Micro ENDS SOW analyses testing FINAL v1 10.25.21.docx

DESCRIPTION/SPECIFICATIONS/WORK STATEMENT

EVALUATION OF THE MICROBIAL PARAMETERS OF E-LIQUIDS (ENDS)

General Requirements The Food and Drug Administration (FDA), Center for Tobacco Products (CTP) requires a contractor to provide microbiological analyses of the following parameters in electronic nicotine delivery systems (ENDS) e-liquids:

· water activity (aw)

· antimicrobial effectiveness testing (AET)

· total aerobic microbial counts (TAMC)/total yeast and mold count (TYMC)

· endotoxin

· (1→3)-β-D-glucan

· N-nitrosnornicotine (NNN) and 4-(N-methyl-N-nitrosoamino)-1-(3-pyridyl)-1-butanone (NNK) The purpose of this project is to determine baseline levels of each parameter in a variety of ENDS e-liquids. We will test laboratory-prepared e-liquids first, in order to examine the role of specific parameters (PG/VG levels, nicotine levels, flavors) in anti-microbial properties of the e-liquid. Next, we will test commercial e-liquid samples (at least three batches per e-liquid). Samples will be stored at ambient temperature in original containers and may be pooled by batch using aseptic techniques in order to obtain enough volume for all testing. Triplicate samples will be tested for each parameter at defined time points from initiation of study in order to provide data over a simulated stability period. Expiry of each product should be noted at the time of purchase prior to initiation of the study.

Specific Tasks

1. Samples The contractor shall conduct phase 1 tests with laboratory-prepared e-liquids containing PG, VG, and nicotine at varying levels. We will also initiate testing with three flavors: unflavored, tobacco, and menthol. The contractor shall prepare all 36 laboratory-prepared e-liquids from sourced PG, VG, nicotine, and flavors (FDA will not provide these samples). PG, VG, and nicotine should be USP-grade. The following samples should be prepared:

a. Laboratory-prepared samples (Phase I testing): total of 36 samples to be prepared 3 PG/VG ratios × 4 nicotine levels × 3 flavors = 36 samples total

50% / 50%

35% / 65%

1%

3%

5%

Tobacco

Menthol

Container closures to be tested in this phase (10 mL containers, 36 samples × 4 time points for LER testing):

· Type I glass: 144 containers

· Low density polyethylene (LDPE): 144 containers

· High density polyethylene (HDPE): 144 containers

· Polyethylene terephthalate (PET): 144 containers Method(s) to modify the nicotine concentrations in e-liquids shall be proposed by the Contractor, based on technical expertise and laboratory capabilities. Laboratory methods shall include a description of procedures to add nicotine to the nicotine-free base e-liquid to produce the e-liquid solutions containing the desired nicotine concentrations. Additionally, the methods shall include a description of how the nicotine concentrations of the resulting study e-liquids will be verified.

The contractor shall conduct phase 2 tests with commercial tobacco products (see Appendix A for list of products and quantity for testing). FDA will supply phase 2 tobacco product samples. Upon receiving the samples, the contractor shall record product information, when possible, including: full product name, image, manufacturer, lot/batch number (#), product identification number (ID) if any (e.g., UPC code), product category and subcategory, number of samples, receiving date, manufacturing date (if any), sell-by date (if any), and storage conditions by the laboratory before analysis. The contractor shall keep a copy or photo of the front of the product package/label for record.

2. Analytical Test Method The contractor shall use methods that have been validated under appropriate quality management system and determined to be fit for purpose which includes the method characteristics given below. The contractor shall provide FDA with method validation reports along with detailed analytical methodologies which shall include:

a. Accuracy

b. Precision

c. Robustness

d. Limit of detection (LOD)

e. Limit of quantitation (LOQ)

f. Range

g. Linearity

h. Specificity

i. Recoveries Analytical testing may utilize compendial methods (e.g., USP <85> for endotoxin or <61> for TAMC/TYMC). Any exceptions to method validation as outlined in these methods should be justified.

3. Testing Phase 1: laboratory-prepared e-liquid testing

The contractor shall conduct test with 36 laboratory-prepared e-liquids produced or purchased by the contractor containing PG, VG, nicotine and flavors and it should be USP-grade (see section 1a). The contractor shall test with three flavors: unflavored, tobacco, and menthol. The FDA will not provide samples for phase 1 testing. The following testing should be conducted:

· Anti-microbial effectiveness testing studies:

Compendial testing per USP <51> will be performed on laboratory prepared e-liquids (outlined in sample SOW). Recovery of each compendial microbe will be assessed over the required 28-day period to determine if the e-liquid has anti-microbial properties and how these properties vary based on levels of PG, VG, nicotine, or flavors. Based on the outcome of this testing, FDA will determine whether TAMC/TYMC need to be evaluated in commercial tobacco products in Phase 2.

· Water activity (aw) testing:

Laboratory prepared e-liquids will be tested for water activity over time to determine if these parameters (PG, VG, nicotine, or flavors) affect water activity (aw) during storage/shelf life.

· Endotoxin testing:

Laboratory-prepared e-liquids will be tested for inhibition/enhancement per USP <85>. These studies will allow us to determine whether levels of PG, VG, nicotine, or flavors affect endotoxin recovery. Low endotoxin recovery (LER) testing per PDA TR 82 will also be performed to ensure that endotoxin can be recovered over shelf life of the product. LER testing will be performed using containers of different materials, identical to those used for commercial e-liquids; this testing will allow us to understand the impact of the container closure on endotoxin recovery for e-liquids.

Phase 2: commercial e-liquid testing

Based on the results from phase 1, commercial tobacco products (closed ENDS e-liquids with defined PG/VG and nicotine levels in a variety of flavors) will be selected for testing of some/all of the parameters outlined above in section 1a (aw, TAMC/TYMC, NNN/NNK, endotoxin, (1→3)-β-D-glucan). The contractor shall test the following methods, but the contractor can propose alternatives for FDA’s approval:

· aw - water activity meter

· TAMC/TYMC – enumeration by serial dilution, identification testing according to the Bacteriological Analytical Manual, based on lab availability; VITEK®, Biolog®, PCR® upon approval and/or request

· Endotoxin - per USP <85> using LAL methods, including low endotoxin recovery hold time studies as described in PDA TR 82

· (1→3)-β-D-glucan – commercial Glucatell assay

· NNN and NNK - HPLC mass spectrometry

The contractor shall test at least three batches per e-liquid on the 21 samples provided by the FDA (see Appendix A for list of products and quantity for testing).

4. Period of Performance The Contractor is expected to complete these tasks within 18 months of the award. We anticipate delivery of samples within two months after the award. This may provide the contractor time to access validated methods and methods that need to be validated.

5. Deliverables

a. If the sample preparation requires a pre-concentration or derivatization step, the contractor shall provide a report on the recovery/efficiency studies described in Section 2a of this document. The Contractor shall provide this report no later than 15 days from day of discovery.

b. The contractor shall provide status monthly updates. Updates can include emails, conference calls or face-to-face meetings.

c. The contractor shall provide a draft report that includes the raw data and tabulated results (means, averages, coefficient of variation and standard deviations) of all analyses of tobacco products specifically identified by FDA and for quality control samples; chromatograms; full descriptions of analytical test methods used; validation reports; a brief summary of the quality management system under which the test methods were used and validated to complete the analysis; standard operating procedures; running control charts; descriptions of any laboratory issues encountered along with their solutions; and any other issues relevant to the study. FDA to discuss and/or provide a draft template as guidance and discuss how costs are billed, i.e. increment billing. The Contractor shall provide the draft report no later than 30 days after completion of testing. The contractor shall consider the following items for the final report:

i. The number of documents provided and include representative data, results, and chromatograms with a brief explanation in the appropriate report(s) (e.g., collate chromatograms and insert them into the appropriate sections of the report instead of sending in numerous individual, unidentified data files; label chromatograms/data).

ii. When a report refers to an internal document, please provide all documents in an appendix or in the report (e.g., if you refer to an internal method/SOP, provide the method/SOP).

iii. The validation report must be for the method used to complete the analyses.

d. The contractor shall provide a final report to include an approved draft (this can be in an appendices). The Contractor shall provide the final report no later than 30 days after FDA approves final draft.

Other Requirements FDA may, at the agency’s discretion, publicly release information from this study on e-liquids; however, details of the analytical method used in the quantification will not be released publicly. The contractor should inform FDA of any concerns regarding the release of confidential commercial information prior to award.

FDA considers the sharing of FDA-funded research, including digital data, an important means to enhance its value and support future research. When the findings associated with research developed with FDA funds are published, they are required to be made readily available to the public. In addition, investigators seeking FDA funding, in whole or in part, via a contract, grant, or assistance agreement must have an FDA-approved Data Management Plan – a plan for digital data management and sharing – prior to commencing any related services or work.

Upon acceptance for publication, researchers are also responsible for submitting the author’s final manuscript of any peer-reviewed scientific publication resulting from research supported, in whole or in part, with FDA funds to the NIH National Library of Medicine's (NLM) PubMed Central (PMC). FDA defines the author's final manuscript as the final version accepted for journal publication, which includes all modifications resulting from the publishing peer review process. The PMC archive is the designated repository for these manuscripts for use by the public, health care providers, educators, scientists, and FDA. FDA expects timely release and sharing of final research data from FDA-funded studies for the research community’s use in accordance with the submitted Data Management Plan. Please see the FDA Public Access Policy (provided as Attachment/Exhibit XXYY; or, available at http://www.fda.gov/downloads/aboutfda/reportsmanualsforms/staffmanualguides/ucm479268.pdf).

Evaluation Criteria FDA will evaluate the proposals based on the following criteria. Factors are listed in descending order of importance:

· Factor 1-Scientific merits (e.g., methods used for analysis) The methods proposed by the offeror are in accordance with the parameters listed in section 2, and are appropriate to complete the work listed in the SOW

· Factor 2-Ability to complete entire analysis (i.e., ability to analyze for all parameters in the ITO) The offeror demonstrates the understanding and ability to analyze all of the parameters listed in the task orders

· Factor 3-Price The offeror’s proposed price is fair and reasonable to conduct the work listed in the SOW

· Factor 4-Time frame to complete analysis The time frame for the offeror to complete the work is reasonable and appropriate to do the work in a timely manner

Conflicts of Interest The Contractor or Offeror warrants that, to the best of its knowledge and belief, and except as otherwise disclosed to the Contracting Officer, it does not have any actual, potential, or apparent conflict of interests pertaining to the subject contract, as defined in FAR Subpart 9.5 and HHS and FDA policies, for its organization, employees, or subcontractors working or proposed to be working under this contract.

The Contractor or Offeror agrees that, if after award, it discovers a conflict of interest with respect to this contract, it shall make an immediate and full disclosure in writing to the FDA Contracting Officer for this contract.

The Government reserves the right to exercise any remedy available at law or equity, including termination of the contract for cause or convenience, should the Government determine remedial action is necessary to address any actual, potential, or apparent conflict of interest.

Appendix A

Phase 2-Closed e-liquids tobacco product samples