Bioequivalence Assessment Update · 2018-10-05 · New guidances being added regularly 50 guidances...

1 Copenhagen, Denmark 24 – 27 September 2018

Prequalification Team – Medicines

(PQTm)

Bioequivalence Assessment

Update

Dr. John Gordon

Bioequivalence on the PQTm website

Notes on bioequivalence study design Product specific guidance

Bioequivalence Trial Information Form (BTIF)

Additional supporting data requirements

Comparator products

Biowaivers

Zinc

Overview

Copenhagen, Denmark 24 – 27 September 2018 2

3 Copenhagen, Denmark 24-27 September 2018

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)

Now 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


Product specific guidance

Based on best information available to PQTm

Maybe revised if more information becomes

available

New guidances being added regularly

50 guidances + RH guidance currently posted

28 guidances added since last meeting!

Most recent additions include advice on the design

of studies for:

Lopinavir/ritonavir

Primaquine

Notes on bioequivalence study design

6 Copenhagen, Denmark 24 – 27 September 2018

Must be completed in Word format for every

bioequivalence study submitted to PQTm

New version of BTIF posted in 20 September 2018

Clarification to Section 2.4.3.2 c

Information on Purchase, shipment, storage of the comparator

Revision to Section 8.4 a

Intra-day precision and accuracy summary not required

Addition of Section 10

Appendix 1: Individual pharmacokinetic results (AUC and

Cmax) for each subject

List of all bioequivalence studies conducted

Bioequivalence Trial Information Form

(BTIF)


Purchase, shipment, storage of the comparator product (Indicate from which company/pharmaceutical distributor the

comparator product has been obtained. Clearly indicate in

chronological order the steps and dates of shipment/transport from

company of purchase to the study site. In addition, the storage

conditions should be given. This information should be cross-

referenced to location in submission of documents (e.g. receipts)

proving conditions.

BTIF Section 2.4.3.2


For example:

A = Name and location of Pharmaceutical Distributor (date of purchase);

location in dossier of purchase invoice;

Shipped from A to B (date shipped, method of shipment); location in dossier of

bill of lading and shipping temperature record;

B = Sponsor’s site (date received, storage conditions at site); location in dossier

of record of storage conditions over period stored at site

Shipped from B to C (date shipped, method of shipment); location in dossier of

bill of lading and shipping temperature record;

C = CRO site (date received, storage conditions at site); location in dossier of

record of storage conditions over period stored at site)

BTIF Section 2.4.3.2


10.1 Electronic copy of Study AUC and Cmax data in

Appendix 1 to BTIF (A MS Excel file containing the AUC and Cmax data from the study

should be included in Module 1.4.1 of the CTD identified as Appendix 1

to the BTIF. The Excel file template provided on the PQTm website

should be used and its format should not be modified except to add

extra columns for studies larger than a two-way design.

Confirm below that the requested Excel spreadsheet has been provided

in the dossier.)

BTIF Section 10

Additional supporting data


10.2 List of all bioequivalence studies conducted with

proposed product and studies conducted during

product development

Confirm below that the list of studies is provided as required. If no

additional studies (beyond the study summarized in this BTIF) have

been conducted, please so indicate here.)

BTIF Section 10

Additional supporting data


1. A list of all bioequivalence studies, including pilot studies, conducted with the

proposed product i.e., same formulation and manufacturing process as that

submitted for prequalification, regardless of the comparator (reference)

product employed and regardless of the study outcome. Complete study

synopses should be provided for all listed studies, in accordance with Annex

I of ICH Guideline E3: Structure and Content of Clinical Study Reports.

2. A list of all bioequivalence or comparative bioavailability studies, including

pilot studies, conducted during pharmaceutical development (development

of formulation and/or manufacturing processes) of the product, regardless of

the comparator (reference) product employed and regardless of the study

outcome. Complete study synopses should be provided for all listed studies,

in accordance with Annex I of ICH Guideline E3: Structure and Content of

Clinical Study Reports.

Full study reports for all listed studies should be available upon request.

Module 2.7


Lists for comparator products for each treatment area

available on PQTm website

All lists updated regularly

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 PQTm

Comparator products


A regulatory authority that is

a member of ICH prior to 23 October 2015, namely: the US

Food and Drug Administration, the European Commission

and the Ministry of Health, Labour and Welfare of Japan also

represented by the Pharmaceuticals and Medical Devices

Agency; or

an ICH observer prior to 23 October 2015, namely: the

European Free Trade Association, as represented by

Swissmedic and Health Canada; or

a regulatory authority associated with an ICH member

through a legally-binding, mutual recognitionagreement prior

to 23 October 2015, namely: Australia, Iceland, Liechtenstein

and Norway.

Comparator products:

Where can they be purchased?


If WHO comparator product cannot be located in those

markets, consult PQTm

Identification of alternate markets for sourcing

particular products

Assistance identifying pharmaceutical distributors

If a comparator is not indicated on our PQTm list then

contact PQTm

Comparator Products


Biowaivers

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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 Biowaivers

eligible APIs

20

Medicines for HIV/AIDS and

related diseases Abacavir sulfate (Class III)

Emtricitabine (Class I)

Fluconazole Polymorphs II & III (Class I)

Lamivudine (Class III)

Stavudine (Class I)

Zidovudine (Class I)

Neglected Tropical Disease

medicines

Diethylcarbamazine (Class III)*

Anti-tuberculosis medicines Ethambutol (Class III)

Isoniazid (Class III)

Levofloxacin (Class I)

Linezolid (Class I)

Moxifloxacin HCl (Class I)

Ofloxacin (Class I)

Pyrazinamide (Class III)

Copenhagen, Denmark 24-27 September 2018

BCS-based Biowaivers

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Do not use classifications provided in 2006 WHO TRS 937, Annex 8

ECSPP overseeing the development of a new

biowaiver classification list Living document

Information on equilibrium solubility experiments Appendix 2 of WHO TRS 1003, Annex 6 (2017)

Document with more technical detail under

development by ECSPP

ZINC PRODUCTS UPDATED DOCUMENTS


Safe quality

medicines

Bioequivalence Assessment Update · 2018-10-05 · New guidances being added regularly 50 guidances...

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