SATPC0033837 Tab 04 4 SOW.pdf

NASA Johnson Space Center Exploration Medical Capability (ExMC)

STATEMENT OF WORK

Accelerated Stability Analysis

August 1, 2023

Table of Contents

1.0 General

1.1 Points of Contact

1.2 Place of Performance

1.3 Period of Performance

2.0 Background

3.0 Programmatic Requirements

3.1 Kickoff Meeting

3.2 Progress Meetings

3.3 Schedule

3.4 Test Plans

3.5 Medication List ............................................................... Error! Bookmark not defined.

4.0 Technical Requirements

4.1 Samples

4.2 Medication Packaging

4.3 Storage Conditions

4.4 Chromatographic Capabilities ......................................... Error! Bookmark not defined.

4.5 Impurities

4.6 Dissolution Capabilities

4.7 Tablet Breaking Force

4.8 Solid Dosage Form Moisture Content

5.0 Reports

5.1 Time-point Reports

5.2 Comprehensive Report

6.0 Deliverables

7.0 Acronyms

1.0 General

This statement of work (SOW) provides the minimum requirements to be fulfilled by [Contractor Name] to perform pharmaceutical analyses as required to ascertain drug stability, and thereby inform NASA Human Research Program (HRP) Exploration Medical Capability (ExMC) on drug readiness for spaceflight missions.

[Contractor Name] will be referred to as “Contractor” in this agreement.

Exploration Medical Capability will be referred to as “Government” in this agreement.

1.1 Points of Contact

Contractor:

[Name] [Title] [Email Address]

Government:

John Reichard Sr. Pharmaceutics Strategist john.f.reichard@nasa.gov

Aaron Allcorn Project Manager aaron.j.allcorn@nasa.gov

1.2 Place of Performance

1.3 Period of Performance

The period of performance (PoP) is December 15, 2023 through September 30, 2024 with a one-year option to extend through September 30, 2025.

2.0 Background

ExMC projects are designed to provide information that enables the mitigation of medical risks to the crew during spaceflight missions, including lunar exploration and planetary surface habitats. An identified risk to missions is that the appropriate pharmaceuticals will not be available, have the desired efficacy, or present the expected pharmacokinetics to treat medical conditions experienced during a mission. Such circumstance would endanger the mission success and crew health and safety. Knowledge of drug stability over extended durations mitigates the risk by allowing informed pharmaceutical selection for the medical kit and identifying the need for storage mitigations and/or resupply for pharmaceuticals.

Previous studies have shown that some medications undergo more rapid degradation during spaceflight compared than under terrestrial conditions. This effect has been attributed to several factors, including humidity, temperature and especially space radiation. Although some spaceflight medications exhibited a somewhat greater degree of degradation compared to matched terrestrial controls, control samples also exhibited far greater degradation than expected. A likely explanation for this observation was the oral solid medications were removed from manufacture packaging and placed into non-protective packaging. The objective of this experiment is to characterize the effect of current operational drug packaging on the stability of representative drugs under accelerated stability testing conditions.

3.0 Programmatic Requirements

3.1 Kickoff Meeting

The Contractor shall organize and execute the Kickoff Meeting with the Government no later than 30 calendar days after period of performance begins.

3.2 Progress Meetings

The Contractor shall organize and execute monthly Progress Meetings with the Government. The Progress Meetings shall consist of status updates, notification of errors/failures and corrective actions taken, and schedule updates, as applicable.

3.3 Schedule

The Contractor shall provide a schedule of the work to be accomplished no later than 30 days after period of performance begins. The Contractor shall provide any schedule updates at the monthly Progress Meetings, or as soon as possible via email.

3.4 Test Plans

The Contractor shall provide a detailed testing plan no later than 30 calendar days after period of performance begins. The test plans shall include:

Quality control and validation protocols/methods Planned tests in accordance with Technical Requirements Analytical methods/protocols associated with each planned test Equipment name and serial number planned for each test Medication samples with associated packaging planned for each test Number of samples (3 replicates analyzed in duplicate for assay) for each test Anticipated timeline for analysis

4.0 Technical Requirements

The Contractor shall provide the longitudinal analysis of pharmaceutical drugs under different packaging scenarios. The Contractor shall expect to procure lot-matched sets of representative medications for accelerated stability testing at multiple time-points. All medications will be solid dosage forms. The following requirements, regarding testing, are required to ensure the fidelity of sensitive pharmaceutical testing with constrained pharmaceutical test supply.

4.1 Medications

The Contractor shall procure a sufficient number units of three (3) medications to perform the specified assay, impurity and physical stability tests as described below, as well as additional medications or standards required for analytical quality control and validation. All units of a single medication should be from the same manufacturer and lot (matched lot numbers). The Contractor shall provide the pharmaceutical samples with distinct labeling with Sample ID such that samples are clearly identified throughout analytical process.

The procured medications may include:

Amoxicillin 500 MG / Clavulanate 125 MG tablet Diltiazem 60 MG tablet Levothyroxine 0.025 MG tablet

As necessary, the Contractor shall purchase the materials (zip lock PE bags) required repackaging a subset of medications for testing. Materials will be consistent with current NASA procedure for oral drug repackaging.

The contractor will provide a list that includes name, strength, quantity, manufacturer, expiration date, manufacturing lot, and National Drug Code (NDC) number within 7 calendar days after receipt of procured medication.

4.2 Samples

The Contractor shall perform the specified accelerated stability evaluations with measurement of assay, impurity and physical characteristics as described below, as well as is required for analytical quality control and validation.

The Contractor shall analyze each lot-matched drug sample at a minimum of four time-points: Day-Zero, Day-180, and different intermediate points (e.g. Day-60, Day- 120). Each replicate, duplicate analysis is expected. Each test will be performed with a minimum of three independent replicates in duplicate (no aggregation of samples or data).

The Contractor shall provide all equipment, reagents, standards, and materials required for analysis of the pharmaceuticals.

4.3 Medication Packaging

The Contractor shall evaluate medication stability under two packaging conditions:

Condition 1: Manufacturer packaging (or other protective packaging) Condition 2: Repackaging in accordance with current NASA operational procedures using zip lock polyethylene bags such as those manufactured by Consolidated Plastics (Minigrip® Reclosable Bags).

4.4 Storage Conditions

The Contractor shall perform accelerated stability studies of representative medications using a controlled climate storage chamber that maintains environmental conditions at 40°C ± 2°C and 75% ± 5% relative humidity for up to 6 months.

The Contractor shall maintain retains of each sample at low temperature (e.g. -70°C) for 60 days minimum to allow for analysis review and any clarifying rework that may be requested.

4.5 Assay

The Contractor shall use stability-indicating quantitative analytical methods to assess drug product API content for the provided samples. USP methods are preferred;

however, deviations from USP methods are permissible to accommodate technological improvements and testing efficiencies when there is a rationale supporting the deviation, or with Government approval, provided in writing prior to testing.

Analytical methods may utilize High Performance Liquid Chromatography (HPLC) or similar equipment with a quantitative detector (e.g. photodiode array (PDA) or mass spectrometer (MS)) capable of distinguishing API from structurally similar degradation products and isomers.

Chromatographic methods shall include demonstration of standard system suitability for each drug product. Validation of chromatographic methods should include including sensitivity, linearity, accuracy and precision.

Furthermore, acceptable inter-day and intra-day results will be demonstrated as well as retention (capacity) factor (k’), injection precision (relative standard deviation), peak area, theoretical plates (N), USP tailing factor (Tf), and resolution (Rs) between the API and major impurities. Minimum detection and quantitation limits in the range of 2 or 3, and 10 times noise level, respectively, are acceptable for API quantitation.

Chromatographic methods shall include a satisfactory number of independent replicates (not less than three) with independent calculation of relative response factor based on a multipoint API standard curve prepared with a verified API reference standard (e.g. USP standard). Each experimental replicate shall be repeated in duplicate, at minimum.

Equipment supporting chromatographic analysis including API and impurity extraction are required, including centrifuges (Eppindorf microfuge or equivalent), shakers, sonicator or sonication bath, analytical scale (weight sensitivity of ± 0.1mg), suitable pH meter, etc.

4.6 Impurities

The Contractor shall use validated methods for impurity analysis and evaluated prior to use. All suitability included in those methods will be demonstrated and included in reporting using suitable method capable of distinguishing the parent API from structurally similar degradation products, as justified based on scientific literature or USP mongraphs.

Methods shall be adequate for detection, and relative quantitation of impurities (compared to control samples maintained in manufacture packaging under label- compliant environmental conditions).

Impurities shall be reported in terms of chromatogram area percent to the levels indicated in the FDA guidance [Q3B(R) Impurities in New Drug Products, rev3] to the extent possible, typically as a percent area as compared to the API standard peak (or as otherwise specified).

Significant emerging impurities y to levels that exceeds qualification level (per ICH Q3B), as calculated on chromatographic peak shall be identified either based on retention time as an API-related compound or by mass spectrum, or other suitable methods, to the extent possible.

4.7 Dissolution Capabilities

The Contractor shall provide API release characteristics (release rate / extent) from the solid dosage forms by use of a dissolution apparatus based consistent with USP methods ( 711 DISSOLUTION) or published literature.

Dissolution studies shall be performed as described by the relevant USP qualification monograph or, if multiple methods are described, one method shall be selected with an accompanying rational for method selection.

Deviations from USP methods are permissible to accommodate technological improvements and testing efficiencies with Government approval provided in writing prior to testing.

4.8 Moisture Content

Moisture content will be determined by Karl Fischer titration compliant with USP<921>.

4.9 Tablet Breaking Force

The Contractor shall perform analysis of tablet breaking force consistent with USP methods <1217> or published literature.

4.10 Solid Dosage Form Moisture Content

The Contractor shall perform analysis on solid dosage form moisture content using USP methods <921> (e.g. Karl Fisher titration or gravimetric analysis) or <922> Water Activity, as appropriate.

5.0 Reports

The Contractor shall provide four Time-point Reports and a Comprehensive Report as specified below. The Contractor shall deliver all reports in PDF format via email to Government POC.

5.1 Time-point Reports

The Contractor shall provide time-point results 30 calendar days after completion of all tests performed on each sample time-point. The report shall provide (1) a comprehensive summary of the analyses in tabulated formats; (2) a peak table of all chromatographic results (see details below); (3) all results as supplementary documents; (4) analytical values with units and other notation as required for clarity; (5) explanations for any deviations from agreed-upon methodology.

Each set of drug products will consist of a single common drug with samples from 4 time-points with 3 replicates at each time-point. Within each replicate, duplicate analysis is expected. Each replicate and duplicate should be reported independently (no aggregation of sample data).

Peak tables for assay and impurity results shall consist of the following:

Time stamped chromatograms for each assay and impurity sample analyzed

Chromatograms peak tables consisting of sample number, key sample descriptors, detector channel, retention time, peak area, percent peak area, height retention time, calibrated drug content or impurity percentage for each analyzed sample

Any deviations or issues with the analyses Physical characteristics for the dissolution, break force and moisture content

Individual results each sample tested identified by sample number, key sample descriptors

Summary table of mean and variance results for replicate sample sets

Any deviations or issues with the analyses

5.2 Comprehensive Report

The Contractor shall provide a final comprehensive report in scientific report format inclusive of introduction, methods, results and conclusions that can be adapted for publication is expected within 60 days after study completion. The comprehensive report shall include the following:

Comprehensive summary of the analytical results based on compilation of individual drug/timepoint/packaging condition results obtained

Medication sample names and NDC numbers used with each test (to include packaging type used)

Equipment and methods used for each test (to include reason for deviation from test plans, if appropriate)

Summary peak table for assay results inclusive of mean and variance on retention time, peak area, and content

Summary peak table for impurity results inclusive of mean and variance on retention time, peak area, and content

Summary (mean and variance) dissolution results

Summary (mean and variance) break force results

Summary (mean and variance) moisture content results

Recorded errors/failures with any corrective actions taken

Analytical values with units and other notation as required for clarity

Explanations for any deviations from agreed-upon methodology

6.0 Deliverables

Deliverable Description Para. Ref. Due Date Frequency Qty.

Kick-off Meeting Initial meeting to begin work 3.1

30 Days after PoP begins Once 1

Progress Meetings Meeting to provide status updates 3.2 As appropriate Monthly N/A

Schedule Schedule of work to be performed 3.3 30 Days after PoP As appropriate 1

7.0 Acronyms

API Active pharmaceutical ingredient ExMC Exploration Medical Capability FDA Food and Drug Administration HPLC High Performance Liquid Chromatography HRP Human Research Program LC Liquid chromatography MS Mass spectrometry NDC National Drug Code PDA Photodiode array PoP Period of Performance SOW Statement of Work USP United States Pharmacopeia begins; As needed

Test Plans Detailed plans of testing to be performed 3.4

30 Days after PoP begins Once 1

Medication List

Detailed list of medications procured 4.1

7 Days after shipment receipt

Once 1

Time-point Reports

API, Impurities, Dissolution (as applicable), Tablet breaking force (as applicable), Moisture (as applicable)

5.1 30 Days after each time-point

As appropriate 4

Comprehensive Report

Study results and testing completed 5.2

60 Days after study completion

Once 1