and formulation attributes. • Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval change process.

15. Current State Executed batch records as regulatory commitments (“design points”) SUPAC “Levels” Level 1 is “still a change” Scale-up factor 10X Significant Body of Data Equipment of similar “design and operating principles” Additional “characterization” (e.g., dissolution – f2, stability) and process validation BCS/IVIVC based biowaivers Desired State No additional “process understanding” = Current State Additional product and process development information Reduce the need for regulatory application commitments to “material attributes”. Describing why a proposed product & process control strategy should give confidence that a process will be in a state of control (without the need for regulatory spec) Also, when it is necessary to change process parameters and other manufacturing options Science based specifications Design Space (Examples)

16. Design Space can potentially go beyond “make your own SUPAC” concept! Limited information in NDA/ANDA SUPAC Change Levels based on prior knowledge from the pharmaceutical community (AAPS SUPAC Workshops) + Research; Yet difficult to generalize because of multi-factorial aspects + lots of subjectivity Gap = Uncertainty Prior knowledge within a company + structured product and process development can improve decisions towards mechanistic understanding (ICH Q8 Can fill this gap)

17. Many options for constructing a “design space” • Key elements – a structured scientific knowledge base (not just “experience”) and appropriate tools • Tools outlined in the FDA’s PAT Guidance • Multivariate tools for design, data acquisition and analysis (e.g., formal Design of Experiments) • Process analyzers • Process control tools • Continuous improvement and knowledge management tools (e.g., leveraging prior knowledge) • ICH Q8 adopted the definition and principles of PAT as outlined in the FDA’s guidance http://www.fda.gov/cder/guidance/6419fnl.pdf

18. Design Space Example #1 • In process controls • Controlling a process to an end-point based on desired material attributes (e.g., particle or granule size, moisture content, degree of homogeneity of powder mix, etc.) • Reduce the need for application commitment with respect to process parameters (e.g., time) and manufacturing options (e.g., equipment, scale, site, etc.) • Process validation becomes “modular” – controlling a process using validated controls (PAT Guidance) • Improvement in quality of end product (e.g., reduced variability) and move towards “real time release” • Reduced cycle time, improved productivity

19. Design Space Example #2 • Structured product development strategy • Leveraging pre-formulation characterization • Physico-chemical attributes of API and excipients, compatibility evaluation, and pharmaceutical development experiments • Connection to early clinical evaluation of development products and pivotal clinical trials (e.g., PK/PD, population PK/PD, other clinical measurements) • Does the selected formulation and its manufacturing process ensure that “reaction chemistry has been sufficiently curtailed”? – no degradation expected; then the focus can be on “physical” characteristics that relate to performance and their stability • What is the relationship between formulation and manufacturing process on product quality and performance? • Design of Experiments and judicious connection to stability and clinical • Science and risk-based specifications

20. Emerging Opportunities (longer term) • Emerging technologies may dramatically improve our ability to connect product/process design space with clinical design space • Non-destructive assessment of product quality and performance (e.g., dissolution or release rate, particle size and delivered dose to an individual patient) + clinical tools (PK/PD, imaging, biomarkers, pharmacogenomics, etc.) • Improved ability to address uncertainty with respect to clinical relevance of quality characteristics and acceptable variability in critical quality characteristics

21. Example: Pharmaceutical Development & Dissolution Specification • Without pharmaceutical development information • Decision focus only on dissolution test data • Test often used for both “in-process control” and final product testing • Decision characteristics focus only on “mean” • Variability managed indirectly -“discriminating” test conditions and “tight” procrustean acceptance criteria • Leads to a deterministic interpretation of specification (ignores the impact of random variability) • “Specifications are Standards” – can not be risk-based • “Event Trees” not “Decision Trees” • Difficult to resolve “out of specification” observations • Post-approval changes and optimization or continuous improvement difficult

22. Mean Dissolution Profiles (n=6) Pivotal clinical lots Test 1 Test 2 75% Discriminating test FDA Applicant Dissolution specification without pharmaceutical development information

23. ICH Q6A [EVENT] DECISION TREES #7: SETTING ACCEPTANCE CRITERIA FOR DRUG PRODUCT DISSOLUTION What specific test conditions and acceptance criteria are appropriate? [IR] Clin. Pharm. What? Product Design (Postulate - Confirmed Based on mechanism and/or empirically) YES Develop test conditions and acceptance distinguish batches with unacceptable BA dissolution significantlyaffect BA? Design of Manufacturing and Controls How (reliable)? NO Do changes informulation ormanufacturing variables affect dissolution? Are these changes controlledby another procedure and acceptancecriterion? YES So what? Overall Risk-based CMC:Why? YES NO NO Adopt appropriate test conditionsand acceptance criteria without regard to discriminating power, to pass clinically acceptable batches. Adopt test conditions and acceptance criteria which can distinguish these changes. Generally, single point acceptance criteria are acceptable. Overall CMC Systems approach (e.g., link to morphic form, particle size, stability failure mechanisms) CMC: Why? Then How?

24. Mechanistic Understanding in ICHQ6A? • For example – “Particle size distribution testing may also be proposed in place of dissolution testing when development studies demonstrate that particle size is the primary factor influencing dissolution; justification should be provided.” • ICHQ6A 3.3.2.3 Parenteral Drug Products • Mechanistic understanding – identification and scientific justification of causal physical or chemical relationships between pharmaceutical materials and/or process factors • Note – establishment of “correlation” between two characteristics may not always be causal

25. Specifications - Standards and Continuous Improvement Process capability based acceptance criteria Incentive for continuous improvement? Risk-based specifications State of control Action/alert limits Real time release

26. Controlling Dissolution Rate: Options Dissolution = f (Ex1, Ex2, P1, P2, PS…) Drug Substance Formulation Process Bio PK/PD Disso Test NIR Product Stability Real Time Release (Stability?) “Market Standard”

27. Reactive (examples) Testing to document quality Repeating deviation and out of specification investigations Prior Approval Supplement for process optimization and continuous improvement efforts Multiple NDA CMC review cycles Procrustean approach for demonstrating therapeutic equivalence of generic products Proactive (examples) Quality by design and “real time release” Right First Time Process optimization and continuous improvement efforts within a facilities quality system Single NDA CMC review cycle and risk-based specifications QbD approaches for demonstrating therapeutic equivalence of generic products From a “Reactive” to a “Proactive” Decision System for Pharmaceutical Quality ICH Q8 can be the engine for this journey

28. Summary • Described the common vision – desired state • Scope and content of P2 section • Defined “design space” and provided a few examples • Discussed minimal and optional information • Identified opportunities for “regulatory flexibility” for those who utilize optional information • Discussed the role of PAT and how real time release may be realized • Note – the PAT Guidance covers API and drug products and ICH Q8 only addresses drug product • Design Space for API manufacturing can be achieved using the PAT guidance!!