Working document QAS/20.850 July 2020

DRAFT WORKING DOCUMENT FOR COMMENTS: 1

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WHO Biowaiver Project - Preparation for cycle IV 3

(2021): Prioritization exercise of active pharmaceutical 4

ingredients on the WHO Model List of Essential 5

Medicines for solubility determination and 6

Biopharmaceutics Classification System-based 7

classification 8

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Please send your comments to Dr Valeria Gigante, Technical Officer, Norms and Standards for Pharmaceuticals, Technical Standards and Specifications (gigantev@who.int), with a copy to Ms Claire Vogel (vogelc@who.int) before 20 August 2020. Please use our attached Comments Table for this purpose.

Our working documents are sent out electronically and they will also be placed on the WHO Medicines website (http://www.who.int/medicines/areas/quality_safety/quality_assurance/guidelines/en/) for comments under the “Current projects” link. If you wish to receive all our draft guidelines, please send your email address to jonessi@who.int and your name will be added to our electronic mailing list.

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© W o rld Health Organization 2020 11

All rights reserved. 12

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. Th e draft 13 may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in 14 any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member 15 organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. 16

Please send any request for permission to: Dr Sabine Kopp, Team Lead, Norms and Standards for Pharmaceuticals, Technical 17 Standards and Specifications, Department of Health Products Policy and Standards, World Health Organization, CH-1211 Geneva 18 27, Switzerland, email: kopps@who.int. The designations employed and the presentation of the material in this draft do not 19 imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any 20 country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on 21 maps represent approximate border lines for which there may not yet be full agreement. 22

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended 23 by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions 24 excepted, the names of proprietary products are distinguished by initial capital letters. 25

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. 26

However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibi lit y 27 for the interpretation and the use of the material lies with the reader. In no event shall the World Health Organization be liable 28 for damages arising from its use. 29

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 30

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Working document QAS/20.850 page 2

SCHEDULE FOR DRAFT WORKING DOCUMENT QAS/20.850: 32

WHO Biowaiver Project - Preparation for cycle IV (2021): 33

Prioritization exercise of active pharmaceutical ingredients 34

on the WHO Model List of Essential Medicines for solubility 35

determination and Biopharmaceuticals Classification 36

System-based classification 37

Description of activity Date

The Forty-seventh meeting of the World Health Organization (WHO)

Expert Committee on Specifications for Pharmaceutical Preparations

(ECSPP) recommended to update the WHO Biowaiver List, originally

developed in 2006.

October 2012

• Several consultations with experts were held to discuss the

potential approach to implement this recommendation. 2012-2016

Presentation from the WHO Secretariat to the Fifty-second ECSPP

proposing to initiate the revision of the WHO Biowaiver List based on

experimental solubility data through the WHO Biowaiver Project to be

initiated in form of a pilot exercise.

16–20 October 2017

Development of WHO Protocol to conduct equilibrium solubility

experiments for the purpose of a Biopharmaceutics Classification

System (BCS)-based classification of active pharmaceutical ingredients

(APIs) (WHO Technical Report Series, No. 1019, 2019, Annex 4).

November 2017- February

2018

Start of WHO Biowaiver Pilot Project (cycle I) to classify the first set of

APIs prioritized from the WHO Model List of Essential Medicines (EML). February- May 2018

Presentation of the Protocol and test results during the Joint Meeting

on Regulatory Guidance for Multisource Products with the Medicines

Quality Assurance group (MQA) and Prequalification of Medicines

team (PQTm) in Copenhagen, Denmark

18–19 May 2018

Working document QAS/20.850 page 3

First set of APIs classified for the revised WHO Biowaiver List posted

for public consultation. Comments invited on the second set of APIs

prioritized for classification during cycle II.

July–September 2018

Consolidation of comments received and review of feedback. End of September 2018

Presentation to the Fifty-third meeting of the ECSPP of the first set of

APIs classified within the WHO Biowaiver Project (WHO Technical

Report Series, No. 1019, 2019).

22–26 October 2018

Start of WHO Biowaiver Project cycle II. November 2018 - October

2019

Presentation of the preliminary test results and prioritization exercise

of APIs for study in cycle III during the Joint Meeting on Regulatory

Guidance for Multisource Products with the Norms and Standards for

Pharmaceuticals (NSP) Team (previously known as the Medicines

Quality Assurance group) and PQTm in Copenhagen, Denmark.

May 2019

Mailing of the draft working document with the third set of APIs for

classification in cycle III inviting comments, including to the WHO

Expert Advisory Panel on the International Pharmacopoeia and

Pharmaceutical Preparations (EAP), and posting the working document

on the WHO website for public consultation.

August - 20 September

2019

Consolidation of comments received and review of feedback. End of September 2019

Presentation from the WHO Secretariat of test results from cycle II and

draft list of APIs for classification in cycle IIII to the Fifty-fourth meeting

of the ECSPP (WHO Technical Report Series, No. 1025, 2020, Annex

12).

14-18 October 2019

Start WHO Biowaiver Project cycle III November 2019

Working document QAS/20.850 page 4

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Presentation of the preliminary test results and prioritization exercise

of APIs for study in cycle IV during the Joint Meeting on Regulatory

Guidance for Multisource Products with the NSP Team and PQTm.

22 June 2020

Mailing of the draft working document with the fourth set of APIs for

classification in cycle IV inviting comments, including to the WHO EAP,

and posting the working document on the WHO website for public

consultation.

July – August 2020

Consolidation of comments received and review of feedback. September 2020

Presentation from the WHO Secretariat of results from cycle III and

draft list of APIs for classification in cycle IV to the Fifty-fifth meeting of

the ECSPP.

12-16 October 2020

Any other follow-up action as required.

Working document QAS/20.850 page 5

WHO Biowaiver Project 51

Preparation for cycle IV (2021): 52

Prioritization exercise of active 53

pharmaceutical ingredients on the 54

WHO Model List of Essential Medicines 55

for solubility determination and 56

Biopharmaceutical Classification 57

System-based classification 58

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1. Introduction and scope 60

2. Background 61

3. The revised WHO Biowaiver List 62

4. Prioritization exercise of active pharmaceutical ingredients for Biopharmaceutical Classification 63

System-based classification in WHO Biowaiver Project 64

References 65

Further reading 66

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Working document QAS/20.850 page 6

1. Introduction and scope 69

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In October 2019, the World Health Organization (WHO) Expert Committee on Specifications for 71

Pharmaceutical Preparation (ECSPP) took note of the results achieved within the WHO Biowaiver Project 72

and recommended continuing the Biopharmaceutics Classification System (BCS)-based classification of 73

active pharmaceutical ingredients (APIs) contained in medicines listed in the WHO List of Essential 74

Medicines (EML) (1) and prioritized according to public health priorities, Member States’ and WHO 75

partners’ needs (2). 76

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This document is intended to support the prioritization exercise of APIs that will be characterized in their 78

solubility profile in cycle IV of the WHO Biowaiver Project, to take place in 2021 according to the ECSPP 79

decision (2). 80

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The WHO Biowaiver Project is organized into study cycles. Previous and current cycles are summarized 82

below in order to provide an overview of the project development: 83

• 2018: cycle I; also referred to as the pilot phase. 84

• 2019: cycle II. 85

• 2020: cycle III; current study cycle. 86

• 2021: cycle IV. Note: this prioritization exercise is propaedeutic to this study cycle. 87

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2. Background 89

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When evaluating multisource (generic) products, the goal is to ensure that they have a comparable 91

bioavailability (BA) with respect to their originator in order to assume comparability in their efficacy and 92

safety profiles. 93

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The WHO recognizes the possibility to waive in vivo bioequivalence studies for immediate-release, solid 95

oral dosage forms APIs belonging to classes I and III according to the BCS, using comparative dissolution 96

studies as surrogate proof of bioequivalence (3). 97

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The aim of WHO biowaiver guidance documents is to reduce the risk of “bioinequivalence” to an 99

acceptable level when granting biowaivers supporting pharmaceutical development and access to 100

Working document QAS/20.850 page 7

medicines. In this context, the solubility, the release from the drug product and the subsequent 101

absorption phase are considered critical processes underlying the equivalence of the test and reference 102

product. 103

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Equilibrium solubility profiles of APIs contained in medicines in the EML (1) can be used in conjunction 105

with absorption/permeability data, finished pharmaceutical products (FPP) dissolution studies and 106

comparative consideration of FPP-excipient content in order to provide an informed decision on 107

whether or not a biowaiver could be granted safely. 108

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3. The revised WHO Biowaiver List 110

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According to the recommendations from the Fifty-second, Fifty-third and Fifty-fourth ECSPP, the WHO 112

Secretariat has published the revised WHO Biowaiver List: Proposal to waive in vivo bioequivalence 113

requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms (4). 114

The List is published in form of a living document and is meant to be regularly updated with new data 115

and in accordance with the scientific and technical progress in this area. In addition, the List replaces 116

the existing literature-based compilation published in 2006 that is reported in the Proposal to waive in 117

vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid 118

oral dosage forms (5). 119

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The WHO Protocol to conduct equilibrium solubility experiments for the purpose of biopharmaceutics 121

classification system-based classification of active pharmaceutical ingredients for biowaiver (6) is a tool 122

available to all participants in this research. This protocol was developed with the purpose of providing 123

a harmonized methodology for the equilibrium solubility experiments, thereby minimizing the variability 124

amongst centres and studies. 125

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4. Prioritization exercise of active pharmaceutical 127

ingredients for Biopharmaceutical Classification 128

System-based classification in WHO Biowaiver 129

Project 130

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A fourth set of APIs is proposed for BCS-based classification within the WHO Biowaiver Project. The 132

criteria underpinning the APIs prioritization are as follows: 133

• the API must be contained in medicines listed in the EML; 134

• the API must be intended to be formulated as an immediate-release, solid oral dosage form; 135

• the API must belong to therapeutic areas of major public interest; and 136

• the specific physical-chemical properties for the API must be known. 137

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Consideration should be given to narrow therapeutic index drugs (NTIs) as the BCS-based biowaiver 139

approach is not considered to be a suitable surrogate for the establishment of bioequivalence of NTIs. 140

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COVID-19 emergency use 142

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During this prioritization exercise, propaedeutic to the study of the solubility profiles of APIs, particular 144

attention has been made of potential candidates currently in clinical trials to address the COVID-19 145

pandemic. In addition great efforts are being made to conduct an expedite characterization to address 146

this public health emergency. Dexamethasone followed by hydroxychloroquine are therefore suggested 147

as high priority APIs for the solubility characterization. 148

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Note: the inclusion of these substance in the list does not imply any endorsement from WHO but is 150

intended only to promote access to medicines in case they will be deemed suitable for the intended 151

purpose. 152

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Working document QAS/20.850 page 9

Proposed list of active pharmaceutical ingredients for study in cycle IV 158

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The list of APIs to be prioritized for BCS-based classification in the next cycle of the project (cycle IV- 160

2021) are proposed below (in alphabetic order) and comments are invited. When providing comments, 161

you might wish to indicate their order of priority. 162

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N API contained in medicines on the

EML

Therapeutic Area Indication Highest therapeutic single dose [mg]

1 Abacavir Antiretrovirals Treatment and prevention of HIV

600 mg

2 Dexamethasone (1) Gastrointestinal medicines/ (2) Immunomodulators and

antineoplastics/ (3) Medicines for other common symptoms in

palliative care

(1) Antiemetic medicines/ (2) Acute

lymphoblastic leukaemia

(2) Multiple myeloma/

(3) Medicines for other common

symptoms in palliative care

(1) (3) 0.75 to 9 mg a day depending on the

disease being treated/ (2) 40 mg

3 Doxycycline (1) Antiprotozoals (2) Antibacterials

(1) Antimalarial medicines (2)

Antibiotics (access group)

(1) and (2) 100 mg (as hyclate)

4 Ethambutol Antibacterials Antituberculosis medicines

2 g

5 Isoniazid Antibacterials Antituberculosis medicines

300 mg

6 Hydroxy-chloroquine

Medicines for diseases of joints Disease-modifying agents used in

rheumatoid disorders (DMARDs)

400 to 600 mg

7 Lamivudine

Antiretrovirals Treatment and prevention of HIV

300 mg

8 Levonorgestrel Medicines for reproductive health and perinatal care

Oral hormonal contraceptives

1.5 mg

9 Nifurtimox Antiprotozoal medicines African trypanosomiasis and

American trypanosomiasis

10.0 mg/kg

10 Proguanil Antiprotozoals Antimalarial 100 mg (as hydrochloride)

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Note: For exemption from an in vivo bioequivalence study, an immediate release, multisource product 165

should exhibit very rapid or rapid in vitro dissolution characteristics that are comparable to the reference 166

Working document QAS/20.850 page 10

product. The excipients used in the formulation must be considered together with a risk-based 167

approach in terms of the therapeutic index and clinical indications. 168

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References 171

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1. WHO Model List of Essential Medicines, 21st list. Geneva: World Health Organization; 2019 173

(https://apps.who.int/iris/bitstream/handle/10665/325771/WHO-MVP-EMP-IAU-2019.06-174

eng.pdf?ua=1, accessed 4 November 2019). 175

176

2. WHO Expert Committee on Specifications for Pharmaceutical Preparations: fortieth report. In: 177

Geneva: World Health Organization; 2020 (WHO Technical Report Series, No. 1025; 178

https://www.who.int/publications-detail/978-92-4-000182-4, accessed 12 May 2020). 179

180

3. Multisource (generic) pharmaceutical products: guidelines on registration requirements to 181

establish interchangeability. In: WHO Expert Committee on Specifications for Pharmaceutical 182

Preparations: fifty-first report. Geneva: World Health Organization; 2017: Annex 6 (WHO 183

Technical Report Series, No. 1003; http://apps.who.int/medicinedocs/ 184

documents/s23245en/s23245en.pdf, accessed 18 November 2019). 185

186

4. WHO “Biowaiver List”: proposal to waive in vivo bioequivalence requirements for WHO Model 187

List of Essential Medicines immediate-release, solid oral dosage forms. In: WHO Expert 188

Committee on Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World 189

Health Organization; 2020: Annex 12 (WHO Technical Report Series, No. 1025; 190

https://www.who.int/publications-detail/978-92-4-000182-4, accessed 12 May 2020). 191

192

5. Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential 193

Medicines immediate-release, solid oral dosage forms. In: WHO Expert Committee on 194

Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World Health 195

Organization; 2006: Annex 8 (WHO Technical Report Series, No. 937; 196

https://apps.who.int/medicinedocs/documents/ s19640en/s19640en.pdf, accessed 18 197

November 2019). 198

199

6. Protocol to conduct equilibrium solubility experiments for the purpose of Biopharmaceutics 200

Classification System-based classification of active pharmaceutical ingredients for biowaiver. In: 201

WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-third report. 202

Working document QAS/20.850 page 12

Geneva: World Health Organization; 2019: Annex 4 (WHO Technical Report Series, No. 1019; 203

https://apps.who.int/iris/bitstream/handle/10665/312316/9789241210287-eng.pdf?ua=1, 204

accessed 12 May 2020). 205

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Further reading 207

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• Guidance for organizations performing in vivo bioequivalence studies. In: WHO Expert 209

Committee on Specifications for Pharmaceutical Preparations: fiftieth report. Geneva: World 210

Health Organization; 2016: Annex 9 (WHO Technical Report Series, No. 996; 211

http://apps.who.int/medicinedocs/documents/s22406en/s22406en.pdf, accessed 18 212

November 2019). 213

214

• General background notes and list of international comparator pharmaceutical products. In: 215

WHO Expert Committee on Specifications for Pharmaceutical Preparations: fifty-first report. 216

Geneva: World Health Organization; 2017: Annex 5 (WHO Technical Report Series, No. 1003; 217

http://apps.who.int/medicinedocs/documents/s23244en/s23244en.pdf, accessed 18 218

November 2019). 219

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• Guidance on the selection of comparator pharmaceutical products for equivalence assessment 221

of interchangeable multisource (generic) products. In: WHO Expert Committee on 222

Specifications for Pharmaceutical Preparations: forty-ninth report. Geneva: World Health 223

Organization; 2015 (http://apps.who.int/medicinedocs/documents/s21901en/s21901en.pdf, 224

accessed 18 November 2019). 225

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• List of international comparator products (September 2016). Geneva: World health 227

Organization; 2016 (http://www.who.int/medicines/areas/quality_safety/quality_assurance/ 228

list_int_comparator_prods_after_public_consult30.9.xlsx?ua=1, accessed 18 November 2019). 229

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