1. Theo Dekker -- CPH59 -- January 2011 1 WHO Prequalification Programme Training Workshop on Assessment of Quality Part of Dossier Copenhagen 19 to 22 January 2011 Dissolution case studies Theo Dekker

2. Theo Dekker -- CPH59 -- January 2011 2 Design of session What is:  Dissolution testing?  Multi-point dissolution (dissolution profile)?  Comparative dissolution?  Similarity of dissolution profiles? Applications:  Pharmaceutical development  Setting of dissolution specification  Up-scaling and Variations  In biowaiver studies (BCS-based biowaiver & additional strengths)  Disintegration and dissolution  API solid state properties Focus: IR release tabs/caps

3. Theo Dekker -- CPH59 -- January 2011 3 Immediate-release (IR) dosage forms IR dosage forms are preparations showing a release of the API(s) which is not deliberately modified by a special formulation design and/or manufacturing method (EP)  Also called Conventional-release dosage forms  Duration of the test is typically 20 to 60 minutes (USP ) The BCS introduced two specific terms  Rapidly dissolving: ≥ 85% in ≤ 30 minutes  Very rapidly dissolving: ≥ 85% in ≤ 15 minutes oIn 3 BCS media (WHO BE guideline definition)

4. Theo Dekker -- CPH59 -- January 2011 4 What is dissolution testing? It measures the portion (%) of the API 1.that has been released from tablets/capsules matrix and 2.that has dissolved in the dissolution medium during controlled testing conditions within a defined period In simple terms:  The tablet thus first disintegrates  Then the API will be able to dissolve  Slow disintegration ➜ slow dissolution

5. Theo Dekker -- CPH59 -- January 2011 5 Dissolution conditions paddle and basket Make sure the conditions are specified by manufacturer ConditionsTypical for Ph.Int. BCS class 1 and 3 APIs ApparatusPaddle, 75 rpm Dissolution mediumpH 6.8 phosphate buffer Volume of medium500 ml (can go to 900 ml – rare cases 1000 ml) Degassed?Yes or No (degassed = mostly faster dissolution) Temperature37°C ± 0.5°C (fixed) Sampling time(s)30 minutes AnalysisUV/HPLC validated Requirement≥ 80% of label claim dissolved in 30 min, etc

6. Theo Dekker -- CPH59 -- January 2011 6 Single point dissolution test Simplest form of dissolution  One sample is withdrawn from the dissolution medium oThrough an in-line or end-of-sampling probe filter  at a pre-determined time point and  the sample is analysed for the % API(s) dissolved oUV/VIS or HPLC most common Result is given as e.g.  93 % in 30 minutes  No decimal is required Mostly for FPP release/stability

7. Theo Dekker -- CPH59 -- January 2011 7 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

8. Theo Dekker -- CPH59 -- January 2011 8 Multi-point dissolution Example of dissolution profile

9. Theo Dekker -- CPH59 -- January 2011 9 Comparative dissolution testing The principle and basic requirements  Comparison of 2 or more products or batches containing the same API  by means of multipoint dissolution (comparing profiles) 1.The strength of products / batches may OR may not be the same depending on purpose of test 2.The dissolution conditions must be similar, e.g. Apparatus, medium, volume, rotation speed & temperature Minimize possible experimental differences in conditions 3.Samples are taken at the same time points for data comparison

10. Theo Dekker -- CPH59 -- January 2011 10 Comparative dissolution testing Example

11. Theo Dekker -- CPH59 -- January 2011 11 Comparative dissolution testing When are dissolution profiles similar?

12. Theo Dekker -- CPH59 -- January 2011 12 Comparative dissolution testing Profile similarity determination 1.If both the test and reference product show ≥ 85% dissolution within 15 minutes,  the profiles are considered to be similar oNo calculations are required If this is not the case, apply point 2 (next point) 2.Calculate the f2 value (similarity factor):  If f 2 ≥ 50 othe profiles are regarded similar oNo decimal required (f 2 = 49.51 ≡ 50)

13. Theo Dekker -- CPH59 -- January 2011 13 Comparative dissolution testing Similarity factor f 2 n = number of time points R t = % API dissolved of reference product at time point x T t = % 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 reference product has reached 85 % dissolution (or asymptote is reached) RSD: ≤ 20% at early time point & ≤ 10% at later time points (apply with some discretion)

14. Theo Dekker -- CPH59 -- January 2011 14 Typical mistakes Often manufacturers include the following points in the f 2 calculation Time zero in the f 2 calculation  % dissolved = 0 at t = 0 minutes Points beyond the reference product reaches 85% It is not according to the “rules” What is the problem with including these points? The f2 value will increase – may lead to false positive f2

15. Theo Dekker -- CPH59 -- January 2011 15 Comparative dissolution testing Similarity factor f 2 Take note - apply WHO requirement in PQP: Unfortunate differences between WHO, FDA and EMEA guidelines on determination of “dissolution last point” for f 2 calculations: Only one measurement (of both products) should be considered after: Source BOTH the reference AND test products have reached 85 % dissolution (or asymptote is reached) FDA (2000) the REFERENCE product has reached 85 % dissolution (or asymptote is reached) WHO (2006) ANY ONE of the reference OR test product has reached 85 % dissolution (or asymptote is reached) EMEA (2010)

16. Theo Dekker -- CPH59 -- January 2011 16 Comparative dissolution testing f 2 calculation – spread-sheet design provided

17. Theo Dekker -- CPH59 -- January 2011 17 Comparative dissolution testing Dissolution conditions (study design) Apparatus (choice) Paddle, 75 (or 50) rpm or Basket, 100 rpm Dissolution media (All three media for full comparison) 1.pH 6.8 phosphate buffer 2.pH 4.5 acetate buffer 3.Buffer pH 1.2 or 0.1 M HCl Volume of media900 ml or less Temperature37°C ± 0.5°C Sampling points5,10, 15, 20, 30, 45, (60, 120) min. (short intervals) Units (vessels)12 for “official” studies For development, up-scaling, variation and biowaiver purposes

18. Theo Dekker -- CPH59 -- January 2011 18 Comparative dissolution testing Comparison of products / batches When are the dissolution properties of two products (batches) regarded similar? When their dissolution profiles are similar  in all three BCS media Statements of instability or insolubility are not acceptable unless demonstrated / justified (literature also acceptable) oAssessor must query unjustified statements like this oOften the manufacturer knows submitted data might be queried…

19. Theo Dekker -- CPH59 -- January 2011 19 Profile comparison Some examples Start the lap tops Open the file:  Similarity factors f2 & f1.xls  Some of you may have other programs – use them

20. Theo Dekker -- CPH59 -- January 2011 20 Example 1 Determination of similarity of profiles Example 1-B % API dissolved Time (min) Tablet D (Ref) Tablet E (Test) 105557 157278 208591 3097100 45102100 60102101 f2 required?Yes f2 (n = 3 ?)64 (similar) Example 1-A % API dissolved Time (min) Tablet A (Ref) Tablet B (Test) 108794 159699 2099 3010099 4510199 6010199 f2 required?No, ≥ 85% in 15 min f2 (n = N/A ?)profiles similar

21. Theo Dekker -- CPH59 -- January 2011 21 Example 1 Determination of similarity of profiles (cont.) Example 1-D % API dissolved Time (min) Tablet D (Ref) Tablet A (Test) 101534 153955 206073 308390 459899 60100101 f2 required?Yes f2 (n = 5 ?)44 (not similar) Example 1-C % API dissolved Time (min) Tablet X (Ref) Tablet Y (Test) 102934 153841 204750 306364 458079 609591 f2 required?Yes f2 (n = 6 ?)74 (similar)

22. Theo Dekker -- CPH59 -- January 2011 22 Sampling intervals Why must samples be taken at short intervals for profile comparison? To prevent false positive results Test:Let us take previous example 1-D and omit some points

23. Theo Dekker -- CPH59 -- January 2011 23 Applicants like to give data collected at: 15, 30, 45 and 60 minutes Example 1-D (acceptable intervals) % API dissolved Time (min) Tablet D (Ref) Tablet A (Test) 101534 153955 206073 308390 459899 60100101 f2 required?Yes f2 (n = 5 ?)44 (not similar) Example 1-D (poor intervals) % API dissolved Time (min) Tablet X (Ref) Tablet Y (Test) 153955 308390 459899 60100101 f2 required?Yes f2 (n = 3 ?)50 (similar) Query data

24. Theo Dekker -- CPH59 -- January 2011 24 Applications Pharmaceutical development Setting of dissolution specification Up-scaling: biobatch to validation batches  To support any differences in formulation/processing Variations In biowaiver studies  BCS-based biowaiver & additional strengths Disintegration and dissolution

25. Theo Dekker -- CPH59 -- January 2011 25 Application Pharmaceutical development Comparative dissolution integral part of  3.2.P.2 Pharmaceutical Development  3.2.P.2.2.1 Formulation Development oIn vitro dissolution or drug release Comparative dissolution also applicable to 1.3.2.P.2.1.1 Active Pharmaceutical Ingredient oIntrinsic dissolution (polymorph solubility comparison) oPowder dissolution (particle size / polymorphism studies) –See rifampicin (later) 2.Development of pharmacopoeial dissolution tests

26. Theo Dekker -- CPH59 -- January 2011 26 Pharmaceutical development Target the dissolution profiles of the comparator product  All 3 BCS media – unless justified oSome APIs are unstable in acid medium –e.g. the artemisinins  Data to be provided in dossier  Scientific approach - quality target product profile (QTPP) oOptimize chances of BE against comparator Derive QC dissolution conditions + acceptance criteria  Product specific – discriminating power oConsult the Generic Guideline, 3.2.P.2.2.1 (in vitro dissolution) oThe compendial method is not mandatory

27. Theo Dekker -- CPH59 -- January 2011 27 Formulation Development Kaletra generic 0.06 M Polyoxyethylene 10 lauryl ether / 900 ml / paddle 75 (FDA)

28. Theo Dekker -- CPH59 -- January 2011 28 Application Scale-up and variations Scale up: biobatch to proposed production batches  To demonstrate in vitro similarity of such batches oThis is considered essential for retention of efficacy oTo support any differences in formulation/processing Post-approval variation applications  A requirement of a particular variation (against biobatch) oSimilar to scale-up oConsult WHO’s Variation Guide

29. Theo Dekker -- CPH59 -- January 2011 29 Application Biowaivers There are 2 types of biowaivers 1.BCS-based biowaivers (surrogate for BE studies)  Selectively applied in PQP 2.Additional strength biowaivers  Generally applied in PQP On PQP website you can find the  PQP specific guides oReferring to WHO main guideline on BE  Templates for applications / assessments  Applicant must also provide a study protocol

30. Theo Dekker -- CPH59 -- January 2011 30 BCS-based biowaiver Currently possible in PQP for FPPs containing the following APIs: HIV/AIDS  BCS class 1: Lamivudine, Stavudine, Zidovudine Anti-TB  BCS class 1:Ofloxacin, Levofloxacin  BCS class 3/1:Ethambutol, Isoniazid, Pyrazinamide * * Comparator and generic containing class 3 APIs must both be: very rapidly dissolving (≥ 85% in ≤ 15 minutes)

31. Theo Dekker -- CPH59 -- January 2011 31 The BCS The Biopharmaceutics Classification System (BCS) of an API is based on its  aqueous solubility and  intestinal permeability According to the BCS an API falls in one of four classes: PermeabilitySolubilityClass High 1 Low2 High3 Low 4

32. Theo Dekker -- CPH59 -- January 2011 32 The BCS High solubility definition  The highest single unit dose of an API is completely soluble in 250 ml or less of aqueous medium over the pH range 1.0 - 6.8 (at 37°C) oDose/solubility volume ≤ 250 ml (PQP Generic Guideline) oNo relevance to pharmacopoeial definitions of solubility High permeability definition (WHO, TRS937, Annex 7, 2006)  When the extent of absorption in humans is ≥ 85% based on a mass balance determination or in comparison with an intravenous comparator dose oNote: FDA and EU are currently ≥ 90%, APPLY WHO REQUIREMENT

33. Theo Dekker -- CPH59 -- January 2011 33 Case studies APIs of BCS high solubility (BCS Class 1 and 3)  Isoniazid/ethambutol 150/400mg tablets APIs of BCS low solubility (BCS class 2 and 4) 1.High solubility at certain pH rages  Ciprofloxacin 500mg tablets  Rifampicin oFDC tablets and API 2.Low solubility over full pH range 1 – 6.8  Lopinavir/Ritonavir 200mg/50mg tablets  Efavirenz 50mg and 600mg tablet  Mebendazole tablets

34. Theo Dekker -- CPH59 -- January 2011 34 Ph.Int. test method development Isoniazid/Ethambutol tablets  Strength: 150mg/400mg No innovator/comparator product  Method development based on commercial samples The APIs are both Class 3/1  Highly soluble across pH 1 – 6.8  Thus buffer pH 6.8 was selected as first choice  Expect APIs in one sample to show similar profiles oAmazingly so

35. Theo Dekker -- CPH59 -- January 2011 35 Isoniazid/Ethambutol tablets Medium: pH 6.8 phosphate buffer Disintegration = 7 min Disintegration = 11 min

36. Theo Dekker -- CPH59 -- January 2011 36 Isoniazid/Ethambutol tablets Medium: pH 6.8 phosphate buffer Disintegration = 11 min Disintegration = 21 min Fails: <80%

37. Theo Dekker -- CPH59 -- January 2011 37 Isoniazid/Ethambutol tablets Test conditions and acceptance criteria  The medium and acceptance criteria are first choice tablets/caps containing Class 1 or 3 APIs.  Disintegration as alternative ApparatusPaddle, 75 rpm Dissolution mediumpH 6.8 phosphate buffer Volume of medium500 ml (degassed or undegassed) Temperature37°C ± 0.5°C RequirementAll 6 units ≥ 80% of label claim in 30 min. If one tablet fails, average of 12 tablets ≥ 75%, none <60% Disintegration (alternative) 10 minutes ≥ stringent than dissolution test? Previous slides

38. Theo Dekker -- CPH59 -- January 2011 38 Ciprofloxacin tablets 2 batches of same product Containing 500mg of ciprofloxacin (as hydrochloride) Apparatuspaddle 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) Analysis:HPLC ProductManufacturerBatch NrExpiry dateStatus Cipro 500ABC Ltdxxx06/2008Test Cipro 500ABC Ltdzzz07/2008Reference

39. Theo Dekker -- CPH59 -- January 2011 39 Ciprofloxacin tablets pH 1,2Acetate buffer pH 4,5 ≥ 85 in 15 min

40. Theo Dekker -- CPH59 -- January 2011 40 Ciprofloxacin tablets Phosphate buffer pH 6.8 Why is only 40% dissolution reached in buffer pH 6.8? Asymptote (saturated) In-house data

41. Theo Dekker -- CPH59 -- January 2011 41 Questions: 1.May change in particle size affect the dissolution rate at pH 6.8? 2.And at pH 4.5 and pH 1.2? X. Yu et al. Pharm. Research, 11, 522-527 (1994) Ciprofloxacin (cont.) Solubility is pH dependent:  “Highly soluble” at pH < 6 100% dissolution obtained in pH 4.5 and pH 1.2  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 ▼

42. Theo Dekker -- CPH59 -- January 2011 42 Ciprofloxacin tablets QC method – acceptance criteria From data 1.Buffer pH 6.8 = not useable for quality control  Far from sink conditions 2.pH 1.2 or pH 4.5 = suitable (900 ml)  paddle 50 rpm  80% (Q) in 20 minutes considered as product specific / tight USP monograph  900 ml 0.01 N hydrochloric acid  paddle 50 rpm  80% (Q) in 30 minutes

43. Theo Dekker -- CPH59 -- January 2011 43 Special case Rifampicin FDC products containing rifampicin  Class 2 API  BCS low solubility oAt higher pH (highly soluble in buffer pH 1.2) 1.WHO recommendation for dissolution test  Rifampicin as “marker” 2.Polymorphism and particle size  Intrinsic dissolution  Powder dissolution

44. Theo Dekker -- CPH59 -- January 2011 44 TB FDC IR tablets Recommendation For conventional immediate release TB fixed-dose combination tablets containing rifampicin WHO recommends:  Rifampicin could serve as the marker for dissolution testing in the relevant FDCs, as it is the least soluble substance. oWHO Technical Report Series 937, page 8 The applicant would need justification  (at least 3 batches) in support of a specification where only rifampicin would be included in the specifications.

45. Theo Dekker -- CPH59 -- January 2011 45 TB FDC IR tablets The rationale USP conditions Similar dissolution profiles Isoniazid, pyrazinamide & ethambutol hydrochloride  High solubility (BCS) – expected to be similar Rifampicin shows slower dissolution rate  Low solubility (BCS)

46. Theo Dekker -- CPH59 -- January 2011 46 Rifampicin solid state properties Rifampicin shows polymorphism  But pharmacopoeias do not mention it – or specify a form Forms I (stable) and II (metastable) + amorphous  Form II (and mixtures?) mainly in current FPPs ???  Both API forms in commerce (also as uncontrolled mixtures) Rifampicin is known for  Variable bioavailability of FDCs oIs this due to polymorphism? PQP may soon be confronted with this problem

47. Theo Dekker -- CPH59 -- January 2011 47 Rifampicin solid state properties Detection of polymorphs by  IR (~1725 cm -1 )  XRPD  DSC Panchagnula Drug Dev Ind Pharm 34, 642 (2008) Exo

48. Theo Dekker -- CPH59 -- January 2011 48 Rifampicin solid state properties Powder dissolution Special method: No excipients in test – only API material  No influence of matrix / excipients To prevent agglomeration or floating of particles  API material + small glass beads in 2 ml dissolution medium. Vortex 1 minute. Transfer to the dissolution medium. Method and data in:  Agrawal, …, Panchagnula. Eur. J. Pharm. Sci. 22, 127 (2004)  Initially developed by Prof A P Lötter, from our laboratory

49. Theo Dekker -- CPH59 -- January 2011 49 Rifampicin solid state properties Powder dissolution (Example: pure form II) 900 ml buffer pH 3.0, paddle 50 rpm and analyzed at 475 nm

50. Theo Dekker -- CPH59 -- January 2011 50 Rifampicin solid state properties Powder dissolution Dissolution rate of rifampicin powder is 1.Not significantly affected by the polymorphic form  Polymorphism seems to have no significant in vitro effect oSupported by intrinsic dissolution data (in publication)  Bioavailability ?? 2.Significantly affected by particle size  < 100 µm → high rate, irrespective of form  > 100 µm → reduced (significantly) dissolution rate What is in it for the evaluator ?  Particle size distribution is important for rifampicin !!!

51. Theo Dekker -- CPH59 -- January 2011 51 Powder dissolution Comments An important tool for studying dissolution behaviour of APIs of low solubility according to the BCS Polymorphic forms  Supplemented by intrinsic dissolution Particle size differences More than often polymorphism and particle size are mixed up in development studies  Study polymorphs? Then particle size should be constant  Excellent example by Panchagnula to separate the variables

52. Theo Dekker -- CPH59 -- January 2011 52 BCS (very) low soluble APIs Over full pH range 1 – 6.8 Lopinavir/Ritonavir 200mg/50mg tablets Data provided 0.06 M Polyoxyethylene 10 lauryl ether, 900ml, paddle, 75 rpm Applicant proposed:75 % (Q) in 120 minutes Assessor requested: 1.Limit should be tightened to Q = 75% in 90 minutes. 2.Additional limit at 45 minutes 120906045302010Time (min) 102988368493315% Lopinavir dissolved Challenge if necessary !

53. Theo Dekker -- CPH59 -- January 2011 53 BCS (very) low soluble APIs Examples of APIs of BCS low solubility over pH 1 – 6.8 Lopinavir, Ritonavir, Lumefantrine, Efavirenz Be careful when assessing Surfactants (about 0.25% to max. 2%) are normally added to increase solubility of BCS low soluble APIs  E.g. SLS (SDS), benzalkonium chloride, polysorbate 80  Too much surfactant may result in BCS high solubility!! oThen discrimination power may be lost oSolubility should be determined using different surfactant concentrations / different surfactants  API particle size distribution specification very important  Can be very difficult to assess

54. Theo Dekker -- CPH59 -- January 2011 54 Efavirenz tabs – water as medium 22 % 3 % 50mg tab 600mg tab

55. Theo Dekker -- CPH59 -- January 2011 55 Efavirenz tabs – 2% SLS – release medium Read EPAR of Atripla on dissolution issue

56. Theo Dekker -- CPH59 -- January 2011 56 Efavirenz tablets The profiles in 2% SLS are similar  For 50 mg tablets vs 600 mg tablets Without SLS it shows huge differences in dissolution rate Would 2% SLS medium detect particle size differences between tablet batches?  Hardly so if the 50mg and 600mg shows similar profiles  Better rely on particle size distribution control of the API batches oAnd that accounts for all APIs with low solubility over the full pH range 1 to 6.8 Take note

57. Theo Dekker -- CPH59 -- January 2011 57 Mebendazole (chewable) tablets Ph.Int. API monograph (revised)  Additional information. Mebendazole exhibits polymorphism. The polymorph specified in the monograph (form C) corresponds to the crystal form of mebendazole RS (IR test) FPP monograph  Manufacture. The formulation, manufacturing process and product packaging of Chewable mebendazole tablets are designed and controlled so as to minimize the conversion of the polymorphic form of mebendazole from C to A. They ensure that, at any stage of the life-cycle of the product, when tested by a suitable method such as infrared spectrometry or X-ray powder diffractometry, the mebendazole in the tablets is predominantly in the form of polymorph C.

58. Theo Dekker -- CPH59 -- January 2011 58 Mebendazole (chewable) tablets Ph.Int. Accelerated products subjected to accelerated conditions Some products showed change from polymorph form C to A over the period of 6 months  Detection: IR and XRPD  Form C = metastable The polymorphic change is clearly shown by dissolution, due to solubility difference between forms C and A  900 ml 0.1 N HCl (paddle 75 rpm)  USP: 900 ml 0.1 N HCl + 1%SLS (paddle 75 rpm) M. Brits et al. J. Pharm. Sci., p1 (2009)

59. Theo Dekker -- CPH59 -- January 2011 59 Mebendazole (chewable) tablets Ph.Int. Stable product  Profiles at start, 2, 4, 6 months – no change

60. Theo Dekker -- CPH59 -- January 2011 60 Mebendazole (chewable) tablets Ph.Int. Product showing polymorphic change  Profiles at start, 2, 4, 6 months start 6 months Form C Form A

61. Theo Dekker -- CPH59 -- January 2011 61 Some practical matters Evaluators should be aware of 1.Coning (heap formation) in dissolution vessel 2.Dissolution results > than assay ??  Do not query to easily 3.Filtration of dissolution samples 4.Chewable tablets 5.Disintegration may replace dissolution as release test  BCS Class 1 and 3 APIs / very rapidly dissolving tabs/caps  Consult ICH Q6A

62. Theo Dekker -- CPH59 -- January 2011 62 Practical matters Coning / Heap formation Coning (heap formation) in dissolution vessel With paddle speed = 50 rpm This may slow down (suppress) the dissolution Affects some products WHO avoids this by paddle 75 rpm in BE guide & Ph.Int.  Thus avoiding possible product-to-product variable due to hydrodynamics

63. Theo Dekker -- CPH59 -- January 2011 63 Practical matters Coning / Heap formation  Coning sometimes seen at lower paddle speed  The API / tablet is covered by excipient heap heap

64. Theo Dekker -- CPH59 -- January 2011 64 Practical matters Coning / Heap formation  Can result in incomplete dissolution / big data variance oIncrease paddle speed OR switch to basket  M. Lagace et al., Dissolution Technologies. Feb, 2004 (13-17) Flow patterns cone

65. Theo Dekker -- CPH59 -- January 2011 65 Practical matters Results above assay value ? Variables in dissolution test De-aeration+ 1 %(reduction in volume) Volume measurement± 1 %(as per pharmacopoeias) Evaporation during test+ 1 %(as per pharmacopoeias) Excipient interference+ 2 %(UV, as allowed by validation) Analytical variance *± 2 % === Total nominal+ 7 %?? *Validation acceptance criterion: ± 2 % and Reference standard solution check: ± 2 %

66. Theo Dekker -- CPH59 -- January 2011 66 Practical matters Filtration of dissolution samples Check during assessment: 1.Dissolution samples should be filtered immediately  To stop dissolution  Through in-line filter or filter at tip of sampling probe  Unless otherwise validated 2.Adsorption of the API(s) onto the filter needs to be evaluated (validated)  Important for low dose tablets/capsules  Ideally no absorption should occur  Discard first portion filtered (saturation of filter)

67. Theo Dekker -- CPH59 -- January 2011 67 Practical matters Chewable tablets Chewable tablets should have a dissolution / disintegration requirement  because they might be swallowed by a patient without proper chewing (FDA’s BA and BE studies, March 2003) Examples:  Didanosine tablets (chewable/dispersible)  Mebendazole tablets (USP)  Chewable mebendazole tablets Ph.Int. (adopted) oThe designation on the container should state that the tablets may be chewed, swallowed whole or crushed and mixed with food or liquid…

68. Theo Dekker -- CPH59 -- January 2011 68 Guidelines 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)  Main guideline for biowaivers US-FDA. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System ( August 2008) EMEA. Guideline on the investigation of bioequivalence  CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** (Jan 2010)

69. Theo Dekker -- CPH59 -- January 2011 69 Guidelines PQP specific (on website): Recommendations for conducting and assessing comparative dissolution profiles Appendix 1 to:  Guideline on submission of documentation for a multisource (generic) finished pharmaceutical product (FPP): quality part o(Generic guideline) General notes on Biopharmaceutics Classification System (BCS)- based biowaiver applications (2/2009) Biopharmaceutics Classification System (BCS)-based biowaiver applications: anti-tuberculosis medicines (2/2009)

70. Theo Dekker -- CPH59 -- January 2011 70 Closing remarks Comparative dissolution plays an important role in:  product development  Up-scaling: biobatch to production batches  setting of dissolution specifications  BCS-based and additional strength biowaivers  post-approval changes (variations)  API solid state properties Assessors should  understand multipoint / comparative dissolution requirements obe able to determine similarity of profiles obe able to assess release dissolution specifications oknow how to assess development and biowaiver data oknow when and how disintegration can replace dissolution