Understanding the Essentialities in Establishing the Bioequivalence of Oral Inhalation Drug Products to be Marketed in the USA

Abstract

Background

Oral inhalation drug products (OIDPs) are combination products comprising two components, i.e., a device and the corresponding formulation, and are manufactured with ‘patient use’ being the key consideration. The formulation is designed to be compatible with the device, as the device and formulation have to work in tandem for the intended effect of the drug to be imparted to the patient. OIDPs are generally categorized into three sections: pressurized metered dose inhalers (pMDIs or MDIs), dry powder inhalers (DPIs), and nebulizers.

Area Covered

As OIDPs are most convenient in the treatment of asthma and COPD, it makes these drugs all the more vital in terms of inhalational therapy. The introduction and sustenance of a generic market for these drugs is extremely essential as prices of innovator OIDPs have always been a point of contention with respect to ensuring adequate patient care. Since generic drug approvals require the conduct of bioequivalence studies, it becomes imperative for regulatory authorities to establish strict guidelines for the same. For a long time now, the lack of an appropriate approach for the conduct of bioequivalence studies for OIDPs has proven to be a major obstacle.

Expert Opinion

With the publication of individual guidance documents for OIDPs, the US FDA has paved a path for future approvals of generic OIDPs guided by the ideology that “no one-size-fits-all.” This approach, known as the “weight-of-evidence” approach, requires manufacturers to submit in vitro studies, pharmacokinetic studies, and pharmacodynamic studies, in order to seek authorization for marketing generic OIDPs.

This is a preview of subscription content, log in to check access.

Figure 1.

References

  1. 1.

    Soriano JB, Abajobir AA, Abate KH, et al. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Respir Med. 2017;5(9):691–706. https://doi.org/10.1016/S2213-2600(17)30293-X.

    Article  Google Scholar 

  2. 2.

    3 M. Mastering change in inhalation drug delivery. 2014. [cited 1 May 2019]. http://multimedia.3m.com/mws/media/1159481O/mastering-change-in-inhalation-drug-delivery.pdf.

  3. 3.

    Hess DR. Metered-dose inhalers and dry powder inhalers in aerosol therapy. Respir Care. 2005;50(10):1376–83.

    PubMed  Google Scholar 

  4. 4.

    Islam N, Gladki E. Dry powder inhalers (DPIs)—a review of device reliability and innovation. Int J Pharm. 2008;360(1–2):1–11. https://doi.org/10.1016/J.IJPHARM.2008.04.044.

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Sahiti KG. Nebulizers: a review paper. Int J Adv Res Comput Sci. 2017;8(5):1697–9.

    Google Scholar 

  6. 6.

    Sapakal V. Bioequivalence of orally inhaled drug products: focus on current regulatory perspectives. Ind Med Gaz. 2015;1107:151–61.

    Google Scholar 

  7. 7.

    Al-Numani D, Colucci P, Ducharme MP. Rethinking bioequivalence and equivalence requirements of orally inhaled drug products. Asian J Pharm Sci. 2015;10(6):461–71. https://doi.org/10.1016/j.ajps.2015.08.006.

    Article  Google Scholar 

  8. 8.

    Santos GML, Li Y, Lee SL, et al. Regulatory considerations for approval of generic inhalation drug products in the US, EU, Brazil, China, and India. AAPS J. 2015;17(5):1285–304. https://doi.org/10.1208/s12248-015-9787-8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Office of Federal Register. CFR—Code of federal regulations title 21. 2018. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=320. Accessed 1 Mar 2019.

  10. 10.

    Daley-Yates PT, Parkins DA. Establishing bioequivalence for inhaled drugs; weighing the evidence. Expert Opin Drug Deliv. 2011;8(10):1297–308. https://doi.org/10.1517/17425247.2011.592827.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Reille H. Implications of the new CHMP guideline on the pharmaceutical quality of inhalation and nasal products. MSc thesis; 2007. https://dgra.de/media/pdf/studium/masterthesis/master_reile_h.pdf.

  12. 12.

    Adams WP, Conner DP, Lee SL, Li BV, Yu LX, Chowdhury BA. In vitro considerations to support bioequivalence of locally acting drugs in dry powder inhalers for lung diseases. AAPS J. 2009;11(3):414–23. https://doi.org/10.1208/s12248-009-9121-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Lionberger RA, Lee SL, Choi S, et al. International guidelines for bioequivalence of locally acting orally inhaled drug products: similarities and differences. AAPS J. 2015;17(3):546–57. https://doi.org/10.1208/s12248-015-9733-9.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    FDA. Draft guidance on albuterol sulfate bioequivalence. 2013. [cited 30 April 2019]. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM346985.pdf.

  15. 15.

    FDA. Draft guidance on budesonide. 2012. [cited 1 May 2019]. https://www.fda.gov/downloads/Drugs/.../Guidances/UCM319977.pdf.

  16. 16.

    GlaxoSmithKline. Advair Diskus prescribing label. 2013. p. 50. [cited 1 May 2019]. https://www.humira.com/.

  17. 17.

    FDA. Draft guidance on fluticasone propionate; salmeterol xinafoate. 2013. p. 2–8. [cited 3 May 2019]. https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm367643.pdf.

  18. 18.

    Hou S, Wu J, Li X, Shu H. Practical, regulatory and clinical considerations for development of inhalation drug products. Asian J Pharm Sci. 2015;10(6):490–500. https://doi.org/10.1016/j.ajps.2015.08.008.

    Article  Google Scholar 

  19. 19.

    Food and Drug Administration. Referencing approved drug products in ANDA submissions guidance for industry. 2017. [cited 3 May 2019]. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.

  20. 20.

    Tamboli AM, Todkar P, Zope P, Sayyad FJ. An overview on bioequivalence: regulatory consideration for generic drug products. J Bioequiv Availab. 2010. https://doi.org/10.4172/jbb.1000037.

    Article  Google Scholar 

  21. 21.

    Thakkar K, Mhatre S, Jadhav M, Goswami S, Shah R. Pharmacokinetic studies for proving bioequivalence of orally inhaled drug products-critical issues and concepts. Front Pharmacol. 2015;6:117–20. https://doi.org/10.3389/fphar.2015.00117.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.

    U.S. Food and Drug Administration. Guidance for industry: food-effect bioavailability and fed bioequivalence studies. Guid Ind. 2002. [cited 3 May 2019]. http://www.fda.gov/cder/guidance/index.htm.

  23. 23.

    Haughie S, Allan R, Wood N, Ward J. Equivalent systemic exposure to fluticasone propionate/salmeterol following single inhaled doses from Advair Diskus and Wixela Inhub: results of three pharmacokinetic bioequivalence studies. J Aerosol Med Pulm Drug Deliv. 2019;32:1–9. https://doi.org/10.1089/jamp.2019.1537.

    CAS  Article  Google Scholar 

  24. 24.

    Dhanure S, Savalia A, Nayak SK, Das AK, Kotha SK, Patra AK. Bioequivalence study of tramadol + paracetamol (37.5 + 325 mg) in healthy human volunteers in fasting condition. J Appl Pharm Sci. 2013;5(4):179–83.

    CAS  Google Scholar 

  25. 25.

    Bhupathi C. Sample size recommendation for a bioequivalent study. Statistica. 2017. https://rivista-statistica.unibo.it/article/download/6699/6597.

  26. 26.

    FDA. Guidance for industry, bioequivalence studies with pharmacokinetic endpoints for drugs submitted under an ANDA. 2013. [cited 4 May 2019]. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/uc.

Download references

Acknowledgements

The authors wish to acknowledge the N.G.S.M. Institute of Pharmaceutical Sciences, Nitte (Deemed to be University), Mangaluru, Karnataka, India for providing necessary facilities and support to carry out this study.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Swapnil Dylan Fernandes.

Ethics declarations

Conflict of interest

The authors confirm that the article content has no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fernandes, S.D., Koland, M. Understanding the Essentialities in Establishing the Bioequivalence of Oral Inhalation Drug Products to be Marketed in the USA. Ther Innov Regul Sci 54, 738–748 (2020). https://doi.org/10.1007/s43441-019-00007-3

Download citation

Keywords

  • Oral inhalation drug products (OIDPs)
  • Chronic obstructive pulmonary disease (COPD)
  • pMDIs
  • DPI
  • Bioequivalence (BE)
  • US FDA
  • Reference listed drug (RLD)