John Arigo, PhD1 and Erika Pfeiler, PhD2- 1 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; 2 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
Abstract
A goal within the FDA Division of Microbiology Assessment is to improve the quality of the sterility assurance submission for Abbreviated New Drug Applications (ANDA) and New Drug Applications (NDA). To meet this goal, we ask industry to provide a well-organized and complete submission. This article discusses themes to improve the sterility assurance submission to allow for more efficient assessment of the application within the microbiology divisions.
Introduction
In the Division of Microbiology Assessment (DMA), located in the Center for Drug Evaluation and Research (CDER), Office of Pharmaceutical Quality (OPQ), Office of Pharmaceutical Manufacturing Assessment (OPMA), we assess hundreds of original Abbreviated New Drug Applications (ANDA) and New Drug Applications (NDA) annually and are in the unique position to see many levels of pharmaceutical submissions in terms of quality and completeness. A major goal within our office is to approve high quality submissions in the timeliest and most efficient way possible. To meet this goal, we ask industry to provide us with a well-organized and complete submission. The difference in time to review a disorganized and incomplete submission compared to an organized and complete submission can cost the applicant weeks if not months of extra time before approval (longer assessment time, multiple rounds of information requests, etc.). The purpose of this article is to share a few of the most common issues that we in DMA see for ANDA and NDA original and supplement small molecule submissions hopefully bringing awareness to these issues to encourage more complete submissions which will result in faster more efficient drug review and ultimately approvals.
Application Clarity
One of the most straightforward ways to improve a submission is to make it as clear as possible. One way to do this is to include a well written introduction and summary for each section. You should not assume that the assessor begins their work with a complete understanding of the exact nuances of your product, process, facility or manufacturing proposals. The assessor must assemble a puzzle and understand what is being proposed based solely on the information you have provided. For example, in a steam sterilization section, rather than simply providing all documents full of only results from various validation studies, it is better to include a summary document with an introduction and a clear explanation of the thinking behind the validation program to support the proposed process. This also puts the supporting documents in context and provides a valuable starting point for the assessor. The following example is an example of such a summary:
“Autoclave X is used for sterilization of all product contact components. There are four different loading patterns used during commercial production sterilization. Validation of these four loading patterns is performed using a worst-case autoclave load that was determined to be worst case based on the hardest to heat components we propose as well as the load having the largest mass size. The autoclave is set for 122°C for 12 minutes for production and 122°C for 11 minutes for validation studies. Page 3 of the following document includes results from three empty chamber heat distribution studies that were performed in March 2022. Data supporting the heat distribution and penetration of the worst-case load with biological indictors is provided beginning on page 10. This data was compiled from December 2022-Feburary 2023. The acceptance criteria for each study are included prior to the data tables and all data met the criteria. The requalification program is described in detail on page 25 and includes an annual HP/BI run of the worst-case load.”
It may not be obvious to the applicant to include this type of introductory summary, but the value is enormous to the assessor as it helps them understand your overall process, identify exactly what the validation study comprises, and provides them with insight into your thought process when establishing your validation/qualification program. Without a summary, the assessor must work backwards from reading the data and hopefully piece together an overall picture of the validation program. The latter typically results in numerous clarifying questions being sent in an information request. FDA reviewers are highly trained scientists who are trained and equipped to assess a range of validation/qualification scenarios; however, the assessor does not have infinite time to do this, and summary statements can assist in making the assessment more efficient.
Continuing with the idea of clarity in your application, most applications contain references to drug master files (DMF). The DMF might contain information ranging in complexity from the depyrogenation of a single component to all the supporting information for a contract manufacturing facility. If you can include all data for an application in the A/NDA submission itself, that is ideal; however, we understand that due to confidentiality issues this might not be possible. If a DMF reference is needed, you should plan to provide a clear and concise summary of what is being referenced. Additionally, stating the submission date and DMF volume that the information is in can significantly expedite assessment. Simply providing a letter of authorization to a DMF leaves the assessor potentially searching through hundreds of files trying to find relevant data to support your proposals. Specifically citing a date and volume of the submission with a summary of what type of data is being referenced will allow the assessor to immediately identify what you are referencing while minimizing additional information requests asking for the necessary data or the location of this data within the DMF.
Pivoting away from the role of application clarity and its role in expediting the application assessment, the following sections deal with technical issues that are commonly encountered in the assessment of A/NDAs. Numerous DMA assessors with many years of experience were queried asking for common deficiencies that they routinely observe in A/NDA submissions. The resulting items are presented below.
Bulk Solution Bioburden Monitoring
Bulk solutions prior to filtration are not typically sterile and should have microbial controls to ensure that they maintain appropriate microbiological quality throughout the manufacturing process. To achieve this, we request that firms implement a routine bulk bioburden sampling program; however, we often see that this sampling step is performed after a 0.45µm or 0.22µm filtration step. Bioburden sampling after filtration defeats the purpose of sampling the bulk solution and does not allow for an understanding of the microbial load of the nonsterile bulk. Even sampling after a 0.45µm filter, while not a sterilizing filter, defeats the purpose as this type of filter can still remove a majority of organisms. Sampling and monitoring of the bulk solution should be performed prior to any filtration step, as this allows for a better understanding of its microbial composition. It is worth noting that any excessive growth in a bulk solution prior to filtration could allow for microbial metabolites or endotoxins to pass through the filters and could cause quality issues in the subsequent downstream processes.
Biological Indicator Incubation
For sterilization validation studies where biological indicators (BI) are used to support a sterility assurance of 10-6, the incubation time of the BI should be seven days (USP, ISO 11138). There has been some confusion within the pharmaceutical industry as well as from the BI manufacturers regarding the conditions under which it is appropriate to reduce the typical seven day incubation to 24 hours. This comes from an FDA guidance1 published by the Center for Devices and Radiologic Health (not CDER) that is specific for healthcare facility sterilization and treats the healthcare facility sterilizer as a medical device. The guidance discusses the acceptability of 97% of positive indicators showing appropriate growth at the 24-hour incubation period versus the full seven day period. While we appreciate the utility of this reduced incubation time for healthcare sterilization, this guidance was not intended to address a pharmaceutical manufacturing facility that produces sterile injectable drug products. The expectation for BIs to support sterilization validation studies is that a seven day incubation period is observed.
Pooling of Endotoxins Samples
Finished product bacterial endotoxins testing is critical to ensure that a high-quality pharmaceutical product is released. The most common test observed in A/NDA submissions is the USP<85>gel clot test. This test requires the consideration of a maximum valid dilution (MVD) which accounts for the endotoxins limit, the sensitivity of the test and the concentration of the drug product. The maximum valid dilution specifies the limit that the drug product can be diluted while still giving a valid result. We also see that many times in testing, a drug product vial is pooled with other vials to allow for one test to screen multiple vials; however, applicants will often forget to adjust the MVD accordingly. The pooling of three vials makes an additional three-fold dilution which needs to be considered as an adjusted MVD2. The adjusted MVD ensures that even with vial pooling that you have not gone beyond the detection capabilities of the test. We routinely will see methods for endotoxins testing that vaguely reference pooling without the mention of how many vials can be pooled and whether the MVD will be adjusted accordingly. Including this information will expedite review of this section of the submission.
Aseptic Process Simulations
Aseptic process simulations to support a filling line are commonly performed irrespective of the specific drug product that is being manufactured, as the facility chooses to perform the media fill on a multi-product line that intends to cover many drug product filling scenarios with a bracketed approach simulation study. This is perfectly acceptable if the filling durations of all the proposed drug products on the line are accounted for. The problem arises, for example, if a 15-hour filling duration is proposed for an NDA or ANDA, and then a general aseptic process simulation study of eight hours is provided as qualifying data. This will not adequately support the proposed filling duration of the 15-hour fill maximum filling duration (also covering interventions, filling pauses, shift changes, etc.) that is proposed for commercial production in an application. When designing media fill studies to cover many products it would expedite the review to consider worst case filling durations that will cover all the future submissions that propose the filling line studied. In addition, applicants should be clear in listing which equipment is used in a media fill simulation study. If a particular lyophilizer is proposed for production, the expectation is that this exact lyophilizer is also included in the simulation studies. Also be very clear in the identification of the filling line/machine used in the media fill. It is always helpful to an assessor when the submission clearly indicates the make and model and internal naming of equipment. It might not be obvious to an assessor that “the filling line” is the only line you have functional at the moment. Clarifying that it is “filling line 1 in room 1234” avoids deficiencies asking for clarification of equipment.
Supplement Filing Tips
Lastly, when there are changes to an approved application which are filed as a supplement,3 applications are commonly deficient in clearly describing what is being proposed as a change or to clarify the relevance of a change. If a supplement is being filed for a new filling line, for example, but there are also large amounts of additional studies provided for various other items such as annual autoclave requalification, more recent aseptic process simulations or other items, this can significantly slow down the assessment of the supplement. To ensure workload is manageable and due dates are met, the assessors can only spend time on the actual change being proposed. To expedite the review of a supplement, it is best to focus the submission only on the change being proposed. Other details that were previously approved in the original submission should still be implemented and would not require additional assessment. Therefore, it is critical that the supplement clearly outlines in the cover letter what exactly is changing and include only the relevant data to support the proposed change.
In summary, assessment of the sterility assurance application requires a complete understanding of the proposed manufacturing process as well as the studies provided to support the efficacy of the sterilization process and manufacturing process microbial controls.4 A clearly written and scientifically complete application that is submitted to the Agency with logical and relevant protocols will significantly expedite the assessment and lead to faster application approval.
References
- Food and Drug Administration (FDA) Guidance Document. Biological Indicator BI pre-market notification 510k submissions. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/biological-indicator-bi-premarket-notification-510k-submissions. Accessed May 15, 2023.
- Food and Drug Administration (FDA) Guidance Document. Pyrogen and Endotoxins Testing Questions and Answers. Available at: https://www.fda.gov/regulatory-information/ search-fda-guidance-documents/pyrogen-and-endotoxins-testing-questions-and-answers. Accessed May 15, 2023.
- Food and Drug Administration (FDA) Guidance Document. Changes to an Approved NDA or ANDA. Available at: https://www.fda.gov/regulatory-information/search-fda-guidancedocuments/changes-approved-nda-or-anda. Accessed May 15, 2023.
- Food and Drug Administration (FDA) Guidance Document. Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submission-documentation-sterilization-process-validation-applications-human-and-veterinary-drug. Accessed May 15, 2023.
Author Biographies
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.
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.
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