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Dissolution Profile Similarity Assessment—Best Practices, Decision Trees and Global Harmonization

  • Commentary
  • Current and Novel Approaches towards Dissolution Profile Comparison Harmonization
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Abstract

During the write-up of the meeting summary reports from the 2019 dissolution similarity workshop held at the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI), several coauthors continued their discussions to develop a “best-practice” document defining the steps required to assess dissolution profiles in support of certain biowaivers and postapproval changes. In previous reports, current challenges related to dissolution profile studies were discussed such that the steps outlined in the two flow charts (“decision trees”) presented here can be applied. These decision trees include both recommendations for the use of equivalence procedures between reference and test products as well as application of the dissolution safe space concept. Common approaches towards establishing dissolution safe spaces are described. This paper encourages the preparation of protocols clearly describing why and how testing is performed along with the expected pass/fail criteria prior to generating data on the materials to be evaluated. The target audience of this manuscript includes CMC regulatory scientists, laboratory analysts, as well as statisticians from industry and regulatory health agencies involved in the assessment of product quality via in vitro dissolution testing. Building upon previous publications, this manuscript provides a solution to the current ambiguity related to dissolution profile comparison. The principles outlined in this and previous manuscripts provide a basis for global regulatory alignment in the application of dissolution profile assessment to support manufacturing changes and biowaiver requests.

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References

  1. Suarez S, Abend A, Hoffelder T, Leblond D, Delvadia P, Kovacs E, et al. In vitro dissolution profiles similarity assessment in support of drug product quality: what, how, when—workshop summary report. AAPS J. 2020;22(4):74.

  2. Hoffelder T, Leblond D, Van Alstine L, Diaz DA, Suarez-Sharp S, Witkowski K, et al. Dissolution profile similarity analyses-statistical principles, methods and considerations. AAPS J. 2022;24(3):54.

    Article  CAS  PubMed  Google Scholar 

  3. Abend A, Zhang L, Fredro-Kumbaradzi E, Hoffelder T, Cohen M, Anand O, et al. Current approaches for dissolution similarity assessment, requirements, and global expectations. AAPS J. 2022;24(3):50.

  4. Nosal R. The Value of Similarity Testing in Drug Product Development. In: In vitro Dissolution Profiles Similarity Assessment in Support of Drug Product Quality Workshop. Baltimore, MD; 2019. Available at: https://www.pharmacy.umaryland.edu/media/SOP/wwwpharmacyumarylandedu/centers/cersievents/dissolution-similarity/nosal-slides.pdf.

  5. European Medicines Agency. Committee for medicinal products for human use. Guideline on the investigation of bioequivalence CPMP/EWP/QWP/1401/98 Rev.1/Corr**. EMA guidance. 2010. Available at: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-investigation-bioequivalence-rev1_en.pdf

  6. U.S. Department of Health and Human Services - Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry - dissolution testing of immediate release solid oral dosage forms. FDA; 1997. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/dissolution-testing-immediate-release-solid-oral-dosage-forms.

  7. Pereira VG. ANVISA’s current practice and challenges in the evaluation of dissolution profile comparisons in support of minor/moderate product quality changes: case studies. In: In vitro Dissolution Profiles Similarity Assessment in Support of Drug Product Quality Workshop. Baltimore, MD; 2019. Available at: https://www.pharmacy.umaryland.edu/media/SOP/wwwpharmacyumarylandedu/centers/cersievents/dissolution-similarity/pereira-slides.pdf.

  8. Lum S. Health Canada’s current practice and challenges in the evaluation of dissolution profile comparisons in support of minor/moderate product quality changes: case studies. In: In Vitro Dissolution Profiles Similarity Assessment in Support of Drug Product Quality Workshop. Baltimore, MD; 2019. Available at: https://www.pharmacy.umaryland.edu/media/SOP/wwwpharmacyumarylandedu/centers/cersievents/dissolution-similarity/lum-slides_revised.pdf.

  9. Abend A, Heimbach T, Cohen M, Kesisoglou F, Pepin X, Suarez S. Dissolution and translational modeling strategies enabling patient-centric drug product development: M-CERSI workshop summary report. AAPS J. 2018;20(3):60.

    Article  PubMed  Google Scholar 

  10. Suarez-Sharp S, Cohen M, Kesisoglou F, Abend A, Marroum P, Delvadia P, et al. Applications of clinically relevant dissolution testing: workshop summary report. AAPS Journal. 2018;20(6):93.

    Article  PubMed  Google Scholar 

  11. Davit B, Braddy AC, Conner DP, Yu LX. International guidelines for bioequivalence of systemically available orally administered generic drug products: a survey of similarities and differences. AAPS J. 2013;15(4):974–90.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Davit BM, Kanfer I, Tsang YC, Cardot J-M. BCS biowaivers: similarities and differences among EMA, FDA, and WHO requirements. AAPS J. 2016;18(3):612–8.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Diaz DA, Colgan ST, Langer CS, Bandi NT, Likar MD, Van Alstine L. Dissolution similarity requirements: how similar or dissimilar are the global regulatory expectations? AAPS J. 2016;18(1):15–22.

    Article  PubMed  Google Scholar 

  14. Van Oudtshoorn JE, García-Arieta A, Santos GML, Crane C, Rodrigues C, Simon C, et al. A survey of the regulatory requirements for BCS-based biowaivers for solid oral dosage forms by participating regulators and organisations of the International Generic Drug Regulators Programme. J Pharm Pharm Sci. 2018;21(1):27–37.

    Article  CAS  PubMed  Google Scholar 

  15. Hermans A, Abend A, Kesisoglou F, Flanagan T, Cohen MJ, Diaz DA, et al. Approaches for establishing clinically relevant dissolution specifications during drug development. AAPS J. 2017;19(6):1537–49.

    Article  CAS  PubMed  Google Scholar 

  16. Mandula H. Rational statistical analysis practice in dissolution profile comparison: FDA perspective. In: In Vitro Dissolution Profiles Similarity Assessment in Support of Drug Product Quality Workshop. Baltimore, MD; 2019. Available at: https://www.pharmacy.umaryland.edu/media/SOP/wwwpharmacyumarylandedu/centers/cersievents/dissolution-similarity/mandula-slides.pdf.

  17. U.S. Department of Health and Human Services - Food and Drug Administration, Center for Drug Evaluation and Research (CDER). The use of physiologically based pharmacokinetic analyses — biopharmaceutics applications for oral drug product development, manufacturing changes, and controls, draft guidance for industry. FDA; 2020. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-physiologically-based-pharmacokinetic-analyses-biopharmaceutics-applications-oral-drug-product.

  18. FDA. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human use. Biopharmaceutics Classification System-based Biowaivers M9. 2019. Available at: https://database.ich.org/sites/default/files/M9_Guideline_Step4_2019_1116.pdf.

  19. U.S. Department of Health and Human Services - Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Bioavailability Studies Submitted in NDAs or INDs — General Considerations. FDA; 2022. Available at: https://www.fda.gov/media/121311/download.

  20. Altan S. Weibull model approach for similarity testing, preformance and limitations. In: In Vitro Dissolution Profiles Similarity Assessment in Support of Drug Product Quality Workshop. Baltimore, MD; 2019. Available at: https://www.pharmacy.umaryland.edu/media/SOP/wwwpharmacyumarylandedu/centers/cersievents/dissolution-similarity/altan-slides.pdf.

  21. Wellek S. Testing statistical hypotheses of equivalence and noninferiority, 2nd edn. Boca Raton: Chapman & Hall/CRC; 2010.

  22. Suarez-Sharp S, Abend A, Hoffelder T, Leblond D, Delvadia P, Kovacs E, et al. In vitro dissolution profiles similarity assessment in support of drug product quality: what, how, when-workshop summary report. AAPS J. 2020;22(4):74.

    Article  PubMed  Google Scholar 

  23. Siewert M. FIP Guidelines for dissolution testing of solid oral products. Pharm Ind. 1995;57:362–9.

    Google Scholar 

  24. Abend A, Curran D, Kuiper J, Lu X, Li H, Hermans A, et al. Dissolution testing in drug product development: workshop summary report. AAPS J. 2019;21(2):21.

  25. Marroum PJ. Clinically relevant dissolution methods and specifications. Am Pharm Rev. 2012;15(1):36–41.

    CAS  Google Scholar 

  26. U.S. Department of Health and Human Services - Food and Drug Administration, Center for Drug Evaluation and Research (CDER). Guidance for industry: extended release oral dosage forms: development, evaluation, and application of in vitro/in vivo correlations. FDA; 1997. Available at: https://www.fda.gov/media/70939/download.

  27. Kesisoglou F, Hermans A, Neu C, Yee KL, Palcza J, Miller J. Development of in vitro-in vivo correlation for amorphous solid dispersion immediate-release suvorexant tablets and application to clinically relevant dissolution specifications and in-process controls. J Pharm Sci. 2015;104(9):2913–22.

    Article  CAS  PubMed  Google Scholar 

  28. Davit B. Establishing clinical relevant specifications during product life cycle: case studies. In: Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development Workshop. Baltimore, MD; 2017. Available at: https://www.pharmacy.umaryland.edu/media/SOP/wwwpharmacyumarylandedu/centers/cersievents/dissolution/day3_barbara-davit.pdf.

  29. Pepin XJH. In silico PBPK modelling in support of drug product dissolution and drug substance particle size specifications. In: Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development Workshop. Baltimore, MD; 2017. Available at: https://www.pharmacy.umaryland.edu/media/SOP/wwwpharmacyumarylandedu/centers/cersievents/dissolution/day2_xavier-pepin.pdf.

  30. Pepin XJH, Flanagan TR, Holt DJ, Eidelman A, Treacy D, Rowlings CE. Justification of drug product dissolution rate and drug substance particle size specifications based on absorption PBPK modeling for lesinurad immediate release tablets. Mol Pharm. 2016;13(9):3256–69.

    Article  CAS  PubMed  Google Scholar 

  31. Heimbach T, Suarez-Sharp S, Kakhi M, Holmstock N, Olivares-Morales A, Pepin X, et al. Dissolution and translational modeling strategies toward establishing an in vitro-in vivo link—a workshop summary report. AAPS J. 2019;21(2):29.

    Article  PubMed  Google Scholar 

  32. Pepin XJH, Parrott N, Dressman J, Delvadia P, Mitra A, Zhang X, et al. Current state and future expectations of translational modeling strategies to support drug product development, manufacturing changes and controls: a workshop summary report. J Pharm Sci. 2021;110(2):555–66.

    Article  CAS  PubMed  Google Scholar 

  33. Laisney M, Heimbach T, Mueller-Zsigmondy M, Blumenstein L, Costa R, Ji Y. Physiologically based biopharmaceutics modeling to demonstrate virtual bioequivalence and bioequivalence safe-space for ribociclib which has permeation rate-controlled absorption. J Pharm Sci. 2022;111(1):274–84.

    Article  CAS  PubMed  Google Scholar 

  34. Pharmaceutical and Medicinal Product Agency (Japan). Guideline for Bioequivalence Studies for Formulation Changes of Oral Solid Dosage Forms. In: Ministry of Health and Welfare J, editors. Yakuji Nippo Ltd.; 2020. Available at: https://www.nihs.go.jp/drug/be-guide(e)/2020/GL3_formation_changes_2020.pdf.

  35. Pharmaceutics and Medical Device Agency (PMDA). Guideline for bioequivalence studies of generic products. In: Ministry of Health and Welfare J, editor. Yakuji Nippo Ltd.; 2020. Available at: https://www.nihs.go.jp/drug/be-guide(e)/2020/GL1_BE_2020.pdf.

  36. United States Pharmacopeia and the National Formulary (USP-NF). Chapter 711 Dissolution. Rockville; US Pharmacopeial Convention; 2022. Available at: https://www.uspnf.com/notices/711-dissolution-nitr-20220527.

  37. Koziolek M, Grimm M, Becker D, Iordanov V, Zhou H, Shimizu J, et al. Investigation of pH and temperature profiles in the GI tract of fasted human subjects using the Intellicap® system. J Pharm Sci. 2015;104:2855–63.

    CAS  Google Scholar 

  38. Kambayashi A, Blume H, Dressman J. Understanding the in vivo performance of enteric coated tablets using an in vitro-in silico-in vivo approach: case example diclofenac. Eur J Pharm Biopharm. 2013;85:1337–47.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors express their gratitude to the organizers, presenters, break-out facilitators, scribes, and attendants of the 2019 workshop on the state of dissolution profile comparison which convened at the University of Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI). Special thanks to Sandra Suarez (Simulations Plus) and David LeBlond (Consultant in CMC statistical studies) for their input.

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Authors and Affiliations

  1. Pharmaceutical Sciences and Clinical Supplies, Merck Sharp & Dohme LLC, 126 E. Lincoln Avenue, Rahway, New Jersey, 07065, USA

    Andreas M. Abend & Tycho Heimbach

  2. Global Biostatistics and Data Sciences, Boehringer Ingelheim Pharma GmbH & Co. KG, Binger Straße 173, 55216, Ingelheim Am Rhein, Germany

    Thomas Hoffelder

  3. Global Product Development, Chemistry Manufacturing and Controls, Pfizer Inc, Groton, Connecticut, USA

    Michael J. Cohen & Dorys Argelia Diaz

  4. Pharmaceutical Sciences and Manufacturing Statistics, Pfizer Worldwide Research & Development, Groton, Connecticut, USA

    Leslie Van Alstine

  5. Biowaivers, Biocorrelation and Statistical Support, Global Research and Development, Apotex Inc., Toronto, Canada

    Emilija Fredro-Kumbaradzi

  6. Data and Statistical Sciences, AbbVie Inc., North Chicago, Illinois, 60064, USA

    James Reynolds & Yanbing Zheng

  7. Center for Mathematical Sciences, Merck & Co., Inc., Merck Manufacturing Division, Kenilworth, New Jersey, 07033, USA

    Krista Witkowski

Authors
  1. Andreas M. Abend
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  8. Yanbing Zheng
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Contributions

All authors contributed to the manuscript, commented on previous versions, read, and approved the final manuscript.

Corresponding author

Correspondence to Thomas Hoffelder.

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Abbreviations

ACLMD

Approximate confidence limit of Mahalanobis distance

ANVISA

Brazilian Health Surveillance Agency

BCS

Biopharmaceutics Classification System

BE

Bioequivalence

BO

Breakout (session)

boot f2

Bootstrapped f2

cGMP

Current good manufacturing practices

CMA

Critical materials attribute

CMC

Chemistry, manufacturing and controls

CPP

Critical process parameter

CRDS

Clinically relevant dissolution specifications

CV

Coefficient of variation

DR

Delayed release

EMA

European Medicines Agency

ER

Extended release

FDA

Food and Drug Administration

HC

Health Canada

ICH

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

IR

Immediate release

LC

Label claim

IVIVC

in vitro–in vivo Correlation

M-CERSI

(University of) Maryland(’s) Center of Excellence in Regulatory Science and Innovation

MD

Mahalanobis distance

MR

Modified release

MSD

Multivariate statistical distance

NMT

Not more than

PBBM

Physiologically based biopharmaceutics modeling

PBC

Pairwise batch comparison

PK

Pharmacokinetic(s)

PMDA

Pharmaceutics and Medical Device Agency

Q

Amount (quantity) of dissolved active ingredient, expressed as a percentage of the labeled content of the dosage form (from USP <711>)

QC

Quality control

QMD

Quadratic mean difference

SD

Standard deviation

SUPAC

Scale-up and post-approval changes

T1E

Type 1 error

UBEL, LBEL

Upper/lower bioequivalence limit

VAR

Variant

VBE

Virtual bioequivalence

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Abend, A.M., Hoffelder, T., Cohen, M.J. et al. Dissolution Profile Similarity Assessment—Best Practices, Decision Trees and Global Harmonization. AAPS J 25, 44 (2023). https://doi.org/10.1208/s12248-023-00795-5

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