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Drs. Jan Welink WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010 Biowaivers
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Page 1: 2 2 Bioaivers Experience (2)

Drs. Jan Welink

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

Biowaivers

Page 2: 2 2 Bioaivers Experience (2)

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

GuidanceGuidance

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

Page 3: 2 2 Bioaivers Experience (2)

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

BioequivalenceBioequivalence

PD studiesclinicalstudies

in vitromethods

Different approach for

establishing equivalence

Standard: in vivo BE studies

Page 4: 2 2 Bioaivers Experience (2)

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

BioequivalenceBioequivalence

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

Page 5: 2 2 Bioaivers Experience (2)

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

BCSBCS

low permeability

high

solubility

low

solubility

HS/HP

Class I

HS/LP

Class III

LS/HP

Class II

LS/LP

Class IV

high permeability

Biowaivers based on BCS

Page 6: 2 2 Bioaivers Experience (2)

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

BCSBCS

Solubility

Permeability

2 variables:

Page 7: 2 2 Bioaivers Experience (2)

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

BCSBCS

BCS VIEW of BIOEQUIVALENCE

• if two products, containing the same drug, 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

- formulation components do not effect the membrane

permeability and/or intestinal transit

(Amidon et al.1995)

Page 8: 2 2 Bioaivers Experience (2)

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

BCSBCS

Biopharmaceutics Classification System (BCS)

dissolution

drug product drug substance in solution

membrane transport

drug substance in the system

simplified mechanistic view of bioavailability

Page 9: 2 2 Bioaivers Experience (2)

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

BCSBCS

TIME (hours)

Fluid volumepH

hydrodynamicssurface tension

other….

Stomach

Small Intestine (major site for absorption)

Dissolution, solubility, 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

Page 10: 2 2 Bioaivers Experience (2)

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

BCSBCS

BCS Class Boundaries: Objectives

Solubility (Drug) High solubility- ensure that solubility

is not likely to limit dissolution and, therefore, absorption

Dissolution(Product) Very rapid/rapid dissolution - ensure that

in vivo dissolution is not likely to be the“rate determining” step

Permeability

(Drug)

High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine

Page 11: 2 2 Bioaivers Experience (2)

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

BCSBCS

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

Page 12: 2 2 Bioaivers Experience (2)

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

BCSBCS

High solubility: The highest single unit dose is completely soluble in 250

ml or less of aqueous solution at pH 1 – 6.8 (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

Page 13: 2 2 Bioaivers Experience (2)

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

BCSBCS

pH in the gastro-intestinal tract

site fasted pH fed pH

stomach 1.4 – 2.1 4.3 – 5.4

small intestine: duodenum 4.9 – 6.4 4.2 – 6.1 jejunum 4.4 – 6.6 5.2 – 6.2 ileum 6.5 – 7.4 6.8 – 7.5

large intestine: cecum upper colon lower colon

6.46.07.5

Page 14: 2 2 Bioaivers Experience (2)

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

BCSBCS

Highly permeable: A drug substance is considered HIGHLY

PERMEABLE when extent of absorption in humans is determined to be > 85% of an administered dose, based on a mass balance determination or in comparison to an intravenous reference dose, in the absence of evidence suggesting instability in the gastrointestinal tract.

Intestinal membrane permeability may be determined by in vitro or in vivo methods that can predict extent of drug absorption in humans.

Page 15: 2 2 Bioaivers Experience (2)

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

BCSBCS

Highly permeable: EU guidance: linear and complete absorption

reduces the possibility of an IR dosage form influencing the bioavailavility (absorption >85%).

FDA guidance: absolute bioavailability >90%.

Page 16: 2 2 Bioaivers Experience (2)

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

BCSBCS

Rapid (and similar)Dissolution

High Solubility

High Permeability

3 variables:

Page 17: 2 2 Bioaivers Experience (2)

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

BCSBCS

4 variables:

Rapid (and similar)Dissolution

High Solubility

High Permeability

Therapeutic Window

Candidatesfor

Biowaivers

Page 18: 2 2 Bioaivers Experience (2)

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

Biowaivers Biowaivers

BCS-based ‘Biowaiver’.....

.....is defined as

in vitro instead of in vivo ‘bioequivalence’ testing

comparison of test and reference

....is not defined as no equivalence test

Page 19: 2 2 Bioaivers Experience (2)

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

Biowaivers Biowaivers

acc. to the FDA guidance:

”BCS-based biowaivers are intended only for bioequivalence studies. They do not apply to food effect bioavailability studies or other pharmacokinetic studies.”

(e.g., rel. bioavailability)

Page 20: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

Evaluation of drug substance and drug product

Drug substance

pharmacodynamic / therapeutic aspects

physicochemical aspects

Drug product

in vitro dissolution

Page 21: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

RISK assessment

(see e.g. WHO guidance; sect. 9.2 and 5.1.(a))

♦ “critical use medicines”

♦ “narrow therapeutic index drugs”

♦ “documented evidence for BA or BE problems

♦ “scientific evidence that API polymorphs, excipients or the manufacturing process affects BE”

Page 22: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-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

Page 23: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-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 - 6.8 (37 °C)

generate a pH-solubility profile possible stability problems have to be considered discussion on ‘intermediate solubility’, i.e., pH-

dependent (high) solubility

Page 24: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

High permeability♦ WHO guidance: at least 85 % absorption in humans

Pharmacokinetic studies in humans:- Mass balance or absolute bioavailability

Intestinal Perfusion Methods- Humans (In Vivo)- Animals (In Vivo or In Situ)

In Vitro Methods Using Appropriate Membranes- Excised intestinal tissue- Monolayer of functional cultured human intestinal cells

Fraction of Dose Absorbed (F%) Vs.Permeability (Peff)

Peff x 10 -4 (cm/sec)

0 1 2 3 4 5 6 7 8 9 10

F %

0

10

20

30

40

50

60

70

80

90

100

High Permeability

Page 25: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

Dissolution

in vitro dissolution prerequisites

reasonable, stability-indicating, validated methods

discriminative methods

reproducible methods

biorelevant methods ?

Page 26: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-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, pH 4.5 acetate buffer, pH 6.8 phosphate buffer) – no further profile comparison of T and R is required

reasonable, validated experimental conditions/methods are strongly recommended!

Page 27: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-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 1.2, pH 4.5 acetate buffer, pH 6.8 phosphate buffer)

reasonable, validated experimental conditions/methods are strongly recommended!

Page 28: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

In vitro comparison of immediate release oral drug products (T and R):

Proving similarity of dissolution profiles of T and R e.g., using f2-test, unless similarity is obvious.

)see e.g. WHO guidance sect. 9.2 or app. 2 of the EU guidance; note prerequisites(

f2 = 50 x log {[ 1 + (1/n) t=1n (Rt – Tt)2 ]-0.5 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)

Page 29: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

f2-test:

Acceptance value based on 10 % difference between profiles

• „identical“ profiles: f2 =100

• „similar“ profiles: f2 between 50 and 100

0

2

4

6

8

10

12

14

16

18

20

0 5 10 15 20

time

%

Page 30: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

Excipients

Additional issues to be addressed

Pharmacokinetics

Linear..BA problems.. Well know/established..

Acceptable quantities..No interaction PK active substance..

)surfactants, absorption enhancers ,GIT transit time..(

Page 31: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

And the other classes?n

eed

fo

r B

E s

tud

y

risk for differences

HS/HP

LS/HP

HS/LP

LS/LP

Page 32: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

Class II (LS/HP):- critical parameter solubility

- due to pH, may be acceptable

solubility (mg/ml)

pH1 2 3 4 5 6 7 8 9

0

20

40

60

80

100Verapamil HCl

aqueous solubility at 25°C

Page 33: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

Example of a dissolution profile of an ibuprofen (Class II) tablet formulation at different pH levels:

X X

X XX

X X X X X

O O O O

OOO

OO

O

pH

2

4

6

8

dis

so

luti

on

(%

)

50

100

time (min)

30 60

X X

O O

pH

ibuprofen

Page 34: 2 2 Bioaivers Experience (2)

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

BCS-based biowaiverBCS-based biowaiver

Class III (HS/LP):

critical parameter permeability;but to which extent?

• less dependent on formulation

• often exhibit site-dependent absorption(transit time may be critical:

dissolution criteria!!)

Page 35: 2 2 Bioaivers Experience (2)

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

Experience BCS-based biowaiverExperience BCS-based biowaiver

Biowaivers accepted by FDA Cefadroxil

Galantamine HBr

Labetalol

Levetiracetam

Levofloxin

Memantine HCl

Metoprolol

Ofloxacin

Pramipexole dihydrochloride

Pregabalin

Propanolol

Ramelteon

Rivastigmine HCl

Sotalol HCl

Tiagabine HCl

Timolol

Venafaxine HCl Presentation LX Yu, January 2006, SODD workshop, Lake Tahoe

Page 36: 2 2 Bioaivers Experience (2)

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

Experience BCS-based biowaiverExperience BCS-based biowaiver

Biowaivers accepted by Sweden

Phenoxymethylpenicillin

Prednisolone

Transexamic acid

Acetaminophen and codeine

Ibuprofen

Presentation of C. Graffner, “Practical Applications of MPA”, Lisboa, April, 2003.

Page 37: 2 2 Bioaivers Experience (2)

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

Experience BCS-based biowaiverExperience BCS-based biowaiver

Biowaivers accepted by The Netherlands Amoxicillin

Dextromethorfan

Doxycycline

Phenoxymethylpenicillin

Flunarizine

Indomethacin

Isosorbide-5-mononitrate

Lorazepam

Salbutamol

www.cbg-meb.nl

Lormetazepam

Metoprolol

Naproxen

Nitrazepam

Oxprenolol

Acetaminophen

Pindolol

Piroxicam

Temazepam

www.cbg-meb.nl

Page 38: 2 2 Bioaivers Experience (2)

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

Current situation WHO biowaiversCurrent situation WHO biowaivers

Based upon this information (Programme experience and applied biowaivers by other NRAs) decision made to select drug substances.

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

Page 39: 2 2 Bioaivers Experience (2)

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

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)

Current situation WHO biowaiversCurrent situation WHO biowaivers

Page 40: 2 2 Bioaivers Experience (2)

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

The identified comparators:

HIV/AIDS:– Lamivudine: Epivir 150 and 300 mg tablet– Stavudine: Zerit 30 mg capsule– Zidovudine: Retrovir 300 mg tablet, 100 and 250 mg capsule– combination: lamivudine/zidovudine: Combivir (150/300 mg)

Anti-tuberculosis medicines

– Ethambutol: Myambutol 400 mg tablet– Isoniazid: Isozid (100 mg tablet)/Isoniazid 100 and 300 mg

(US RLD)– Levofloxacin: Tavanic and Levaquin (US RLD)– Ofloxacin: Tarivid and Ofloxacin (US RLD)– Pyrazinamide: Pyrazinamide Lederle

Current situation WHO biowaiversCurrent situation WHO biowaivers

Page 41: 2 2 Bioaivers Experience (2)

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

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.g., mannitol, sorbitol, surfactants), if

present, should not differ qualitatively or quantitatively

Page 42: 2 2 Bioaivers Experience (2)

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

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 1.2, 4.5, and 6.8

• 12 units• Paddle apparatus at 75 rpm or basket apparatus at 100 rpm• Use of surfactants strongly discouraged

Page 43: 2 2 Bioaivers Experience (2)

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

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, 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.g., f2 testing) required

Page 44: 2 2 Bioaivers Experience (2)

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

Class III/I Drug Substances

Drug substances are highly soluble but limitations to absorption due to various reasons

Comparison of products (test vs. 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

Page 45: 2 2 Bioaivers Experience (2)

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

Guidance:

Biowaiver application form, identifying clearly what should be submitted.

Detailed information on Test product (generic)

Detailed Information on comparator/reference product (identification).

Comparability between Test and comparator

In vitro dissolution data

Quality assurance

Page 46: 2 2 Bioaivers Experience (2)

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

ReportReport

1. Purpose of study2. Products / batch information

• Batch numbers, manufacturing and expiry dates, 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.

3. Full dissolution conditions and method, as well as the number of units (tablets, capsules, etc) per study. It should be indicated how and when the samples were filtered. Any problems with pH related stability of samples should be indicated and discussed in terms of preventive handling measures, analysis and interpretation of data.4. Analytical method including validation, or reference to the quality part of the dossier.5. Results (% API dissolved)

• Tabulated (individual results, mean and %CV)• Graphically• Similarity determination / f2 calculation if necessary and

applicable6. Conclusion/recommendation.

Format reportdissolution test:

Page 47: 2 2 Bioaivers Experience (2)

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

Problems identified:

Wrong comparator

Failing comparability regarding excipients

Failing excluding/including critical excipients

Failing dissolution tests

Page 48: 2 2 Bioaivers Experience (2)

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

Example: 1.

Page 49: 2 2 Bioaivers Experience (2)

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

Example: 2.

CombivirCombivir

Page 50: 2 2 Bioaivers Experience (2)

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

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

Page 51: 2 2 Bioaivers Experience (2)

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

Biowaivers normally accepted in BEBiowaivers normally accepted in BE

Immediate release (IR) oral dosage forms:

aqueous solution (incl. syrups, elixirs, but no suspensions)

Possible BE exemptions:

gases

aqueous otic or opthalmic products (containing the same actives and excipients)

nebulizer inhalation products or nasal sprays (containing the same actives and excipients)

Page 52: 2 2 Bioaivers Experience (2)

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

Biowaivers and dose proportionalityBiowaivers and dose proportionality

Immediate release (IR) oral dosage forms:

Bioequivalence proven for one strength

If a product concerns several strengths (EU):

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)

Page 53: 2 2 Bioaivers Experience (2)

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

Dose proportionalityDose proportionality

Page 54: 2 2 Bioaivers Experience (2)

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

ExperienceExperience

Page 55: 2 2 Bioaivers Experience (2)

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

GCP overview

Bioanalytical partCritical deviations in %

% critical deviation

Raw data not available

calculation errors

exclusion of QC for P&A

batch acceptance

manual re-integration notconsistent

forged peak

Page 56: 2 2 Bioaivers Experience (2)

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

GCP overview

Bioanalytical partMajor deviations in %

% major deviation

no fresh CC for LT

QC not adequate tu subconc

exclusion of QC for P&A

discrepanciesdata/report

Page 57: 2 2 Bioaivers Experience (2)

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

DeficienciesDeficiencies

Overall:

no bio-study submitted

insufficient clinical data

Test and Reference productoutside the 90% confidence intervalsInadequate validation method of the bioanalysis

no submission of dissolution test

study design

outliers

GLP/GCP

Page 58: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

Subjects included:

- subjects: normal healthy volunteers, male, 18-55 years

* report all demographic data

* report all withdrawals from study and reasons why

* protocol: handling!

Exclusion only when:

- subject had vomited shortly after intake of product

- analytical problem

subjects

Page 59: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

subjects Case: Report stated that 32 subjects were selected and included in the study.

Page 60: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

subjects Case: Exclusion of subjects (1).

- protocol 28 subjects enrolled

- PK data 24 subjects used as defined by protocol

- two drop-outs (for personal reason)

- 26 subjects completed the study

- selection procedure replacements not defined!!

- replacements subjects 25 and 27

Page 61: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

subjects Case: Exclusion of subjects (1).

Subject 26:

Page 62: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

- number of subjects: 36

- used for statistical analysis: 35

- reason: low drug plasma levels in one subject

calculated 90% CI: AUC0-t 0.83 – 1.07

Cmax 0.82 – 1.04

Conclusion: Bioequivalent!

subjects Case: Exclusion of subjects (2).

Page 63: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

subjects Case: Exclusion of subjects (2).

subject excluded!

Page 64: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

- number of subjects: 36

- used for statistical analysis: 36

calculated 90% CI: AUC0-t 0.76 – 1.03

Cmax 0.79 – 1.02

Conclusion: not bioequivalent!

subjects Case: Exclusion of subjects (2).

Page 65: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

Blood sampling

Adequate sampling times and period.

- reliable estimation of Cmax

- reliable estimation of extent of absorption (AUC)

AUC0-t / AUCinf > 80%

Page 66: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

Case: sampling scheme.

Drug: literature reported tmax 2 – 7 hours

Blood sampling

Page 67: 2 2 Bioaivers Experience (2)

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

Case: tmax.Blood

sampling

Page 68: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

Test product

Case: formulation.

Application:

Studied:

Page 69: 2 2 Bioaivers Experience (2)

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

ExamplesExamples

Specificity/selectivity:Analytical

method

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ExamplesExamples

Results: Pharmacokinetic data

- check PK results; also C-t curves

- in line with to be expected

- normal variability

PK data

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Case: Cmax.PK data

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ExamplesExamples

Case: C-t curves.PK data

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ExamplesExamples

GCP/GLP

criteria local market ≠ world market

GLP

fraud

original data/documents not available

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ExamplesExamples

Case: manipulationGCP/GLP

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ExampleExample

Case: remarkable dataGCP/GLP

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ExampleExample

Case: integration (1)GCP/GLP

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ExampleExample

Case: integration (2)

GCP/GLP

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ExampleExample

Case: falsified data

GCP/GLP

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ExampleExample

Case: falsified data

GCP/GLP

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End End

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