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Biowaivers

Drs. Jan Welink

WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

Guidance
 WHO – Technical Report Series No. 937, May 2006
Annex 7: Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability Annex 8: Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate release, solid oral dosage forms  FDA - Guidance for Industry: “Waiver of in vivo bio-equivalence studies for immediate release solid oral dosage forms containing certain active moieties/active ingredients based on a Biopharmaceutics Classification System” (2000)  EU-guidance: “Note for Guidance on the Investigation of Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98; paragraph 5.1
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

Bioequivalence

Different approach for establishing equivalence

Standard: in vivo BE studies

PD studies

clinical studies

in vitro methods

WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

Bioequivalence

Cases, where the regulatory authorities have to decide whether a bioequivalence study is mandatory or not:
• inside a product:

- scale up processes - line extensions - variation after marketing authorisation • between different products: - application of generics without clinical data

WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

Abu Dhabi.BCS Biowaivers based on BCS high permeability high solubility HS/HP Class I LS/HP Class II low permeability HS/LP Class III LS/LP Class IV low solubility WHO Workshop on Prequalification of Medicines Programme. 11-13 October. 2010 .

2010 . 11-13 October.BCS 2 variables: Solubility Permeability WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi.

formulation components do not effect the membrane permeability and/or intestinal transit (Amidon et al.1995) WHO Workshop on Prequalification of Medicines Programme. containing the same drug. 11-13 October. 2010 . have the same concentration-time profile at the intestinal membrane surface then they will have the same rate and extent of absorption • same in vivo dissolution profile under all luminal conditions .BCS BCS VIEW of BIOEQUIVALENCE • if two products. Abu Dhabi.

Abu Dhabi. 2010 . 11-13 October.BCS Biopharmaceutics Classification System (BCS) dissolution drug product  drug substance in solution membrane transport  drug substance in the system simplified mechanistic view of bioavailability WHO Workshop on Prequalification of Medicines Programme.

solubility. Abu Dhabi. and intestinal permeability are the three major factors that govern the rate and extent of absorption of a drug that is stable in the GI tract Fluid volume pH hydrodynamics surface tension other…. 11-13 October. Stomach Small Intestine (major site for absorption) TIME (hours) WHO Workshop on Prequalification of Medicines Programme.BCS Dissolution. 2010 .

therefore. 11-13 October. Abu Dhabi.BCS BCS Class Boundaries: Objectives Dissolution (Product) Solubility (Drug) Very rapid/rapid dissolution .ensure that solubility is not likely to limit dissolution and.ensure that in vivo dissolution is not likely to be the “rate determining” step High solubility.ensure that drug is completely absorbed during the limited transit time through the small intestine Permeability (Drug) WHO Workshop on Prequalification of Medicines Programme. absorption High permeability . 2010 .

2010 . Abu Dhabi. 11-13 October.BCS Very rapid dissolution:  An IR drug product is considered VERY RAPIDLY DISSOLVING when >85% of the labeled amount of drug substance dissolves within 15 minutes Rapid dissolution:  An IR drug product is considered RAPIDLY DISSOLVING when >85% of the labeled amount of drug substance dissolves within 30 minutes WHO Workshop on Prequalification of Medicines Programme.

2010 .8 (37°C) 250 ml: derived from typical BE study protocols that prescribe the administration of a drug product to fasting human volunteers with a glass (approximately 250 ml) water WHO Workshop on Prequalification of Medicines Programme.BCS High solubility:  The highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 – 6. 11-13 October. Abu Dhabi.

8 – 7.2 6. 2010 .2 – 6.4 – 2.1 4. Abu Dhabi.0 7.4 fed pH 4.6 6.4 4.5 – 7.1 5.BCS pH in the gastro-intestinal tract site stomach small intestine: duodenum jejunum ileum large intestine: cecum upper colon lower colon fasted pH 1. 11-13 October.3 – 5.2 – 6.9 – 6.4 4.4 6.4 – 6.5 WHO Workshop on Prequalification of Medicines Programme.5 6.

WHO Workshop on Prequalification of Medicines Programme. 11-13 October. Abu Dhabi.BCS Highly permeable:  A drug substance is considered HIGHLY PERMEABLE when extent of absorption in humans is determined to be > 85% of an administered dose. Intestinal membrane permeability may be determined by in vitro or in vivo methods that can predict extent of drug absorption in humans. in the absence of evidence suggesting instability in the gastrointestinal tract. 2010 . based on a mass balance determination or in comparison to an intravenous reference dose.

Abu Dhabi.  FDA guidance: absolute bioavailability >90%.BCS Highly permeable:  EU guidance: linear and complete absorption reduces the possibility of an IR dosage form influencing the bioavailavility (absorption >85%). 2010 . WHO Workshop on Prequalification of Medicines Programme. 11-13 October.

2010 . 11-13 October.BCS 3 variables: Rapid (and similar) Dissolution High Solubility High Permeability WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi.

BCS 4 variables: Rapid (and similar) Dissolution Candidates for Biowaivers High Permeability WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi. 2010 High Solubility Therapeutic Window . 11-13 October.

... 11-13 October...Biowaivers BCS-based „Biowaiver’.is not defined as no equivalence test WHO Workshop on Prequalification of Medicines Programme..is defined as  in vitro instead of in vivo „bioequivalence‟ testing  comparison of test and reference .. Abu Dhabi. 2010 . .....

” (e.Biowaivers acc. 2010 . rel. 11-13 October.g. to the FDA guidance: ”BCS-based biowaivers are intended only for bioequivalence studies.. Abu Dhabi. They do not apply to food effect bioavailability studies or other pharmacokinetic studies. bioavailability) WHO Workshop on Prequalification of Medicines Programme.

2010 . 11-13 October. Abu Dhabi.BCS-based biowaiver Evaluation of drug substance and drug product Drug substance  pharmacodynamic / therapeutic aspects  physicochemical aspects Drug product  in vitro dissolution WHO Workshop on Prequalification of Medicines Programme.

sect.2 and 5.1. WHO guidance. 2010 . excipients or the manufacturing process affects BE” WHO Workshop on Prequalification of Medicines Programme.(a)) ♦ “critical use medicines” ♦ “narrow therapeutic index drugs” ♦ “documented evidence for BA or BE problems ♦ “scientific evidence that API polymorphs.g. Abu Dhabi. 11-13 October.BCS-based biowaiver RISK assessment (see e. 9.

Abu Dhabi. 2010 .BCS-based biowaiver  meaningful literature data may be used for drug substance characteristics (and excipients)  product related data must always be actually generated for the particular product WHO Workshop on Prequalification of Medicines Programme. 11-13 October.

i..BCS-based biowaiver Class I drugs are candidates for a biowaiver: but what to be adressed? High solubility  the highest single unit dose is completely soluble in 250 ml or less of aqueous solution at pH 1 .6. 2010 .8 (37 °C)  generate a pH-solubility profile  possible stability problems have to be considered  discussion on „intermediate solubility‟. pHdependent (high) solubility WHO Workshop on Prequalification of Medicines Programme. 11-13 October.e. Abu Dhabi.

Permeability (Peff) 100 90 80 70 High Permeability F% 60 50 40 30 20 10 In Vitro Methods Using Appropriate Membranes .BCS-based biowaiver High permeability ♦ WHO guidance: at least 85 % absorption in humans Pharmacokinetic studies in humans: .Animals (In Vivo or In Situ) Fraction of Dose Absorbed (F%) Vs. Abu Dhabi.Humans (In Vivo) .Monolayer of functional cultured human intestinal cells 0 0 1 2 3 4 5 6 7 8 9 10 Peff x 10 -4(c m/sec) WHO Workshop on Prequalification of Medicines Programme. 11-13 October. 2010 .Excised intestinal tissue .Mass balance or absolute bioavailability Intestinal Perfusion Methods .

2010 . validated methods  discriminative methods  reproducible methods  biorelevant methods ? WHO Workshop on Prequalification of Medicines Programme.BCS-based biowaiver Dissolution in vitro dissolution prerequisites  reasonable. stability-indicating. 11-13 October. Abu Dhabi.

BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R): first option: very rapidly dissolving products  Not less than 85 % of labeled amount are dissolved within 15 min in each of three buffers (pH 1.2.8 phosphate buffer) – no further profile comparison of T and R is required  reasonable. 11-13 October. validated experimental conditions/methods are strongly recommended! WHO Workshop on Prequalification of Medicines Programme. pH 6. pH 4. Abu Dhabi.5 acetate buffer. 2010 .

Abu Dhabi.5 acetate buffer. 2010 .8 phosphate buffer)  reasonable. 11-13 October.BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R): Second option: rapidly dissolving products  Not less than 85 % of labeled amount are dissolved within 30 min in each of three buffers (pH 1. pH 6. pH 4.2. validated experimental conditions/methods are strongly recommended! WHO Workshop on Prequalification of Medicines Programme.

unless similarity is obvious. WHO guidance sect. (see e.g.5 x 100 inversely proportional to the average squared difference between the R and T profile and measures the closeness between the two profiles (similarity factor) WHO Workshop on Prequalification of Medicines Programme.BCS-based biowaiver In vitro comparison of immediate release oral drug products (T and R):  Proving similarity of dissolution profiles of T and R e. 2 of the EU guidance.g.2 or app. using f2-test. note prerequisites)  f2 = 50 x log {[ 1 + (1/n) t=1n (Rt – Tt)2 ]-0. 2010 . 11-13 October. Abu Dhabi. 9..

2010 . 11-13 October. Abu Dhabi.BCS-based biowaiver f2-test: Acceptance value based on 10 % difference between profiles 20 18 16 14 12 % 10 8 • „identical“ profiles: f2 =100 6 4 2 0 0 5 10 time 15 20 • „similar“ profiles: f2 between 50 and 100 WHO Workshop on Prequalification of Medicines Programme.

Well know/established.. 11-13 October. BA problems...BCS-based biowaiver Additional issues to be addressed Pharmacokinetics Excipients Linear. Acceptable quantities.. GIT transit time). No interaction PK active substance. absorption enhancers.. Abu Dhabi. WHO Workshop on Prequalification of Medicines Programme. (surfactants.. 2010 .

Abu Dhabi.BCS-based biowaiver And the other classes? need for BE study LS/LP LS/HP HS/LP HS/HP risk for differences WHO Workshop on Prequalification of Medicines Programme. 11-13 October. 2010 .

BCS-based biowaiver Class II (LS/HP): . 2010 .due to pH. Abu Dhabi. may be acceptable solubility (mg/ml) 100 80 60 40 Verapamil HCl aqueous solubility at 25°C 20 0 1 2 3 4 5 6 7 8 9 pH WHO Workshop on Prequalification of Medicines Programme. 11-13 October.critical parameter solubility .

Abu Dhabi. 11-13 October.BCS-based biowaiver Example of a dissolution profile of an ibuprofen (Class II) tablet formulation at different pH levels: O O O dissolution (%) X X pH X X X 50 X X X O X O X O X O X O O O 30 60 time (min) WHO Workshop on Prequalification of Medicines Programme. 2010 pH 8 6 4 2 100 O O ibuprofen .

BCS-based biowaiver Class III (HS/LP): critical parameter permeability. 2010 . but to which extent? • less dependent on formulation • often exhibit site-dependent absorption (transit time may be critical: dissolution criteria!!) WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi. 11-13 October.

Abu Dhabi. January 2006. Lake Tahoe  Metoprolol  Ofloxacin  Pramipexole dihydrochloride WHO Workshop on Prequalification of Medicines Programme. 2010 . 11-13 October. SODD workshop.Experience BCS-based biowaiver Biowaivers accepted by FDA  Cefadroxil  Galantamine HBr  Labetalol  Levetiracetam  Levofloxin  Memantine HCl  Pregabalin  Propanolol  Ramelteon  Rivastigmine HCl  Sotalol HCl  Tiagabine HCl  Timolol  Venafaxine HCl Presentation LX Yu.

2010 . Lisboa. 11-13 October. 2003. “Practical Applications of MPA”. April. Abu Dhabi.Experience BCS-based biowaiver Biowaivers accepted by Sweden  Phenoxymethylpenicillin  Prednisolone  Transexamic acid  Acetaminophen and codeine  Ibuprofen Presentation of C. WHO Workshop on Prequalification of Medicines Programme. Graffner.

nl  Lormetazepam  Metoprolol  Naproxen  Nitrazepam  Oxprenolol  Acetaminophen  Pindolol  Piroxicam  Temazepam www.nl WHO Workshop on Prequalification of Medicines Programme. 2010 . 11-13 October. Abu Dhabi.Experience BCS-based biowaiver Biowaivers accepted by The Netherlands  Amoxicillin  Dextromethorfan  Doxycycline  Phenoxymethylpenicillin  Flunarizine  Indomethacin  Isosorbide-5-mononitrate  Lorazepam  Salbutamol www.cbg-meb.cbg-meb.

 The following drug substances have been identified as eligible for a BCS-based biowaiver application as either monocomponent or fixed-dose combination (FDC) products  Monocomponent or FDC products containing other drug substances must be supported with in vivo BE data WHO Workshop on Prequalification of Medicines Programme. 2010 . 11-13 October. Abu Dhabi.Current situation WHO biowaivers  Based upon this information (Programme experience and applied biowaivers by other NRAs) decision made to select drug substances.

11-13 October.Current situation WHO biowaivers  Medicines for HIV/AIDS and related diseases – Lamivudine (Class I) – Stavudine (Class I) – Zidovudine (Class I)  Anti-tuberculosis medicines – Ethambutol (Class III/I) – Isoniazid (Class III/I) – Levofloxacin (Class I) – Ofloxacin (Class I) – Pyrazinamide (Class III/I) WHO Workshop on Prequalification of Medicines Programme. 2010 . Abu Dhabi.

100 and 250 mg capsule lamivudine/zidovudine: Combivir (150/300 mg) – Ethambutol: – Isoniazid: – Levofloxacin: – Ofloxacin: – Pyrazinamide: Myambutol 400 mg tablet Isozid (100 mg tablet)/Isoniazid 100 and 300 mg (US RLD) Tavanic and Levaquin (US RLD) Tarivid and Ofloxacin (US RLD) Pyrazinamide Lederle WHO Workshop on Prequalification of Medicines Programme. 2010 . Abu Dhabi. 11-13 October.Current situation WHO biowaivers  The identified comparators: HIV/AIDS: – Lamivudine: – Stavudine: – Zidovudine: –  combination: Anti-tuberculosis medicines Epivir 150 and 300 mg tablet Zerit 30 mg capsule Retrovir 300 mg tablet.

surfactants). sorbitol. 2010 . Abu Dhabi.Class I Drug Substances  Selection of comparator product  Biobatch reflective of proposed commercial product  Comparison of products – Should employ well known excipients in usual amounts – Beneficial to contain similar amounts of the same excipients – Critical excipients (e. if present.. mannitol.g. should not differ qualitatively or quantitatively WHO Workshop on Prequalification of Medicines Programme. 11-13 October.

8 • 12 units • Paddle apparatus at 75 rpm or basket apparatus at 100 rpm • Use of surfactants strongly discouraged WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi.5. 11-13 October.2. and 6. 2010 . 4.Class I Drug Substances  Comparative in vitro dissolution – Comparative testing should ensure the similarity of the test and comparator product in three different pH media considered relevant for absorption from the GI tract – Comparative in vitro dissolution testing should be conducted in at least three media of pH 1.

2010 .g. profile comparison is not needed  „Rapidly‟ dissolving products – At least 85% of the labelled amount is released within 30 minutes or less from the test and comparator product – Profile comparison (e. Abu Dhabi.. 11-13 October. f2 testing) required WHO Workshop on Prequalification of Medicines Programme.Class I Drug Substances  „Very rapidly‟ dissolving products – At least 85% of the labelled amount is released within 15 minutes or less from the test and comparator product – In this case.

2010 .Class III/I Drug Substances  Drug substances are highly soluble but limitations to absorption due to various reasons  Comparison of products (test vs. 11-13 October. Abu Dhabi. comparator) – Qualitatively the same excipients – Quantitatively very similar (as per Level 1 change according to SUPAC)  Comparative in vitro dissolution – At least 85% dissolved within 15 minutes for both products – At least 85% dissolved within 30 minutes is acceptable if dissolution profiles are similar and product compositions are very similar WHO Workshop on Prequalification of Medicines Programme.

11-13 October. identifying clearly what should be submitted. 2010 . Abu Dhabi.  Detailed information on Test product (generic)  Detailed Information on comparator/reference product (identification).Guidance:  Biowaiver application form.  Comparability between Test and comparator  In vitro dissolution data  Quality assurance WHO Workshop on Prequalification of Medicines Programme.

Purpose of study 2. mean and %CV) • Graphically • Similarity determination / f2 calculation if necessary and applicable 6. Abu Dhabi.Report Format report dissolution test: 1. as well as the number of units (tablets. Results (% API dissolved) • Tabulated (individual results. 11-13 October. or reference to the quality part of the dossier. Full dissolution conditions and method. 5. batch size of the test product. Certificates of Analysis (CoAs) and packaging of the batches used in the study • Batch manufacturing record(s) for the batch of the test product used in the comparative dissolution study. analysis and interpretation of data. It should be indicated how and when the samples were filtered. capsules. Analytical method including validation. manufacturing and expiry dates. 2010 . WHO Workshop on Prequalification of Medicines Programme. 3. 4. Any problems with pH related stability of samples should be indicated and discussed in terms of preventive handling measures. Conclusion/recommendation. Products / batch information • Batch numbers. etc) per study.

2010 . Abu Dhabi.Problems identified:  Wrong comparator  Failing comparability regarding excipients  Failing excluding/including critical excipients  Failing dissolution tests WHO Workshop on Prequalification of Medicines Programme. 11-13 October.

11-13 October.Example: 1. WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi. 2010 .

Example: 2. 11-13 October. Abu Dhabi. 2010 . Combivir WHO Workshop on Prequalification of Medicines Programme.

2010 . Abu Dhabi. 11-13 October.Good news:  Successful BCS-based biowaiver applications have been submitted for HIV/AIDS and anti-tuberculosis products  Successful BCS-based biowaiver applications for FDCs have been submitted  BCS-based biowaiver approach for certain drug substances introduced in 2009 – Approaches employed by regulatory authorities considered carefully  Drug substances on Expressions of Interest being reviewed – Potential additions to list of eligible drug substances WHO Workshop on Prequalification of Medicines Programme.

Abu Dhabi. but no suspensions)  gases  aqueous otic or opthalmic products (containing the same actives and excipients)  nebulizer inhalation products or nasal sprays (containing the same actives and excipients) WHO Workshop on Prequalification of Medicines Programme. 11-13 October. syrups.Biowaivers normally accepted in BE Immediate release (IR) oral dosage forms: Possible BE exemptions:  aqueous solution (incl. 2010 . elixirs.

Biowaivers and dose proportionality

Immediate release (IR) oral dosage forms: If a product concerns several strengths (EU):
 Bioequivalence proven for one strength  Same manufacturer and manufacturing process  Linear pharmacokinetics  Same qualitative composition of different strengths (WHO)  Same ratio between active substance and excipients, or same excipients in case of low concentration active substance (less than 5%)

 Similar dissolution profiles (WHO)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

Dose proportionality

WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

Experience

WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

GCP overview
Bioanalytical part Critical deviations in %
% critical deviation
Raw data not available calculation errors exclusion of QC for P&A batch acceptance manual re-integration not consistent forged peak

WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010

GCP overview Bioanalytical part Major deviations in % % major deviation no fresh CC for LT QC not adequate tu sub conc exclusion of QC for P&A discrepancies data/report WHO Workshop on Prequalification of Medicines Programme. 11-13 October. Abu Dhabi. 2010 .

Deficiencies Overall: GLP/GCP no bio-study submitted insufficient clinical data Test and Reference product outside the 90% confidence intervals Inadequate validation method of the bioanalysis no submission of dissolution test study design outliers WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi. 2010 . 11-13 October.

male. 2010 .Examples subjects Subjects included: .subjects: normal healthy volunteers. 18-55 years * report all demographic data * report all withdrawals from study and reasons why * protocol: handling! Exclusion only when: . Abu Dhabi.analytical problem WHO Workshop on Prequalification of Medicines Programme.subject had vomited shortly after intake of product . 11-13 October.

2010 .Examples subjects Case: Report stated that 32 subjects were selected and included in the study. 11-13 October. Abu Dhabi. WHO Workshop on Prequalification of Medicines Programme.

Examples subjects Case: Exclusion of subjects (1).selection procedure replacements not defined!! .protocol 28 subjects enrolled .two drop-outs (for personal reason) .replacements subjects 25 and 27 WHO Workshop on Prequalification of Medicines Programme. 11-13 October. 2010 .PK data 24 subjects used as defined by protocol . Abu Dhabi. .26 subjects completed the study .

2010 .Examples subjects Case: Exclusion of subjects (1). Subject 26: WHO Workshop on Prequalification of Medicines Programme. 11-13 October. Abu Dhabi.

Examples subjects Case: Exclusion of subjects (2). Abu Dhabi.04 Conclusion: Bioequivalent! WHO Workshop on Prequalification of Medicines Programme. 2010 .reason: low drug plasma levels in one subject calculated 90% CI: AUC0-t 0.number of subjects: 36 .used for statistical analysis: 35 .83 – 1. .82 – 1. 11-13 October.07 Cmax 0.

Examples subjects Case: Exclusion of subjects (2). subject excluded! WHO Workshop on Prequalification of Medicines Programme. 2010 . 11-13 October. Abu Dhabi.

03 Cmax Conclusion: not bioequivalent! 0.79 – 1.Examples subjects Case: Exclusion of subjects (2).used for statistical analysis: 36 AUC0-t 0. 11-13 October.02 calculated 90% CI: WHO Workshop on Prequalification of Medicines Programme.number of subjects: 36 . Abu Dhabi. . 2010 .76 – 1.

Abu Dhabi.Examples Blood sampling Adequate sampling times and period. 11-13 October. 2010 .reliable estimation of Cmax . .reliable estimation of extent of absorption (AUC) AUC0-t / AUCinf > 80% WHO Workshop on Prequalification of Medicines Programme.

2010 .Examples Blood sampling Case: sampling scheme. 11-13 October. Drug: literature reported tmax 2 – 7 hours WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi.

WHO Workshop on Prequalification of Medicines Programme. 2010 . Abu Dhabi. 11-13 October.Blood sampling Case: tmax.

Application: Studied: WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi.Examples Test product Case: formulation. 2010 . 11-13 October.

11-13 October. Abu Dhabi. 2010 .Examples Analytical method Specificity/selectivity: WHO Workshop on Prequalification of Medicines Programme.

check PK results. also C-t curves . Abu Dhabi.normal variability WHO Workshop on Prequalification of Medicines Programme.in line with to be expected . 2010 . 11-13 October.Examples PK data Results: Pharmacokinetic data .

PK data Case: Cmax. WHO Workshop on Prequalification of Medicines Programme. 11-13 October. 2010 . Abu Dhabi.

WHO Workshop on Prequalification of Medicines Programme.Examples PK data Case: C-t curves. Abu Dhabi. 2010 . 11-13 October.

2010 . Abu Dhabi. 11-13 October.Examples GCP/GLP  criteria local market ≠ world market  GLP  fraud original data/documents not available WHO Workshop on Prequalification of Medicines Programme.

2010 . 11-13 October. Abu Dhabi.Examples GCP/GLP Case: manipulation WHO Workshop on Prequalification of Medicines Programme.

11-13 October. Abu Dhabi. 2010 .GCP/GLP Example Case: remarkable data WHO Workshop on Prequalification of Medicines Programme.

2010 . 11-13 October.GCP/GLP Example Case: integration (1) WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi.

Abu Dhabi. 2010 .Example GCP/GLP Case: integration (2) WHO Workshop on Prequalification of Medicines Programme. 11-13 October.

2010 . 11-13 October. Abu Dhabi.Example GCP/GLP Case: falsified data WHO Workshop on Prequalification of Medicines Programme.

2010 . 11-13 October. Abu Dhabi.Example GCP/GLP Case: falsified data WHO Workshop on Prequalification of Medicines Programme.

11-13 October. 2010 .End Thank you for your attention WHO Workshop on Prequalification of Medicines Programme. Abu Dhabi.