Regulatory Compliance for Global Pharma Market

1. Regulatory Compliance for Global Pharma Market Quality by Design (QbD) in Product Development Dr. Nitin Dharmadhikari Sun Pharma Advanced Research Company Ltd., Mumbai

2. What is QbD? • Systematic, holistic and proactive approach to pharmaceutical development. • Begins with predefined objectives • Emphasizes product and process understanding and process control • Based on sound science and quality risk management Ref.: ICH Q8 (R2)

3. Why QbD? Generic industry business model: Regulator’s perspective • File first, learn later • Major amendments during review process - Exhibit batch stability failure, formulation revision • Longer time for generic product approval • Approved product may not be marketed • Post approval changes – prior approval supplements

4. How QbD will help improve? • Ensure higher level of assurance of product quality for patient • Improved product and process design & understanding • Monitoring, tracking & trending of product & process. • More efficient regulatory oversight • Efficiency and cost saving for industry • Increase efficiency of manufacturing process • Minimize / eliminate potential compliance actions

5. Overview of QbD Quality Target Product Profile Product Design and Understanding Process Design and Understanding Control Strategy Continuous Improvement

6. Elements of QbD • Quality Target Product Profile (QTPP) • Define Critical Quality Attributes (CQAs) • Perform risk assessment • Link raw material attributes and process parameters to CQAs • Design and implement a control strategy • Manage product lifecycle, including continuous improvement

7. Quality Target Product Profile-QTPP What is QTPP? • A set of elements that defines the drug product • The target or goal set in advance • A guide to Drug Product development What forms the basis for QTPP? • The RLD and its label • Applicable regulatory guidelines When to define QTPP? • At the start of development • Knowledge gained in development may change some elements

8. Components of QTPP Components related to safety, efficacy, identity, purity and potency Critical and non-critical components, e.g. • Critical: Assay, content uniformity • Non-critical: Appearance Fixed and variable components • Fixed elements must be present e.g. Dosage form, strength • Variable elements may have a range of acceptable values e.g. Tablet weight, assay

9. QTPP components for IR tablet -Example

10. Specific requirements in QTPP • Scored tablets • Weight variation between two halves • Dissolution of half tablet • Orally Disintegrating tablets • Hardness • Disintegration time • Container closure • Extended Release products • Alcohol induced dose dumping

11. Critical Quality Attributes – CQAs • CQAs are a subset of the QTPP • Include critical parameters that are likely to change based upon variations in raw materials and processes -Identity test for dosage form – Not a CQA -Assay, Content uniformity – CQAs • CQAs are monitored throughout the DP development. • CQAs ensure that DP remains within safe and effective levels.

12. QTPP and CQAs

13. QTPP Desired target for developmental work Components of QTPP may or may not be in specification Not in spec – Dosage form, strength In spec – Assay, impurities Does not include acceptance criteria Specifications Includes all of the CQAs Specification is a list of tests, references to analytical procedures - acceptance criteria Establishes the set of criteria to which DP should conform to be considered acceptable for its intended use QTPP and Specifications Defining a QTPP does not mean setting all acceptance criteria or the product specifications before development work begins.

14. QbD Tools – Risk Assessment Why risk assessment in product development? • To identify relative risk levels at the beginning of product development • To prioritize limited development resources • To document the decision making process throughout development • To assess the needs of additional studies for scale up and technology transfer • To identify appropriate specifications, critical process parameters and manufacturing controls • To decrease variability of critical quality attributes

15. Risk Assessment Risk assessment for • Formulation – starting material properties, levels of components • Manufacturing process Steps for risk assessment • List out all components / processes • Prepare the process flow chart • Identify all potential failure modes for each item with risk query (what might go wrong?) • Risk analysis • Risk evaluation

16. Risk Assessment Various formal methodologies available for risk assessment • Failure Mode Effects Analysis & Failure Mode Effects & Criticality Analysis • Hazard & Operability Analysis • Supporting statistical tools • It is neither always appropriate nor always necessary to use a formal risk management process….. The use of informal risk assessment processes can also be considered acceptable. – ICH Q9 • A risk-based justification based on experience and data is always necessary!

17. Risk Assessment Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms • Generic product development for Acetriptan Tablets, 20 mg. • Acetriptan is a BCS Class II compound displaying poor aqueous solubility (less than 0.015 mg/mL) across the physiological pH range. • It exists in three different polymorphic forms which may affect dissolution. • Polymorph III is the most stable polymorph. • Drug product is prepared with roller compaction process.

18. Risk assessment Risk assessment for formulation components

19. Risk assessment Risk assessment of DP manufacturing process * RC: Roller compaction

20. Justification for assigned risks

21. CMAs, CPPs and CQAs What factors affect drug product CQAs? • Properties of Input Materials- Identify Critical Material Attributes (CMAs) • Properties of in-process materials- CQAs of one step become CMAs for a downstream unit operation • Manufacturing process parameters- Identify Critical Process Parameters (CPPs) CPPs2 CPPs1 CMAs1 CMAs2 CQAs Unit Operation 1 Unit Operation 2 Product Input Materials Output Materials

22. Critical Material Attributes (CMAs) Risk Assessment of the drug substance attributes Solid state form and particle size of DS are CMAs

23. CPPs • Risk assessment of manufacturing process • Identify high risk steps (unit operation) that affect the CQAs of DP.

24. CPPs Process Step: Compression

25. Control Strategy “A planned set of controls, derived from current product and process understanding that ensures process performance and product quality…..” ICH Q8 (R2) & Q10 Control Strategy includes following elements (but not limited to): • Input material attributes (e.g. drug substance, excipients, container closure) • Equipment operating conditions (process parameters) • In-process controls • Finished product specifications • Controls for each unit operations • Methods and frequency of monitoring and control.

26. Control Strategy

27. Control Strategy Control Strategy Implementation Options Enhanced Approach Level 1 Real-time automatic control + Flexible process parameters Level 2 Reduced end product testing + Flexibility for critical material attributes and critical process parameters within design space Level 3 End product testing + tightly constrained material attributes and process parameters Traditional Approach

28. QbD Tools – DoE Design of experiments (DoE) • Useful for screening of variables with significant impact on DP CQAs • Classical approach uses OFAT (One Factor At A Time) • Limited number of experiments gives limited information. • DoE helps study effects of interaction of multiple factors at a time • Used in optimization studies, enables creation of “design space” • “Design space” is proposed by the applicant and subject to regulatory assessment and approval. • “Design space” developed at lab or pilot scale can be proposed for commercial scale, but needs to be verified at production scale for scale dependant parameters.

29. Process Analytical Technology (PAT) • Timely measurements during processing • Critical quality and performance attributes • Raw and in-process materials • At-line, on-line or in-line measurements • Founded on “Process Understanding” Opportunities for improvement • More reliable and consistent processes (& product) • Less failures, less reworks, less recalls • Flexibility w.r.t. scale and equipment • Better / faster Quality Systems • Process Enhancement Opportunities

30. PAT in Tablet manufacturing

31. PAT Examples Spectral Probe NIR Analyzer installed on viewing window of Glatt FBD without any dryer modification.

32. PAT Examples Real-time Blend Uniformity by using TruProcess™ Analyzer

33. QbD: Required or Optional? Required • Quality target product profile (QTPP) including critical quality attributes (CQAs) of the drug product and including Product design and understanding • Product design and understanding • Critical material attributes (CMAs) of the drug substance and excipients • Process design and understanding • Critical process parameters (CPPs) • Control strategy, including justification Optional • Design Space • Process Analytical Technology

34. QbD

35. QbD

36. References for QbD • Guidance for Industry: Q8(R2) Pharmaceutical Development • Guidance for Industry: Q9 Quality Risk Management • Guidance for Industry: Q10 Pharmaceutical Quality System • Guidance for Industry PAT: A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance • Quality by Design for ANDAs: An Example for Modified Release Dosage Forms • Quality by Design for ANDAs: An Example for Immediate Release Dosage Forms • GPhA presentations • Draft QbR updated