Attachment5-SampleTO_Area2.pdf

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

Sample Task Order Request for CMC- Peptide Drug Substance

Contractor: TBD STO Title: Process development, manufacture and stability studies of SPDC for use as a treatment for pain

Contract No.: TBD

NCATS Ref. No.: Contracted Technical Area(s): Technical Area 2

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

(Completion/Non-Severable)

STO 2 – Part I: Task Order Request for Proposals (TORP)

A. Period of Performance: 43 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 2 of the Statement of Work.

The task involves the development, manufacture and stability studies of SPDC, a peptide therapeutic candidate. The clinical use of SPDC has historically been limited due to its pharmacokinetics, including stability in plasma and ability to penetrate the blood-brain barrier. To facilitate its clinical use, a novel formulation is being developed. The Government is supporting preclinical and clinical development activities. The required cGMP batch of SPDC will support further preclinical evaluation of its safety and Phase 1 clinical studies.

Structure of SPDC peptide: H-X-X-X-X-X-X-X-X-X-X-X-X-NH2 Counter ion: Chloride

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. The comprehensive report must be of sufficient detail to include all observations in the process development.

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Offerors may propose a different scale for the demonstration run.

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

XX 2 ± 0.1 XXX 3 ± 0.2

USP <1052>, current edition

X 1 ± 0.1 XX 2 ± 0.1

XX 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) ≥80%

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

Water Content (Karl Fischer) ≤10% 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%

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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.

The Contractor shall deliver a comprehensive campaign report describing the manufacture and analysis of the cGMP batch. The report shall include process observations made during the cGMP 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.

Although changes to specifications may be introduced based on the process development results, the Offeror’s

4 | P a g e proposal 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), MS, residual water, identity and appearance.

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.