The role and future of dissolution testing in a QBD product development framework

Transcription

1 The role and future of dissolution testing in a QBD product development framework Paul Dickinson, AstraZeneca, Alderley Park, Cheshire Senior Clinical Pharmacology Scientist paul.dickinson@astrazeneca.com Sept 2012

2 The future The future is already here. But it is very unevenly distributed. William Gibson. 2 Paul Dickinson GMD Clinical Pharmacology and Pharmacometrics

3 Outline and Acknowledgements specifically looking for a forward-looking view of how the need for and development of dissolution QC methodology can be better linked to clinical performance So I ll focus on that but at the end I want to be a bit more future looking Obviously these ideas have been developed in conjunction with a lot of colleagues but particularly some of these slides were co-authored by David Holt and presented at - Note: the views expressed in this presentation reflect my personal interpretation and the experience of some individuals within AstraZeneca 3 Paul Dickinson GMD Clinical Pharmacology and Pharmacometrics

4 QbD New CMC Approach: What is Different? Aspects Traditional QbD Pharmaceutical Development Manufacturing Process Process Control Product Specification Control Strategy Lifecycle Management Empirical; typically univariate experiments Fixed In-process testing for go/nogo; offline analysis slow response Primary means of quality control; based on batch data Mainly by intermediate and end product testing Reactive to problems & OOS; post-approval changes needed Risk-based; Systematic; multivariate experiments Adjustable within design space; opportunities for innovation (PAT) PAT utilized for feedback and feed forward at real time Part of the overall quality control strategy; based on desired product performance (safety and efficacy) Risk-based; controls shifted upstream; reducing product variability; real-time release Continual improvement enabled within design space 4 Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

5 QbD and Biopharm: ICHQ8R1 (Nov 2008) ( - Quality By Design is defined as 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 - Defining the quality target product profile (QTPP) as it relates to quality, safety and efficacy, Biopharmaceutics Biopharmaceutics

6 QTPP From ICH Q8R1 Quality Target Product Profile (QTPP): A prospective summary of the quality characteristics of a drug product that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the drug product. Quality Target Product Profile The quality target product profile forms the basis of design for the development of the product. 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) appropriate to the drug product dosage form being developed; - Drug product quality criteria (e.g., sterility, purity, stability and drug release) appropriate for the intended marketed product. Specifications?

7 A changing perception (post 2008) There is some ground swell that puts patients at the centre of drug product development The FDA have moved the biopharmaceutics reviewers from clinical pharmacology into ONDQA Selen A, Cruañes MT, Müllertz A, Dickinson PA, Cook JA, Polli JE, Kesisoglou F, Crison J, Johnson KC, Muirhead GT, Schofield T, Tsong Y. Meeting report: applied biopharmaceutics and quality by design for dissolution/release specification setting: product quality for patient benefit. AAPS J. 2010;12: doi: /s Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

8 Patient Needs: QTPP: Specifications Based on Desired product Performance Mechanistic understanding? Prior knowledge? Mechanistic understanding? Predictive tools? Risk Assessment? Clinical studies? Cruañes and Dickinson Patient Needs QTPP Clinically Relevant Specs Specification to ensure Manufacturing Consistency / QC method My talk limited to Standard IR tablets so the PK part of the QTPP is ensuring rapid and complete release and then bioequivalence between batches

9 What evidence is required to build confidence that a QC-like method controls drug exposure in patients Probably up until recently most of us have thought that an IVIVC is required for poorly soluble compounds. However Amidon and co-workers recognised some time ago that variation in dissolution rate may not lead to a change in in vivo performance This is because other physiological absorption processes can be (are) slower than dissolution - Gastric emptying, permeation This means dissolution could guarantee in vivo performance without an IVIVC - Across a limited dissolution range to ensure dissolution never becomes slower than physiological processes ( safe space ) BCS Class IVIVC Expectation IVIVC if dissolution rate slower than gastric emptying rate, otherwise limited or no correlation IVIVC expected if in vitro dissolution rate is similar to in vivo dissolution rate, unless dose is very high Absorption (permeability) is rate determining and limited or no IVIVC with dissolution rate Limited or no IVIVC expected Amidon et al. Pharm. Res. 12:413-20, 1995

10 What evidence is required to build confidence that a QClike method controls drug exposure in patients Possible relationships between dissolution and drug bioavailability in subjects: 2. IVIVR (Safe Space) 3. Mixed safe space / IVIVC Change in C max or AUC (%) = standard and side batches incorporating the highest risk drug product and process variables IVIVC + + Time to x% dissolution (min) For any product three* potential outcomes exist for the relationship between in vitro dissolution and bioavailability, these are: 1. A Level A or C IVIVC could be established, where changes in in vitro dissolution are directly correlated to changes in bioavailability. 2. An IVIVR in which no effect on bioavailability would be observed across a range of in vitro dissolution rates (referred to below as a Safe Space ). 3. The final option is a mixed safe space / IVIVC result in which bioavailability is only affected for a few of the variants tested clinically. * Assuming in vitro dissolution mechanistically similar to in vivo dissolution. A 4 th outcome is differences in vivo that are not replicated in vitro.

11 Dissolution limits which assure exposure by BCS Class for a QbD based development High Solubility Low Complete dissolution within 30 minutes in most discriminating simple media (physiological ph range). If slower: bioavailability data or additional mechanistic information Limit set based on clinical bioavailability data Complete dissolution within 15 minutes in most discriminating simple media (physiological ph range). If slower: bioavailability data or additional mechanistic information Limit set on case by case basis: Bioequivalence Study Or Follow principles of BCS2 or BCS3 if can demonstrate that compound behaves more like BCS2 or BCS3 in vivo Dickinson et al. (2008) AAPS Journal. 10:

12 Overview of Steps in A Typical QbD development Construct Quality Target Product Profile Collate Prior Knowledge Perform High Level Risk Assessment Conduct Experimental Evaluation 2 nd Iteration of Risk Assessment Evaluate impact of highest risk variables on in vivo performance Develop detailed process understanding Review Risk Assessment Construct Design Space Establish Control Strategy Product Risk Product Knowledge

13 Overview of Steps in A Typical QbD development Construct Quality Target Product Profile Collate Prior Knowledge Perform High Level Risk Assessment Conduct Experimental Evaluation 2 nd Iteration of Risk Assessment Evaluate impact of highest risk variables on in vivo performance Develop detailed process understanding Review Risk Assessment Construct Design Space Establish Control Strategy Product Risk Product Knowledge

14 Development of in vivo understanding Overview of Steps in a typical QbD Development Focus of the AZ Case Studies 1. Conduct Quality Risk Assessment Construct Quality Target Product Profile Collate Prior Knowledge Perform High Level Risk Assessment 2. Develop Appropriate CQA tests Conduct Experimental Evaluation Product Risk 2 nd Iteration of Risk Assessment Evaluate impact of highest risk variables on in vivo performance Develop detailed process understanding Review Risk Assessment Construct Design Space Establish Control Strategy Product Knowledge 3. Understand the in vivo importance of changes 4. Establish Appropriate CQA limits 5. Use the product knowledge in subsequent QbD steps

15 Structured five-step approach to build in vivo understanding: Specific Example for Dissolution CQA Step 1. Conduct Quality Risk Assessment (QRA) 2. Develop appropriate CQA tests Example QRA to allow the most relevant risks (product and process variables) to in vivo dissolution to be identified (ICH Q9) Develop in vitro dissolution test(s) with physiological relevance that is most likely to identify changes in the relevant mechanisms for altering in vivo dissolution (identified in Step 1). 3. Understand the in vivo importance of changes Determine the impact of the most relevant risks (from Step 1) to clinical pharmacokinetics based on in vitro dissolution data combined with: 1. prior knowledge including BCS and/or mechanistic absorption understanding 2. and/or clinical bioavailability data 4. Establish appropriate CQA limits 5. Use the Product Knowledge in Subsequent QbD steps Establish the in vitro dissolution limit that assures acceptable bioavailability. Define a Design Space to deliver product CQAs e.g. ensure in vitro dissolution performance within established limits. Develop a Control Strategy to ensure routine manufacture remains within the design space e.g. that assures dissolution limits are met during routine manufacture (ICH Q10).

16 Structured five-step approach to build in vivo understanding: Specific Example for Dissolution CQA Step 1. Conduct Quality Risk Assessment (QRA) 2. Develop appropriate CQA tests Example QRA to allow the most relevant risks (product and process variables) to in vivo dissolution to be identified (ICH Q9) Develop in vitro dissolution test(s) with physiological relevance that is most likely to identify changes in the relevant mechanisms for altering in vivo dissolution (identified in Step 1). 3. Understand the in vivo importance of changes Determine the impact of the most relevant risks (from Step 1) to clinical pharmacokinetics based on in vitro dissolution data combined with: 1. prior knowledge including BCS and/or mechanistic dissolution absorption understanding 2. and/or clinical bioavailability data In some cases: Make product variants with retarded Test in man 4. Establish appropriate CQA limits 5. Use the Product Knowledge in Subsequent QbD steps Establish the in vitro dissolution limit that assures acceptable bioavailability. Define a Design Space to deliver product CQAs e.g. ensure in vitro dissolution performance within established limits. Develop a Control Strategy to ensure routine manufacture remains within the design space e.g. that assures dissolution limits are met during routine manufacture (ICH Q10).

17 My interpretation of FDA View in this area P. Marroum, PSWC2010, New Orleans, October, Paul Dickinson June 2011 GMD Pharmaceutical Development

18 Case Study 1: A BCS2 compound with reasonable solubility

19 Case Study 1: In vivo data needed BCS2 Step 1: QRA Step 2: Develop CQA Test Produce Tablets variants with highest risks Test tablets in several dissolution conditions and find best Step 3: Understand in vivo importance BCS2: Need clinical data Step 5: Use in subsequent QbD steps Design space boundaries defined to ensure CQA limits are always met 19 SAFE SPACE: Variant D is the limit Step 4: Establish appropriate CQA limit Exposure is the same for all tablet variants EMEA/Efpia QbD Application Workshop - London

20 Step 5: Use the product knowledge in subsequent QbD Steps Design Space The Design Space was defined using the in vivo knowledge in conjunction with formulation and process understanding to ensure the delivery of the CQAs Design space boundaries defined to ensure that batches with acceptable bioavailability would always be produced (i.e. batches that have dissolution faster than Variant D). Encompassing: Formulation Composition Input material quality (API and excipients) Manufacturing Process Standard Tablet Design Space verified : Variant X: Multivariate worse case from design space Variant D 20 Paul Dickinson GMD Clinical Pharmacology and Pharmacometrics

21 Final QC Method and Specification

22 Pharmacopoieal QC Method Requirements e.g. USP <1092> THE DISSOLUTION PROCEDURE: DEVELOPMENT AND VALIDATION General Comments method capability (e.g. discrimination, reproducibility, variability) Dissolution Media aqueous buffered media, sink conditions, surfactants Dissolution Volume 500, 900, 1000ml most common Deaeration assess the impact of air bubbles IVIVC Considerations e.g. biorelevance of media choice Apparatus/Agitation e.g. Apparatus 1 (baskets) at 100 rpm or Apparatus 2 (paddles) at 50 or 75 rpm are most common Use of Sinkers e.g. for capsules Study Design during development - A sufficient number of time points should be selected to adequately characterize the ascending and plateau phases of the dissolution curve. For immediaterelease dosage forms, the duration of the procedure is typically 30 to 60 minutes. Visual Observations e.g. of product dissolution and disintegration behaviour are very useful because dissolution and disintegration patterns can be indicative of variables in the formulation or manufacturing process. Sampling/Filters Manual vs. Autosampling; adsorption of the drug(s) onto the filter needs to be evaluated. Assay of samples usually sample assay is either spectrophotometric determination or HPLC Validation Requirements e.g. specificity, linearity, range, accuracy, precision, robustness, solution stability Acceptance Criteria Typical acceptance criteria for the amount of active ingredient dissolved, expressed as a percentage of the labelled content (Q), are in the range of 75% to 80% dissolved. 22 Paul Dickinson Sept 2012 GMD Pharmaceutical Development

23 Clinically Relevant Dissolution Specifications: My interpretation of FDA View Clinically relevant dissolution specification help assure: Consistent in-vivo performance Consistent safety and efficacy profiles for the marketed product relative to those achieved in the clinical trials Delivery of the intended dose to the patient Optimal rate of drug delivery to the patient Clinically relevant dissolution methods: Are required to set clinically relevant dissolution specification Demonstrate in vivo predictability Predict the in-vivo impact of changes in the formulation and/or manufacturing processes Do not always require sophisticated dissolution methods C. Moore, DIA CMC Workshop: Translating Science into Successful Submissions, Washington, D.C. February 9, Paul Dickinson Sept 2012 GMD Pharmaceutical Development

24 ICH Q6A Decision tree 24 Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

25 ICH Q6A Decision tree 25 Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

26 Dissolution - What are the aspects we are trying to balance? Under- Discrimination (Patient Risk) Poor Quality batches released impact on safety & efficacy Fail to measure important failure mechanisms Over- Discrimination (Producer Risk) Fail clinically acceptable batches Impact Manufacturing Process Capability (introduce variation) Challenges Global method and specification Based on ensuring BE between batches That allows the manufacturing process capability to be monitored (Continuous Process Verification) and corrective actions taken if trends observed That considers traditional quality aspects To understand and justify all these aspects a quite complicated dataset needs to be presented and interpreted. Interpretation may depend on which of above aspects is most important to whoever is looking at the data 26 Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

27 QC Dissolution Method Selection assessing capability requirements Performance of the different dissolution methods against desired method capabilities Desired method capability The ability to detect the impact of minor process and formulation changes (within design space) ph 1.2 aqueous buffer ph 4.5 aqueous buffer ph 6.8 aqueous buffer Surfactant Low. Only able to discriminate the extreme retardation mechanism Low. Shows same rank order discrimination as surfactant, however high intra-batch variability, hence poor method capability/robustness. High. Able to discriminate between tablet variants and hence all dissolution retardation mechanisms probed in clinical study. High. Able to discriminate between tablet variants and hence all dissolution retardation mechanisms probed in clinical study. The ability to detect changes in performance of the product on storage (stability indicating) Low. Does not discriminate stability changes Not tested due to high intrabatch variability. Not tested due to incomplete release in a reasonable time (and shows same rank order discrimination as surfactant). High. Discriminates minor stability changes To achieve complete dissolution within a timescale appropriate for a routine control test Yes. Complete release in a reasonable time for an IR tablet Yes. Complete release in a reasonable time for an IR tablet No. Incomplete release in a reasonable time. Yes. Complete release in a reasonable time for an IR tablet. Practical for routine use (timescale, ease of use of media) The methodology should be able to assure in vivo performance, ie, it can be used to set a specification which assures that tablets will give equivalent clinical performance to those used in pivotal clinical studies Physiological relevance of the media Yes. Media simple to prepare. Medium/High. Overdiscriminatory with respect to one in vivo failure mode. Based on the knowledge of clinical study, and dissolution in the small intenstinal environment (ph 6.8, FaSSIF) a conventional IR specification can be set to assure equivalent exposures to pivotal clinical studies. Medium/High. Acidic media reflects average stomach environment and resonance time. No. Small changes in media ph likely to affect dissolution performance. Low. There is high intra-batch variability, hence poor method capability/robustness; difficult to set a specification that would pass acceptable batches and fail unacceptable batches. Low. At best ph 4.5 is only found at the proximal duodenum. No. Complete release not achieved within a timescale appropriate for a routine control test. Low. Over-discriminatory with respect to all in vivo failure modes. Incomplete release means that it is difficult to set a conventional IR specification to assure equivalent exposures pivotal clinical studies. Medium. ph 6.8 reflects the small intestine, but solubility lower due to lack of bile acid mixed micelle solubilisation. Yes. Media relatively simple to prepare. Medium/High. Overdiscriminatory with respect to all in vivo failure modes; specification can be set to assure equivalent exposures to pivotal clinical studies. Medium/High. Surfactant mimics small intestinal environment including bile acid mixed micelle solubilisation, and similar drug solubility as HIF and FaSSIF. 27 Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

28 Traditional vs QbD approach to Specification Setting C. Moore, DIA CMC Workshop: Translating Science into Successful Submissions, Washington, D.C. February 9, Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

29 My interpretation of FDA View in this area C. Moore, DIA CMC Workshop: Translating Science into Successful Submissions,Washington, D.C. February 9, 2011 Suggested three possible situations: Situation 1: No in vivo data / clinical relevance not clear Conventional and tight spec based on batch history, potentially narrow design space Situation 2: In vivo data of different disso profile inc Safe space Wider dissolution spec could be acceptable (later timepoint but Q = 80%), potential for design space with more regulatory flexibility opportunities Situation 3: IVIVC Spec controls differences in C max and AUC to <20% 29 Paul Dickinson Sept 2012 GMD Pharmaceutical Development

30 My interpretation of FDA View in this area e.g. F2 similarity testing vs target formulation as reference C. Moore, DIA CMC Workshop: Translating Science into Successful Submissions, Washington, D.C. February 9, Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

31 My interpretation of FDA View in this area Most applicable to IR products C. Moore, DIA CMC Workshop: Translating Science into Successful Submissions, Washington, D.C. February 9, Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

32 My interpretation of FDA View in this area Most applicable to MR products C. Moore, DIA CMC Workshop: Translating Science into Successful Submissions, Washington, D.C. February 9, Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

33 Specification Setting Process Capability considerations Lean manufacturing criteria can be applied to set a specification limit based on Six Sigma manufacturing capability (if it is known that this would not affect clinical performance): Evaluated data from development batches Pass clinically acceptable batches (ICHQ6A) Minimise unnecessary Stage 2 testing Specification to apply throughout shelf life so should take into account stability data 33 Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

34 Case Study 1: A BCS2 compound with reasonable solubility

35 Where we ended up with a Release Test / QC Method and Specification: FDA Dissolution profiles in aqueous buffers and optimum surfactant: AstraZeneca FDA ph 1.2 ph 4.5 Okay with Surfactant for Design Space definition but felt it was over discriminating changes in the product that was not clinically relevant, and more comfortable with a more conventional method, with some biorelevance, and conventional Q value and time point for IR product ph 6.8 surfactant

36 Where we ended up with a Release Test / QC Method and Specification: EMA Dissolution profiles in aqueous buffers and optimum surfactant: AstraZeneca EMA ph 1.2 ph 4.5 Day 180: A discriminating dissolution method has been developed. Results of a study comparing different formulation and process variants showed that important in vitro ph 6.8 surfactant Day 150: The tightened dissolution specification as proposed, Q=x% in y minutes, can be considered acceptable based on the dissolution results of the batches used in the clinical studies and manufactured using typical and realistic process parameters ranges differences did not have an impact on in vivo performance. An issue remains dealing with the dissolution specification to be set in order to ensure consistency in the quality of drug product. 36 Paul Dickinson July 2012 GMD Clinical Pharmacology and Pharmacometrics

37 Other Developments in the Future Complex dissolution No dissolution RTR In silico dissolution Exposure or Disease Outcome

38 Advanced dissolution models: becoming more common Allow more and more of the complexity of the human GI Tract to be captured - Ideally these could be used to develop a product that meets the patients needs without extension clinical investigations - At the moment most reports are to solve unexpected problems - Currently an adjunct to standard dissolution - But could it build product understanding and mean standard dissolution is defunct (see later) TNO TIM-1 James Mann PBL Dynamic Gastric Model Dickinson et al., An Investigation into the Utility of a Multi-compartmental, Dynamic, System of the Upper Gastrointestinal Tract to Support Formulation Development and Establish Bioequivalence of Poorly Soluble Drugs. AAPS J. 4: DOI: /s x 38 Paul Dickinson GMD Clinical Pharmacology and Pharmacometrics

39 James Mann 39 Paul Dickinson GMD Clinical Pharmacology and Pharmacometrics

40 Real Time Release (RTR) is all about product understanding Quality cannot be tested into products. Quality by Design and Real Time Release depends on the sound, scientific understanding of our products, processes and test methods. Sound understanding requires a structured development approach from product conception through launch to the end of a products life. This structured development approach allows us to understand how product and process attributes relate to product performance. In turn this can be used to establish a Design Space. Thorough knowledge and understanding supports the establishment of a rational, science based Control Strategy and where appropriate Real Time Release pdf 40 Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

41 Real Time Release (RTR) Example based on a multivariate predictive model 41 Paul Dickinson Sept 2012 GMD Clinical Pharmacology and Pharmacometrics

42 A priori mathematical prediction of dissoltuion performance We are getting much better at mathematical prediction of dissolution (at least for primary and aggregates particles) As QbD drives better formulation understanding I could see a future where fundamental mathematical description of dissolution replace dissolution testing I think this is an obvious step from the empirical models used in RTR currently Concentration (µμ) Aggregates, 200 rpm Aggregates, 25 rpm Theoretcial dissolution for aggregates Theoretical dissolution for primary particles Primary, 200 rpm Primary, 25 rpm Time (min) Bertil Abrahamsson

43 Complex models that link through to clinical outcomes Are being discussed at least at a theoretical level Arzu Selen See also Short et al. J. Pharm. Sci Paul Dickinson GMD Clinical Pharmacology and Pharmacometrics

44 Summary The QTPP links product quality to product performance in the patient and biopharmaceutics is a key element of a Quality by Design Development CQAs should be linked to safety and efficacy Thinking in this area has been evolving over the last few years and the Regulatory landscape is evolving A framework exists for developing clinically relevant specifications Dissolution can be used to ensure similar bioavailability and therefore guarantee safety and efficacy. The specification can be derived from: Prior knowledge (e.g. BCS 1) and consideration of conventional QC requirements in line with ICH An IVIVC An IVIVR which allows a safe space to de defined, that is the extent by which dissolution can slow without affecting bioavailability For well-designed moderate BCS2/4 product safe space is a likely outcome Review EMA and FDA accept linking dissolution to clinical performance Wrt specification setting FDA seem to place a higher emphasis on bio / clinical relevance, standard conditions and complete release EMA seem to place higher emphasis on discriminatory QC method and Q reflecting current batch history Potential to end up with different specifications in different regions 44 Paul Dickinson GMD Clinical Pharmacology and Pharmacometrics