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Biopharmaceutics Risk Assessment—Connecting Critical Bioavailability Attributes with In Vitro, In Vivo Properties and Physiologically Based Biopharmaceutics Modeling to Enable Generic Regulatory Submissions

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Abstract

Quality risk assessment following ICH Q9 principles is an important activity to ensure optimal clinical efficacy and safety of a drug product. Typically, risk assessment is focused on product performance wherein critical material attributes, formulation variables, and process parameters are evaluated from a manufacturing perspective. Extending ICH Q9 principles to biopharmaceutics risk assessment to identify factors that can impact in vivo performance is an upcoming area. This is evident by recent regulatory trends wherein a new term critical bioavailability attributes (CBA) has been coined to identify such factors. Although significant work has been performed for biopharmaceutics risk assessment for new molecules, there is a need for harmonized biopharmaceutics risk assessment workflow for generic submissions. In this manuscript, we attempted to provide a framework for performing biopharmaceutics risk assessment for generic regulatory submissions. A detailed workflow for performing biopharmaceutics risk assessment includes identification of initial CBA (iCBA), their confirmatory evaluation followed by definition of the control strategy. Tools for biopharmaceutics risk assessment, i.e., bio-discriminatory dissolution method and physiologically based biopharmaceutics modeling (PBBM) were discussed from a practical perspective. Furthermore, a case study for CBA evaluation using PBBM modeling for an extended-release product for regulatory submission has been described using the proposed workflow. Finally, future directions of integrating CBA evaluation, biopharmaceutics risk assessment to the FDA Knowledge Aided Structured Assessment (KASA) initiative, the necessity of risk assessment templates, and knowledge sharing between industry and academia are discussed. Overall, the work described in this manuscript can facilitate and provide guidance for biopharmaceutics risk assessment for generic submissions.

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Abbreviations

ANDA:

Abbreviated new drug application

ANVISA:

Agência Nacional de Vigilância Sanitária (Brazilian Health Regulatory Agency)

API:

Active pharmaceutical ingredients

ARA:

Acid-reducing agents

BCS:

Biopharmaceutics classification system

BioRAM:

Biopharmaceutics risk assessment road map

BMR:

Batch manufacturing record

BP:

Blueprint

CBA:

Critical bioavailability attributes

CFV:

Critical formulation variables

CMA:

Critical material attributes

CMC:

Chemistry, manufacturing, and controls

CPP:

Critical process variables

CQA:

Critical quality attribute

CRCG:

Center for Research on Complex Generics (CRCG)

CRDS:

Clinically relevant dissolution specifications

DDDPlus:

Dose disintegration and dissolution plus

DoE:

Design of experimentation

DR:

Delayed release

EMA:

European Medicines Agency

ER:

Extended release

FDA:

Food and drug administration

GDF:

Generic drug forum

iCBA:

Initial critical bioavailability attributes

ICH:

International Council for Harmonization

IR:

Immediate release

IVIVC:

in vitro in vivo Correlation

IVIVR:

in vitro in vivo Relation

KASA:

Knowledge Aided Structured Assessment

MR:

Modified release

NCE:

New chemical entity

NTI:

Narrow therapeutic index

OGD:

Office of generic drugs

PAS:

Prior approval supplement

PBBM:

Physiologically based biopharmaceutics model

PBPK:

Physiologically based pharmacokinetic model

PCQS:

Patient centric quality standards

PK:

Pharmacokinetics

PPI:

Proton pump inhibitors

Q1/Q2:

Qualitatively similar/quantitatively similar

QbD:

Quality by design

QC:

Quality control

QRM:

Quality risk management

QTPP:

Quality target product profile

SBIA:

CDER Small Business & Industry Assistance

SUPAC:

Scale-up and post-approval changes

TGA:

Therapeutic goods administration

USFDA:

United States Food and drug administration

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Acknowledgements

The authors would like to thank Dr. Reddy’s Laboratories Ltd. for providing an opportunity to publish this review article.

Funding

This article is funded by Dr. Reddy’s Laboratories Ltd.

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Authors and Affiliations

  1. Biopharmaceutics Group, Global Clinical Management, Integrated Product Development Organization (IPDO), Dr. Reddy’s Laboratories Ltd, Bachupally, Medchal Malkajgiri District, Hyderabad-500 090, Telangana, Hyderabad, India

    Tausif Ahmed, Sivacharan Kollipara, Rajkumar Boddu & Adithya Karthik Bhattiprolu

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  1. Tausif Ahmed
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Contributions

Tausif Ahmed: concept and design, writing the manuscript, manuscript review, approval for the version to be published; Sivacharan Kollipara: concept and design, writing the manuscript; Rajkumar Boddu: concept and design, writing manuscript; Adithya Karthik Bhattiprolu: concept and design, writing the manuscript.

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Correspondence to Tausif Ahmed.

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Ahmed, T., Kollipara, S., Boddu, R. et al. Biopharmaceutics Risk Assessment—Connecting Critical Bioavailability Attributes with In Vitro, In Vivo Properties and Physiologically Based Biopharmaceutics Modeling to Enable Generic Regulatory Submissions. AAPS J 25, 77 (2023). https://doi.org/10.1208/s12248-023-00837-y

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