Misc.
Name at least 2 Microbiology standards applicants reference?
BAM: Chapter 18: TYMC
BAM: Chapter 3: TAMC
CORESTA
USP
An abbreviated TPMF review is conducted when no new relevant information has been added to the TPMF since the last review.
True. When no new relevant information has been added to the TPMF since it was last reviewed, a full updated scientific review is not needed. The reviewer confirms that the previously reviewed information remains sufficient for the current application and notes this in the review.
This statistical test is used for finished product TSNA data and is performed by Chemistry.
TOST — Two One-Sided Test. It tests whether the means of two datasets are practically equivalent by determining whether both means fall within pre-specified lower and upper equivalence bounds.
If an applicant changes the container closure system of a new product compared to the predicate product but does not provide stability data, what type of deficiency would microbiology likely issue?
A stability deficiency requesting water activity (aw), TSNA levels (NNN and NNK), and potentially microbial counts (TAMC and TYMC) measured over the shelf life of both the new and predicate products to demonstrate that the CCS change does not impact microbial stability. This is because a change in CCS can affect water vapor transmission, which can alter the product's water activity and in turn impact microbial growth and TSNA formation.
At what aw level is bacterial growth generally supported? At what aw level is mold growth generally supported?
Bacterial growth is generally supported at aw greater than 0.86. Mold growth is generally supported at aw greater than 0.61. Both thresholds are important because they help assess the potential for different types of microbial proliferation at different water activity levels.
Humectants function to keep a product moist, thereby impacting the _____ and _____ of the product, which in turn may impact _____ and _____.
Humectants function to keep a product moist, thereby impacting the moisture content and water activity (aw) of the product, which in turn may impact microbial growth and product stability.
Water is evaluated as a humectant in microbiology reviews.
False. It is important to note that while water is evaluated in this context, it is not classified the same way as traditional humectants like propylene glycol or glycerin. Water impacts product moisture which in turn may impact microbial growth.
This federal law provides the public the right to request access to records from any federal agency and is processed by FDA under 21 CFR Part 20.
FOIA — Freedom of Information Act
Name the four key validation parameters that FDA typically requests when issuing a method validation deficiency.
Accuracy, sensitivity, specificity, and reproducibility. Precision, limit of detection (LOD), and limit of quantitation (LOQ) may also be acceptable answers.
Why is aw considered a better indicator of microbial risk than moisture content?
Because only unbound (free) water is available to support microbial growth. Moisture content measures both bound and unbound water, so it can overestimate the water actually available for microbial activity. Water activity specifically measures the free water available, making it the more accurate and appropriate parameter for assessing microbial risk in tobacco products.
During tobacco fermentation, microbial-mediated reduction of _____ generates _____ that further reacts with ____ present in tobacco, which could potentially result in increased levels of _____ in finished tobacco product over shelf life.
During tobacco fermentation, microbial-mediated reduction of Nitrate generates nitrite that further reacts with alkaloids present in tobacco, which could potentially result in increased levels of tobacco-specific nitrosamines (TSNAs) in finished tobacco product over shelf life.
TOST and Stats Consult could be used to evaluate ingredient quantities provided by the applicant.
False. TOST and Stats Consults are only for measured stability data. They should not be used for ingredient, container closure system, or tobacco processing issues that arise during a review. Using these tools for ingredient quantities would be an inappropriate application of statistical analysis.
What standard must a new tobacco product meet under the SE pathway to receive a marketing order?
The new product must not raise different questions of public health compared to the predicate product. This is often abbreviated as DPQH — Different Questions of Public Health.
An applicant submits an SE report for a cigar product. The submission contains conflicting container closure system information — one section states carboard box for both the new and predicate products, while another section states metal tin for the new product and cellophane wrap for the predicate product. What is the first thing microbiology would request in a deficiency and why?
Microbiology would first request a clarification statement clearly identifying the CCS for both the new and predicate products. This is needed because a difference in CCS could potentially affect water vapor transmission, which can alter the product's water activity and in turn impact microbial growth and TSNA formation over the product's shelf life. Without clarification, FDA cannot determine whether a CCS difference actually exists and therefore cannot assess its potential impact on microbial stability.
If a product's aw increases over its shelf life, what two types of data would FDA typically look for to determine whether the increase raises public health concerns?
Microbial counts (TAMC and TYMC) and TSNA levels (NNN and NNK). If microbial counts and TSNAs remain stable or decrease despite the aw increase, the increase may be considered acceptable from a microbiology perspective. The aw increase alone is not automatically a deficiency — it must be evaluated in the context of the full stability picture.
What is Four-Part Harmony and can you name the parts?
An approach to writing clear, concise deficiencies that help the applicant fully understand FDA's needs for additional information.
•Part 1: Restate the information the applicant provides related to the deficiency.
Demonstrates that relevant information was reviewed.
•Part 2: Describe what is deficient about the provided information.
Describes what the provided information is missing or the issue of concern
•Part 3: Explain why the missing/additional information is needed.
Justifies the reason for the request/why it is necessary for FDA review
•Part 4: State what new information is needed to resolve the deficiency.
Specifically and directly states the information/data needed.
Anyone can file a FOIA request to see specific discipline reviews.
True. Any person can submit a FOIA request including individuals, companies, journalists, researchers, and foreign nationals regardless of citizenship. However, substantive unredacted discipline review records for specific individuals are unlikely to be released as those records are strongly protected under privacy exemptions.
What standard must a new tobacco product meet under the PMTA pathway to receive a marketing order?
The product must be appropriate for the protection of public health (APPH). Unlike the SE pathway, there is no predicate product comparison. The applicant must demonstrate through the totality of scientific evidence that marketing the product is appropriate for the protection of public health.
If a new product and its predicate product are manufactured by different companies, what tobacco processing information would microbiology likely request in a deficiency
A description of the tobacco processing method for both the new and predicate products, including the type of processing such as fermentation, curing, or heat treatment, duration and conditions including temperature, humidity, and pH, ingredients added during processing that could impact microbial stability, and the method used to stabilize or stop the process.
Why does FDA evaluate complex flavor ingredients from a microbiology perspective, even if the flavors themselves are not the primary focus of the review?
Because complex flavor ingredients may contain humectants or preservatives that could affect water activity and microbial growth. Without knowing the single ingredient composition of complex flavors, FDA cannot fully assess their impact on product stability
What is CTP Microbiology Mission?
To evaluate data methods, and other measurements or information, develop product standards, and initiate and develop research projects to fill knowledge gaps related to tobacco product microbiology.
An applicant submitted a tobacco product application that did not include water activity (aw) or microbial count data. Instead, the applicant submitted finished product TSNA data (NNN and NNK) through a Tobacco Product Master File (TPMF). Microbiology referred the TSNA method evaluation to Chemistry, but Chemistry was unable to complete its evaluation. Why?
No Letter of Authorization (LOA) was provided for the testing laboratory referenced in the TPMF. Without the LOA, Chemistry could not access or review the full method information, and therefore Microbiology could not accept the TSNA data, making its public health conclusion tentative
A reviewer submits a Stats Consult request to the Stats Branch for water activity data. The Stats Branch reports back with their findings. The reviewer writes in their review that the water activity data are analytically equivalent based on the Stats Consult results. True or False: The reviewer is correct.
False. A Stats Consult is used to determine statistical significance, not analytical equivalence. Analytical equivalence is determined by a TOST analysis performed by Chemistry. The reviewer used the wrong conclusion for the wrong test. Statistical significance and analytical equivalence are two separate concepts measured by two separate tests that answer two different questions and cannot be used interchangeably.
Name at least four factors that can influence microbial stability and TSNA formation during a tobacco product's shelf life.
Any four of the following: container closure system, tobacco processing method such as fermentation, curing, or heat treatment, water activity, humectants, preservatives, microbial content, nitrate and nitrite concentrations, and product storage conditions including temperature and moisture content. All of these factors are evaluated in microbiology reviews because changes in any one of them can potentially affect the microbial stability of the finished product and consequently impact TSNA formation and public health risk over the product's shelf life.
Final Jeopardy
An applicant submits an SE report for a new smokeless tobacco product. The submission contains the following information:
Deficiency 1 — Tobacco Processing: Request a description of the tobacco processing method for both the new and predicate products including the type of processing, duration, conditions such as temperature and humidity, ingredients added during processing, and the method used to stabilize or stop the process. This is needed because different manufacturers may use different fermentation or curing processes that affect microbial community composition and TSNA formation potential, and without this information FDA cannot determine whether differences in processing could impact microbial stability.
Deficiency 2 — Complex Ingredient Composition / TPMF LOA: Request either the Letter of Authorization for the referenced TPMF or the single ingredient composition and quantities for the complex flavor ingredient directly in the submission, including identification of any humectants or preservatives. This is needed because complex flavors may contain humectants or preservatives that affect water activity and microbial growth, and without an LOA FDA cannot access the TPMF to evaluate this information.
Deficiency 3 — Stability / CCS Change: Request water activity data for both the new and predicate products, and if aw increases are found then TSNA levels (NNN and NNK), and if TSNA increases are found then full microbial stability data including TAMC and TYMC measured at the beginning, middle, and end of the defined shelf life under standard storage conditions. This is needed because the CCS change can affect water vapor transmission and therefore water activity, which can impact microbial growth and TSNA formation. Moisture content alone is not an acceptable substitute for water activity data