Attachment4-SampleTO_Area1.pdf

1 | P a g e Department of Health and Human Services Acquisition Plan (AP)

Sample Task Order Request for CMC- Small Molecule Drug Substance

Contractor: TBD STO Title: Process development, manufacture and analysis of SMDC for perioperative pain

Contract No.: TBD

NCATS Ref. No.: Contracted Technical Area(s): Technical Area 1

TO Originator: NCATS COR TO Type: Cost plus Fixed Fee or Firm Fixed Price

(Completion/Non-Severable)

STO 1 – Part I: Task Order Request for Proposals (TORP)

A. Period of Performance: 38 months

B. Task Leader: COR

C. Deliverables: The Contractor must submit reports and deliverables in accordance with Contract Articles C.2.

Reporting Requirements and F.2. Deliveries.

D. Proposal Instructions: See Part II Contractor’s Response to TORP.

E. Task Description: The following study involves work described in Technical Area 1 of the Statement of Work.

The task involves the development, manufacture and analysis of SMDC, a small molecule therapeutic candidate.

Initial multi-gram quantities of SMDC were synthesized (in 11 steps) by the Government and another Contract Research Organization (CRO). A total of 70 g of SMDC hydrochloride was delivered (largest batch: 51 g). A 250-g cGMP lot (on free base basis) of SMDC salt is required to support further preclinical and Phase I clinical development of SMDC.

Task 1. Evaluation of the Physical Properties of SMDC Free Base and Salts Thereof

The activities described in this section shall be done in parallel with process development. Samples of SMDC free base, and any salts thereof, will be provided by the Government (~5 g each).

• For SMDC free base and each of its salts, the Contractor shall determine their solid-state properties.

• For SMDC free base and each of its salts, the Contractor shall evaluate equilibrium (thermodynamic) solubility at 25 °C and 37 °C in D. I. water, different organic solvents, and different biorelevant media, and determine stability of SMDC free base and each of its salts in aqueous solutions with difference pH and the residue solid state properties.

• For SMDC free base and each of its salts, the Contractor shall determine osmolality of the solution by freezing point depression.

• For SMDC free base and each of its salts, the Contractor shall determine hygroscopicity.

• The data generated above will be used by NCATS to finalize salt form selection.

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• For the selected salt, the Contractor shall prepare 80 mg/mL (on free base basis) solution in water;

lyophilize the solution; evaluate reconstitution time (to initial volume); and report the results.

• For the selected salt, the Contractor shall perform a polymorph screening and identify the thermal stable form of the selected salt.

• If selection of a salt form is confirmed, the Contractor shall optimize conditions for conversion of free base to the salt form.

Task 2. Process Development and Demonstration Batch

The Contractor shall perform process development necessary for delivery of a cGMP batch of SMDC salt. The Contractor shall outline proposed development activities in the proposal. Among other activities, the Contactor shall evaluate the use of the Cbz protecting group, instead of BOC, to enable formation of SMDC free base and avoid desalting. To evaluate potential liabilities of a reductive deprotection step early in development, a small amount of SMDC free base will be provided. The Contractor shall complete a demonstration run to deliver a multi-gram (>30 g) sample of SMDC salt. The Government and the Contractor will review the development proposal. Development activities will only be conducted after approval by the Government. The Contractor shall provide a comprehensive development report describing the process development for the synthesis of SMDC salt.

Task 3. Delivery of cGMP Lot of SMDC Salt

The Contractor shall deliver a cGMP lot of SMDC salt. The required amount of the deliverable is 250 g on free base basis. Final salt form selection will be done after completion of activities described above. The salt form that is currently being considered for further development is succinate. For proposal preparation and initial planning purposes, the contractor shall use 327 g of SMDC salt as the target amount.

Specifications for cGMP lot:

Test Specifications Appearance White to off-white powder Identity

FTIR Conforms to structure 1H NMR Conforms to structure MS Confirms mass of parent

Assay (HPLC) 98.0 – 102.0 % Impurities (HPLC) Individual ≤ 0.25 %

Report all impurities ≥ 0.05 % Total ≥ 1.5 %

Residual solvents used in process < Current ICH Q3C (R4)/USP<467> limits Counterion content (method TBD) * Report result Water content by Karl Fisher titration Report result Loss on drying ≤ 2.0 %

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Residue on ignition ≤ 0.1 % XRPD Report result Heavy metals NMT USP<232> limits Total aerobic microbial count, USP <61> ≤ 100 CFU/g Endotoxin, USP <85> ≤ 1 EU/mg

*Counterion Content: IC in case of succinate; Cl content determination in case of hydrochloride

The contractor shall deliver a QA reviewed Certificate of Analysis (COA) for the batch and generate a Material Safety Data Sheet (MSDS).

The contractor shall deliver a comprehensive campaign report describing the manufacture and analysis of GMP batch. The report shall include process observations made during the GMP campaign and recommendations for possible future campaigns.

The contractor shall deliver a CMC report in CTD format with sufficient detail to include in a regulatory (IND) submission to the FDA. See M4Q(R1) ICH Guidelines for reference.

Task 4. Reference Standard

The Contractor shall deliver a 25 g lot of qualified Reference Standard (RS). The RS qualification protocol and report shall be provided to the Government for review and comments before finalizing. The Contractor shall propose an RS test schedule. The Contractor shall plan for at least two re-tests of the Reference Standard, assuming a 1-year re-test period.

Task 5. Stability-Indicating HPLC Method

The Contractor shall develop and validate a stability indicating HPLC method for assay and purity determination of SMDC. The validation work shall assess the analytical characteristics listed in Table 1 of United States Pharmacopoeia General Chapter <1225>. The stability indicating properties of the HPLC method shall be evaluated by performing forced degradation studies that include acid, base, heat, light and oxidation. The peak purity and the weight percent of the main component shall be determined. The Contractor shall specify in the proposal the parameters that will be evaluated as part of method validation.

The Contractor shall provide an HPLC method validation protocol and an HPLC method validation report with description of study results and representative chromatograms. The report shall be reviewed and released by Contractor’s Quality Assurance (QA) unit. The HPLC method validation protocol and validation report shall be provided to the Government for review and comments before finalizing.

Task 6. Other Analytical Methods

The Contractor shall develop and qualify other analytical methods needed for release of the cGMP lot. The Contractor shall list the methods that will be qualified in the proposal.

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Task 7. Stability Studies

The Contractor shall conduct a 2-year stability study of SMDC (per ICH guidelines) using developed and validated stability-indicating analytical methods and the material from the cGMP batch, and deliver a final report describing these studies. The Contractor shall provide stability protocol to the Government for review. The report is to be of sufficient detail to include in a regulatory submission to the US Food and Drug Administration (FDA). The report is due 1 month after completion of the stability studies. In addition, the Contractor shall deliver interim stability reports after each sample pull. These reports should be completed within 1 month of the sample pull.

Conditions/Time Intervals

• 25°C/60% relative humidity (RH) at 0, 3, 6, 9, 12, 18, and 24 months

• 40°C/75% RH at 3 and 6 months

• Tests: Assay, impurities, loss on drying, appearance, and other tests necessary for the compound

Task 8. Storage

The Contractor shall store the cGMP batch for up to 24 months, if the Government determines that storage will be needed.

F. Conformance and Compliance: The Contractor shall perform all tasks described in this SOW according to the standard operating procedures (SOPs) of the Contractor, and any deviations shall be documented. At the request of the Government, the Contractor shall submit to the Government any SOPs, method descriptions, and references used in the implementation of studies. The Government will treat Contractor SOPs as confidential. All operations related to handling and testing of cGMP material shall comply with applicable FDA regulations and guidance.

The Contractor shall ensure that all data generated in support of the manufacture of cGMP material undergo strict quality review of raw data and transcription, technical supervisor approval, and QA release.