Transcript Guidelines

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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
in vitro
methods
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
BCS
Biowaivers based on BCS
high permeability
high
solubility
low
solubility
low permeability
HS/HP
HS/LP
Class I
Class III
LS/HP
LS/LP
Class II
Class IV
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BCS
2 variables:
Solubility
Permeability
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BCS
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)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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,
Abu Dhabi, 11-13 October, 2010
BCS
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
Fluid volume
pH
hydrodynamics
surface tension
other….
Stomach
Small Intestine (major site for absorption)
TIME (hours)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BCS
BCS Class Boundaries: Objectives
Dissolution
(Product)
Solubility
(Drug)
Permeability
(Drug)
Very rapid/rapid dissolution - ensure that
in vivo dissolution is not likely to be the
“rate determining” step
High solubility- ensure that solubility
is not likely to limit dissolution and,
therefore, absorption
High permeability - ensure that drug
is completely absorbed during the limited
transit time through the small intestine
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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,
Abu Dhabi, 11-13 October, 2010
BCS
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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BCS
pH in the gastro-intestinal tract
site
fasted pH
fed pH
stomach
1.4 – 2.1
4.3 – 5.4
small intestine:
duodenum
jejunum
ileum
4.9 – 6.4
4.4 – 6.6
6.5 – 7.4
4.2 – 6.1
5.2 – 6.2
6.8 – 7.5
large intestine:
cecum
upper colon
lower colon
6.4
6.0
7.5
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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,
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.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BCS
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%.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BCS
3 variables:
Rapid (and similar)
Dissolution
High
Permeability
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
High
Solubility
BCS
4 variables:
Rapid (and similar)
Dissolution
High
Solubility
Candidates
for
Biowaivers
High
Permeability
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Therapeutic
Window
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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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,
Abu Dhabi, 11-13 October, 2010
BCS-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”
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 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,
Abu Dhabi, 11-13 October, 2010
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 - 6.8 (37 °C)
 generate a pH-solubility profile
 possible stability problems have to be considered
 discussion on ‘intermediate solubility’, i.e., pHdependent (high) solubility
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BCS-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)
Fraction of Dose Absorbed (F%) Vs.
Permeability (Peff)
100
90
80
High Permeability
F%
70
60
50
In Vitro Methods Using Appropriate Membranes
- Excised intestinal tissue
- Monolayer of functional cultured human intestinal cells
40
30
20
10
0
0
1
2
3
4
5
6
7
Peff x 10 -4(c m/sec)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
8
9
10
BCS-based biowaiver
Dissolution
in vitro dissolution prerequisites
 reasonable, stability-indicating, validated methods
 discriminative methods
 reproducible methods
 biorelevant methods ?
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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, 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!
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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 1.2, pH 4.5
acetate buffer, pH 6.8 phosphate buffer)
 reasonable, validated experimental conditions/methods are
strongly recommended!
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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.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)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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
15
time
• „similar“ profiles: f2 between 50 and 100
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
20
BCS-based biowaiver
Additional issues to be addressed
Pharmacokinetics
Linear..
BA problems..
Excipients
Well know/established..
Acceptable quantities..
No interaction PK active substance..
(surfactants, absorption enhancers,
GIT transit time)..
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BCS-based biowaiver
need for BE study
And the other classes?
LS/LP
LS/HP
HS/LP
HS/HP
risk for differences
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
BCS-based biowaiver
Class II (LS/HP):
- critical parameter solubility
- due to pH, may be acceptable
solubility (mg/ml)
Verapamil HCl
100
aqueous solubility at 25°C
80
60
40
20
0
1
2
3
4
5
6
7
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
8
9
pH
BCS-based biowaiver
O
O ibuprofen
X
X
dissolution (%)
100
O
O
O
pH
pH
Example of a dissolution profile of an ibuprofen (Class II)
tablet formulation at different pH levels:
8
X
X
X
6
50
X
X
X
X
X
O
O
O
O
O
X
X
4
O
O
2
30
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
60
time (min)
BCS-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!!)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Experience 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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Presentation LX Yu, January 2006,
SODD workshop, Lake Tahoe
Experience 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.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Experience BCS-based biowaiver
Biowaivers accepted by The Netherlands
 Amoxicillin
 Lormetazepam
 Dextromethorfan
 Metoprolol
 Doxycycline
 Naproxen
 Phenoxymethylpenicillin
 Nitrazepam
 Flunarizine
 Oxprenolol
 Indomethacin
 Acetaminophen
 Isosorbide-5-mononitrate
 Pindolol
 Lorazepam
 Piroxicam
 Salbutamol
 Temazepam
www.cbg-meb.nl
www.cbg-meb.nl
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Current 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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
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,
Abu Dhabi, 11-13 October, 2010
Current situation WHO biowaivers
 The identified comparators:
HIV/AIDS:
– Lamivudine:
– Stavudine:
– Zidovudine:
–  combination:
Epivir 150 and 300 mg tablet
Zerit 30 mg capsule
Retrovir 300 mg tablet, 100 and 250 mg capsule
lamivudine/zidovudine: Combivir (150/300 mg)
Anti-tuberculosis medicines
– 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,
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
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
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
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
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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Report
Format report
dissolution
test:
1. Purpose of study
2. 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
applicable
6. Conclusion/recommendation.
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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Example: 1.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Example: 2.
Combivir
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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Biowaivers normally accepted in BE
Immediate release (IR) oral dosage forms:
Possible BE exemptions:
 aqueous solution (incl. syrups, elixirs, 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,
Abu Dhabi, 11-13 October, 2010
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,
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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,
Abu Dhabi, 11-13 October, 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, 11-13 October, 2010
Examples
subjects
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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
subjects
Case: Report stated that 32 subjects were selected and
included in the study.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
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
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
subjects
Case: Exclusion of subjects (1).
Subject 26:
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
subjects
Case: Exclusion of subjects (2).
- 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
Conclusion: Bioequivalent!
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
0.82 – 1.04
Examples
subjects
Case: Exclusion of subjects (2).
subject excluded!
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
subjects
Case: Exclusion of subjects (2).
- number of subjects: 36
- used for statistical analysis: 36
calculated 90% CI:
AUC0-t 0.76 – 1.03
Cmax
Conclusion: not bioequivalent!
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
0.79 – 1.02
Examples
Blood
sampling
Adequate sampling times and period.
- reliable estimation of Cmax
- reliable estimation of extent of absorption (AUC)
AUC0-t / AUCinf > 80%
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
Blood
sampling
Case: sampling scheme.
Drug: literature reported tmax 2 – 7 hours
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Blood
sampling
Case: tmax.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
Test
product
Case: formulation.
Application:
Studied:
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
Analytical
method
Specificity/selectivity:
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
PK data
Results: Pharmacokinetic data
- check PK results; also C-t curves
- in line with to be expected
- normal variability
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
PK data
Case: Cmax.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
PK data
Case: C-t curves.
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
GCP/GLP
 criteria local market ≠ world market
 GLP
 fraud
original data/documents not available
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Examples
GCP/GLP
Case: manipulation
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
GCP/GLP
Example
Case: remarkable data
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
GCP/GLP
Example
Case: integration (1)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Example
GCP/GLP
Case: integration (2)
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Example
GCP/GLP
Case: falsified data
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
Example
GCP/GLP
Case: falsified data
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010
End
Thank you for your attention
WHO Workshop on Prequalification of Medicines Programme,
Abu Dhabi, 11-13 October, 2010