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WHO workshop on

WHO workshop on Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics Jiaxing, China 5 to 9 November 2007. Comparative dissolution testing and applications. Theo Dekker, D.Sc. Research Institute for Industrial Pharmacy

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  1. WHO workshop on Quality, good manufacturing practice and bioequivalence with a focus on antituberculotics Jiaxing, China 5 to 9 November 2007 Comparative dissolution testingand applications Theo Dekker, D.Sc. Research Institute for Industrial Pharmacy North-West University, Potchefstroom, South Africa

  2. What is dissolution testing?Tablets and capsules (conventional IR) It measures the portion (%) of the API that • has been released from tablets/capsules and • has dissolved in the dissolution medium during controlled testing conditions within a defined period • The tablet thus first disintegrates • Then the API will be able to dissolve • Slow disintegration➜ slow dissolution • The % API dissolved is determined with an appropriate validated method: UV/VIS, HPLC, AA, GC, etc

  3. Oral suspensions &powders for oral suspensions Dissolution also applicable to the following oral preparations • Oral suspensions • Use unit dose (e.g. 5 ml) of well mixed suspenion • Example: Ibuprofen Oral Solution USP • Powders for oral suspensions • Sample: reconstituted suspension • Using unit dose of well-mixed reconstituted suspension • Principle • No disintegration (like tablets) - only rate of API dissolution • Importantfor APIs of low solubility (BCS)

  4. GlossarySolid oral dosage forms Immediate release (IR) typically means that 75% of the API is dissolved within 45 minutes • Rapidly dissolving: ≥ 85% in ≤ 30 minutes • Very rapidly dissolving: ≥ 85% in ≤ 15 minutes Modified-release dosage forms (consult IntPh, PhEur/BP, USP) • Formulation deliberately changes release (slows down) • Extended-release (prolonged-release) Slower release throughout the gastro-intestinal tract • Delayed-release(enteric coated tablets) Resists gastric fluid & disintegrates in intestinal fluid • Not part of presentation

  5. What is multi-point dissolution? In multipoint dissolution • multiple (≥ 3) samples are withdrawn from the dissolution medium during dissolution testing • at pre-determined time points (intervals) and • each sample is analysed for the % API dissolved A graph of % API dissolved against time = the dissolution profile

  6. Multi-point dissolutionExample of dissolution profile

  7. Comparative dissolution testingThe principle • Two or more products or batchescontaining the same API are compared • by means of multipoint dissolution • The strength of products / batches may or may not be the same (depending on purpose of test) • The dissolution conditions are similar, e.g. • Apparatus, medium, volume, rotation speed & temperature • Minimize possible experimental differences in conditions • Samples are taken at the same time points and the data (dissolution profiles) compared • Calculations: correct for volume change of dissolution medium

  8. Comparative dissolution testingExample

  9. Comparative dissolution testing When are dissolution profiles similar?

  10. Comparative dissolution testingProfile similarity determination • If both the test and reference product show more than 85% dissolution within 15 minutes, • the profiles are considered to be similar • No calculations are required If this is not the case, apply point 2 • Calculate the f2 value (similarity factor): • If f2 ≥ 50 • the profiles are regarded similar

  11. Comparative dissolution testingSimilarity factor f2 n = number of time points Rt = % API dissolved of reference product at time point x Tt = % API dissolved of test product at time point x • Minimum of 3 time points (zero excluded) • 12 units(one / vessel) for each batch (for “official” purposes) • Only one measurement should be considered after the comparator product has reached 85 % dissolution (or asymptote is reached) • RSD: ≤ 20% at early time point & ≤ 10% at higher time points

  12. Comparative dissolution testingf2 calculation – spread-sheet design

  13. Comparative dissolution testingDissolution conditions (study design)

  14. Typical time pointsImmediate release tablets (capsules) Rationale: • Condition 1 • ≥ 85% dissolution of both products within 15 min. • 15 minute time point thus essential • Condition 2, for calculation of f2 • a minimum of 3 points are required • Only one measurement should be considered after 85 % dissolution • 20 minute time point thus first possible one(if 15 minute fails 1st condition)

  15. Comparative dissolution testingComparison of products When are the dissolution properties of two products (batches) regarded similar? When the dissolution profiles are similar • in all three media • Statements of instability or insolubility are not acceptable, but should be demonstrated / justified (literature?)

  16. Example 1Determination of similarity of profiles

  17. Example 1 Determination of similarity of profiles (cont.)

  18. Example 2Ciprofloxacin: two batches of same product Apparatus paddle at 50 rpm Media: 1pH 1.2 HCl solution (900 ml) 2pH 4.5 acetate buffer (900 ml) 3pH 6.8 phosphate buffer (900 ml) Temp.: 37°C ± 0.5°C (start, middle, end) Units: Twelve tablets per medium, each batch Sampling:Manual, through in-line filter (0.45 μm PVDF)at 10, 15, 20, 30 and 45 minutes Analysis: HPLC

  19. Example 2Ciprofloxacin: two batches (cont.) Conclusion: The profiles in all three media can be regardedsimilar / not similar, since …………

  20. Example 2Ciprofloxacin: two batches (cont.) pH 1.2 Acetate buffer pH 6.8

  21. Example 2Ciprofloxacin: two batches (cont.) Phosphate buffer pH 6.8 Why is only 40% dissolution reached in buffer pH 6.8?

  22. Ciprofloxacin (cont.) Solubility is pH dependent: • “Highly soluble” at pH < 6 • 100% dissolution obtained in pH 4.5 and pH 1.16 • At pH 6.8 and 40°C the solubility is about 0.2 mg/ml • this explains 40% dissolution for 500 mg dose !! 40°C▼ Questions: • May change in particle size affect the dissolution rate at pH 6.8? • What dissolution level should ciprofloxacin 250 mg tablets be able to reach in pH 6.8 medium? X. Yu et al. Pharm. Research, 11, 522-527 (1994)

  23. Example 3Clarithromycin tablets – Proportional formulations • 2 strengths prepared from same granulate • f2 = 31 • Profiles not similar ! • Solubility of the API in buffer pH 6.8 “low” according to BCS • Do you expect that particle size or polymorphism may have effect on the profiles?

  24. Example 4Isoniazid/Ethambutol tablets Purpose of study • Part of quality testing according to PhInt monograph Samples studied • Note that the Product A is double strength • (though it has fastest dissolution rate !)

  25. Example 4Isoniazid/Ethambutol tablets Conditions and requirement according to • Monograph for Isoniazid and Ethambutol hydrochloride tablets in • International Pharmacopoeia (PhInt)

  26. Isoniazid/Ethambutol tablets (1)Medium: pH 6.8 phosphate buffer

  27. Isoniazid/Ethambutol tablets (2)Medium: pH 6.8 phosphate buffer fails requirement: <85%

  28. Isoniazid/Ethambutol tablets (3)Medium: pH 6.8 phosphate buffer A B C D

  29. Isoniazid/Ethambutol tablets (4)Discussion of results • The dissolution profiles of the 2 APIs in a particular product are similar (this is true for all 4 products) • Both APIs are highly soluble (BCS definition) • The products show different dissolution rates • Dissolution rate A > B ≈ C >> D • Disintegration (min) 7 11 11 21 • Dissolution rate related to disintegration time • f2 values show that B & C have similar profiles • Dissolution method discriminating • Typical type of results during pharmaceutical R&D

  30. Example 54FDC TB tablets Rifampicin/Isoniazid/Pyrazinamide/Ethambutol 150mg/75mg/400mg/275mg Dissolution conditions (USP) • 900 ml pH 6.8 phosphate buffer (not degassed) • paddle, 100 rpm • 37°C ± 0.5°C • Sampling points: 10, 15, 20, 30 and 45 minutes • USP requirement: 75% (Q) in 45 minutes (all APIs) Rifampicin stability • Good in pH 6.8 buffer (reason for choice) • Poor at lower pH

  31. Example 54FDC TB tablets (2) Similar dissolution profiles • Isoniazid, pyrazinamide & ethambutol hydrochloride • high solubility (BCS) – expected to be similar Rifampicin shows slower dissolution rate • Low solubility (BCS)

  32. Example 54FDC TB tablets (3) • WHO Technical Report Series 937, page 8: • The Expert Committee “agreed that rifampicin should serve as the marker for dissolution testing in the relevant FDCs, as it was the least soluble substance.” • This data supports the decision

  33. Example 6Rifamicin powder • Rifampicin exist in 3 solid state forms: • Polymorph I • Polymorph II • Amorphous form • Commercial material contains: • Polymorph II (predominantly) or • Mixture of polymorph II and amorphous form • Five commercial samples (A to E) tested Samples A, B & E: Form II Samples C & D: Form II + amorphous form

  34. Example 6Rifamicin powder (2) Medium: Water • Profiles A, B & E are similar (f2 ≥ 50) • Profiles C & D are similar (f2 ≥ 50) - dissolution incomplete • Profiles A, B, E dissimilar from profiles C,D (f2 < 50) A, B, E(form II) C, D(form II + amorph)

  35. Example 6Rifamicin powder (3) • Presence of amorphous form slows down dissolution of raw material powder at higher pH (f2 test) • Reason: Agglomeration / wettability • Comparative powder dissolution powerful tool for • selection of API manufacturer and • even in-house specification ? • Dissolution method for API powders • overcome floating on mediumsee reference below Reference: S.Q Henwood et al. Drug Dev. & Ind. Pharm.26, 403-408 (2000) (RIIP) amorphous form

  36. Applications • Comparative dissolution: basic tool for selection of the formulation during product development • By comparison of the dissolution profiles of comparator product with those of development batches • Optimise, to get similar profiles • Hint: start with comparator product before development • To get dissolution profiles required for the generic product • Disintegration testing can aid in the early phases • Maximize the chances of bioequivalence • Integral part of development report • dossier and PQIF

  37. Applications (cont.) • Scale up from development (pivotal) to production batches • To demonstrate in vitro similarity of such batches • This is considered essential for retention of efficacy and quality • Note that bioequivalence studies are done normally only once on a bio-batch during development • It must be demonstrated that the product retains the dissolution characteristics up to production scale • The studies should be submitted in dossier as part of the FPP development report

  38. Applications (cont.) • Selection of the dissolution specifications for product release & stability purposes • Conditions and acceptance criteria to be set • The dissolution profiles of the bio-batch should be used for this purpose • A dissolution specification should be able to detect inadequate release properties of the commercial batches • A “generous” dissolution limit has no quality selectivity • Example: Isoniazid/Ethambutol hydrochloride tablets

  39. Applications (cont.) • Demonstration of in vivo bioequivalence of one or more of the lower strength(s) of an FPP may be waived based on • an acceptable in vivo BE study of the highest strength against the comparator product • demonstration of similarity of dissolution profiles between the higher (bio-batch) and lower strength • if the lower strength is proportionally similar in formula to the higher strength (bio-batch) • if all pharmacokinetic requirements are met • Consult the bio-guideline, also for reverse situation

  40. Applications (cont.) • Post-approval amendment application • A requirement of a particular change may be to demonstrate that the profiles of the amendment batch and the current batch are similar • Consult guideline on variations

  41. Reporting Comparative dissolution data Full report, including • Purpose of study • Products/batches information • Batch number, manufacturing/expiry date, packaging, etc. • CoA & size for “own” batches (and BMR for bio-studies report) • Dissolution conditions and method • Analytical method or reference to part of dossier • Results (% API dissolved) • Tabulated • Graphically • Similarity determination / calculation • Conclusion

  42. Comparative dissolution testingGuidelines • Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability • Paragraph 9: In vitro testing (dissolution) • WHO Technical Report Series 937, Annex 7 (2006) • Dissolution testing. Supplement 1 to • Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis • (Generic guideline)

  43. Comparative dissolution testingRelevant training material WHO/FIP Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceuticals Classification System (BCS) • Kiev, Ukraine, 25 - 27 June 2007 • On WHO Prequalification website Strongly recommended

  44. Closing remarks • Comparative dissolution plays an important role in: • product development • up-scaling from development to production • setting of quality dissolution specifications • waiving of BE studies in proportionally similar formulations • post-approval changes (variations) • Manufacturers should • understand the basic requirements of conducting comparative dissolution testing • know how and where to apply it • be able to determine similarity of profiles All data in presentation generated at the RIIP

  45. Multipoint dissolutionExample of (fast) manual sample pulling

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