Quality by Design ( QbD )

Quality by Design is pharmaceutical product development which ensures the product quality, ICH Guideline Q8 is provide the guidelines about QbD.

1. SEMINAR PRESENTATION I M.Pharm II Semester QUALITY BY DESIGN QBD Presented By NAVANEETHAKRISHNAN P Department of Pharmaceutics KARPAGAM COLLEGE OF PHARMACY, COIMBATORE - 32 Department of Pharmaceutics, KCP, CBE-32 1 Monday, July 23, 2019

2. CONTENTS INTRODUCTION ICH GUIDELINE Q8 REGULATORY AND INDUSTRY VIEW ON QBD 2 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

3. QbD Introduction: The pharmaceutical Quality by Design ( QbD ) is a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management. 3 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

4. QbD Will Enhance 4 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

5. QbD 5 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

6. QbD 6 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

7. QbD A more systematic approach to development (also defined as QUALITY BY DESIGN ) for example, incorporation of prior knowledge, results of studies using design of experiments, use of quality risk management, use of knowledge management (ICH Q10) throughout the lifecycle of the product. 7 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

8. QbD Benefits of QBD QbD is good for Pharmaceutical formulation Eliminate batch failures Minimize deviations and costly investigations Avoid regulatory compliance problems Organizational learning is an investment in the future QbD is good Science Better development decisions Empowerment of technical staff 8 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

9. Steps in QbD 9 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

10. Elements For Pharmaceutical Development ELEMENTS OF PHARMACEUTICAL DEVELOPMENT The section that follows elaborates on possible approaches to gaining a more systematic, enhanced understanding of the product and process under development . Quality Target Product Profile (QTPP) Critical Quality Attributes (CQA) Risk Assessment Design Space Selection of Variables Describing a Design Space in a Submission Unit Operation Design Space(s) Relationship of Design Space to Scale and Equipment Design Space Versus Proven Acceptable Ranges Design Space and Edge of Failure Control Strategy Product Lifecycle Management and Continual Improvement 10 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

11. Elements For Pharmaceutical Development Quality Target Product Profile (QTPP) The quality target product profile forms the basis of design for the development of the product . (it mainly focus on the safety and efficacy . ) Considerations for the quality target product profile could include Intended use in clinical setting, route of administration, dosage form, delivery systems. Dosage strength(s) Container closure system Therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g., dissolution, aerodynamic performance) Drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for the intended marketed product. 11 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

12. Elements For Pharmaceutical Development Benefits in the Quality Target Product Profile Identifies risks and best approaches to manage. Uses tools/enablers in an optimized fashion (such as integration of QbD and biopharmaceutics ) Generates and enables knowledge sharing. An iterative, learning, life-cycle process for optimizing decision making and the therapeutic outcomes for the patient benefit. A drug product designed, developed and manufactured according to Quality Target Product Profile with specification (such as dissolution/release acceptance criteria) consistent with the desired in vivo performance of the product. 12 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

13. Elements For Pharmaceutical Development Critical Quality Attributes (CQA) A CQA is a physical, chemical, biological, or microbiological property that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) and drug product. 13 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

14. Elements For Pharmaceutical Development CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, drug release and stability. CQAs for other delivery systems can additionally include more product specific aspects, such as aerodynamic properties for inhaled products, sterility for parenterals , adhesion properties for transdermal patches. CQAs For drug substances, raw materials and intermediates , It include the particle size distribution, bulk density 14 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

15. Elements For Pharmaceutical Development Risk assessment Risk assessment is a valuable science-based process used in quality risk management that can aid in identifying which material attributes and process parameters potentially have an effect on product CQAs. Risk assessment is typically performed early in the pharmaceutical development process and is repeated as more information becomes available and greater knowledge is obtained. 15 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

16. Cont.., They can overcome by Once the significant parameters are identified, they can be further studied (e.g., through a combination of design of experiments, mathematical models, or studies that lead to mechanistic understanding ) to achieve a higher level of process understanding. 16 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

17. Elements For Pharmaceutical Development Examples Use of a risk assessment tool. For example, a cross-functional team of experts could work together to develop an Ishikawa (fishbone) diagram that identifies potential variables which can have an impact on the desired quality attribute. 17 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

18. Elements For Pharmaceutical Development 18 Department of Pharmaceutics, KCP, CBE-32 Ishikawa Diagram for Tablets Monday, July 23, 2019

19. Elements For Pharmaceutical Development Design Space The relationship between the 1. Process inputs ( Material attributes and process parameters ) & 2. Critical quality attributes Can Be Described In The Design Space 19 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

20. Elements For Pharmaceutical Development SELECTION OF VARIABLES The risk assessment and process development experiments can lead to an understanding of the linkage and effect of process parameters and material attributes on product CQAs, and also help identify the variables and their ranges within which consistent quality can be achieved. 20 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

21. Elements For Pharmaceutical Development Example Design space determined from the common region of successful operating ranges for multiple CQAs. The relations of two CQAs, i.e., tablet friability and dissolution, to two process parameters of a granulation operation. 21 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

22. Elements For Pharmaceutical Development 22 Department of Pharmaceutics, KCP, CBE-32 Contour plot of dissolution as a function of Parameters 1 & 2. Monday, July 23, 2019

23. Elements For Pharmaceutical Development 23 Department of Pharmaceutics, KCP, CBE-32 Contour plot of friability as a function of Parameters 1 & 2. Monday, July 23, 2019

24. Elements For Pharmaceutical Development 24 Department of Pharmaceutics, KCP, CBE-32 Proposed design space, comprised of the overlap region of ranges for friability and or dissolution. Monday, July 23, 2019

25. Elements For Pharmaceutical Development CONTROL STRATEGY A control strategy can include, Control of input material attributes (e.g., drug substance, excipients , primary packaging materials) based on an understanding of their impact on processability or product quality; Product specification(s) Controls for unit operations that have an impact on downstream processing or product quality (e.g., the impact of drying on degradation, particle size distribution of the granulate on dissolution); In-process or real-time release testing in lieu of end-product testing (e.g. measurement and control of CQAs during processing); A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate prediction models. 25 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

26. REGULATORY VIEWS ON QBD As defined by an FDA official (Woodcock, 2004), “The QbD concept represents product and process performance characteristics scientifically designed to meet specific objectives, not merely empirically derived from performance of test batches.” “Another FDA representative (Shah, 2009) states that introduction of the QbD concept can lead to cost savings and efficiency improvements for both industry and regulators.” 26 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

27. REGULATORY VIEWS ON QBD QBD facilitate 27 Department of Pharmaceutics, KCP, CBE-32 enhance opportunities for first cycle approval, streamline post approval changes and regulatory processes, enable more focused inspections, provide opportunities for continual improvement (Shah, 2009). innovation, increase manufacturing efficiency, reduce cost/product rejects, minimize/eliminate potential compliance actions, Monday, July 23, 2019

28. REGULATORY VIEWS ON QBD EMA representatives ( Korakianiti , 2009) point out that it is preferable for a design space to be complemented by an appropriate control strategy. The review of variations regulations and the revised Variations Classifications Guideline (2008) has taken into account QbD submissions, to enable easier updates of the registration dossier. EMA templates and guidance documents used for the assessment of any new drug application in the centralized procedure include the possibility of design space appointment (e.g. Day 80 Quality AR Template). 28 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

29. REGULATORY VIEWS ON QBD EMA, FDA, and ICH working groups have appointed the ICH quality implementation working group (Q-IWG), which prepared various templates, workshop training materials, questions and answers, as well as a points- to-consider document (issued in 2011) that covers ICH Q8(R2), ICH Q9, and ICH Q10 guidelines. This document provides an interesting overview on the use of different modeling techniques in QbD . 29 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

30. REGULATORY VIEWS ON QBD There were several EMA marketing authorization applications (MAA) with QbD and PAT elements for the following products: Avamys ®, Torisel ® , Tyverb ® , Norvir ® , Exjade ® , Revolade ® , Votrient ® , etc.). Up to 2011, there was a total of 26 QbD submissions to EMA (for the new chemical entities) 18 of them were initial MAAs (4 including the realtime release), 6 of them were concerning post- authorization, and 2 were scientific advice requests. An additional two MAAs were submitted for biological products, but none of the submissions were related to the generics industry Up to 2011, there were approximately 50 QbD related applications to the FDA ( Miksinski , 2011). FDA authorities state that QbD is to be fully implemented by January 2013 ( Miksinski , 2011). 30 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

31. INDUSTRY VIEWS ON QBD Pfizer was one of the first companies to implement QbD and PAT concepts . Through these concepts, the company gained enhanced process understanding, higher process capability, better product quality, and increased flexibility to implement continuous improvement change. 31 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

32. QbD for industry and regulatory bodies Industry Regulatory agency Development of scientific understanding of critical process and product attributes. Scientifically based assessment of product and manufacturing process design and development. Controls and testing are designed based on limits of scientific understanding at development stage. Evaluation and approval of product quality specifications in light of established standards (e.g. purity, stability, content uniformity, etc.). Utilization of knowledge gained over the product’s lifecycle for continuous improvement. Evaluation of post- approval changes based on risk and science. 32 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

33. References Jelena Djuris Computer-aided applications in pharmaceutical technology 2013 ( 1 to 7 ) PHARMACEUTICAL DEVELOPMENT – ANNEX. ICH Harmonised Tripartite Guideline. 2013 (9 to 14 ) Nishendu P . Nadpara, Rakshit V. Thumar, Vidhi N. Kalola, Parula B. Patel. Quality By Design ( Qbd ) : A Complete Review, International Journal of Pharmaceutical Sciences Review and Research. ISSN 0976 – 044X. 2012 (2 0 to 28 ) . 33 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019

34. Thank You 34 Department of Pharmaceutics, KCP, CBE-32 Monday, July 23, 2019