Multidose Preservative-Free Container Closure Systems: Developmental Considerations for Sterile Small Molecule Drug Products

Erika Pfeiler, PhD¹ and John Arigo, PhD² - ¹ Branch Chief, Division of Microbiology Assessment 2, Office of Pharmaceutical Manufacturing Assessment, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration; ² Division Director, Division of Microbiology Assessment 1, Office of Pharmaceutical Manufacturing Assessment, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, Food and Drug Administration

Abstract

Novel container closure system (CCS) technology may allow multiple-dose drug products to be marketed without added antimicrobial preservatives to meet clinical and formulation needs. In order to ensure patient safety, however, these CCS must be appropriately validated to ensure that they operate as purported. This article outlines general recommendations for validation studies for CCS intended for use with small molecule drug products.

Packaging Concerns

Drug products can be packaged as multiple-dose (containing more than one dose per container) in order to facilitate their use, either by a healthcare provider or by the patient. However, ease-of-use considerations must be balanced by the need for patient safety, which may be jeopardized if the product becomes contaminated with microorganisms during repeated manipulations. This may result in an unacceptable exposure of the patient to harmful microorganisms which puts the patient at risk for infection. Therefore, multiple-dose drug products typically contain antimicrobial preservatives, added as excipients, to inhibit the growth of microorganisms that may be introduced during the course of repeated manipulations.¹ This mitigates the risk that a patient may be exposed to harmful microorganisms originating from the drug product and subsequent infection. Unsafe handling/preparation practices with sterile products, such as withdrawing multiple doses from an unpreserved single dose vial of a drug product, were deemed to be a significant enough public health risk for the Centers for Disease Control and Prevention to launch the ‘One and Only’ campaign to educate healthcare providers on safe injection practices. Part of the educational material in this campaign include a description of the difference between single-dose and appropriately preserved multiple-dose products in the hopes of making practitioners more aware of the differences between product formats and appropriate handling and administration techniques for both.² Despite the important role that antimicrobial preservatives play in patient safety for multiple-dose drug products, there may be circumstances in which the addition of an antimicrobial preservative to a drug product is not desirable, due to clinical concerns over repeated exposure to these chemicals,³ or due to the excipients having a detrimental effect on the formulation of complex drug products. In these cases, drug manufacturers may wish to explore other options, including the use of novel primary packaging systems that are intended to physically block the introduction of microorganisms into the drug product when the container-closure system is manipulated. The use of packaging systems to prevent microbiological contamination of drug products is a relatively new concept for drug products. As such, collective terminology to describe these container closure systems has not been established in the pharmaceutical microbiology community. These authors suggest that these packaging systems be referred to as ‘Multiple-Dose Preservative-Free Container Closure Systems’ or MDPF-CCS. This terminology will be utilized for the remainder of this article.

Regulatory Guidance

In a guidance, the Food and Drug Administration describes multiple-dose (or multi-dose) drug products to be containers of sterile medication (either active drug product or diluent) which are intended to contain more than one dose.⁴ This guidance description continues on to state that multiple-dose products are those that have met antimicrobial effectiveness testing requirements, or otherwise utilize specially designed packaging and delivery systems that permit the use of preservative-free injectable products – essentially defining and stating the Agency’s position on the use of MDPF-CCS. Interestingly, this guidance refers to parenteral and other injectable products, but does not address ophthalmic products, which are frequently packaged as multiple-dose. Some clarity may be provided in USP Chapter,⁵ which discusses quality tests for ophthalmic products and states that a container closure system that can maintain sterility of the product through its shelf life is an acceptable condition for which the product does not need to contain an added antimicrobial preservative. Regardless of the range of definitions provided for sterile products (whether they be parenteral, ophthalmic, or other route of administration) these may all be considered for the use of multiple-dose preservative-free container closure systems for small molecule drug products (as submitted to FDA in Abbreviated New Drug Applications and New Drug Applications) provided that appropriate validation data are provided to demonstrate the microbial ingress preventing capabilities of the container closure system. Please note that the recommendations in this article are put forward by microbiologists in the Center for Drug Evaluation and Research’s group that assesses the microbiological quality attributes of small molecule drug products.

Typical multiple-dose products either contain an antimicrobial preservative as an excipient, or because of the inherent properties of their formulation are antimicrobial on their own. The arbitrator of whether a multiple-dose product is sufficiently preserved is whether it can meet the acceptance criteria outlined in USP Chapter, or equivalent test. If an antimicrobial preservative cannot be added to a product, and the product is not capable of passing USP on its own, a manufacturer should either opt to reformat their packaging to single-dose or utilize one of the novel container closure systems designed to prevent microbial ingress during use. Notably, CDER does not approve the use of specific container closure systems, only drug products that may use a particular container closure system. Therefore, while a system may have achieved an approval in an application for one product, it does not give the system blanket approval for use with all drugs. MDPF-CCS that are used for different drug products should each be described in their own applications, although non-product specific studies may be submitted to multiple filings as needed. In a similar vein, CDER does not approve or recommend ingress-preventing mechanisms; rather, any appropriately validated mechanism should be described in a marketing application and subsequently assessed. To date, CDER has assessed CCS with ingress-preventing mechanisms which include seals, filters, and backflow prevention mechanisms.

Testing Methods and Recommendations

Container-closure integrity testing has been established by Agency guidance as a regulatory expectation for almost 30 years ⁶ to demonstrate that the typical primary container closure system can maintain its integrity, and therefore the sterility of the drug product. In container closure integrity testing, the CCS is examined as a passive system, traditionally through submersion in a dye or microbial suspension and assessed to ensure that it maintains its integrity. Positive controls for this type of testing include intentionally breached CCS, such as those that have been laser-drilled with a hole of definitive size. Notably, the methods described in USP Chapter <1207>⁷ are gaining popularity among A/NDA applicants. Container closure integrity of all sterile product CCS plays an important role to ensure that the critical quality attribute of sterility is maintained over the product’s shelf life and use. However, in the case of the novel MDPF-CCS, the additional attributes of this new class of container closure system require validation – can the CCS maintain sterility and prevent microbial ingress when it is undergoing repeated use? We suggest that this new class of testing be referred to as ‘container-closure ingress testing.’ While all CCS for marketed sterile products must undergo integrity testing, CCS that also purport to maintain the microbiological quality of the drug product during use must also undergo ingress testing to demonstrate their ability to actively prevent contamination over its shelf life and use.

Given the novelty of MDPF-CCS, a specific set of methods acting as best practices for container-closure ingress testing has not been established. CDER is open to assessing any validation study that represents worst-case conditions and challenges the CCS while it is in use. While no single best practice has been established, there is one general type of method that is unacceptable, since it does not represent a worst-case challenge of the CCS. An example scenario for this unacceptable testing protocol is, as follows: An MPPF-CCS is actuated in a laboratory setting by a laboratory technician once per day over the span of the product’s labeled in-use period. At the conclusion of this period, the product remaining in the CCS is tested for sterility. The manipulation of the MDPF-CCS in a laboratory setting with a trained technician does little to represent actual administration conditions or challenge the system. In this scenario, it is unclear if the product is ever truly exposed to contamination. Further, reliance on the sterility test exposes the method to the possibility of false negative results. A true test of the ingress-preventing properties of an MDPF-CCS directly challenges the system with microorganisms and includes appropriate controls. One example of a successful method that has been presented in marketing applications is the repeated actuation of a growth media-filled MDPF-CCS in a microbial suspension, followed by an incubation period and examination of the contents of the CCS. This relatively simple method has the benefits of directly challenging the system, and the use of properly growth-promoted media helps to eliminate the possibility of false negative test results. It is also recommended to consider any unique mechanisms that are specific to a particular CCS and ensure that these mechanisms are discussed and validated as applicable.

Developing Standards and Components

As MDPF-CCS products attain wider use in the pharmaceutical community, the regulatory standards for them will continue to develop. However, at this time, the authors recommend examining two additional aspects of MDPF-CCS to ensure that the systems perform as expected both in their interaction with the drug product and over the shelf-life of the product. Given that MDPF-CCS may encompass a variety of bacterial ingress preventing mechanisms, there may be mechanism components that have significant interaction with the drug product. It is important to know if and when these interactions affect the CCS’s ingress-preventing capabilities. Therefore, applicants should plan to devise testing methods to ensure that such interactions are not detrimental. Finally, how does age affect the ingress-preventing mechanisms of the MDPF-CCS? Regardless of the in-use periods 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 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 MDPF-CCS 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 a 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 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. United States Pharmacopeia Antimicrobial Effectiveness Testing
2. 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
3. Goldstein MH, Silva FQ, Blender N, Tran T, Vantipalli S. Ocular benzalkonium chloride exposure: problems and solutions, Eye. 2022; 36(2):361-368.
4. Food and Drug Administration (FDA). Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable Medical Products Packaged in Multiple-Dose, 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-and-recommendations-labeling-injectable-medical-products. Accessed 15 May 2023
5. United States Pharmacopeia Ophthalmic Products – Quality Tests
6. 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/search-fda-guidance-documents/submission-documentation-sterilization-process-validation-applications-human-and-veterinary-drug. Accessed 15 May 2023.
7. United States Pharmacopeia Container Closure Integrity Testing
8. 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/formal-meetings-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/formal-meetings-between-fda-and-anda-applicants-complex-products-under-gdufa-guidance-industry. 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.

Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special
offers from American Pharmaceutical Review delivered to your inbox!
Sign up now!