Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Wa

1. Pharmaceutical Development Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Protea Hotel Victoria Junction, Waterfront Cape Town, South Africa Date: 16 to 20 April 2007

2. Pharmaceutical Development Quality Specifications & Testing of the Finished Pharmaceutical Product (FPP) Presenter: Susan Walters Email: susanw@netspeed.com.au

3. Quality Specifications & Testing of the FPP My background • Pharmacist • PhD Pharmaceutical Chemistry • 2.5 years pharmaceutical manufacturing • 27 years regulation of prescription medicines (TGA Australia) Now: • Teaching pharmaceutical development of medicines (UNSW) • Ad hoc consultancies for WHO and others

4. Quality Specifications & Testing of the FPP Outline of presentation We will: • Discuss the meaning of ‘quality’ in the context of FPPs • Define key terminology • List relevant pharmacopoeias & guidelines, & discuss their roles • Outline typical tests for finished products • Discuss the development & validation of dissolution test methods & acceptance criteria

5. What does ‘quality’ mean in the context of FPPs? - 1 “Quality: The suitability of either a drug substance [=API] or drug product [=FPP] for its intended purpose” ICH Q6A (1999) Some of the elements of FPP quality: • Meets suitable criteria for content of active(s) • Meets suitable criteria for content of impurities • Does not contain toxic excipients or unexpected contaminants

6. What does ‘quality’ mean in the context of FPPs? - 2 The product: • Is reproducible from batch to batch in terms of all characteristics that may affect the patient • Has container labelling & prescribing information that is clear, contains all the necessary information, & accurately represents the FPP’s efficacy & safety profile • For FPPs containing new APIs: Has the same efficacy & safety profile as the batches used in pivotal clinical studies • For generics: Has the same plasma concentration/time profile as the innovator whose efficacy & safety profile is known

7. Quality Specifications & Testing of the FPP ICH: “Specifications are part of a total quality strategy… designed to ensure product quality & consistency” How to ensure the quality of FPPs • Know your API! • Ensure you have the results of pharmaceutical development studies • Validate: • Manufacturing procedures • Test methodology • Acceptance criteria • Implement Good Manufacturing Practice at all sites of manufacture • Undertake appropriate end-product testing for conformance to specifications • Conduct stability studies on the FPP exactly as it is to be marketed • Validate any subsequent variations The message: End-product testing is one element of the quality package

8. Quality Specifications & Testing of the FPP Some terminology

9. “Specification” - 1 • “A list of tests, references to analytical procedures, ranges or other criteria for the tests described”. • “[The specification] establishes the set of criteria to which [an API or FPP] should conform to be considered acceptable for its intended use.” • [and for excipients, containers, intermediates & others] • “ ‘Conformance to specifications’ means that the [API or FPP], when tested according to the listed analytical procedures, will meet the listed acceptance criteria”. ICH Q6a (1999)

10. “Specification” - 2 • “Specifications are critical quality standards that are proposed & justified by the manufacturer & approved by regulatory authorities”. • “Specifications are chosen to confirm the quality of the [API or FPP] rather than to establish full characterization, & should focus on those characteristics found to be useful in ensuring … safety & efficacy”. ICH Q6a (1999)

11. “Acceptance criteria” “Numerical limits, ranges or other suitable measures for acceptance of the results of analytical procedures” ICH Q6a (1999) Quantitative acceptance criteria are sometimes referred to as ‘limits’.

12. A typical monograph for an FPP might include: - 1 • Description • Eg size, shape, colour • Identity tests for API(s) • Assay of API(s) • Purity tests • API-related impurities • Solvents (often water) • Physicochemical properties as appropriate to the dosage form (includes performance/functionality testing) • Eg particle size of API(s) in suspensions • Dissolution rate of tablets

13. A typical monograph for an FPP might include: - 2 • Identification & assay of any critical excipients • Eg antimicrobial preservatives, antioxidants • Uniformity of dosage units for solid dosage forms • Eg uniformity of weight (high dose tablets) • Content uniformity (low dose tablets) • Microbiology • Eg sterility (injections etc) • Microbial load (non-sterile oral products & others)

14. The monograph as a whole “A product is not of pharmacopoeial quality unless it complies with all the requirements stated in the [relevant monograph]” my emphasis WHO TRS 908 (2003)

15. Sources of guidance as to the content ofmonographs for FPPs • Pharmacopoeias • General monographs • Eg for parenteral products, capsules • Specific monographs • Eg dapsone tablets, artemether injection • Guidelines • WHO PQP • Especially p16/26 Control of the FPP • ICH • Technically ICH guidelines apply only to new APIs. In practice regulators apply them more widely (eg PQP)

16. Internationally recognised pharmacopoeias • International Pharmacopoeia (Ph Int) • Published by WHO • United States Pharmacopeia (USP) • Japanese Pharmacopoeia (JP) • European Pharmacopoeia (EP) • British Pharmacopoeia (BP)

17. Pharmacopoeias – PQP’s view? • PQP has not published a formal decision as to acceptable pharmacopoeial monographs for FPPs • But precedents suggest that monographs of all of the preceding pharmacopoeias would be acceptable, with the caveat that monographs in Japanese are not easily understood outside Japan

18. ICH guidelines & FPP specifications • From ICH’s early days, there have been working groups that focussed on harmonisation of pharmacopoeial requirements among the three ICH regions • But to date no harmonised monographs have been published on the ICH website • These are the three relevant topics that appear on the ICH website • Q4 Pharmacopoeias • Q4A Pharmacopoeial Harmonisation • Q4B Regulatory Acceptance of Analytical Procedures and/or Acceptance Criteria (RAAPAC) • Of these, only Q4B has published a draft consensus guideline. It deals with bureaucratic processing of documentation. • Keep an eye on the ICH website for updates

19. An important ICH guideline • Q6A: Specifications: Test procedures & acceptance criteria for new [APIs] & new [FPPs]: Chemical substances • Applies to products containing synthetic APIs (including antibiotics), semi-synthetic antibiotics, & synthetic peptides of low molecular weight, but not to higher molecular weight peptides, & complex biotechnological or biological APIs. • This ICH guideline is referenced by PQP in its guidelines for generics, & is a key guideline for this training course. • I recommend that you read it in detail !

20. Other relevant ICH guidelines • Q3A(R2) Impurities in new [APIs] (2006) Q3B(R2) Impurities in new [FPPs] (2006) • Q3C Impurities: Guideline for residual solvents (1997) • Impurities in non-new APIs • Pharmacopoeial monographs • Review route of synthesis • Compare chromatographic profiles with those of innovator

21. Impurities in non-new FPPs “Generally specifications for impurities in an existing API &/or an associated finished product are acceptable if one or more of the following criteria are met: • Levels of impurities are below ICH qualification thresholds • Nature of impurities & their limits match those of a transparent [pharmacopoeial] monograph • The new product does not contain impurities in concentrations that exceed those in a market leader (normally the innovator)” TGA (2004)

22. Deciding acceptance criteria • The justification (for acceptance criteria) should refer to relevant development data, pharmacopoeial standards, test data for [APIs & FPPs] used in toxicology & clinical studies, & results from long term stability studies, as appropriate. • Additionally a reasonable range of expected analytical & manufacturing variability should be considered. Adapted from ICH Q6A (1999)

23. Parametric release & end product testing • Sterility testing is probably the most well known example of the parametric release option • Q6A describes it as “an operational alternative to routine release testing” • In the case of sterility, “release of each batch is based on satisfactory results from monitoring specific parameters, eg temperature, pressure & time during the terminal sterilization phases of...” manufacturing (Q6A) • In principle parametric release can be substituted for other end product testing, but there are few examples • All batches must nevertheless meet the full product specification if tested

24. Periodic & skip testing - 1 • “Periodic or skip testing is the performance of specified tests at release on preselected batches &/or at predetermined intervals, rather than on a batch-to-batch bases” • All batches must nevertheless meet the full product specification if tested • Once a manufacturer has developed confidence in the manufacturing process & a number of consecutive batches have passed the test in question, testing may be reduced to one in every x batches, or once every x months, where x is a number that varies with the test in question

25. Periodic & skip testing - 2 • Certain tests are considered ‘critical’ in terms of GMP, & must be conducted on every batch. Examples include identification & assay of the active(s). • Regulatory approval must be obtained (on a product-specific basis) before periodic testing may be implemented • In the event that a batch is tested & fails to meet acceptance criteria, regulatory authorities must be immediately informed. The batch may be recalled. The reason for the failure must be identified in order to assess the consequences for other batches.

26. Release & expiry limits • Manufacturers (almost always) have separate release & expiry limits for tests that have a quantitative result. The main reasons are: • To allow for any observed deterioration of the measurement during stability studies • To incorporate a safety margin so that batches are less likely to be recalled in the event of testing by a regulatory laboratory • Effect on product image • Immediately after a batch has been released, the expiry limits apply. • Some regulatory authorities consider this ‘in-house’ information & do not require disclosure of the release limits. Most do. • PQP seeks both sets of limits.

27. Alternative test procedures • Pharmacopoeias & regulators allow manufacturers to use alternative test methodology • In the event of a dispute, the approved methodology must be used. • Why? • Science moves on ! Methodology improves. Regulators should not discourage improvements. • Alternative methodology may be simpler &/or cheaper to conduct, but equally effective. For example if the product has been shown not to degrade during manufacture, a titration method may be more accurate, precise & cheaper to perform than HPLC/MS, although less specific for the target analyte.

28. Dissolution testing

29. Dissolution test methods & acceptance criteria:Available guidelines • “Dissolution Testing of Immediate Release Solid Oral Dosage Forms” • FDA, CDER (1997) • <1092> “The Dissolution Procedure: Development & Validation “ • USP • “Dissolution testing of solid oral dosage forms” • BP, Supplementary Chapter E • “FIP Guidelines for Dissolution Testing of Solid Oral Products” • http://www.fip.org/www2/statements/index.php • “Dissolution testing” • WHO PQP: Guideline on Submission of Documentation for Prequalification of Multisource (Generic) FPPs: Supplement 1.

30. For what purposes are dissolution studies conducted? • During productdevelopment, selecting formulations for further development • During end-product quality control, determining whether each batch meets predetermined in vitro release criteria • During stability studies, determining whether in vitro release rate changes with product age • In the context of bioequivalence studies, to determine the extent to which in vitro dissolution results mirror in vivo results. • During the product’s market lifetime, determining whether variations affect in vitro release rate • Eg change of manufacturing site or equipment

31. What constitutes a good dissolution test? • Repeatability • Within & between equipment, analysts, labs etc • Over time (eg this year vs next year) • Discriminatory power • Discriminates between batches that perform well in vivo & those that do not

32. Formal ‘validation’ of dissolution test methodology Examples: • Repeatability studies • System suitability tests • Eg using USP dissolution calibrators • Manual vs automated procedures • Analytical methodology

33. What should we take into account when choosing dissolution test methods & acceptance criteria? - 1 • The APIs in question & their characteristics • Especially solubility in aqueous media • Known history of dissolution &/or bioavailability problems • Biopharmaceutical classification (see FDA’s Waiver of In Vivo Bioavailability & Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, 2000) • The purpose for which the test is being conducted [this affects acceptance criteria] • Routine batch release • Stability testing • For registration purposes • To support results of a bioequivalence study • To justify a waiver of in vivo BE data

34. What information should we take into account when choosing dissolution test methods & acceptance criteria? - 2 • Recommendations made by FIP, by pharmacopoeias & in regulatory guidelines • Regulatory requirements for registration • Eg those of WHO’s PQP • Whether an in vivo/in vitro correlation (of any type) has been established • May or may not have been published • See especially the website for the FIP Special Interest Group for BABE at http://www.fip.nl/www2/sciences/index.php?page=pharmacy_sciences&pharmacy_sciences=sciences_bioavail_groupbcs • Precedents • Concerning the API in question, related APIs or related dosage forms • Published • Or known only to you • But only if there are facts/data that you can cite in support

35. Dissolution testing: Decisions to make • Apparatus • Medium (solvent) • Sampling times • Acceptance criteria

36. Dissolution test methods: Apparatus - 1 Options (all described in the Ph Int, BP & USP): • Stirred methods • Rotating paddle • Rotating basket • Modifications • For floating dosage forms, especially capsules • May need to change medium during the test, eg pH for enteric coated products • Flow through methods • Reciprocating cylinder (USP only) • Useful for modelling media changes & predicting in vivo profiles of modified release products(Personal Communication David Elder 2007)

37. Dissolution test methods: Apparatus - 2 • Ingeneral milder agitation conditions are preferred • More likely to be able to discriminate between good & bad batches • May have to increase speed in some cases in the event of coning due to insoluble excipients

38. Dissolution test methods: Apparatus - 3 • Recommendations by PQP for immediate release products: • Paddle (USP Apparatus 2) usually at 50 or 75 rpm • Basket (USP Apparatus 1) usually at 100 rpm

39. Dissolution test methods: Medium/solvent Prefer media that are: • Not dissimilar to physiological conditions • Eg avoid 50% acetone! • Discussed in pharmacopoeias • Defined in regulatory requirements • Eg WHO’s PQP Dissolution testing: Guideline on Submission of Documentation for Prequalification of Multisource (Generic) FPPs: Supplement 1. • FDA/CDER’s Dissolution Testing of Immediate Release Solid Oral Dosage Forms • Water is now out of favour because pH is uncontrolled

40. Dissolution test methods: Sampling times - 1 Prefer sampling times that are: • Recommended in pharmacopoeias • Defined in regulatory requirements Prefer: • Profiles (multipoint) vs one or two point tests • Profiles are more discrimating than one or two point tests • Formulation comparisons should normally be profiles • One or two point tests may be adequate for routine batch release if fully justified

41. Dissolution test methods: Sampling times - 2 Some relatively recent (but non-official) non-numerical terminology: • ‘Very rapidly dissolving’ ≥ 85% in 15 minutes • ‘Rapidly dissolving’ ≥ 85% in 30 minutes

42. Dissolution test methods: Sampling times - 3 • The FDA guidance describes three categories of dissolution test: • Single-point specifications • Two-point specifications • Dissolution profile comparison From: Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA (1997)

43. Dissolution test methods: Sampling times - 4 • Single-point specifications. Can be used: • As a routine quality control test for highly soluble and rapidly dissolving drug products • Definition of rapidly dissolving? • Recently defined as >85% in 30 minutes but the FDA dissolution guideline did not define the termSingle-point specifications. Can be used: • As a routine quality control test for highly soluble and rapidly dissolving drug products • Definition of rapidly dissolving? • Recently defined as >85% in 30 minutes but the FDA dissolution guideline did not define the term

44. Dissolution test methods: Sampling times - 5 • Two-point specifications. Can be used: • For characterizing the quality of the drug product. • As a routine quality control test for products that contain slowly dissolving or poorly water soluble APIs such as carbamazepine. • Dissolution profile comparison. Can be used: • For accepting product sameness in the context of variations. • To waive bioequivalence requirements for lower strengths of a dosage form. • To support waivers for other bioequivalence requirements, especially for BCS #1 APIs.

45. Dissolution test methods: Sampling times - 6 • So for routine quality control of immediate release products: Either specify a dissolution profile Acceptable for most types of product Or specify a two point dissolution test Acceptable for most immediate release products Or specify a single point dissolution test Acceptable for most immediate release products that contain highly soluble & rapidly dissolving APIs • But each case must be considered individually

46. Deciding acceptance criteria - 1 • Approaches for setting dissolution specifications for a new chemical entity • Approaches for setting dissolution specifications for generic products From: Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA (1997)

47. Deciding acceptance criteria - 2 • Considerations when setting dissolution specifications for a new chemical entity: • pH solubility profile • pKa of active • GI permeability or octanol/water partition • Dissolution characteristics of batches used in pivotal clinical trials and/or in confirmatory bioavailability studies. • If the formulation intended for marketing differs significantly from the drug product used in pivotal clinical trials, dissolution and bioequivalence testing between the two formulations are recommended. From: Dissolution Testing of Immediate Release Solid Oral Dosage Forms FDA (1997)

48. Deciding acceptance criteria - 3 • Considerations when setting dissolution specifications for a generic product: • Has a pharmacopoeial dissolution test been published? • Is a dissolution test publicly available for a reference listed drug product? • Conduct comparative dissolution testing using test & reference products under a variety of test conditions

49. Comparing dissolution profiles When comparing two immediate release products: • If both are >85% dissolved in 15 minutes, the profiles may be considered similar. Statistical calculation is not required. PQP (2005 ) • Calculate the similarity factor f2 where……… • Need minimum of 3 points

50. Summary and conclusion • It is important to understand the place of end-product testing in the total quality context • Monographs for FPPs should be based on: • Pharmacopoeial general monographs • Pharmacopoeial precedents • ICH & PQP guidelines • Characteristics of the API & FPP in question • The bottom line is safety, efficacy & reproducibility for the patient