上海CMC培训 Case Study Product and Process Understanding in Supporting Post-approval Changes.ppt

1、Yihong Qiu, Ph.D. Abbott Laboratories AAPS/CPA Workshop: Chemistry, Manufacturing Raw materials; Composition; Shelf-life; Process; Equipment; Site; Packaging; Specifications; Test methods, etc.,4,AAPS/CPA Workshop June 28-29, 2010,Introduction,Requirements and expectations Studies need to be conduct

2、ed to understand and demonstrate the effect of changes Assess the effect of post-approval changes on the identity, strength, quality, purity and potency, and ensure a safe and effective product Assess the level of risk posed by changes Demonstrate that products manufactured prior to and subsequent t

3、o a change are equivalent Make and report changes to an approved application and meet requirements Comply with reporting requirements for an AR, CBE, CBE-30 and Prior Approval Supplement and remain in compliance Use comparability protocols to save time and effort by reducing reporting requirements a

4、nd streamlining processes Determine the extent of validation needed for post-approval changes and meet the regulatory requirements Work with FDA in a collaborative manner to achieve and maintain compliance,5,AAPS/CPA Workshop June 28-29, 2010,Justification for Changes and Scientific Understanding,Re

5、gulatory guidance FDA SUPAC-IR/MR (1995/1997) IVIVC-MR (1997) IR-Dissolution (1997) SUPAC-Addendum (1999) BCS/Biowaiver (2000) BA/BE (2003) Changes to Approved NDA/ANDA (2004) EMA (EMEA) Variations: Directive 2001/82(83)/EC; Regulation (EC) No 1084(1085)/2003 (2003); No 1234/2008 (2009) Stability te

6、sting: CPMP/QWP/576/96 (1996) BA/BE/Dissolution: CPMP/EWP/QWP/1401/98 (2001); CPMP/EWP/QWP/1401/98 Rev.1(2010) IVIVC: CPMP/EWP/280/96 (1999); CPMP/QWP/155/96 (1998) Product/process understanding and control Design and operating principles, prior knowledge and history Control measures Critical qualit

7、y attributes (CQA) and in vivo relevance In vitro-in vivo correlation (IVIVC),http:/www.ema.europa.eu/htms/human/humanguidelines/quality.htm http:/www.ema.europa.eu/htms/human/raguidelines/post.htm,6,AAPS/CPA Workshop June 28-29, 2010,Justification for Changes and Scientific Understanding,Relationsh

8、ip Between In Vitro and In Vivo Performance IVIVR: Qualitative, rank order IVIVC: Quantitative, predictive, validated Challenges No universal model Development: Case by case,7,AAPS/CPA Workshop June 28-29, 2010,Justification for Changes and Scientific Understanding,In Vitro-In Vivo Correlation (IVIV

9、C) A predictive mathematical model describing the relationship between an in vitro property (usually extent or rate of drug release) and a relevant in vivo response (e.g., plasma concentration or amount of drug absorbed) Type of IVIVC Level A: Profile correlation Level B: Summary parameter correlati

10、on Level C: Characteristic parameter correlation Multiple Level C: Multiple parameter correlation (AUC, Cmax, Qt, etc.),*FDA Guidance for Industry: Extended release oral dosage forms: Development, evaluation, and application of in vitro/in vivo correlation. 09/1997,8,AAPS/CPA Workshop June 28-29, 20

11、10,IVIVC: Utility and Regulatory Expectation,Goal Use in vitro test to predict in vivo performance of dosage forms Link quality attributes to clinical performance Provide increased assurance for consistent product quality and performance (QbD) Application Guide product development Assure product qua

12、lity by setting meaningful specifications Justify waiver of in vivo bioequivalence studies Support changes/variations,9,AAPS/CPA Workshop June 28-29, 2010,Illustration: Level A IVIVC,Deconvolution,Observed or predicted Cp profiles,In vitro drug release,Estimated in vivo input,Disposition Function IV

13、 or IR Cp profiles,IVIVC model,Biostudy,Modeling relationship,Y. Qiu. In: Developing Oral Dosage Forms: Pharmaceutical Theory and Practice. Edited by Y. Qiu et al. Academic Press, San Diego, CA. 2009. pp-379-408,Convolution,C(t) = f(t)*C(t),Validation Prediction,10,AAPS/CPA Workshop June 28-29, 2010

14、,Regulatory Opportunity and Strategy,With a validated IVIVC Establish in vitro dissolution as one of the most important CQA Serve as a critical tool for product and process understanding Predict and control in vivo performance within the life cycle of a product Prior to product approval Guide formul

15、ation and process design Facilitate application of QbD principles in product development Aid scale-up, optimization and risk management Assess and define CPP, design space, risks, control strategy, etc Justify meaningful specifications for regulatory submission Post-approval Planned or unintentional

16、 changes/variations of raw materials, composition, process, site or equipment Ensure consistent quality and performance during commercial production Reduce regulatory burdens via biowaiver IR products (BCS 2, 3, 4 drugs); MR products,11,AAPS/CPA Workshop June 28-29, 2010,Regulatory Opportunity and S

17、trategy,Illustration of mapping in vitro and in vivo results,Without a validated IVIVC With IVIVR Map in vitro and in vivo performance During development Guide formulation and process screening and understanding Justify biorelevant specifications Post-approval Ensure consistent quality of commercial

18、 products Justify biowaiver Without IVIVR Lower confidence in in vitro test More restrictive for changes,12,AAPS/CPA Workshop June 28-29, 2010,Case Studies (within and outside guidance) Justify changes of composition, process, equipment, site, specification Set meaningful dissolution specification a

19、nd control product quality Biowaiver,13,AAPS/CPA Workshop June 28-29, 2010,Case Study #1: A Delayed-Release Tablet,Drug and Product BCS I/II, Narrow therapeutic index Enteric coated tablets (HP-55; solvent based) Strength: 500 mg, 250 mg and 125 mg Process: Wet granulation and pan coating Background

20、 On the market for 20 yrs. Transfer of manufacturing site from North America to South America due to plant sale PAC: Multiple related changes: Site/Composition/Process/Equipment Objectives Understand potential impact on product quality and performance Justify a biowaiver,14,AAPS/CPA Workshop June 28

21、-29, 2010,Case Study #1: A Delayed-Release Tablet,Summary of Changes Composition: Ink for printing Processing/Equipment (SUPAC L-3) Low-shear planetary mixer/oven drying = high-shear Single Pot Processor (SPP) Granulation and coating solvents (EtOH = IPA; grade) Slightly different total solids conte

22、nt of coating solution 125 mg strength: Perforated coating pan = a conventional pan and the smaller batch size Site (SUPAC L-3) Approach Review of product and manufacturing history Product licensed and manufactured in various markets Formulation for various markets: Same Process: Slightly variable d

23、ue to local equipment availability Specifications, in-process control and test methods: Same Consistent product quality and robust manufacturing for 20 yrs,15,AAPS/CPA Workshop June 28-29, 2010,Case Study #1: A Delayed-Release Tablet,Approach (Contd) Comparison of product performance Tablet Characte

24、ristics: All tablets met the established acceptance criteria (potency, content uniformity, acid resistance, hardness and physical inspection, etc.) In Vitro Drug Release Two lots for each of the three strengths from both sites Testing at pH 1.0, 4.5, 6.5 and 7.5 to evaluate effective enteric protect

25、ion and subsequent drug release In Vivo Performance Evaluate potential impact of the changes: (1) In vivo BE study or (2) In vitro-in vivo correlation (IVIVC) In vitro-in vivo relationship (IVIVR): Distinguish between acceptable and unacceptable drug products or ensure batch-to-batch consistency wit

26、hin a range which ensures acceptable in vivo performance In the absence of a quantitative IVIVC, a mapping study can be used to define drug release limits of a product that will ensure bioequivalence of batches prepared within the limits,16,AAPS/CPA Workshop June 28-29, 2010,Case Study #1: A Delayed

27、-Release Tablet,In Vivo Performance (Contd) A previous BE study of the US product was used to investigate IVIVR A single dose, fasting, 3-way crossover study (n=15) Mapping in vitro drug release,Tablets studied differ in granulation solvent, rate-controlling polymer, coating solvent and process para

28、meters (details in backup slides) Two different formulations manufactured by varying amounts of rate-controlling polymer (10% vs. 14%) to provide fastest and slowest drug release are bioequivalent Tablets made with changes are expected to be bioequivalent Near 100% bioavailability Similar and more r

29、apid drug release than the lower limit of the verified range that offers maximum likelihood of ensuring bioequivalence,17,AAPS/CPA Workshop June 28-29, 2010,Case Study #1: A Delayed-Release Tablet,Justification of a Biowaiver Drug properties Stable, soluble and permeable. 90% BA demonstrated with bo

30、th DR and ER tablets in multiple biostudies Formulation The tablet core consists of high loading of the soluble active, and hydrophilic excipients, resulting in rapid drug release upon dissolution of the enteric coating The enteric polymer has a long history of proven performance. Changes are unlike

31、ly to result in changes in functionality of the core composition and the enteric coating. The in vivo performance remains unaltered when more significant changes in core and coating compositions were made with the two formulations tested in the mapping study. Processing Major changes: Low shear to h

32、igh shear granulation and drying = did not lead to changes in subsequent tablet processing because the in-process control remain unchanged A long history of manufacturing the same product using high shear granulation and fluid-bed drying in other markets that showed consistent in vivo performance,18

33、,AAPS/CPA Workshop June 28-29, 2010,Case Study #1: A Delayed-Release Tablet,Justification of a Biowaiver (Contd) Product characteristics Tablets met the same specifications and in-process tests: Unchanged stability and functionality In vitro drug release test: More sensitive and discriminating than

34、the in vivo test From a QA point of view, a more discriminative in vitro method is preferred: the test will indicate possible changes in product quality before in vivo performance is affected Pharmacokinetic and safety/efficacy considerations Risks to patients are analyzed using four theoretically p

35、ossible scenarios (details in the backup slides) (1) If enteric protection is either inadequate or compromised (2) If enteric coating does not dissolve quickly in the proximal bowel (3) If the core tablet does not disintegrate and dissolve following dissolution of the enteric coating in the small in

36、testine (4) If a combination of “Scenarios # 2 and #3” occurs Outcome: Biowaiver granted,19,AAPS/CPA Workshop June 28-29, 2010,Case Study 2: An Extended-Release Tablet,Drug and Product API: BCS I/II; NTI ER tablets Strength: 500 mg and 250 mg Process: Wet granulation Background Near zero-order in vi

37、vo absorption for 20 hrs A validated IVIVC established during development Objectives Development: Setting dissolution specification; New strength Post-approval: Biowaiver for Site change; New strength Production: Quality control,20,AAPS/CPA Workshop June 28-29, 2010,Level A IVIVC In Vitro Release vs

38、. In Vivo Absorption Conventional test Slower Under-discriminating Different kinetics IVIVR is formulation-dependent New test Investigated in vitro release test conditions (DOE) Match (1) release rate, (2) mechanism, (3) differentiation IVIVC independent of formulation,Case Study 2: An Extended-Rele

39、ase Tablet,Qiu et al. J. Pharm. Sci. 92(6): 1166-1173 and 92(11):2317-2325, (2003),In vitro vs. in vivo,21,AAPS/CPA Workshop June 28-29, 2010,Case Study 2: An Extended-Release Tablet,Level A IVIVC (Contd) Model Validation and Prediction Six different formulations Modeling and internal validation: Th

40、ree formulations External validation: (1) two variants of commercial formulation (2) new formulation (strength) (3) commercial batch,Validation/prediction,22,AAPS/CPA Workshop June 28-29, 2010,Case Study 2: An Extended-Release Tablet,Applications (I) Setting Dissolution Specification Proposed spec l

41、imits based on the pivotal biobatch Evaluate using IVIVC Statistical Assessment Review of all R stable Strength: 120 and 240 mg; Wet granulation Background On the market for 20 yrs Marketed in 50 Countries with essentially the same formulation/process, but different drug release specs. A review of 3

42、000 commercial batches made between 1990 2006 Consistent drug release performance New study under ICH: Shifted drug release observed Objectives Understand potential in vivo impact and assure product quality Develop and justify common spec for the product,25,AAPS/CPA Workshop June 28-29, 2010,Case St

43、udy 3: An Extended-Release Tablet,Approach Review of original NDA Two biobatches IVIVC evaluation Existing spec (#1) does not allow a reasonable spread of the data wrt the biobatch data Propose new spec (#2) based on IVIVC and justify per IVIVC guidance Outcome Approved by regulatory agencies in EU,26,AAP