5-STO_Peptides.pdf

Sample Statement of Work Technical Area: Drug Substance Development – Peptides

A. Background Information

SPDC is an endogenous small peptide with pain killing or opiate activity. The clinical use of SPDC has historically been limited due to pharmacokinetic issues, including plasma stability and blood-brain barrier permeability. To overcome its limitation for clinical use, a novel formulation is being developed. NCATS is supporting preclinical and clinical development, including CMC development of SPDC. The required cGMP batch of SPDC will support further preclinical evaluation of its safety and Phase 1 clinical studies.

SPDC peptide structure:

H-X-X-X-X-X-OH

Counter ion: chloride

B. Scope and Objectives

The overall scope of this Task Order (TO) is for the Contractor to support the chemistry, manufacturing, and controls (CMC) development of SPDC.

The objectives of this TO include:

1. Process development and demonstration.

2. Development and validation of a stability-indicating HPLC method for SPDC.

3. Development and validation of any other analytical methods required for the release and stability studies of cGMP SPDC.

4. Delivery of cGMP lot of SPDC.

5. Delivery of the Chemistry, Manufacturing, and Controls (CMC) report in the Common Technical

Document (CTD) format.

6. Conduct of International Conference on Harmonisation (ICH) stability studies of the cGMP lot.

C. Project Description and Technical Requirements

Task 1: Process Development and Demonstration Batch

The Contractor shall develop a scalable process that is suitable for the manufacture of a 1 Kg cGMP batch of SPDC and deliver a 100 g (on net peptide basis) non-GMP demonstration batch of SPDC that meets all specifications listed below. If the Contractor already has an established process to produce SPDC at large scale, the Contractor can directly perform the 100 g demonstration batch run. The intent of the demonstration run is to demonstrate that the developed process is scalable and that a final product can be delivered that meets specifications.

The Contractor shall provide the demonstration lot with a Certificate of Analysis (COA) and a comprehensive report.

Offerors may propose a difference scale for the demonstration run.

Attachment 5

Specifications for cGMP lot:

Test Acceptance Criteria Method

Physicochemical Properties

Appearance (visual inspection) White or off-white

Identification

Mass spectrometry Average mass: USP <736>, current edition

Tandem mass spectrometry

Conforms to the sequence of

SPDC

USP <736>, current edition

Amino acid analysis x 1 ± 0.1 xx 2 ± 0.1

USP <1052>, current edition x 1 ± 0.1 xx 1 ± 0.1

Peptide Purity by HPLC

Peptide purity ≥98% (By area integration)

Related substances ≤2% Total

Individual Impurities No single impurity ≥ 1%, report impurities ≥ 0.1%

Other Tests

Assay (peptide content by Nitrogen Analysis)

≥75%

Chloride content, titration 5-7% USP <191>, current edition

Water Content (Karl Fischer) ≤5% USP <921>, current edition

Total Mass Balance 90 to 105%

Residual Phosphate (IC) Report result USP <345>, current edition

Acetic Acid Content (RP-HPLC) ≤1% USP <503>, current edition

Residual TFA

(RP-HPLC) ≤ 0.1%

Residual Organic Solvents (GC) ICH limits

ICH Q3C (R6),

USP <467>,

current edition

Bioburden TAMC: ≤100 CFU/g TYMC: ≤100 CFU/g USP <61>, current edition

Bacterial endotoxins (LAL) ≤0.05 EU/mg

USP <85>, current edition

Task 2: Stability-Indicating HPLC Method

The Contractor shall develop and validate a stability-indicating HPLC method for identity, impurities, and purity determination of SPDC. 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 provide the HPLC method validation protocol and HPLC method validation report with description of study results and representative chromatograms. The report shall be reviewed and released by the Contractor’s QA unit. HPLC method validation protocol and validation report shall be provided to NCATS for review and comments before finalizing.

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

Task 3: Development and Validation of Any Other Analytical Methods

The Contractor shall develop and validate any other analytical methods required for release and stability studies of cGMP SPDC.

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

Task 4: 1-Kg (on Net Peptide Basis) cGMP lot of SPDC

The Contractor shall deliver a 1-Kg (on net peptide basis) cGMP lot of SPDC that meets all specifications listed in Task 1. The Contractor shall also deliver a QA-approved Certificate of Analysis for the cGMP batch.

Although changes to specifications may be introduced based on the process development results, the Offerors’ proposals shall be based on specifications as shown in the Task Order Deliverables and Reporting Requirements section of this TORFP.

Task 5: Stability Studies

The Contractor shall conduct three (3) years of stability studies of the SPDC cGMP batch (per ICH guidelines) using the developed and validated stability-indicating analytical methods and the material from the cGMP batch. The Contractor shall describe the container system used for packaging the stability samples and how the samples are to be handled to maintain their integrity.

The Contractor shall deliver interim reports and a final report describing these studies. The interim reports are due within one month after each sample pull. The final report is due within one month after completion of the stability studies and must be of sufficient detail to include in a regulatory submission to FDA.

Conditions/time intervals:

• -20 ± 5 °C at 0, 3, 6, 9, 12, 18, 24 and 36 months

• 5 ± 2 °C / 60 ± 5% RH at 0, 1, 3 and 6 months

Tests: Purity, impurities (report total and individual impurities), residual water, identity and appearance.

D. 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.

E. Task Order Deliverables and Reporting Requirements

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.

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 reporting period

1. 100-g (on net peptide basis) Demonstration Batch

The Contractor shall deliver the demonstration batch. The batch will be 100 g or an amount agreed upon by the Contractor and NCATS.

2. Process Development Report

A comprehensive report describing process research and development for SPDC, up to and including the demonstration run. The report shall include, but not be limited to the detailed experimental procedures; analytical results; and description of analytical methods.

3. Certificate of Analysis (COA) for Demonstration Batch

A COA that describes the results of all testing required for the final product.

4. Material Safety Data Sheet (MSDS) for Demonstration Batch

The MSDS shall be generated for the material manufactured at the Contractor’s facility.

5. HPLC Method Validation Protocol

An HPLC method validation 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 report is due 4 weeks after the start of the TO.

6. HPLC Method Validation Report

An HPLC method validation 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 6 weeks after the start of the TO or 2 weeks after the completion of validation, whichever date is earlier.

7. 1-Kg (net peptide basis) cGMP lot of SPDC peptide

The 1-Kg (net peptide basis) cGMP lot of SPDC is due 4 months after the start of the TO. This lot shall meet the specifications noted in Task 1.

8. 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.

9. Material Safety Data Sheet (MSDS) for cGMP Batch

The MSDS shall be generated for the material manufactured at the Contractor’s facility.

10. Campaign Report

A comprehensive report describing the manufacture and analysis of 1-kg batch of cGMP SPDC. The report shall include process observations made during the scale-up campaign and recommendations for possible future campaigns.

11. CMC Report and Documentation

A CMC report in CTD format that includes sufficient detail to include in a regulatory submission to the FDA. See M4Q(R1) ICH Guidelines for reference. All tasks conducted in support of this SOW shall be well documented in the report. The Contractor shall also provide QA-approved completed batch records and a summary of in-process sample testing.

12. Stability Study Interim Reports

The Contractor shall prepare interim stability reports after each sample pull. These reports shall be completed within 1 month of the sample pull, shall be in CTD format and of sufficient detail to include in a regulatory submission to the FDA.

13. Final Stability Report

The Contractor shall prepare a final stability report after the final sample pull. This final report shall be in CTD format and of sufficient detail to include in a regulatory submission to the FDA.

14. 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.

F. 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 listed 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 Demonstration Batch As directed by the COR

6 weeks after TO start date

2 Process development report Electronically to

CO & COR

With release of Demonstration Batch

3 Certificate of Analysis (COA) Electronically to

CO & COR

With release of Demonstration Batch

4 MSDS for Demonstration Batch Electronically to

CO & COR

With release of Demonstration Batch

5 HPLC Method Validation Protocol Electronically to CO & COR 4 weeks after TO start date

6 HPLC Method Validation Report Electronically to

CO & COR

2 weeks after submission of Deliverable No 4.

7 1 kg cGMP Batch of SPDC As directed by the COR

4 months after TO start date

QA-approved Certificate of Analysis (COA)

Electronically to

CO & COR

With release of cGMP Batch

9 MSDS for cGMP Batch Electronically to CO & COR With release of cGMP Batch

10 Campaign Report Electronically to

CO & COR

1 month after release of cGMP Batch

11 CMC Report in CTD Format Electronically to

CO & COR

2 months after release of cGMP Batch

12 Interim Stability Study Reports Electronically to

CO & COR

1 month after each pull date

13 Final Stability Study Report Electronically to

CO & COR

1 month after completion of stability study

14 Final Report Electronically to

CO & COR

TO expiration