Skip to main content
SpringerLink
Log in

Development and Validation of Matrix of Chemistry, Manufacturing, and Control (MoCMC) System for Intramammary Drug Products (IMM)

  • Original Research Article
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Products formulated for intramammary (IMM) infusion are intended for the delivery of therapeutic moieties directly into the udder through the teat canal to maximize drug exposure at the targeted clinical site, the mammary gland, with little to no systemic drug exposure. Currently, to our knowledge, there has been no in-vitro matrix system available to differentiate between IMM formulations. Our goal is to develop A custom tailored in-vitro “Matrix of Chemistry, Manufacturing and Control” (MoCMC) System to be a promising future tool for identifying inequivalent IMM formulations. MoCMC can detect inter and intra batch variabilities, thereby identifying potential generics versus brand product similarities or differences with a single numeric value and a specific & distinctive fingerprint.

Methods

The FDA-approved IMM formulation, SPECTRAMASTⓇ LC, was selected as the reference product for the MoCMC. Twelve in-house test formulations containing ceftiofur hydrochloride were formulated and characterized. The MoCMC was developed to include six input parameters and three output parameters. The MoCMC system was used to evaluate and compare SPECTRAMASTⓇ LC with its in-house formulations.

Results

Based on the MoCMC generated parameters, the distinctive fingerprints of MoCMC for each IMM formulations, and the statistical analyses of MCI and PPI values, in-house formulations, F-01 and F-02 showed consistency while the rest of in-house formulations (F-03-F-12) were significantly different as compared to SPECTRAMASTⓇ LC.

Conclusion

This research showed that the MoCMC approach can be used as a tool for intra batch variabilities, generics versus brand products comparisons, post-approval formulations changes, manufacturing changes, and formulation variabilities.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Lainesse C, Gehring R, Pasloske K, Smith G, Soback S, Wagner S, et al. Challenges associated with the demonstration of bioequivalence of intramammary products in ruminants. J Vet Pharmacol Ther. 2012;35(Suppl 1):65–79.

    Article  PubMed  Google Scholar 

  2. Blowey RW, Edmondson P. Mastitis control in dairy herds. 2nd ed: Cabi; 2010.

  3. Office of New Animal Drug Evaluation, FDA Center for Veterinary Medicine, U.S. Food and Drug Administration. Approved animal drug products (Green Book). Maryland, U.S.A. 2024, [Available from: https://animaldrugsatfda.fda.gov/adafda/views/#/search].

  4. Office of New Animal Drug Evaluation, FDA Center for Veterinary Medicine, U.S. Food & Drug Administration (FDA). Administrative applications and the phased review process: Guidance for industry. (Docket No. FDA-2002-D-0147). Maryland, U.S.A. 2018, [Available from: https://www.fda.gov/media/70029/download].

  5. Animals Drugs @ FDA, FDA Center for Veterinary Medicine, U.S. Food & Drug Administration (FDA). Dry-Clox® Intramammary Infusion-cloxacillin benzathine gel Boehringer lngelheim Animal Health USA Inc. (NADA: N55058). Maryland, U.S.A. 2017 [Available from: https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/055-058].

  6. Animals Drugs @ FDA, FDA Center for Veterinary Medicine, U.S. Food & Drug Administration (FDA). SPECTRAMAST® LC sterile suspension: Ceftiofur hydrochloride liquid (suspension), Zoetis, Inc. (NADA 141–238). Maryland, U.S.A. 2018, [Available from: https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/141-238].

  7. FDA Center for Veterinary Medicine, U.S. Food & Drug Administration (FDA). New Animal Drug Application Guidances. Maryland, U.S.A. 2024, [Available from: https://www.fda.gov/animal-veterinary/guidance-industry/new-animal-drug-application-guidances].

  8. Animals Drugs @ FDA, FDA Center for Veterinary Medicine, U.S. Food & Drug Administration (FDA). TOMORROW®: Cephapirin benzathine gel Boehringer lngelheim Animal Health USA, Inc. Maryland, U.S.A. 2022, [Available from: https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/108-114].

  9. Animals Drugs @ FDA, FDA Center for Veterinary Medicine, U.S. Food & Drug Administration (FDA). TODAY®: Cephapirin sodium gel Boehringer lngelheim Animal Health USA, Inc. (NADA: N97222). Maryland, U.S.A. 2022, [Available from: https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/097-222].

  10. Animals Drugs @ FDA, FDA Center for Veterinary Medicine, U.S. Food & Drug Administration (FDA). ORBENIN DC™: Cloxacillin benzathine liquid (suspension) Intervet, Inc. (NADA: N55069). Maryland, U.S.A. 2022, [Available from: https://animaldrugsatfda.fda.gov/adafda/views/#/home/previewsearch/055-069].

  11. FDA Center for Veterinary Medicine, U.S. Food & Drug Administration (FDA). Generic Animal Drug and Patent Term Restoration Act (GADPTRA). Maryland, U.S.A. 2023, [Available from: https://www.fda.gov/animal-veterinary/guidance-regulations/generic-animal-drug-and-patent-term-restoration-act-gadptra].

  12. Krishnaiah YS, Xu X, Rahman Z, Yang Y, Katragadda U, Lionberger R, et al. Development of performance matrix for generic product equivalence of acyclovir topical creams. Int J Pharm. 2014;475(1–2):110–22.

    Article  CAS  PubMed  Google Scholar 

  13. Helal NA, Martinez MN, Longstaff DG, Mohamed EM, Rahman Z, Khan MA, et al. Development and validation of discriminatory in-vitro release method for intramammary drug product. Pharm Res. 2024;41(1):129–39.

    Article  CAS  PubMed  Google Scholar 

  14. Perez P, Sune-Negre JM, Minarro M, Roig M, Fuster R, Garcia-Montoya E, et al. A new expert systems (SeDeM diagram) for control batch powder formulation and preformulation drug products. Eur J Pharm Biopharm. 2006;64(3):351–9.

    Article  CAS  PubMed  Google Scholar 

  15. ElAgouri G, ElAmrawy F, ElYazbi A, Eshra A, Nounou MI. Male enhancement nutraceuticals in the Middle East market: claim, pharmaceutical quality and safety assessments. Int J Pharm. 2015;492(1):109–19.

    Article  CAS  PubMed  Google Scholar 

  16. United States Pharmacopeial Convention (USP43). (905) Uniformity of dosage units. General Chapter, (General tests and assays). 35(3). Baltimore, MD, USA: United Book Press, Inc: The United States Pharmacopeia (USP 2023–NF 36–38); 2023. p. 6673–7183.

  17. Limberg J, Potthast H. Regulatory status on the role of in vitro dissolution testing in quality control and biopharmaceutics in Europe. Biopharm Drug Dispos. 2013;34(5):247–53.

    Article  CAS  PubMed  Google Scholar 

  18. Dickinson PA, Lee WW, Stott PW, Townsend AI, Smart JP, Ghahramani P, et al. Clinical relevance of dissolution testing in quality by design. AAPS J. 2008;10(2):380–90.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Garg S, Wang W, Song Y, Eats P, Trott DJ, Page SW, et al. Development of intramammary drug delivery systems: novel in vitro release method. J Pharm Sci. 2017;106(3):866–71.

    Article  CAS  PubMed  Google Scholar 

  20. Haster PR. An in vitro dissolution method for the evaluation of an intramammary infusion product: The University of Mississippi; 1991.

  21. United States Department of Agriculture (USDA), Veterinary Services (VS). Dairy 2014: Milk quality, milking procedures, and mastitis on U.S. dairies. (Report No: 704.0916) Fort Collins, CO. 2016.

  22. Pol M, Ruegg PL. Treatment practices and quantification of antimicrobial drug usage in conventional and organic dairy farms in Wisconsin. J Dairy Sci. 2007;90(1):249–61.

    Article  CAS  PubMed  Google Scholar 

  23. Eros I, Soosne-Csanyi E, Selmeczi B. Influence of viscosity on drug release from ointments, creams, gels and emulsions. Acta Pharm Hung. 1994;64(2):57–61.

    CAS  PubMed  Google Scholar 

  24. Ho MJ, Jeong MY, Jeong HT, Kim MS, Park HJ, Kim DY, et al. Effect of particle size on in-vivo performances of long-acting injectable drug suspension. J Control Release. 2022;341:533–47.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

FDA Grant, FDABAA-21-00123, 2022.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Irma Lerma Rangel School of Pharmacy, Texas A&M Health Science Center, Texas A&M University, College Station, TX, USA

    Nada A. Helal, Ziyaur Rahman, Mohammad T. H. Nutan & Mansoor A. Khan

  2. US FDA Center for Veterinary Medicine, Office of New Animal Drug Evaluation, Rockville, MD, USA

    Marilyn N. Martinez & David G. Longstaff

Authors
  1. Nada A. Helal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Marilyn N. Martinez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David G. Longstaff
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ziyaur Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mohammad T. H. Nutan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mansoor A. Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mansoor A. Khan.

Ethics declarations

Disclaimer

The findings and conclusions in this research have not been formally disseminated by the Food and Drug Administration and should not be construed to represent any Agency endorsement, determination, or policy. The mention of commercial products, their sources, or their use in connection with material reported herein is not to be construed as either an actual or implied endorsement of such products by the FDA.

Conflict of Interest

The authors declared no competing interests for this work.

Additional information

Publisher's Note

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

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 118 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Helal, N.A., Martinez, M.N., Longstaff, D.G. et al. Development and Validation of Matrix of Chemistry, Manufacturing, and Control (MoCMC) System for Intramammary Drug Products (IMM). Pharm Res (2024). https://doi.org/10.1007/s11095-024-03689-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11095-024-03689-z

Keywords

Search

Navigation