1. Excipient QbD Concepts to Enhance the Development of Robust Drug Products Priscilla S. Zawislak Global Regulatory Affairs Manager - Ashland Inc. Chair - Compendial Review Committee, IPEC- Americas pszawislak@ashland.com

2. 2 FDA’s QbD Expectations for ANDAs We encourage you to apply Quality by Design (QbD) principles to the pharmaceutical development of your future original ANDA product submissions. A risk-based, scientifically sound submission would be expected to include the following: – Quality Target Product Profile (QTPP) Critical Quality Attributes (CQAs) of the drug product – Product design and understanding including identification of critical attributes of excipients, drug substance(s), and/or container closure systems – Process design and understanding including identification of critical process parameters and in-process material attributes – Control strategy and justification Lawrence X. Yu, Ph.D., Deputy Director (acting), Office of Pharmaceutical Science US FDA

3. 3 ICH Q8/Q9/Q10 Pharmaceutical Development, Quality Risk Management and The Quality System: Foundation for Assuring Ongoing State of Control The Materials System Integral to the Quality System Includes selection, characterizing, qualifying, and monitoring excipients and suppliers

4. Continuous Quality Improvement QbD involves gaining a thorough understanding of a process and the impact on that process of all the input variables and their effect on that process. Manufacturing Equipment Variables Variable Manufacturing Techniques Manufacturing Process Conditions Environmental Conditions Formulation (API and EXCIPIENT ) Chemical & Physical Property Variation Interactions of ALL these factors API Variability Excipients Variability Process Variability Product Variability

5. Formulation Flexibility Flexibility must be part of the Design Space and Control Strategy What is meant by formulation flexibility? – The quantitative composition of different batches may vary within an agreed Design Space. – The qualitative composition of different batches could also vary within an agreed Design Space But this is less likely! Why is formulation flexibility needed? – To compensate for changes in starting components. – To compensate for variability within the process. 5

6. Raising Awareness - Excipients QbD for a drug product drives the need for QbD of the excipient QbD is about building robust formulations and processes which can adapt to normal expected excipient variation The desire for QbD information in registrations may influence formulators’ excipient selection to choose excipients which: Are well characterized for various functionalities Are manufactured under well defined controls Have good batch uniformity and characterization May be Premium Grades designed specifically with Pharmaceutical Uses in mind Are supplied by manufacturers who have good change control and notification programs

7. Impact of QbD At a minimum, the Critical Quality Attributes (CQA)/Critical Material Attributes (CMA) and Functionality-Related Characteristics (FRC) of an excipient must be considered in a drug product QbD – This does NOT mean tighter specifications for existing excipients! QbD controls require a better understanding of: Excipient Batch Uniformity  Batch vs. Continuous processes?? Batch-to-Batch Consistency Supplier-to-Supplier Variability Communication between excipient suppliers and users on a technical level is essential – Allow for the excipient supplier to be involved early in drug development and build long-term relationship – Impact of changes a supplier makes to their manufacturing process and/or test methods

8. 8 Question-based Review for Pharmaceutical Quality Assessment FDA’s Question-based Review (QbR) is a general framework for a science and risk- based assessment of product quality QbR contains the important scientific and regulatory review questions to – Set regulatory standards relevant to product performance (safety and efficacy) – Assess applicants’ understanding and control of product and manufacturing Lawrence X. Yu, Ph.D., Deputy Director (acting), Office of Pharmaceutical Science US FDA

9. 9 Questions Provide a Roadmap Questions guide reviewers – Prepare a consistent and comprehensive evaluation of the application – Assess critical formulation & manufacturing variables Questions guide industry – Recognize issues [FDA] generally considers critical – Direct industry toward QbD Questions inform readers of the review – How QbD was used in the application – Provide the basis for a risk assessment Lawrence X. Yu, Ph.D., Deputy Director (acting), Office of Pharmaceutical Science US FDA

10. 10 FDA’s Expectation for Excipient QbD Information QbR questions - Control of Excipients How are the excipients qualified? What ensures that the excipients are suitable for their intended function? – Compendial specifications or in-house control – Acceptable ranges for identified CMAs of excipients – Adaptive formulation variable or process parameters to accommodate excipient variability Lawrence X. Yu, Ph.D., Deputy Director (acting), Office of Pharmaceutical Science US FDA

11. 11 FDA’s Expectation for Excipient QbD Information QbR questions - Critical Material Attributes of Excipients What attributes of the excipients were identified as critical and how are they related to the drug product CQAs? Lawrence X. Yu, Ph.D., Deputy Director (acting), Office of Pharmaceutical Science, US FDA

12. 12 FDA’s Expectation for Excipient QbD Information QbR questions – Excipient Type, Grade and Levels How were the excipient types and grades selected? What formulation development studies, including screening, characterization, optimization, and verification (robustness) if any, were conducted? Lawrence X. Yu, Ph.D., Deputy Director (acting), Office of Pharmaceutical Science, US FDA

13. Excipient Specific Questions (Draft) Does any excipient exceed the FDA Inactive Ingredient Database (IID) limit for this route of administration calculated based on maximum daily dose? If so, please justify What evidence supports compatibility between the excipients and the drug substance? What is the rationale for the excipient selections? What are the excipient specifications and how are they justified? How do the proposed specifications for the material attributes of the excipients ensure the quality and performance of the final drug product? Lawrence X. Yu, Ph.D., Deputy Director (acting), Office of Pharmaceutical Science US FDA 13

14. Expectations for Submitting Excipient Information in a QbD Application Excipient safety (purity & impurity) Compatibility with drug substance & other excipients Excipient type, grade & levels in the formulation Understand the impact of excipient properties on drug product CQAs and identify critical material attribute of excipients Develop appropriate control strategy to mitigate excipient variability’s impact on drug product CQAs Lawrence X. Yu, Ph.D., Deputy Director (acting), Office of Pharmaceutical Science US FDA

15. Formulation (API and EXCIPIENT ) Chemical & Physical Property Variation API’s typically make up a small portion of a drug formulation Excipient physical & chemical property variation is one of the most important variables that can impact a pharmaceutical manufacturing process Excipients are used for many functions by Users which may not be what the excipient was designed for Excipient Manufacturer’s Process Capability is primarily focused on chemical characteristics and CERTAIN physical/chemical properties for the Excipient Manufacturer’s INTENDED MARKET

16. The Problem There is no real Pharmaceutical Excipient Industry Many excipients are made in large chemical plants primarily designed for producing chemicals for other industries Small fraction of main production volumes Specifications driven by main market (usually not pharma) Varying degrees of dedicated R&D related to excipient uses Global market and manufacturing base

17. Key Considerations for Excipients What parameters are important to assess (not necessarily specified)? Many excipients manufactured by Continuous Production Samples at edges of specifications will rarely be available How homogeneous is a “batch”? Batch to Batch consistency? What kind of samples are representative? 17

18. Functionality Related Characteristics Performance or Functionality Related Characteristics (FRCs) identified by Users may NOT be properties typically controlled by the Maker’s manufacturing process User MUST communicate special needs to the manufacturer and determine if process capability exists to meet these needs FRCs are specific to a particular drug formulation & process not to an excipient alone FRCs MUST be determined experimentally!

19. Excipient Realities! Although QbD sample sets and other advanced approaches may be available from some excipient suppliers, these type of samples and the corresponding supporting information will only be available from a limited number of suppliers of certain excipients – If QbD related samples are available for design space development, it is important to understand what they represent and what they do not! Therefore, it is critical that users and makers frankly discuss what can be done and what cannot be done during the excipient selection and qualification process BEFORE formulations are finalized Various other alternative methodologies will need to be used for many excipients. 19

20. Sample Limitations Excipient companies generally target normal production to be in the center of their sales specification ranges – Samples will usually NOT be available at the extremes of the ranges for specific properties These types of samples cannot be expected by users or regulators! – Other mechanisms must be found to supplement requesting samples representing the limits of the normal specifications This is frequently misunderstood by the User, Industry and Regulators 20

21. Robustness of Formulation It is critical that formulators make sure that they have fully investigated excipient variation and developed the most ROBUST formula possible with excipients meeting standard sales specifications before pursuing specifications with a supplier which are tighter than sales specifications & process norms – Special grades can be expensive and lot selection can be risky!! – Material may not always be available to meet special requirements when needed – Approx. 50% of the time the excipient can’t meet the criteria if limits are tightened!! Otherwise, the Operations and Supply Chain people may have significant difficulties during commercial production – THIS IS THE REAL COST!!!

22. Robustness of Formulation To evaluate the design space, sometimes you need to get creative and evaluate things such as: – Samples of different grades with properties on either side of the target grade properties to determine if this level of variability truly affects performance – If this level of variability can be handled by developing a robust formulation and process, then the typical variation within a given grade should be no problem Can use DOE with limited samples that may not show full range but can determine interaction potential

23. Opportunities What can excipient suppliers do to assist users? – Conduct periodic review of batch data to assess batch uniformity and batch-to-batch consistency – If possible, be prepared to provide samples of excipients at the edges of the agreed specifications related to certain CQA (CMA)/FRCs This can be accomplished by preparing lab batches and blends to achieve specific attributes even if normal production does not reach spec limits 23

24. Opportunities What can users do? – Discuss additional performance related requirements with suppliers to determine potential for availability ! – Make sure that the supplier feels that they have the process capability to supply material meeting any specific requirements – Do not set specifications with lot selection criteria that suppliers are concerned about or are based on testing of a limited number of batches

25. IPEC-America’s Quality by Design (QbD) Committee IPEC-Americas has formed a QbD Product Development Committee to address the following areas:  Proper selection and use of Excipient Performance Tests (addressing functionality) – Decision Tree approach;  Development of robust formulations (including QbD, PAT, etc.);  Introduction of Co-processed Excipients with customized functionalities (removal of regulatory barriers and customer acceptance)

26. The Future QbD will drive pharmaceutical companies to have a much better understanding of the functional effect that excipients have on their process than they may have had in the past. This will create the need for even BETTER COMMUNICATION between makers, users and regulators than in the past when qualifying excipients

27. Acknowledgements David Schoneker, Colorcon Inc. Lawrence X. Yu, Ph.D., Deputy Director (acting), Office of Pharmaceutical Science, US FDA Ulla Paulsen, Ph. D., Director, Regulatory Affairs, CMC, IPEC Europe Chris Moreton, FinnBrit Consulting An example illustrating QbD concepts can be found online at FDA's Generic Drugs: Information for Industry webpage: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/H owDrugsareDevelopedandApproved/ApprovalApplications/Abbreviate dNewDrugApplicationANDAGenerics/UCM286595.pdf http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/H owDrugsareDevelopedandApproved/ApprovalApplications/Abbreviate dNewDrugApplicationANDAGenerics/UCM286595.pdf