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Biowaiver Applications in Support of a Polymorph During Late-Stage Clinical Development of Verubecestat—Current Challenges and Future Opportunities for Global Regulatory Alignment

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Abstract

Dissolution experiments to support an active pharmaceutical ingredient (API) form change in Verubecestat immediate release tablets were performed following current regulatory guidance published by health authorities in Canada, Australia, Japan, the EU, and the USA. Verubecestat API meets the requirements of a Biopharmaceutics Classification System class 1 compound and tablets are very  rapidly dissolving in aqueous dissolution media. While the in vitro data were reviewed favorably by these agencies, the divergence in regulatory requirements led to unnecessary work and highlights several issues companies operating globally face to justify product changes that have very little impact on quality. The data presented in this manuscript provide a compelling case for adjustments to the current draft ICH M9 guidance which provides recommendations for biowaiver applications. Specifically, this manuscript contains recommendations with respect to API attributes, selection of dissolution media and apparatus, and methods to assess dissolution similarity if needed, which should be considered for inclusion in a science- and risk-based global guidance document to benefit patients, regulators, and the pharmaceutical industry.

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Notes

  1. At the time when the API form change was discovered, the requirements described in the 2015 Draft US FDA BCS biowaiver guidance were followed. The experiments are the same as those that are required in the current guidance.

Abbreviations

API:

Active Pharmaceutical Ingredient

BCS:

Biopharmaceutics Classification System

CMA:

Critical Materials Attribute

CPP:

Critical Process Parameter

CQA:

Critical Quality Attribute

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

ICH:

International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use

IR:

Immediate Release

MR:

Modified Release

SUPAC:

Scale-up and Post-approval Change

PBBM:

Physiologically Based Biopharmaceutics Model

PK:

Pharmacokinetic

QC:

Quality Control

XRPD:

X-ray Powder Diffraction

UPLC:

Ultra-performance Liquid Chromatography

USP:

United States Pharmacopeia

JP:

Japanese Pharmacopeia

PMDA:

Pharmaceutics and Medical Device Agency (Japanese health agency)

ANVISA:

Agência Nacional de Vigilância Sanitária (National Health Surveillance Agency Brazil)

RDC:

Resolução da Diretoria Colegiada (Resolution of the Collegiate Board)

TGA:

Therapeutic Goods Agency (Australian Health Agency)

HC:

Health Canada

UV:

Ultraviolet

rpm:

Revolutions per minute

NF:

National Formulary

logP:

Partition Coefficient

P eff :

Effective Permeability

Vc:

Central Volume of Distribution

K 12/K 21 :

Distribution Rate Constants

f up :

Unbound Fraction in Plasma

CL:

Systemic Clearance

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Authors and Affiliations

  1. Pharmaceutical Sciences, Merck & Co., Inc., 126 E. Lincoln Ave, Rahway, NJ, 07065, USA

    Andreas Abend, Leah Xiong, Filippos Kesisoglou & Kevin Reuter

  2. Regulatory Affairs-CMC, Merck & Co., Inc., 126 E. Lincoln Ave, Rahway, NJ, 07065, USA

    Celeste Frankenfeld & Pramod Kotwal

  3. Analytical Commercialization Technology, Merck & Co., Inc., 126 E. Lincoln Ave, Rahway, NJ, 07065, USA

    Xiaohua Zhang

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  1. Andreas Abend
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  2. Leah Xiong
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Correspondence to Andreas Abend.

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Abend, A., Xiong, L., Zhang, X. et al. Biowaiver Applications in Support of a Polymorph During Late-Stage Clinical Development of Verubecestat—Current Challenges and Future Opportunities for Global Regulatory Alignment. AAPS J 22, 17 (2020). https://doi.org/10.1208/s12248-019-0396-9

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