Quality by Design Trevor Schoerie

Transcription

1 Quality by Design Trevor Schoerie

2 Guidelines Please contribute and ask questions Please relax and enjoy yourself Phone on silent / mute? Native presentation can be ed. Slide 2

3 Agenda The what, who, why, where, when but not the how of QbD What is QbD? Who is driving QbD? Why are we talking about QbD? Where will QbD be applicable? When will we need to adopt QbD? How do we do QbD? Slide 3

4 What is QbD? The quality by design (QbD) principle can be simply stated as follows: Once a system has been tested to the extent that the test results are predictable, further testing can be replaced by establishing that the system was operating within a defined design space. Slide 4

5 Who is driving QbD? As we ve said many, many times, FDA Office of Generic Drugs expects QbD applications starting January You heard right, full implementation of QbD in January FDA s Lawrence Yu, deputy director for science and chemistry in the Office of Generic Drugs Joint EU / US QbD program. Slide 5

6 Why are we talking about QbD? Risk Quality Targeted Product Profiles QTPP Design of experiments DOE Other documents Case studies PDA & FDA GMP s EU US FDA PIC/S ICH Q8, Q9 Q10 and Q11 Critical Quality Attributes (CQA) Critical Process Parameters CPP Design space Product Lifecycle QbD Control strategy Slide 6

7 Where will QbD be applicable? Lifecycle concept, but QbD is at the start of the product lifecycle, i.e. product design, R&D FDA Process Validation - 3 stages 1. Process Design = Quality by Design 2. Process Qualification (National Validation Forum) 3. Continued Process Verification National Validation Forum 1 National Validation Forum 2 Slide 7

8 When will we need to adopt QbD? FDA Guide to Process Validation EU Annex 15 FDA: Pharmaceutical cgmps For The 21 st Century ICH Q9 FDA: Quality System Approach to Pharmaceutical cgmp PICS VMP ICH Q10 ICH Q ISPE C&Q Baseline 5 Guide ISPE 21 st Century Qualification White Paper ICH Q8 ASTM E FDA Process Val. Guidance US Law as from 1 st Jan 2013? Slide 8

9 Australian GMPs - Risk Year GMP reference x times risk mentioned 1971 First TGA code of GMP TGA GMP code (Blue Book) First PIC/S code adopted in Australia Current 2009 version of the PIC/S GMP code 390 ICH ICH Title x times risk mentioned Q8 Pharmaceutical Development (2006) 10 Q9 Quality Risk Management (June 2006) 279 Q10 Pharmaceutical Quality System (April 2009) 34 Q11 Development & Manufacture of Drug Substances (May 2012) 51 Slide 9

10 What is QbD? Quality by Design (QbD) is a concept first outlined by Juran ICH - concepts 1. Quality by Design 2. Design Space 3. Design of Experiments 4. Critical Quality Attributes (CQA) 5. Critical Process Parameters (CPP) 6. Control Strategy Slide 10

11 Dosage form Design A rational approach to dosage form design requires a complete understanding of the physicochemical and biopharmaceutical properties of the drug substance. DOSAGE FORM DESIGN: A PHYSICOCHEMICAL APPROACH. Michael B. Maurin (DuPont Pharmaceuticals Company, Wilmington, Delaware, U.S.A.), Anwar A. Hussain and Lewis W. Dittert (University of Kentucky, Lexington, Kentucky, U.S.A.) FDA Publication - Quality by Design: Next Steps to Realize Opportunities? Ajaz S. Hussain, Ph.D. Office of Pharmaceutical Sciences, CDER, FDA, 17 September 2003 Slide 11

12 FDA Process Validation ICH Q11 discusses the Enhanced vs Traditional approach PharmOut White Paper on FDA r_fda_process_validation_guidance_final.pdf Slide 12

13 FDA PV Stages Stage 1 Process Design: The commercial manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. Stage 2 Process Qualification: During this stage, the process design is evaluated to determine if the process is capable of reproducible commercial manufacturing. Stage 3 Continued Process Verification: Ongoing assurance is gained during routine production that the process remains in a state of control. [FDA Guidance for Industry Process Validation: General Principles and Practices, Jan 2011] Slide 13

14 FDA Stage 1 Stage Intent Typical activities Process design To define the commercial process on knowledge gained through development and scale up activities The outcome is the design of a process suitable for routine manufacture that will consistently deliver product that meets its critical quality attributes A combination of product and process design (Quality by Design) Product development activities Experiments to determine process parameters, variability and necessary controls Risk assessments Other activities required to define the commercial process Design of Experiment testing Slide 14

15 FDA Stage 2 Stage Intent Typical activities Process Qualification To confirm the process design as capable of reproducible commercial manufacturing Facility design Equipment & utilities qualification Process Performance qualification (PPQ)* Strong emphasis on the use of statistical analysis of process data to understand process consistency and performance * Note: The term Process Performance Qualification or PPQ has been carried over from the 1987 guidance. This term is analogous with the traditional concept of process validation, as multiple batches of product made at commercial scale under commercial manufacturing conditions. It is not the same as the concept of equipment performance qualification. Slide 15

16 FDA Stage 3 Stage Intent Typical activities Continued Process Verification To provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement initiatives. Product review SOP data collection from every batch Data trending and statistical analysis Equipment and facility maintenance Calibration Management review and production staff feedback Improvement initiatives through process experience Slide 16

17 FDA and Industry publications Quality by Design for ANDAs: An Example for Immediate-Release Dosage Forms April pplicationandagenerics/ucm pdf Quality by Design for ANDAs: An example for Modified Release Dosage Forms Dec pplicationandagenerics/ucm pdf Applying Quality by Design to Vaccines CMC- Vaccines Working Group May Slide 17

18 ICH ICH Q8, Q9, Q10 & Q11are designed as separate but linked in a series of documents exploring pharmaceutical products lifecycle ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Pharmaceutical Quality System ICH Q11 - Development and Manufacture of Drug Substances Slide 18

19 ICH Q8 Concepts Critical Process Parameter (CPP) Control strategy CQA Variable 1 Design Space CQA Variable 4 Design Space CQA Variable 2 CDQ Variable 3 Most profitable Acceptable Range Slide 19

20 Pharmaceutical Development ICH Q8 Slide 20

21 Pharmaceutical Development ICH Q8 Quality by Design (QbD) 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. Slide 21

22 Pharmaceutical Development ICH Q8 Critical Quality Attribute (CQA) Quality attributes that must be controlled within pre defined limits Assurance that product meets its intended safety, efficacy, stability and performance Slide 22

23 Pharmaceutical Development ICH Q8 Critical Process Parameter (CPP) a process parameter that must be controlled within pre defined limits Assurance the product meets its pre defined quality attributes Slide 23

24 Quality Risk Management ICH Q9 PIC/S code of GMP, PE009-8, January 2009 Slide 24

25 Pharmaceutical Quality Systems Q10 Knowledge Management Describes systems that facilitate establishment and maintenance of a state of control for process performance and product quality. Facilitates innovation and continual improvement Applies to drug substance and drug product throughout product lifecycle Control strategy Slide 25

26 Pharmaceutical Quality System (PQS) ICH Q10 Pharmaceutical Development Technology Transfer Commercial Manufacturing Product Discontinuation Investigational products Good Manufacturing Practice Management Responsibilities PQS elements Enablers Process Performance & Product Quality Monitoring System Corrective Action / Preventative Action System Change Managements System Management review Knowledge Management Quality Risk Management Slide 26

27 Development and Manufacture of Drug Substances - ICH Q11 Provides further clarification on the principles and concepts described in ICH guidelines on - Pharmaceutical Development (Q8), Quality Risk Management (Q9) Pharmaceutical Quality Systems (Q10) as they pertain to the development and manufacture of drug substance. Slide 27

28 Development and Manufacture of Drug Substances - ICH Q11 Traditional approach Set points & operating ranges Process reproducibility and testing to meet acceptance criteria Enhanced approach Risk management & science. process parameters and unit operations that impact on CQA Further studies, design space & control strategies over the lifecycle. Slide 28

29 Development and Manufacture of Drug Substances - ICH Q11 A company can choose to follow different approaches in developing a drug substance. For the purpose of this guideline, the terms traditional and enhanced are used to differentiate two possible approaches. Slide 29

30 ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA hydrolysis_impurity At Step F Temp reflux Only 1 impurity is formed hydrolysis_impurity t = c, Conc. = c, H2O = c hydrolysis_impurity = <0.30% Slide 30

31 ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA Slide 31

32 ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA Traditional Approach: Set a proven acceptable range for % water and time that achieves the acceptance criteria for the hydrolysis impurity of 0.30% in intermediate F. Dry Intermediate E to a water content < 1.0%. Target reflux time of 1.5 hours and a maximum reflux time of 4 hours Slide 32

33 ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA Enhanced Approach: Where: [F] o refers to the initial concentration of intermediate F, [H 2 0] o refers to the initial concentration of water, M=[F] o / [H 2 0] o to X F refers to the ratio of the initial concentration of intermediate F the initial concentration of water, and refers to the time-dependent concentration of the hydrolysis degradant of intermediate F. Slide 33

34 ICH Q11 Example Linking Material Attributes & process parameters to a Drug CQA Summary: While both the traditional and enhanced approach provide ranges of water content and time to control the formation of the hydrolysis impurity, the enhanced approach allows more manufacturing flexibility. Slide 34

35 Control Strategy Planned set of controls, derived from current product and process understanding that assures process performance and product quality A control strategy can include, but is not limited to, the following: Material attributes (raw materials, starting materials, intermediates, reagents, primary packaging materials) Controls are implicit in the design of the manufacturing process In-process controls Controls on drug substance Slide 35

36 Control strategy table Drug Substance CQA (3.2.S.2.6) / Limit In Drug Substance In process Controls (Including In-process testing and process parameters) Controls on material attributes (raw materials / starting materials / intermediates) Impact of Manufacturing Process Design Is CQA tested on drug substance / Included in Drug Substance specification (3.2.S.4.1) Organic Purity Impurity X NMT 0.15% Design space of the reflux unit operation composed of a combination of % water in Intermediate E and the reflux time in step 5 that delivers Intermediate F with Hydrolysis Impurity 0.30% (3.2.S.2.2) Yes/Yes Impurity Y NMT 0.20% Any individual unspecified impurity Process parameters step 4 (3.2.S.2.2) P(H2) 2 barg T <50 C In-process test step 4 (3.2.S.2.4) Impurity Y 0.50% Specs for starting material D (3.2.S.2.3) Yes/Yes Yes/Yes NMT 0.10% Total impurities Yes/Yes NMT 0.50% Enantiomeric purity S-enantiomer NMT 0.50% Specs for starting material D (3.2.S.2.3) S-enantiomer 0.50% Stereocentre is shown not to racemize; (3.2.S.2.6) No/No Residual Solvent Ethanol NMT 5000 ppm Slide 36 In-process test during drying after final purification step (3.2.S.2.4) LOD 0.40% In-process results correlated to test results on drug substance No/Yes

37 Extracted from the FDA IM release worked example ednewdrugapplicationandagenerics/ucm pdf Slide 37

38 Submission of Control Strategy Information The information provided on the control strategy should include detailed descriptions of the individual elements of the control strategy plus, when appropriate, a summary of the overall drug substance control strategy. ICH M4Q recommends. Description of Manufacturing Process and Process Controls (3.2.S.2.2) Control of Materials (3.2.S.2.3) Controls of Critical Steps and Intermediates (3.2.S.2.4) Container Closure System (3.2.S.6) Control of Drug Substance (3.2.S.4) Slide 38

39 Common Technical Document (CTD) - Quality (ICH M4Q) guideline Regional Admin Information Module 1 Not Part of the CTD Module 2 Quality Overall Summary Nonclinical Overview Nonclinical Summary Clinical Overview Clinical Summary The CTD Quality Nonclinical Study Reports Clinical Study Reports Module 3 Module 4 Module 5 Slide 39

40 Thanks 1. What is QbD? 2. Who is driving QbD? 3. Why are we talking about QbD? 4. Where will QbD be applicable? 5. When will we need to adopt QbD? 6. How do we do QbD? Slide 40