QbD In Drug Development. Mathew Cherian Ph.D. Director & Senior Fellow Pfizer, USA

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2 QbD In Drug Development Mathew Cherian Ph.D. Director & Senior Fellow Pfizer, USA

3 The Origin of QbD The concept of Quality by Design (QbD) was introduced by Romanian born US engineer Joseph Juran QbD was first used in the automobile industry

4 Recent Changes in Regulatory Environment Quality cannot be tested into products; rather it must be built in. ICH Guidelines provide the underpinnings for QbD ICH Q8(R2): Pharmaceutical Development (2005 R1, 2009 R2) ICH Q9: Quality Risk Management (2005) ICH Q10: Pharmaceutical Quality Systems (2008) ICH Q11: Drug Substance Development (2011)

5 Quality by Design ICH Q 8, 9, 10

6 Pharma Industry vs Others

7 Basic Principles of QbD QbD Processes Quality Target Product Profile (QTPP) Objectives The first objective is to define target and minimum objectives for the product that meet patient needs. A second objective is to define target and minimum development objectives that meet business needs. Pharmaceutical Development (ICH Q8 & Q11) Determine the nexus of clinical safety/efficacy (and business) requirements to quality of drug product and drug substance Carry out development studies that lead to an deeper knowledge of product performance over a wider range of material attributes, processing options and process parameters. Communicate the knowledge that establishes that the formulation and type of dosage form selected are appropriate for the intended use. Ensure that a product of the required quality will be produced consistently by identifying, understanding and controlling sources of variability. Risk Management Process (ICH Q9) Define quality risk management process that encompass development, manufacturing, inspection, distribution and submission/review processes during the lifecycle of drug substances, drug products Regulatory Application Successfully file QbD regulatory applications in each global region Pharmaceutical Quality Systems (ICH Q10) Develop quality systems that support development and manufacture of pharmaceutical drug substances, and drug products, throughout the product lifecycle. Ensure that product quality is consistently achieved throughout a product s lifecycle.

8 Motivation for QbD Financial Less spending for development/ lifecycle management of products Lower cost to maintain marketed products Reduced rework or product rejection Prioritized spending for development and commercialized product Regulatory Because we have to. Most regulatory agencies require QbD submissions Potential for regulatory relief when filing post-approval changes Potential for reduced submission review time or less onerous reporting Enhanced submission quality Consistent with FDA, JP & EU regulatory requirements Quality Robust products and processes leading to reduced rework or product reduction Predictive processes Risk-based, prioritized continuous improvement Rapid troubleshooting Reduced compliance risk Product Development & Commercial Support Clear development focus Resources focused on key development & commercial development objectives Efficient development processes Better definition of development & commercial risks

9 Traditional Approach to Quality Traditionally quality is ensured by testing the product This approach has the obvious weakness that the testing happens after the product is made- any flaw discovered in testing can help in making future products only The oft- repeated cliché is: You cannot test quality into a product

10 ICH and FDA Guidelines ICH Q8 was the first guideline ever on QbD in the pharmaceutical industry FDA followed Q8 with its own guideline, closely aligning with ICH. FDA s guideline states The aim of pharmaceutical development is to design a quality product and its manufacturing process to consistently deliver the intended performance of the product. The information and knowledge gained from pharmaceutical development studies and manufacturing experience provide scientific understanding to support the establishment of the design space, specifications, and manufacturing controls.

11 Challenges in Implementing QbD To successfully implement QbD, we must have thorough knowledge of the product detailed and complete knowledge of the process understanding of the variability in raw materials, and all manufacturing components understanding relationship between the process and CQAs Understanding the relation between CQA and clinical safety and efficacy The goal is to make safe and effective products

12 Design Space & Its Significance Definition of Design Space. Design Space is: the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. ICH Q8(R2) (Step 4, August 2009), Pharmaceutical Development Design space is proposed by the applicant, and is subject to regulatory assessment and approval Typically there is less regulatory burden when using QbD

13 Traditional Approach to Drug Development Select purest active drug and excipients Develop a process, and use knowledge derived from process characterization to define critical, key and non- key process parameters The critical process parameters are then controlled within a narrow range, and the process is validated The narrowest practical range is selected for process parameters, and the ingredients are specified at the narrowest possible ranges

14 Rewards of Design Space Design Space in QbD provides regulatory flexibility Working within the design space is not considered a change by regulatory authorities. Movement out of the design space is considered a change and would normally initiate a regulatory post-approval change process. (FDA Guidance) Movement within design space does not require prior approval At present there are several thousand supplemental applications every year at the FDA Changes made within design space may require reporting- usually less onerous than regular post approval change

15 Steps to Define Design Space It is necessary to define Target Product Profile (TPP) at the beginning of drug development TPP spells out Products desired characteristics and features Studies and activities that must be completed to demonstrate the products efficacy, safety and performance When possible also defines what competitive advantages the product will have over a similar product

16 TPP (continued) TPP is not an unchanging credo TPP is dynamic, and during the course of development can be revised and updated TPP is A strategic tool Useful for communicating with management, peers, investors, partners, and regulatory authorities Useful for tracking progress The first step in development using QbD is to define TPP

17 QTPP- Example Sterile Emulsion QTTP Element Target Justification Dosage form Emulsion Drug poorly water soluble Dosage design Sub- micron particle size Dosage strength Pharmacokine tics Stability Primary Packaging Compatibility with plastics Current emulsion products found safe within this range 5 mg/ml mg of drug to be delivered Immediate release, T1/2 less than 15 minutes 24 months at room temperature Glass vials and syringes Compatible with PVC and polypropylene Onset and maintenance of anesthesia Ideal for worldwide distribution Vials for multiple doses, and syringes for quick dose titration in OR Widely used in bags and tubes

18 QTTP (continued) QTPP Element Target Justification Processing Route of administration Non- aseptic emulsification IV at Y- site and / or from bags Terminally heat sterilizable Typical usage in OR Particle size nm Safety established with other similar products Sterility Sterile Compendial Endotoxin NMT 1 EU / ml Based on total volume expected Anti- microbial preservative Yes Multi-dose presentation

19 Safety & Efficacy-Basis for CQAs

20 Critical Quality Attributes (CQA) Define your Critical Quality Attributes A CQA is a physical, chemical, biological, or microbiological property or characteristic 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. (FDA definition) Process considerations should be kept separate from CQAs and should be listed under Critical Process Parameters (CPP) CQA impact on safety and efficacy is generally independent of CPPs

21 CQAs (continued) For structured products like emulsions and liposomes, CPPs have very strong bearing on CQAs Changes in CPPs likely influence CQAs. In such cases they need to be considered together

22 Critical Process Parameters(CPP) What part of the process inputs (materials and process parameters) most influences the final product quality ICH Q8(R2) A critical process parameter is a process parameter whose variability has an impact on the critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality.

23 Risk Assessment Risk assessment is based on scientific principles Used to determine functional relationship, if any, between material attributes and process parameters on product CQAs Performed early in development and often repeated during development as more refined data are obtained Initially an exhaustive list of all material attributes ad process parameters is prepared. The list is whittled down based on prior knowledge and scientific assessment Additional experimental work is done, based on which the list can be shortened still further, and attributes and parameters prioritized still further

24 Risk assessment (contd) Once significant parameters and attributes have been identified, they can be further investigated by a factorial design of experiments

25 Risk Assessment Some challenging questions How much risk is too much? Are some risks cumulative? What are unforeseen consequences of risks?

26 Risk Assessment of a Drug substance

27 Justification for Initial Risk Assessment

28 Assessing Risk: Ranking CPPs and CQAs

29 Design Space Definition of Design Space. Design Space is: the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. ICH Q8(R2) (Step 4, August 2009), Pharmaceutical Development Design space is proposed by the applicant, and is subject to regulatory assessment and approval Typically there is less regulatory burden when using QbD

30 Design Space ICH Q8 tells us what is meant by design space But it does not spell out how to define the design space

31 QbD Regulatory Applications US FDA requires that all new drug applications follow QbD All ANDAs are submitted with some level of adherence to QbD Although QbD was conceived to give complete freedom to the applicant, at present it has given only a lower level of reporting (e.g. CBE 30) to the regulatory authorities

32 QbD by Phase of Development Use of QbD depends to a great degree on the development phase of the drug At preclinical and Phase I an overt attempt at full adherence to QbD is seldom seen in the industry TPP is drafted early on Select CQAs and CPPs are given attention, and select QbD activities are often embedded in other traditional activities No systematic QbD is typically executed in preclinical / Phase I

33 Implementing QbD

34 Example: Weighting of Quality Attribute on safety and efficacy

35 Impact of QbD Implementation Over the life of the product, QbD is expected to be cost effective in view of more robust and well characterized processes However, during initial development QbD can entail more expenses Edge of failure experiments are not often conducted When properly executed QbD will make life cycle management easier to carry out

36 Where are with QbD US FDA has required sponsors to use QbD in drug development and submissions since January 1, 2013 Typically full-blown QbD is not used in preclinical or Phase I stage Often platform technologies available inhouse are used, with little or no change in parameters Key aspects of QbD like TPP, CQA and CPP are embedded in traditional development practices, and followed in the early phases QbD programs may kick in Phase II

37 Where are we? (cont d) Products by full- blown QbD is significantly more expensive to develop Much product knowledge is gained The regulatory relief expected by traversing the entire design space in development has not materialized- not yet If anything, the level of reporting required has been mitigated somewhat Edge-of-failure conditions are often not studied, especially in CQAs

38 Thank You Acknowledgements: Carol Kirchoff, Pfizer, USA Parag Kohle, Pfizer, USA

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