4-STO_Small_Molecule.pdf

Sample Statement of Work Technical Area: Drug Substance Development – Small Molecules

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

SMDC will have a molecular weight from 260 g/mol to 660 g/mol with at least one fused heterocyclic ring containing at least 2-3 nitrogen atoms, such as imidazo[1,5-a]pyrazine with alkyl substitutes at the 3 and 6 positions of the ring.

The synthesis of the SMDC starts with common commercially available starting materials. Initial multi-gram quantities of SMDC were synthesized (in 11 steps) by the Government and another Contract Research Organization

(CRO).

The 11-step process includes a 5-chloropyrazine-2-methyl ester reduction followed by a chlorination and azidation to form an azide compound which was further reduced to a primary amine. The amine was then reacted with a mono ester protected bicarboxylic acid with 2 Cbz protected amino groups (one is secondary amine, and another is primary). The resulting compound then underwent a palladium catalyzed coupling reaction with a boronic acid followed by a cyclization reaction to form imidazo[1,5-a]pyrazine ring which underwent a hydrolysis reaction followed by amidation with a primary amine to form a key intermediate. The 2 Cbz groups were then removed. The resulting secondary amine was selectively amidated with a carboxylic acid to form the crude SMDC free base (around 90% AUC by HPLC, major impurity is bisamidated byproduct). The crude SMDC free base was then treated with an acid in an aqueous solution and filtrated and basified with ammonium to form purified SMDC free base (>97% AUC by HPLC) after filtration, which was then treated with an acid again to form the pure SMDC salt (>98.5% AUC by HPLC).

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.

• 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.

Attachment 4

• 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 % 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 Method

The Contractor shall develop and qualify a stability indicating method for assay and purity determination of SMDC. The qualification work shall assess the analytical characteristics listed in Table 1 of United States Pharmacopoeia General Chapter <1225>. The stability indicating properties of the 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 qualification.

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

Offerors shall specify in their proposals the parameters that will be evaluated as part of method qualification.

Task 6. Other Analytical Methods

The Contractor shall develop and qualify other analytical methods needed for release of the cGMP lot.

Offerors shall list the methods that will be developed and qualified in the proposal.

Task 7. Stability Studies

The Contractor shall conduct a 2-year stability study of SMDC (per ICH guidelines) using developed and qualified 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.

A. 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.

Where specified, all materials manufactured under this subcontract shall adhere to cGMP under the current United States Code of Federal Regulations, 21 CFR Part 210 & 211, as well as the European Community Directive European Directive 2003/94/EC in relation to medicinal products for human use and investigational medicinal products for human use, as interpreted by ICH Harmonized Tripartite Guideline.

The Contractor will agree to enter into a Quality Agreement and will comply with all local and national laws and regulations and will conform to GMP as defined by provisions of the Federal Food, Drug and Cosmetic Act when engaged in the manufacture of biological products; said GMP provisions are available at:

https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations. 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.

The Contractor shall permit appropriately skilled representatives of the Government, at the inspecting party’s expense, to have access during the Contractor’s normal business hours to inspect Contractor’s records and facilities as may be necessary to verify that the products manufactured by the Contractor are in accordance with cGMP requirements and conform to the specifications outlined in this Subcontract. These audits/inspections shall be conducted as deemed required by the Government and will last approximately 2-5 business days each, depending on the type of audit/inspection, the availability of required data, and the quantity of data to be reviewed. A successful audit outcome will be required prior to GMP activities.

B. Task Order Deliverables and Reporting Requirements:

https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations

The below study deliverables and reports shall be submitted in accordance with the terms and conditions described in the parent IDIQ contract and this SOW. The Contractor shall propose delivery dates / timelines for the listed tasks. Final delivery schedules will be determined through negotiation between the Contractor and the Government.

In addition to specific acceptance criteria included with certain deliverables, the following general quality measures will be applied to each deliverable received from the Contractor under this Statement of Work:

• Accuracy – Deliverables shall be accurate in presentation, technical content, and adherence to accepted elements of style.

• Clarity – Deliverables shall be clear and concise. Any/all diagrams shall be easy to understand and be relevant to the supporting narrative.

• Consistency to Requirements – All deliverables must satisfy the requirements of this SOW.

• Timeliness – Deliverables shall be submitted on or before the due date specified in this SOW or submitted in accordance with a later scheduled date determined by the Government.

Reports submitted shall include the following:

• Contractor Name and Address

• Name of Person Submitting the Report

• Subcontract Number (if required)

• Report Date

• Period Covered by the Report

• A comprehensive Summary of Work performed during the reporting period

1. Physical Properties Reports for SMDC Free Base and Salts Thereof The study should be completed within 7 weeks after TO award. The reports are due 2 weeks after completion of the study.

2. Demonstration Batch The Contractor shall deliver a demonstration batch. The batch will be a multi-gram amount to be agreed upon by the Contractor and NCATS. The Demonstration Batch is due 3 months after TO award.

3. Process Development Report A comprehensive report describing process research and development for the synthesis of SMDC, up to and including the Demonstration Batch. The report shall include, but will not be limited to, detailed experimental procedures; detailed description of evaluated conditions and results; analytical results and description of analytical methods. The report is due 1 month after the delivery of the Demonstration Batch but may be combined with the Campaign Report.

4. Certificate of Analysis (COA) for Demonstration Batch

A COA that describes the results of all testing required for the final product. The COA is due at the time of release of the Demonstration Batch.

5. Material Safety Data Sheet (MSDS) for Demonstration Batch The MSDS shall be generated for the material manufactured at the Contractor’s facility. The MSDS is due at the time of release of the Demonstration Batch.

6. Method Qualification Protocol A method qualification protocol with description of study results and representative chromatograms. The HPLC method validation protocol shall be provided to NCATS for review and comments before finalizing. The protocol is due 3 months after the start of the TO.

7. Method Qualification Report A method qualification report with description of study results and representative chromatograms. The report shall be reviewed and released by the Contractor’s QA unit and shall be provided to NCATS for review and comments before finalizing. The report is due 4 month after the start of the TO.

8. Reference Standard The Contractor shall deliver a 25 g lot of qualified Reference Standard (RS). The RS and qualification report are due 5 months after the start of the TO.

9. 250-g cGMP Lot of SMDC Salt on Free Base Basis (Salt Form TBD) All material must be manufactured and documented according to cGMP criteria and must meet the specifications noted in Task 3. The cGMP lot is due 10 months after the start of the TO.

10. Certificate of Analysis (COA) for cGMP Batch A QA-approved Certificate of Analysis (COA) that describes the results of all testing required for the final product. The COA is to be of sufficient detail to include in a regulatory submission to the FDA. The COA is due upon release of the cGMP batch.

11. Material Safety Data Sheet (MSDS) for cGMP Batch The MSDS shall be generated for the material manufactured at the Contractor’s facility. The MSDS is due upon release of the cGMP batch.

12. Campaign Report A comprehensive report describing preparation and analysis of the 250 g batch of SMDC. The report shall contain process observations made during the scale-up campaign and recommendations for possible future campaigns. The report is due 1 month after delivery of the 250 g cGMP batch. The Campaign report may be combined with the Process Development report.

13. CMC Report in CTD Format All of the tasks conducted in support of this SOW will be well documented. The CMC report shall be in CTD format, and of sufficient detail to include in a regulatory submission to the FDA. See M4Q(R1) ICH Guideline for reference. The report is due 2 months after delivery of the 250 g cGMP batch.

14. Interim Stability Study Reports Interim stability reports shall be prepared after each sample pull. These reports shall be completed within 1 month of the sample pull, shall be in CTD format, and shall be of sufficient detail to include in a regulatory submission to the FDA.

15. Final Stability Study Report The final stability report shall be prepared after the final sample pull. This report shall be completed within 1 month of the final sample pull, shall be in CTD format, and shall be of sufficient detail to include in a regulatory submission to the FDA.

16. Final Report A summation of the work performed, and results obtained, for the entire TO period of performance. This report shall be of sufficient detail to describe comprehensively the results achieved.

C. Task Order Delivery and Reporting Schedule:

Satisfactory performance of the TO shall be determined by the performance of work described in the TO and upon delivery and acceptance of the below deliverables and reports by the Contracting Officer or duly authorized representative.

Offerors may propose alternative deliverable due dates.

Study Deliverables and Reporting Requirements

Deliverable Delivery Due Date

1 Physical Properties Report As directed by the COR

9 weeks after completion of study

2 Demonstration Batch As directed by the COR

3 months after TO award

3 Process Development Report Electronically to CO & COR

1 month after the delivery of Demonstration Batch

4 Certificate of Analysis (COA) Electronically to CO & COR

With release of Demonstration Batch

5 MSDS for Demonstration Batch Electronically to CO & COR

With release of Demonstration Batch

6 Method Qualification Protocol Electronically to CO & COR 3 months after TO award

Method Qualification Report Electronically to CO & COR

1 month after submission of Method Qualification Protocol

8 25 g Reference Standard and Report As directed by the COR

5 months after TO award

9 250 g cGMP Batch of SMDC As directed by the COR

10 months after TO award

10 QA-approved Certificate of Analysis (COA)

Electronically to CO & COR

With release of cGMP Batch

11 MSDS for cGMP Batch Electronically to CO & COR

With release of cGMP Batch

12 Campaign Report Electronically to CO & COR

1 month after release of cGMP Batch

13 CMC Report in CTD Format Electronically to CO & COR

2 months after release of cGMP Batch

14 Interim Stability Study Reports Electronically to CO & COR

1 month after each pull date

15 Final Stability Study Report Electronically to CO & COR

1 month after completion of stability study

16 Final Report Electronically to CO & COR

On or before TO expiration