WHO Prequalification Programme Training Workshop on Assessment of

WHO Prequalification Programme Training Workshop on Assessment of Quality Part of Dossier Copenhagen 19 to 22 January 2011 Dissolution case studies Theo Dekker -- CPH 59 -- January 2011 1

Design of session What is: § § Dissolution testing? Multi-point dissolution (dissolution profile)? Comparative dissolution? Similarity of dissolution profiles? s abs/cap t release IR Focus: 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 Theo Dekker -- CPH 59 -- January 2011 2

Immediate-release (IR) dosage forms l 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 <1092>) l The BCS introduced two specific terms § Rapidly dissolving: ≥ 85% in ≤ 30 minutes § Very rapidly dissolving: ≥ 85% in ≤ 15 minutes o In 3 BCS media (WHO BE guideline definition) Theo Dekker -- CPH 59 -- January 2011 3

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 Theo Dekker -- CPH 59 -- January 2011 4

Dissolution conditions paddle and basket Make sure the conditions are specified by manufacturer Conditions Typical for Ph. Int. BCS class 1 and 3 APIs Apparatus Paddle, 75 rpm Dissolution medium p. H 6. 8 phosphate buffer Volume of medium 500 ml (can go to 900 ml – rare cases 1000 ml) Degassed? Temperature Sampling time(s) Yes or No (degassed = mostly faster dissolution) 37°C ± 0. 5°C (fixed) 30 minutes Analysis UV/HPLC validated Requirement ≥ 80% of label claim dissolved in 30 min, etc Theo Dekker -- CPH 59 -- January 2011 5

Single point dissolution test l Simplest form of dissolution § One sample is withdrawn from the dissolution medium o Through an in-line or end-of-sampling probe filter § at a pre-determined time point and § the sample is analysed for the % API(s)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 y bilit o UV/VIS or HPLC most common a e/st leas P re r FP o l Result is given as e. g. tly f s Mo § 93 % in 30 minutes § No decimal is required Theo Dekker -- CPH 59 -- January 2011 6

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 Theo Dekker -- CPH 59 -- January 2011 7

Multi-point dissolution Example of dissolution profile Theo Dekker -- CPH 59 -- January 2011 8

Comparative dissolution testing The principle and basic requirements v 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 Theo Dekker -- CPH 59 -- January 2011 9

Comparative dissolution testing Example Theo Dekker -- CPH 59 -- January 2011 10

Comparative dissolution testing When are dissolution profiles similar? Theo Dekker -- CPH 59 -- January 2011 11

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 o No calculations are required If this is not the case, apply point 2 (next point) 2. Calculate the f 2 value (similarity factor): § If f 2 ≥ 50 o the profiles are regarded similar o No decimal required (f 2 = 49. 51 ≡ 50) Theo Dekker -- CPH 59 -- January 2011 12

Comparative dissolution testing Similarity factor f 2 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 l Minimum of 3 time points (zero excluded) l 12 units (one / vessel) for each batch (for “official” purposes) l Only one measurement should be considered after the reference product has reached 85 % dissolution (or asymptote is reached) l RSD: ≤ 20% at early time point & ≤ 10% at later time points (apply with some discretion) Theo Dekker -- CPH 59 -- January 2011 13

Typical mistakes Often manufacturers include the following points in the f 2 calculation l Time zero in the f 2 calculation § % dissolved = 0 at t = 0 minutes l Points beyond the reference product reaches 85% It is not according to the “rules” l What is the problem with including these points? The f 2 value will increase – may lead to false positive f 2 Theo Dekker -- CPH 59 -- January 2011 14

Comparative dissolution testing Similarity factor f 2 Take note - apply WHO requirement in PQP: l Unfortunate differences between WHO, FDA and EMEA guidelines on determination of “dissolution last point” for f 2 calculations: Source FDA (2000) WHO (2006) EMEA (2010) Only one measurement (of both products) should be considered after: BOTH the reference AND test products have reached 85 % dissolution (or asymptote is reached) the REFERENCE product has reached 85 % dissolution (or asymptote is reached) ANY ONE of the reference OR test product has reached 85 % dissolution (or asymptote is reached) Theo Dekker -- CPH 59 -- January 2011 15

Comparative dissolution testing f 2 calculation – spread-sheet design d rovide p Theo Dekker -- CPH 59 -- January 2011 16

Comparative dissolution testing Dissolution conditions (study design) Apparatus (choice) Dissolution media (All three media for full comparison) • • 1. 2. 3. Volume of media 900 ml or less Temperature 37°C ± 0. 5°C Sampling points 5, 10, 15, 20, 30, 45, (60, 120) min. (short intervals) Units (vessels) 12 for “official” studies Paddle, 75 (or 50) rpm or Basket, 100 rpm p. H 6. 8 phosphate buffer p. H 4. 5 acetate buffer Buffer p. H 1. 2 or 0. 1 M HCl For development, up-scaling, variation and biowaiver purposes Theo Dekker -- CPH 59 -- January 2011 17

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 l Statements of instability or insolubility are not acceptable unless demonstrated / justified (literature also acceptable) o Assessor must query unjustified statements like this o Often the manufacturer knows submitted data might be queried… Theo Dekker -- CPH 59 -- January 2011 18

Profile comparison Some examples l Start the lap tops l Open the file: § Similarity factors f 2 & f 1. xls § Some of you may have other programs – use them Theo Dekker -- CPH 59 -- January 2011 19

Example 1 Determination of similarity of profiles Example 1 -A Example 1 -B % API dissolved Time (min) Tablet A (Ref) Tablet B (Test) Time (min) Tablet D (Ref) Tablet E (Test) 10 87 94 10 55 57 15 96 99 15 72 78 20 99 99 20 85 91 30 100 99 30 97 100 45 101 99 45 102 100 60 101 99 60 102 101 f 2 required? f 2 (n = N/A ? ) No, ≥ 85% in 15 min profiles similar Theo Dekker -- CPH 59 -- January 2011 f 2 required? f 2 (n = 3 ? ) 20 Yes 64 (similar)

Example 1 Determination of similarity of profiles (cont. ) Example 1 -D Example 1 -C % API dissolved Time (min) Tablet X (Ref) Tablet Y (Test) Time (min) Tablet D (Ref) Tablet A (Test) 10 29 34 10 15 34 15 38 41 15 39 55 20 47 50 20 60 73 30 63 64 30 83 90 45 80 79 45 98 99 60 95 91 60 101 f 2 required? f 2 (n = 6 ? ) Yes 74 (similar) Theo Dekker -- CPH 59 -- January 2011 f 2 required? f 2 (n = 5 ? ) 21 Yes 44 (not similar)

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 Theo Dekker -- CPH 59 -- January 2011 22

Applicants like to give data collected at: Query data 15, 30, 45 and 60 minutes Example 1 -D (acceptable intervals) Example 1 -D (poor intervals) % API dissolved Time (min) Tablet D (Ref) Tablet A (Test) 10 15 34 15 39 55 20 60 73 30 83 45 60 % API dissolved f 2 required? f 2 (n = 5 ? ) Time (min) Tablet X (Ref) Tablet Y (Test) 15 39 55 90 30 83 90 98 99 45 98 99 100 101 60 101 Yes 44 (not similar) Theo Dekker -- CPH 59 -- January 2011 f 2 required? f 2 (n = 3 ? ) 23 Yes 50 (similar)

Applications l Pharmaceutical development l Setting of dissolution specification l Up-scaling: biobatch to validation batches § To support any differences in formulation/processing l Variations l In biowaiver studies § BCS-based biowaiver & additional strengths l Disintegration and dissolution Theo Dekker -- CPH 59 -- January 2011 24

Application Pharmaceutical development Comparative dissolution integral part of § 3. 2. P. 2 Pharmaceutical Development § 3. 2. P. 2. 2. 1 Formulation Development o In vitro dissolution or drug release Comparative dissolution also applicable to 1. 3. 2. P. 2. 1. 1 Active Pharmaceutical Ingredient o Intrinsic dissolution (polymorph solubility comparison) o Powder dissolution (particle size / polymorphism studies) – See rifampicin (later) 2. Development of pharmacopoeial dissolution tests Theo Dekker -- CPH 59 -- January 2011 25

Pharmaceutical development l Target the dissolution profiles of the comparator product § All 3 BCS media – unless justified o Some APIs are unstable in acid medium – e. g. the artemisinins § Data to be provided in dossier § Scientific approach - quality target product profile (QTPP) o Optimize chances of BE against comparator l Derive QC dissolution conditions + acceptance criteria § Product specific – discriminating power o Consult the Generic Guideline, 3. 2. P. 2. 2. 1 (in vitro dissolution) o The compendial method is not mandatory Theo Dekker -- CPH 59 -- January 2011 26

Formulation Development Kaletra generic 0. 06 M Polyoxyethylene 10 lauryl ether / 900 ml / paddle 75 (FDA) Theo Dekker -- CPH 59 -- January 2011 27

Application Scale-up and variations l Scale up: biobatch to proposed production batches § To demonstrate in vitro similarity of such batches o This is considered essential for retention of efficacy o To support any differences in formulation/processing l Post-approval variation applications § A requirement of a particular variation (against biobatch) o Similar to scale-up o Consult WHO’s Variation Guide Theo Dekker -- CPH 59 -- January 2011 28

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 o Referring to WHO main guideline on BE Templates for applications / assessments Applicant must also provide a study protocol Theo Dekker -- CPH 59 -- January 2011 29

BCS-based biowaiver l Currently possible in PQP for FPPs containing the following APIs: l HIV/AIDS § BCS class 1: Lamivudine, Stavudine, Zidovudine l 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) Theo Dekker -- CPH 59 -- January 2011 30

The BCS l The Biopharmaceutics Classification System (BCS) of an API is based on its § aqueous solubility and § intestinal permeability l According to the BCS an API falls in one of four classes: Class Solubility Permeability 1 High 2 Low High 3 High Low 4 Theo Dekker -- CPH 59 -- January 2011 Low 31

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 p. H range 1. 0 - 6. 8 (at 37°C) o Dose/solubility volume ≤ 250 ml (PQP Generic Guideline) o No relevance to pharmacopoeial definitions of solubility High permeability definition (WHO, TRS 937, 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 o Note: FDA and EU are currently ≥ 90%, APPLY WHO REQUIREMENT Theo Dekker -- CPH 59 -- January 2011 32

Case studies APIs of BCS high solubility (BCS Class 1 and 3) § Isoniazid/ethambutol 150/400 mg tablets APIs of BCS low solubility (BCS class 2 and 4) 1. High solubility at certain p. H rages § Ciprofloxacin 500 mg tablets § Rifampicin o FDC tablets and API 2. Low solubility over full p. H range 1 – 6. 8 § Lopinavir/Ritonavir 200 mg/50 mg tablets § Efavirenz 50 mg and 600 mg tablet § Mebendazole tablets Theo Dekker -- CPH 59 -- January 2011 33

Ph. Int. test method development Isoniazid/Ethambutol tablets § Strength: 150 mg/400 mg l No innovator/comparator product § Method development based on commercial samples l The APIs are both Class 3/1 § Highly soluble across p. H 1 – 6. 8 § Thus buffer p. H 6. 8 was selected as first choice § Expect APIs in one sample to show similar profiles o Amazingly so Theo Dekker -- CPH 59 -- January 2011 34

Isoniazid/Ethambutol tablets Medium: p. H 6. 8 phosphate buffer Disintegration = 7 min Theo Dekker -- CPH 59 -- January 2011 Disintegration = 11 min 35

Isoniazid/Ethambutol tablets Medium: p. H 6. 8 phosphate buffer Disintegration = 11 min Disintegration = 21 min Fails: <80% Theo Dekker -- CPH 59 -- January 2011 36

Isoniazid/Ethambutol tablets Test conditions and acceptance criteria Apparatus Dissolution medium Volume of medium Temperature Paddle, 75 rpm p. H 6. 8 phosphate buffer 500 ml (degassed or undegassed) 37°C ± 0. 5°C Requirement All 6 units ≥ 80% of label claim in 30 min. If one tablet fails, average of 12 tablets ≥ 75%, none <60% 10 minutes ≥ stringent than dissolution test? Previous slides Disintegration (alternative) § The medium and acceptance criteria are first choice tablets/caps containing Class 1 or 3 APIs. § Disintegration as alternative Theo Dekker -- CPH 59 -- January 2011 37

Ciprofloxacin tablets Product Cipro 500 Manufacturer ABC Ltd Batch Nr xxx zzz Expiry date 06/2008 07/2008 2 batches of same product Containing 500 mg of ciprofloxacin (as hydrochloride) Apparatus Media: paddle at 50 rpm Analysis: HPLC 1 2 3 p. H 1. 2 HCl solution (900 ml) p. H 4. 5 acetate buffer (900 ml) p. H 6. 8 phosphate buffer (900 ml) Theo Dekker -- CPH 59 -- January 2011 38 Status Test Reference

Ciprofloxacin tablets p. H 1, 2 Acetate buffer p. H 4, 5 ≥ 85 in 15 min Theo Dekker -- CPH 59 -- January 2011 39

Ciprofloxacin tablets Phosphate buffer p. H 6. 8 Why is only 40% dissolution reached in buffer p. H 6. 8? Asymptote (saturated) In-house data Theo Dekker -- CPH 59 -- January 2011 40

Ciprofloxacin (cont. ) Solubility is p. H dependent: § 40°C ▼ “Highly soluble” at p. H < 6 ü 100% dissolution obtained in p. H 4. 5 and p. H 1. 2 § At p. H 6. 8 and 40°C the solubility is about 0. 2 mg/ml ü this explains 40% dissolution for 500 mg dose !! Questions: 1. May change in particle size affect the dissolution rate at p. H 6. 8? 2. And at p. H 4. 5 and p. H 1. 2? X. Yu et al. Pharm. Research, 11, 522 -527 (1994) Theo Dekker -- CPH 59 -- January 2011 41

Ciprofloxacin tablets QC method – acceptance criteria From data 1. Buffer p. H 6. 8 = not useable for quality control § Far from sink conditions 2. p. H 1. 2 or p. H 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 Theo Dekker -- CPH 59 -- January 2011 42

Special case Rifampicin FDC products containing rifampicin § § Class 2 API BCS low solubility o At higher p. H (highly soluble in buffer p. H 1. 2) 1. WHO recommendation for dissolution test § Rifampicin as “marker” 2. Polymorphism and particle size § § Intrinsic dissolution Powder dissolution Theo Dekker -- CPH 59 -- January 2011 43

TB FDC IR tablets Recommendation l 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. o WHO Technical Report Series 937, page 8 l The applicant would need justification § (at least 3 batches) in support of a specification where only rifampicin would be included in the specifications. Theo Dekker -- CPH 59 -- January 2011 44

TB FDC IR tablets The rationale USP conditions Similar dissolution profiles l Isoniazid, pyrazinamide & ethambutol hydrochloride § High solubility (BCS) – expected to be similar Rifampicin shows slower dissolution rate § Low solubility (BCS) Theo Dekker -- CPH 59 -- January 2011 45

Rifampicin solid state properties Rifampicin shows polymorphism § But pharmacopoeias do not mention it – or specify a form l 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 o Is this due to polymorphism? y soon be PQP ma Theo Dekker -- CPH 59 -- January 2011 46 ble th this pro wi onfronted c m

Rifampicin solid state properties Detection of polymorphs by § IR (~1725 cm-1) § XRPD § DSC Exo Panchagnula Drug Dev Ind Pharm 34, 642 (2008) Theo Dekker -- CPH 59 -- January 2011 47

Rifampicin solid state properties Powder dissolution Special method: l No excipients in test – only API material § No influence of matrix / excipients l 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. l Method and data in: § Agrawal, …, Panchagnula. Eur. J. Pharm. Sci. 22, 127 (2004) § Initially developed by Prof A P Lötter, from our laboratory Theo Dekker -- CPH 59 -- January 2011 48

Rifampicin solid state properties Powder dissolution (Example: pure form II) 900 ml buffer p. H 3. 0, paddle 50 rpm and analyzed at 475 nm Theo Dekker -- CPH 59 -- January 2011 49

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 o Supported 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 l What is in it for the evaluator ? § Particle size distribution is important for rifampicin !!! Theo Dekker -- CPH 59 -- January 2011 50

Powder dissolution Comments An important tool for studying dissolution behaviour of APIs of low solubility according to the BCS l Polymorphic forms § Supplemented by intrinsic dissolution l Particle size differences l 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 Theo Dekker -- CPH 59 -- January 2011 51

BCS (very) low soluble APIs Over full p. H range 1 – 6. 8 Lopinavir/Ritonavir 200 mg/50 mg tablets Data provided 0. 06 M Polyoxyethylene 10 lauryl ether, 900 ml, paddle, 75 rpm Time (min) % Lopinavir dissolved 10 15 20 33 30 49 45 68 60 83 90 98 120 102 Applicant proposed: 75 % (Q) in 120 minutes Assessor requested: 1. Limit should be tightened to Q = 75% in 90 minutes. essary ! ec 2. Additional limit at 45 minutes lenge if n Chal Theo Dekker -- CPH 59 -- January 2011 52

BCS (very) low soluble APIs Examples of APIs of BCS low solubility over p. H 1 – 6. 8 Lopinavir, Ritonavir, Lumefantrine, Efavirenz Be careful when assessing l 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!! o Then discrimination power may be lost o Solubility should be determined using different surfactant concentrations / different surfactants § API particle size distribution specification very important § Can be very difficult to assess Theo Dekker -- CPH 59 -- January 2011 53

Efavirenz tabs – water as medium 22 % 50 mg tab 600 mg tab 3% Theo Dekker -- CPH 59 -- January 2011 54

Efavirenz tabs – 2% SLS – release medium Read EPAR of Atripla on dissolution issue Theo Dekker -- CPH 59 -- January 2011 55

Efavirenz tablets The profiles in 2% SLS are similar § For 50 mg tablets vs 600 mg tablets l Without SLS it shows huge differences in dissolution rate l Would 2% SLS medium detect particle size differences between tablet batches? § Hardly so if the 50 mg and 600 mg shows similar profiles § Better rely on particle size distribution control of the API batches o And that accounts for all APIs with low solubility over the full p. H range 1 to 6. 8 e ake not T Theo Dekker -- CPH 59 -- January 2011 56

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. Theo Dekker -- CPH 59 -- January 2011 57

Mebendazole (chewable) tablets Ph. Int. Accelerated products subjected to accelerated conditions l Some products showed change from polymorph form C to A over the period of 6 months § Detection: IR and XRPD § Form C = metastable l 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. , p 1 (2009) Theo Dekker -- CPH 59 -- January 2011 58

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

Mebendazole (chewable) tablets Ph. Int. Product showing polymorphic change § Profiles at start, 2, 4, 6 months start 6 months Theo Dekker -- CPH 59 -- January 2011 60 Form C Form A

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 Q 6 A Theo Dekker -- CPH 59 -- January 2011 61

Practical matters Coning / Heap formation Coning (heap formation) in dissolution vessel l With paddle speed = 50 rpm l This may slow down (suppress) the dissolution l Affects some products l WHO avoids this by paddle 75 rpm in BE guide & Ph. Int. § Thus avoiding possible product-to-product variable due to hydrodynamics Theo Dekker -- CPH 59 -- January 2011 62

Practical matters Coning / Heap formation § Coning sometimes seen at lower paddle speed § The API / tablet is covered by excipient heap Theo Dekker -- CPH 59 -- January 2011 63

Practical matters Coning / Heap formation § Can result in incomplete dissolution / big data variance o Increase paddle speed OR switch to basket Flow patterns § M. Lagace et al. , Dissolution Technologies. Feb, 2004 (13 -17) Theo Dekker -- CPH 59 -- January 2011 64 cone

Practical matters Results above assay value ? Variables in dissolution test De-aeration Volume measurement Evaporation during test Excipient interference Analytical variance * Total nominal +1% ± 1% +2% ± 2% === +7% (reduction in volume) (as per pharmacopoeias) (UV, as allowed by validation) ? ? * Validation acceptance criterion: ± 2 % and Reference standard solution check: ± 2 % Theo Dekker -- CPH 59 -- January 2011 65

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) Theo Dekker -- CPH 59 -- January 2011 66

Practical matters 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) o The designation on the container should state that the tablets may be chewed, swallowed whole or crushed and mixed with food or liquid… Theo Dekker -- CPH 59 -- January 2011 67

Guidelines l 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 l 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) l EMEA. Guideline on the investigation of bioequivalence § CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** (Jan 2010) Theo Dekker -- CPH 59 -- January 2011 68

Guidelines PQP specific (on website): l 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) l General notes on Biopharmaceutics Classification System (BCS)based biowaiver applications (2/2009) l Biopharmaceutics Classification System (BCS)-based biowaiver applications: anti-tuberculosis medicines (2/2009) Theo Dekker -- CPH 59 -- January 2011 69

Closing remarks l l 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 o be able to determine similarity of profiles o be able to assess release dissolution specifications o know how to assess development and biowaiver data o know when and how disintegration can replace dissolution Theo Dekker -- CPH 59 -- January 2011 70