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IGDRP BCS Biowaiver Assessment Report Template - Word Version 1

This document assesses a company's application for a BCS biowaiver for a generic drug product. It provides administrative information on the drug product and applicant. It determines the drug is BCS Class I based on its high solubility and absorption. The test and reference products have very rapid dissolution profiles and sufficiently similar excipients. Therefore, the conclusion is that the test product is approvable for a BCS biowaiver.

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K.m. Ehsan Morshed Rana

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0% found this document useful (0 votes)

111 views16 pages

IGDRP BCS Biowaiver Assessment Report Template - Word Version 1

Uploaded by

K.m. Ehsan Morshed Rana

We take content rights seriously. If you suspect this is your content, claim it here.

Available Formats

Download as DOCX, PDF, TXT or read online on Scribd

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Biopharmaceutics Classification

System (BCS) Biowaiver

Assessment Report

Version 1- Feb 10, 2017

Disclaimer
This document reflects the views of subject matter experts participating in the IPRP Bioequivalence
Working Group for Generics (BEWGG) and should not be construed to represent the official views of
any given regulatory authority participating in the IPRP.
BCS Biowaiver Assessment Report

<Proposed proprietary name>

<Application/Dossier reference number>

Applicant: <Name of the Applicant>

IGDRP Country
Date of application / Start of assessment
Date of assessment report
Deadline for comment (if applicable)
IGDRP countries concerned

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Table of Contents

1 ADMINISTRATIVE INFORMATION.........................................................................................5
2 GLOSSARY / ABBREVIATIONS.................................................................................................6
3 SUMMARY: REQUIREMENTS AND OUTCOMES..................................................................7
4 INTRODUCTION...........................................................................................................................8
4.1 APPLICATION OBJECTIVE...............................................................................................................8
4.2 STATUS OF THE REFERENCE/ORIGINATOR PRODUCT IN OTHER IGDRP/EU COUNTRIES...............8
4.3 BASIC PHARMACOKINETIC INFORMATION.....................................................................................8
4.4 THERAPEUTIC INDICATIONS AND DOSE.........................................................................................8
5 BCS BIOWAIVER ASSESSMENT...............................................................................................9
5.1 SOLUBILITY...................................................................................................................................9
5.2 ABSORPTION (METHODS AND RESULTS)......................................................................................10
5.3 COMPARISON OF TEST AND REFERENCE FORMULATIONS / EXCIPIENTS.....................................11
5.4 IN VITRO DISSOLUTION COMPARISON..........................................................................................11
5.5 DISSOLUTION TESTING LABORATORY..........................................................................................16
5.5.1 Audit(s)...............................................................................................................................16
5.5.2 GMP compliance/certification............................................................................................16
6 ESSENTIAL SIMILARITY / APPROPRIATENESS OF FINAL PRODUCT SPECIFICATIONS
...................................................................................................................................................17
7 LIST OF OUTSTANDING ISSUES / DEFICIENCIES / PROPOSED QUESTIONS.............17
8 CONCLUSIONS AND RECOMMENDATIONS.......................................................................17
9 REFERENCES..............................................................................................................................17

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1 ADMINISTRATIVE INFORMATION

Proposed name / name of the

medicine in the IGDRP country
Active Pharmaceutical Ingredient -
INN or common name of the
API(s)
Pharmaco-therapeutic group (ATC
code/classification)
Dosage form and strength(s)
Dose
Applicant/Sponsor name and
address, contact information
Final (test) product manufacturer
Name and address
API manufacturer(s)
Name and address
Dissolution (and solubility if
applicable) testing laboratory
name and address
Test product details : batch size
and batch number
Reference product details : name,
HCR, country of procurement
Type of application
(generic / formulation or other
variation(s))
Reviewer(s)/Assessor(s)

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2 GLOSSARY / ABBREVIATIONS

API Active pharmaceutical ingredient / Drug Substance

Drug Active pharmaceutical ingredient (API)
Drug product Pharmaceutical product / medicine/ final product
FC / FDC Fixed combination /FDC fixed dose combination
FPP Finished pharmaceutical product
HCR Holder of certificate of registration/marketing authorisation holder
NTI Narrow therapeutic index
PHCR Proposed holder of certificate of registration/marketing authorisation
PK Pharmacokinetics
SPC Summary of Product Characteristics / Product monograph / Package insert /
labelling

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3 SUMMARY: REQUIREMENTS and OUTCOMES

Outcome
Therapeutic range (and dose) Narrow / Non-narrow
Solubility High / Low
Stable Yes / No
Human absorption / Permeability: >85 % / 90 % / < 85 %/90 % : High Low
BCS class I / II / III / IV
Dosage form Oral, systemic, IR same dosage form
Comparison of excipients in the
Sufficiently similar / Unacceptable differences
formulations
Similar and rapidly dissolving / similar and
very rapidly dissolving/ Non-similar / Non-
Dissolution profiles
very rapidly dissolving / Non-rapidly
dissolving
CoAs Assays within 5 %
BCS Class I
Test and reference products very rapid
or rapid dissolution Yes / No
Excipients that may affect BA the
same (quantity and quality) Yes /No

BCS Class III

Test and reference products very rapid
dissolution Yes/No
Excipients that may affect BA the
same Yes/No

Other excipients very similar Yes/No

Benefit risk summary Acceptable/ Not acceptable
Conclusion Approvable / Non-approvable

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4 INTRODUCTION
Include inter alia the following as relevant:

4.1 Application objective

Reason or justification for application of Biowaiver, BCS Classification.
Address if manufacturer and the applied API and FPP are the same as those employed in the
solubility and dissolution studies. (If the formulation proposed for marketing and those used for
comparative dissolution studies are not identical, clear identification and justifications should be given
by applicant).

4.2 Status of the reference/originator product in other IGDRP/EU countries

Indicate which is the reference product in each country or jurisdiction.
Justify that the product applied for has the same dosage form or is a pharmaceutical
alternative if acceptable for a particular country.
Address identicality / differences in API: same or different salts (both BCS class I) for those
countries where a different salt is acceptable; same ester, ether, isomer, mixture of isomers,
complex or derivative as reference product/originator. If different salts were accepted by a
group of countries, it is necessary to show that the literature data justifies that both salts have
the same toxicological profile. If data is not available in the literature the Applicant has to
perform toxicological studies. In both cases this is additional data that needs to be assessed by
other assessors.
Confirm that it is not sublingual, buccal or modified release. If the dosage form is an
orodispersible tablet it is essential to demonstrate that the labelling of the reference product
states that it is taken with water. Some countries / jurisdictions do not allow a BCS Biowaiver
if the product is taken without water.

4.3 Basic pharmacokinetic information

Linear PK is necessary to accept mass balance / absolute BA studies with doses different to
the highest. References attached.

4.4 Therapeutic indications and dose

Confirm that the API is not NTI. Some countries do not allow a BCS Biowaiver for NTI APIs,
different countries may have different criteria to define NTI API. Examples from Health
Canada guideline include: cyclosporine; digoxin; flecainide; lithium; phenytoin; sirolimus;
tacrolimus; theophylline; warfarin. European Union, on a case-by-case basis the CHMP has
agreed the NTID status of cyclosporine and tacrolimus. WHO TRS 937 Annex 8 also
includes examples.
Evidence to support that the API does not have an NTI, e.g. therapeutic range or difference
between minimum effective dose and minimum toxic dose is required.

Reviewer’s comments:
Discuss information on section 4 – including relevant background, appropriateness of
choice of reference as appropriate, etc.

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5 BCS BIOWAIVER ASSESSMENT

5.1 Solubility
Bibliographical and/or experimental (include source of information)
Note whether the following have been submitted:
 A complete report
 A protocol
 Dates and site of study
 Description of solubility method and conditions.
 Description and validation of the stability-indicating analytical method or cross-reference to
the Q section of the dossier
Solubility method

Apparatus
Volume
Time
Dose /amount
Temperature
pH values
Buffer composition

Solubility at different pH values and replicates

Theoretical Repeat Observed Adjusted Individual Cs Quantity dissolved

pH pH pH Cs values (mean) in 250 ml
1
pH 1.2
2
3
1
Intermediate
2
pHs
3
1
pH 4.5
2
3
1
Intermediate
2
pHs
3
1
pH 6.8
2
3
1
Other
2
intermediate
3
pH values **
** Other intermediate pH values e.g. pKa, pKa-1, pKa+1
Plot of Solubility (Concentration at saturation) vs. pH to identify the pH of minimum solubility.
Add plot

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Notes for consideration:
Is the maximum/highest dose (or strength in some jurisdictions) that can be taken in a single
administration according to the SPC, soluble in 250 ml in at least three buffers (preferably 1.2; 4.5;
6.8/7.5) in range pH 1 to 6.8/7.5 buffers and at the pKa if within specified range; at 37 °C +/- 1 °C?
Replicate determinations are required to achieve unequivocal solubility classification (shake flask
method or other justified method). Solution pH should be verified prior and after addition of API to
buffer.
Note whether the drug is stable in the buffers and whether the analytical method is stability-
indicating. For example acetylsalicilic acid or capecitabine are highly soluble but unstable and the
BCS biowaiver is not allowed in the European Union. Capecitabine can however be waived in the
USA based on their recommendations for capecitabine.
In some jurisdictions the concentration at saturation is necessary and the demonstration of solubility
in 250 ml does not suffice.
Reviewer’s comments:
Discuss information on section 5.1

5.2 Absorption (methods and results)

Include source of absorption data, literature data or experimental data

Human
Absolute BA reference (give literature citation)
Oral
Dose
Intravenous
Number of subjects
Result
Mass balance reference (give literature citation)
Dose
Number of subjects
Result
In vivo or in vitro permeability
Test system
Concentrations
Result
Other information
Influence of the transporters to
absorption
Notes for consideration
Complete absorption – measured extent of absorption is ≥ 85 % / 90 % generally related to high
permeability, based on reliable investigations in human.

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Discussion of the literature: mass balance and absolute BA studies.
Supportive information (e. g. Caco-2 monolayers, animal data)
Has complete absorption been shown for the highest dose in case the PK is non-linear (less than
proportional due to saturation of absorption, e.g. gabapentin has complete absorption at low doses, but
incomplete when the transporter is saturated)?
Dose linearity of pharmacokinetics. Absorption should be investigated at the highest dose if PK is not
linear.

Reviewer’s comments:
Discuss information on section 5.2

5.3 Comparison of Test and Reference formulations / Excipients

Component Function Test Reference

Notes for consideration:

BCS I Similar quantities of the same excipients advisable
BCS III Very similar qualitatively and quantitatively to exclude different effects on membrane
transporters
Well established excipients in usual/normal quantities. Description of function of each.
The test and reference product quantities of excipients that might affect bioavailability should be
qualitatively and quantitatively the same, e.g. sorbitol, mannitol, sodium lauryl sulphate or other
surfactants (e.g. PS80, Cremophors, Pluronics), and cyclodextrin.
Fixed combinations (FCs): All APIs/drug substances either BCS I or III and fulfil all the requirements
of the corresponding BCS class.

Reviewer’s comments:
Discuss information on section 5.3

5.4 In vitro Dissolution comparison

Complete documentation submitted– study report, study protocol, batch information on test and
reference batches including CoAs, administrative details of the dissolution studies: person
responsible, centre, dates, etc., detailed experimental conditions, validation of experimental analytical
methods, individual and mean results and respective summary statistics.

Summary of dissolution test method parameters

Apparatus

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Rate of Operation
Dissolution Media
Volume
Temperature
Sampling times
Number of Dosage Units
Sampling
Filtration methods (in-line filtration)
De-aeration method

Usual experimental conditions are e.g.:

 Apparatus: paddle or basket
 Number of Dosage units: 12
 Volume of dissolution medium: 900 ml or less
 Temperature of the dissolution medium: 37±1 °C
 Agitation:
paddle apparatus - usually 50 or 75 rpm as applicable;
basket apparatus - usually 100 rpm (specify for country)
 Sampling schedule: e.g. 10, 15, 20, 30 and 45 min
 Buffer: pH 1.0 – 1.2 (usually 0.1 N HCl or SGF without enzymes), pH 4.5, and pH 6.8 (or SIF
without enzymes); (pH should be ensured throughout the experiment; USP/Ph.Eur. buffers
recommended)
 Other conditions: no surfactant; in case of gelatine capsules or tablets with gelatine
coatings the use of enzymes may be acceptable.

Notes on CoA comparison:

The difference between test and reference product in the assay of the CoA must be less than 5 %.
The objective is to use products with comparable quantities so that a potency correction is not
necessary.

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Test Batches
Dissolution Profiles for Lot #: n = no. of units/ pH medium
n % Label Claim Released
pH of medium x Min x Min x Min x Min x Min
pH 1 (0.1 N HCl)
Mean
%RSD
pH 4.5 (Acetate)
Mean
%RSD
pH 6.8 (Phosphate)
Mean
%RSD
pH of minimum solubility
Mean
%RSD