2 2 bioaivers-experience
TRANSCRIPT
![Page 1: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/1.jpg)
Drs. Jan Welink
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Biowaivers
![Page 2: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/2.jpg)
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
![Page 3: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/3.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Bioequivalence
PD studiesclinicalstudies
in vitromethods
Different approach for
establishing equivalence
Standard: in vivo BE studies
![Page 4: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/4.jpg)
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
![Page 5: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/5.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/6.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS
Solubility
Permeability
2 variables:
![Page 7: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/7.jpg)
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)
![Page 8: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/8.jpg)
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
![Page 9: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/9.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/10.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS
BCS Class Boundaries: Objectives
Solubil i ty (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
Permeabil i ty
(Drug)
High permeability - ensure that drugis completely absorbed during the limitedtransit time through the small intestine
![Page 11: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/11.jpg)
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
![Page 12: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/12.jpg)
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
![Page 13: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/13.jpg)
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 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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/14.jpg)
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.
![Page 15: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/15.jpg)
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%.
![Page 16: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/16.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS
Rapid (and similar)Dissolution
High Solubility
High Permeability
3 variables:
![Page 17: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/17.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS
4 variables:
Rapid (and similar)Dissolution
High Solubility
High Permeability
Therapeutic Window
Candidatesfor
Biowaivers
![Page 18: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/18.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/19.jpg)
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)
![Page 20: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/20.jpg)
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
![Page 21: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/21.jpg)
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”
![Page 22: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/22.jpg)
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
![Page 23: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/23.jpg)
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., pH-dependent (high) solubility
![Page 24: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/24.jpg)
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)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/25.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS-based biowaiver
Dissolution
in vitro dissolution prerequisites
♦ reasonable, stability-indicating, validated methods
♦ discriminative methods
♦ reproducible methods
♦ biorelevant methods ?
![Page 26: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/26.jpg)
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!
![Page 27: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/27.jpg)
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!
![Page 28: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/28.jpg)
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) Σt=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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/29.jpg)
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
• „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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/30.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS-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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/31.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS-based biowaiver
And the other classes?n
eed fo
r BE
stud
y
risk for differences
HS/HP
LS/HP
HS/LP
LS/LP
![Page 32: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/32.jpg)
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)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/33.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
BCS-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
solu
tio
n (
%)
50
100
time (min)
30 60
X X
O O
pH
ibuprofen
![Page 34: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/34.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
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!!)
![Page 35: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/35.jpg)
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 Presentation LX Yu, January 2006, SODD workshop, Lake Tahoe
![Page 36: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/36.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
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.
![Page 37: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/37.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Experience 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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/38.jpg)
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
![Page 39: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/39.jpg)
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 biowaivers
![Page 40: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/40.jpg)
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 biowaivers
![Page 41: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/41.jpg)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/42.jpg)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/43.jpg)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/44.jpg)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/45.jpg)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/46.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Report
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/47.jpg)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/48.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Example: 1.
![Page 49: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/49.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Example: 2.
CombivirCombivir
![Page 50: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/50.jpg)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/51.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Biowaivers 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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/52.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Biowaivers 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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/53.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Dose proportionality
![Page 54: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/54.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Experience
![Page 55: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/55.jpg)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/56.jpg)
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/57.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Deficiencies
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/58.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/59.jpg)
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.
![Page 60: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/60.jpg)
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
![Page 61: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/61.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
subjects Case: Exclusion of subjects (1).
Subject 26:
![Page 62: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/62.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
- 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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/63.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
subjects Case: Exclusion of subjects (2).
subject excluded!
![Page 64: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/64.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
- 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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/65.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
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](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/66.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
Case: sampling scheme.
Drug: literature reported tmax 2 – 7 hours
Blood sampling
![Page 67: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/67.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Case: tmax.Blood
sampling
![Page 68: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/68.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
Test product
Case: formulation.
Application:
Studied:
![Page 69: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/69.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
Specificity/selectivity:Analyticalmethod
![Page 70: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/70.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
Results: Pharmacokinetic data
- check PK results; also C-t curves
- in line with to be expected
- normal variability
PK data
![Page 71: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/71.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Case: Cmax.PK data
![Page 72: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/72.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
Case: C-t curves.PK data
![Page 73: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/73.jpg)
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
![Page 74: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/74.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Examples
Case: manipulationGCP/GLP
![Page 75: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/75.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Example
Case: remarkable dataGCP/GLP
![Page 76: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/76.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Example
Case: integration (1)GCP/GLP
![Page 77: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/77.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Example
Case: integration (2)
GCP/GLP
![Page 78: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/78.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Example
Case: falsified data
GCP/GLP
![Page 79: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/79.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
Example
Case: falsified data
GCP/GLP
![Page 80: 2 2 bioaivers-experience](https://reader031.vdocuments.net/reader031/viewer/2022032114/55aace201a28abfb7a8b45b4/html5/thumbnails/80.jpg)
WHO Workshop on Prequalification of Medicines Programme, Abu Dhabi, 11-13 October, 2010
End
Thank you for your attention