APR May/June 2023 - 20

» FORMULATION AND DEVELOPMENT
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for multiple-dose products, their overall shelf life tends to be 24-36
months, and a large amount of stability data is needed to demonstrate
that the critical quality attributes of the product remain over this
period. The authors recommend that for MDPF-CCS, container
closure ingress testing be performed on at least one batch of drug
product at the end of the product's proposed shelf life. Since some
products, particularly generic products, may be approved prior to the
completion of all stability studies for shelf life, a commitment at the
time of filing to perform ingress testing may be sufficient, provided
that all additional studies (including initial container-closure ingress
studies) yield acceptable results.
Conclusion
To summarize the points discussed above, we propose the following
as a developmental checklist for parties interested in packaging a drug
product in an MDPF-CCS:
* Establish that there is a true need for use of an MDPF-CCS over
an antimicrobial preservative strategy or packaging the drug as
a single dose product.
* Antimicrobial effectiveness testing (USP <51> or equivalent)
should be performed on the drug product to determine if it
has any inherent antimicrobial activity. If the product can pass
antimicrobial effectiveness testing, further ingress validation of
the MDPF-CCS may be considerably reduced.
* Perform container-closure integrity testing on the proposed
MDPF-CCS.
* Perform container closure ingress testing on the MDPFCCS
in such a way as to challenge the CCS so that it is
vulnerable to microbial contamination (e.g., being actuated
while submerged in a microbial suspension). Many kinds of
scenarios can be appropriate in this testing. Plan to articulate
why the methods you choose represent a worst-case risk
for product contamination, including justification for the
challenge organisms selected. If the CCS contains multiple
ingress-preventing mechanisms, each should be tested.
* Perform studies to demonstrate that the presence of the drug
product does not affect the ingress-preventing characteristics of
the CCS.
* Perform or plan to also perform container-closure ingress testing
at the end of product shelf-life to demonstrate that container
age does not degrade its ingress-preventing properties.
If applicants who wish to use an MDPF-CCS with a drug product want
additional information or feedback prior to submitting a marketing
application, CDER has multiple options for meetings between FDA
and industry. For drugs under a 505(b)(1) or 505(b)(2) pathway,
applicants may refer to " Formal Meetings Between the FDA and
Sponsors or Applicants of PDUFA Products Guidance for Industry. " 8
For drugs under a 505(j) pathway, applicants may refer to " Formal
Meetings Between FDA and ANDA Applicants of Complex Products
under GDUFA Guidance for Industry. " 9
In these meetings, applicants
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5.
6.
may propose validation studies and seek guidance from FDA on their
proposed strategy; however, an assessment of data and approval will
be performed as a part of marketing application assessment.
References
1.
2.
3.
4.
United States Pharmacopeia <51> Antimicrobial Effectiveness Testing
Centers for Disease Control and Prevention (CDC). One & Only Campaign. Available at:
https://www.cdc.gov/injectionsafety/one-and-only.html. Accessed 15 May 2023
Goldstein MH, Silva FQ, Blender N, Tran T, Vantipalli S. Ocular benzalkonium chloride
exposure: problems and solutions, Eye. 2022; 36(2):361-368.
Food and Drug Administration (FDA). Selection of the Appropriate Package Type Terms
and Recommendations for Labeling Injectable Medical Products Packaged in MultipleDose,
Single-Dose, and Single-Patient-Use Containers for Human Use: Guidance for
Industry. October 2018. Available at: https://www.fda.gov/regulatory-information/
search-fda-guidance-documents/selection-appropriate-package-type-terms-andrecommendations-labeling-injectable-medical-products.
Accessed 15 May 2023
United States Pharmacopeia <771> Ophthalmic Products - Quality Tests
Food and Drug Administration (FDA). Submission Documentation for Sterilization Process
Validation in Applications for Human and Veterinary Drug Products: Guidance for Industry,
November 1994. Available at:
https://www.fda.gov/regulatory-information/searchfda-guidance-documents/submission-documentation-sterilization-process-validationapplications-human-and-veterinary-drug.
Accessed 15 May 2023.
7.
8.
United States Pharmacopeia <1207> Container Closure Integrity Testing
Food and Drug Administration (FDA). Formal Meetings Between the FDA and Sponsors
or Applicants of PDUFA Products: Guidance for Industry. December 2017. Available at:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/formalmeetings-between-fda-and-sponsors-or-applicants-pdufa-products-guidance-industry.
Accessed
15 May 2023.
9.
Food and Drug Administration (FDA). Formal Meetings Between FDA and ANDA Applicants
of Complex Products under GDUFA: Guidance for Industry. October 2022. Available at:
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/formalmeetings-between-fda-and-anda-applicants-complex-products-under-gdufa-guidanceindustry.
Accessed 15 May 2023.
Author Biography
Dr. Erika Pfeiler is a microbiologist and Branch Chief in the FDA/CDER
Division of Microbiology Assessment, where she performs and oversees
microbiology reviews of ANDAs, NDAs, and INDs. She joined CDER in
2012. Her areas of particular interest in pharmaceutical microbiology
include rapid microbiological testing methods, pharmacy compounding,
and the microbiological aspects of nonsterile products. Dr. Pfeiler has an
educational background in food microbiology and received a B.S. from the
University of Tennessee and a Ph.D. from North Carolina State University.
Dr. John Arigo is the Director of the Division of Microbiology 1 in the
Office of Pharmaceutical Manufacturing Assessment at the FDA. His
division assesses the sterility assurance and manufacturing submissions
to support ANDA, NDA, and INDs. He began his career with the Office
of Generic Drugs Microbiology team in 2008 and has been involved in
multiple reorganizations to the current state. Prior to working at the
FDA, Dr. Arigo obtained his Ph.D. from The Johns Hopkins University
School of Medicine.

https://www.cdc.gov/injectionsafety/one-and-only.html https://www.fda.gov/regulatory-information/search-fda-guidance-documents/selection-appropriate-package-type-terms-and-recommendations-labeling-injectable-medical-products https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submission-documentation-sterilization-process-validation-applications-human-and-veterinary-drug https://www.fda.gov/regulatory-information/search-fda-guidance-documents/formal-meetings-between-fda-and-sponsors-or-applicants-pdufa-products-guidance-industry https://www.fda.gov/regulatory-information/search-fda-guidance-documents/formal-meetings-between-fda-and-anda-applicants-complex-products-under-gdufa-guidance-industry

APR May/June 2023

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