bioequivalence assessment update | who/extranet

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Prequalification Team – Medicines (PQT/MED)

Bioequivalence AssessmentUpdate

Dr. John Gordon

Virtual Joint Meeting 30 November – 3 December 2020

Bioequivalence on the PQT/MED website Notes on bioequivalence study design

Product specific guidance Deficiencies observed in study protocols Comparator products BCS-based biowaivers Bioequivalence Trial Information Form (BTIF)

Overview

Virtual Joint Meeting 30 November – 3 December 2020 2

WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP)

Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability WHO Technical Report Series (TRS) 992, Annex 7 (2015) Re-published in WHO TRS 1003, Annex 6 (2017) with

additional appendix Appendix 2: Equilibrium solubility experiments for the purpose of

classification of active pharmaceutical ingredients according to the Biopharmaceutics Classification System (BCS)

Principal Bioequivalence Guideline

4Virtual Joint Meeting 30 November – 3 December 2020

http://www.who.int/entity/medicines/areas/quality_safety/quality_assurance/trs1003_annex6.pdf?ua=1

Product specific guidance Based on best information available to PQT/MED Maybe revised if more information becomes

available New guidances being added regularly 71 guidances + RH guidance currently posted 7 guidances added and several updated since last

meeting Most recent additions/updates include advice on the

design of studies for: Amoxicillin Clarithromycin/Rifampicin Dexamethasone

Notes on bioequivalence study design


Virtual Joint Meeting 30 November – 3 December 2020 Virtual Joint Meeting 30 November – 3 December 2020 7

Applicants planning to conduct bioequivalence (BE) studies for submission to PQT/MED should submit a final draft of the study protocol to PQT/MED for comment prior to undertaking the study

Purpose: Assist applicants develop studies that will best be able to

detect differences in in vivo performance between drug products

Minimise factors that could introduce variability into the study data

Align with PQT/MED guidelines and requirements

Review of BE Study Protocols


Frequent Deficiencies in Bioequivalence Study Protocols

Purpose is to summarize commonly observed deficiencies so applicants can address these issues during protocol development, prior to submission of the protocol to PQT/MED for comment

Deficiencies noted in several areas: Comparator product Proposed product Inclusion and exclusion criteria Method of administration of drug products Sample size calculations Pharmacokinetic and statistical analyses

Common Deficiencies In Protocols


https://extranet.who.int/pqweb/key-resources/documents/frequeent-deficiencies-bioequivalence-study-protocols

Lists for comparator products for each treatment area available on PQT/MED website

All lists updated regularly 6 lists updated in 2020 2 list added

Therapeutics against COVID-19 Treatment of infections in newborn and young infants and

childhood pneumonia Not all products listed in PQ Expressions of Interest

(EOIs) will have comparators indicated on these lists For example, some dispersible products do not have

comparable references so conventional product may have to be used as comparator If a comparator is not listed, consult PQT/MED

Comparator products


Biowaivers


In vitro approaches for demonstrating safety and efficacy of products in lieu of conducting in vivo bioequivalence studies Biopharmaceutics Classification System (BCS) –

based biowaivers Suitable for products containing eligible APIs Abbreviated submission if API is on the eligibility list

Additional strengths biowaivers Suitable for additional strengths in a product line when

one of the strengths has shown in vivo bioequivalence to the comparator

BCS-based Biowaiver guidance WHO Technical Report Series No. 1003, Annex 6

(2017)

General Notes on Biopharmaceutics Classification System (BCS)-based Biowaiver Applications

Biowaiver Application Form: Biopharmaceutics Classification System (BCS)


BCS-based Biowaiver guidance International Council for Harmonisation of Technical

Requirements for Pharmaceuticals for Human Use (ICH)

M9: Biopharmaceutics Classification System-Based Biowaivers

– Adopted 20 November 2019– https://database.ich.org/sites/default/files/M9_Guideline_

Step4_2019_1116.pdf


ICH M9 Implementation ANVISA, Brazil - In the process of implementation;

Reference: RDC 37/2011

EC, Europe - Implemented; Date: 30 July 2020; Reference: EMA/CHMP/ICH/493213/2018

FDA, United States - In the process of implementation;

HSA, Singapore - In the process of implementation;

Health Canada, Canada - Implemented; Date: 26 August 2020; Reference: File #: 20-109235-116


ICH M9 Implementation MFDS, Republic of Korea - In the process of

implementation; Date: 1 December 2021

MHLW/PMDA, Japan - In the process of implementation;

NMPA, China - In the process of implementation;

Swissmedic, Switzerland - Implemented; Date: 1 August 2020

TFDA, Chinese Taipei - Implemented; Date: 11 August 2016


ICH M9 Implementation

PQT/MED – Planned implementation on 1 January 2021

– Will appear on PQT/MED website along with a companion ‘annotation’ document

• Annotations will highlight any PQT/MED specific issues

Biowaiver Application Form: Biopharmaceutics Classification System (BCS)


Comparison of existing PQT/MED BCS biowaiver guidelines and ICH M9

Classification of APIs within BCS• Solubility determination similar• Clearer emphasis on stability information in M9• Caco-2 permeability data accepted as evidence of

absorption/permeability designation

BCS Class I & III APIs eligible for biowaiver


Comparison of existing PQT/MED BCS biowaiver guidelines and ICH M9 Comparison of FPP with Comparator product

• Excipient requirements similar– Qualitative requirements are the same– Calculation of quantitative differences clarified in M9– Allowable quantitative differences are larger in M9

• In vitro comparative dissolution studies– Similar dissolution conditions and requirements– Main difference is agitation speed for paddle apparatus (50

vs. 75 rpm)– Selection of data points for f2 calculation differs


WHO Expert Committee on Specifications for Pharmaceutical Preparations (ECSPP)

Project to assess the possibility of BCS-based biowaivers for APIs on the Essential Medicines List Initial objective is to assess the BCS-related solubility

characteristics of APIs on the EML Allows for provisional classification of an API as BCS Class I/III

or II/IV Eventual investigation of absorption/permeability

characteristics will allow clear classification as I, II, III, or IV Most recent version of the classification list found in TRS

1025, Annex 12

WHO “Biowaiver List”


https://www.who.int/publications/i/item/978-92-4-000182-4

Must be completed in Word format for every bioequivalence study submitted to PQT/MED

A new version of BTIF was posted on 27 November 2020. Updates included: Revision to Section 10 Addition of comment box

Addition of information requested in Section 8 Identify the analysis instruments employed during bioanalytical

method validation and those employed for the analysis of the bioequivalence study subject samples (e.g., LC/MS/MS-XX)

Bioequivalence Trial Information Form(BTIF)


Safe quality medicines

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