Attachment5 - Sample TO_Area2_4.17.23 Peptides.pdf

1 | P a g e Department of Health and Human Services Acquisition Plan (AP) CMC Drug Product - Sample Task Order for Technical Area 2 (Peptides and Oligos)

Contractor: TBD STO Title: Formulation development, manufacture and stability studies of a sterile injectable freeze-dried dosage form of a 37-amino acid peptide for intravenous administration

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: 48 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 development, manufacture and stability studies of a sterile injectable freeze-dried dosage form of a 37-amino acid peptide (SPDP) for intravenous administration, acetate salt and a freeze-dried placebo formulation.

The amino acid sequence of SPDP is as follows: H-Asp-Trp-Leu-Lys-Ala-Phe-Try-Asp-Lys-Val-Ala-Glu-Lys-Leu-Lys-Glu- Ala-Phe-Pro-Asp-Trp-Ala-Lys-Ala-Ala-Try-Asp-Lys-Ala-Ala-Glu-Lys-Ala-Lys-Glu-Ala-Ala-OH. The formulations are to be prepared aseptically including 0.22 μm filtration. The drug products are intended for single use administration.

Formulation development of sterile freeze-dried peptide formulation and placebo

1. The contractor shall transfer, qualify and modify, if necessary, the stability indicating method for the drug substance to determine drug content and impurities in the dosage form. The method uses a two-component gradient HPLC-UV method: mobile phase A (0.1% trifluoroacetic acid in water) and mobile phase B (0.1% trifluoroacetic acid in acetonitrile) at a flow rate of 1.2 ml/min and a run time of 40 minutes using a Zorbax 300SB-C-18 3.5 μm 4.6 x 150 mm column. The column temperature is 65°C and the peptide is detected at 220 nm. The sample is prepared at 1 mg/ml and injected in a volume of 10 μL.

2. The contractor shall assess the pH vs. stability behavior of the drug substance over a range of pH (2-12) using samples prepared in seven different buffer solutions at a minimum of one temperature over one week at a drug concentration of 1 mg/ml (peptide basis) with a minimum of five time points. The HPLC method qualified in Task 1 is to be utilized.

3. The contractor shall determine the pH vs. solubility behavior of the drug substance over a range of pH (2-12).

Describe the method used to assess solubility of the peptide. For proposal purposes, offerors are to assume that the peptide will have adequate solubility at the pH of maximum stability to deliver the anticipated dose.

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CMC Drug Product - Sample Task Order for Technical Area 2 (Peptides and Oligos)

4. The contractor shall optimize the formula by including certain excipients to yield a formulation with acceptable solubility, osmolality, pH control and stability for the intended route of administration of the drug product during manufacture and after reconstitution (minimum of 72 hours).

5. The contractor shall develop a suitable freeze-drying cycle and formulation to yield a freeze-dried product with acceptable appearance, rapid reconstitution, and low residual moisture. Offerors are to describe their approach to development of a suitable freeze-drying cycle and indicate in their proposal the approximate number of cycles required to develop a suitable freeze-dried product. For proposal purposes, offerors are to assume a fill volume of 2 ml in a 10 ml, 20 mm vial.

6. Using the results from the studies listed above, the contractor shall develop a manufacturing process that results in a stable, easily reconstituted freeze-dried dosage form. Order of addition and approximate mix rates are to be established for the compounding procedure as well as the need, if any, for light protection or inert atmosphere during the manufacturing process. The contractor shall evaluate compatibility of the drug formulation with product contact materials (filters, vessels, mixers, tubing, filling equipment) and container closure system both during drug manufacturing and under simulated use conditions: syringes, infusion fluids (5% Dextrose Injection USP and 0.9% Sodium Chloride Injection USP) and infusion tubing.

7. The contractor shall develop a method and assess cleaning of multiple-use equipment used in manufacture of the drug product. For proposal purposes, offerors are to assume three different surfaces are to be evaluated. Offerors are to describe their approach to demonstrate adequate recovery from surfaces representative of product contact equipment.

8. The contractor shall carry out studies to evaluate the antimicrobial properties of the drug product using the USP method suitability test for sterility (USP <71>) and enhancement/inhibition tests in the bacterial endotoxin test (USP <85>).

9. The contractor shall perform filter integrity testing to demonstrate sterility of the drug product for clinical use. The contractor shall develop a suitable method to determine the integrity of sterile filtration if standard methods typically employed are not suited to the specified candidate.

10. The contractor shall evaluate up to two freeze dried formulations of differing composition as non-GMP pilot batches.

11. The contractor shall carry out a short-term stability study for 1, 2, 3, and 6 months at three storage temperatures

(e.g., 25°C, 60% RH, 2-8°C and -20 °C). The effect of storage condition on assay, impurities, residual moisture, pH, reconstitution rate and appearance of freeze-dried product and reconstituted solution is to be evaluated at each stability pull point.

12. The contractor shall develop a placebo formulation of the drug substance and demonstrate its acceptability for manufacture. Offerors are to assume a 2 ml fill volume in a 10 ml, 20 mm vial.

13. Based on the data obtained in the development of the peptide drug product through the three-month stability time point, the contractor shall prepare a report summarizing the development work. The contractor shall propose to the COR the process to be used to manufacture the drug product, the quantitative composition of the dosage form, the rationale for selection of the formula and justification for final product specifications for moisture, pH and osmolality. The contractor shall also summarize the work that led to the development of the placebo formulation.

The stability data at 6 months on the trial formulations will be reported as an addendum to the development report.

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CMC Drug Product - Sample Task Order for Technical Area 2 (Peptides and Oligos)

GMP Manufacture of sterile freeze-dried dosage form of peptide and its placebo as clinical study materials

1. Following completion of dosage form development studies and analysis of the data, the contractor shall prepare master batch records for sterile freeze-dried dosage form of peptide and of its placebo utilizing the data generated in the dosage form development studies. These batch records will be submitted to the COR for review, comment and approval. Prior to manufacture of the drug products, the contractor shall release drug substance (assay, impurities and “as is” purity), excipients, packaging components and labels. The contractor is also responsible for carrying out “in process” testing to demonstrate content of API, pH, and osmolality prior to redundant sterile filtration. Integrity of the filtration process is to be demonstrated. Testing of the freeze-dried dosage form of peptide and of placebo is to be carried out according to the methods and specifications in Table 1 and Table 2, respectively.

2. For proposal purposes, the compounded batch size is 5 L for the active peptide formulation and 3 L for the placebo.

The fill volume is 2 ml/vial for both active peptide product and its placebo. Yield following inspection is expected to be 2000 vials for the peptide active and 1000 vials for the placebo.

3. The contractor shall carry out 100% inspection of the freeze-dried drug product(s), (peptide and placebo), label each container appropriately, and package for delivery following product release in two shipments to a clinical site designated by the COR. The active peptide product and placebo are to be labeled as to contents of each product.

Offerors are to assume that randomization and blinding will be done at the clinical site pharmacy. Coded labeling at the drug product manufacturing site is not anticipated.

Table 1. Specifications and quality control testing for sterile freeze-dried peptide drug product (Active)

Tests Specification Appearance of freeze-dried product Report result

Reconstitution Time (USP <1>) NMT 2 min

Completeness and clarity of solution Clear, colorless solution within 2 minutes after reconstitution

Identity by HPLC Retention time agrees with that of reference API

Uniformity of dosage units Meets requirements of current USP

Impurities Report % and RRT of all impurities ≥ LOQ

Strength Assay 92.0 – 108.0% of label - average of three vials

Particulate Matter (USP <788>) Meets requirements of current USP

Moisture (Karl Fisher) To be established after development work

Osmolality (freezing point depression) To be determined after development work pH To be established after development work

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Table 2. Specifications and quality control testing for sterile lyophilized dosage form (Placebo)

Stability Studies

The contractor shall carry out stability studies of active peptide freeze-dried product and of its placebo under ICH procedures. Test intervals are 1, 3, 6, 9, 12, 18, 24 and 36 months at 2-8 °C and at 1, 3, and 6 months at 25°C 60% RH. Stability testing is to consist of: appearance, assay and impurities and degradation products plus dissolution by HPLC-UV, pH, reconstitution rate and moisture. In addition, sterility and particulate matter testing are to be carried out on the samples stored at 2-8°C annually and bacterial endotoxin levels are to be determined at 36 months.

Other

Offerors shall indicate in their proposal if any tasks will be subcontracted, the organization that is intended to carry out the subcontracted work, the basis for their selection and the offeror’s audit history of the proposed subcontractor.

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

Sterility (USP <71>) Meets requirements of current USP (membrane method)

Bacterial Endotoxin (USP <85>) ≤ 7.5 EU/ml

Tests Specification Appearance of freeze-dried product Report result

Strength Assay Absence of active by HPLC assay

Particulate Matter (USP <788>) Meets requirements of current USP

Moisture (Karl Fisher) To be established after development work

Osmolality (freezing point depression) To be determined after development work pH To be established after development work

Sterility (USP <71>) Meets requirements of current USP (membrane method)

Bacterial Endotoxin (USP <85>) ≤ 7.5 EU/ml

5 | P a g e 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.

The following table contains a list of deliverables with notation of due dates. All days identified are intended to be normal business days unless otherwise specified. The Contractor may suggest an alternative due date for any or all deliverables in their offer. The final schedule will be agreed to by the COR and the Contractor based on the Contractor’s proposed delivery schedule.

G. 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. The Contractor may propose alternative 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 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

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• Subcontract Number (if required)

• Report Date

• Period Covered by the Report

• A comprehensive Summary of Work performed during the reporting period

1. Stability Indicating Method Development and Qualification Report

The Contractor shall deliver a report on the stability indicating methods used to assay the drug product. This report is due within 90 calendar days following the effective date of the TO.

2. Formulation Development Report

The Contractor shall deliver a Development Report on the formulation. This report must include a summary of the findings of the development work on the solubility study and formulation development. This report is due within 120 calendar days following the effective date of the TO.

3. Pilot Batch Report and Short-Term Stability Data

The most suitable formulations will be used for pilot batch production with a 6-month stability program. The data on the short-term stability of the formulations are due within 270 calendar days following the effective date of the TO.

4. Stability Protocol

The Contractor shall deliver a Stability Protocol. This document is due at least 15 calendar days prior to initiating the stability study.

5. Interim Stability Study Reports in CTD Format

Interim stability reports will be prepared after each sample pull. These reports should be completed within 30 working days of the sample pull and are to be of sufficient detail to include in a regulatory submission to the FDA.

6. Final Stability Study Report in CTD Format

The final stability report will be completed within 30 working days after the final sample pull and is to be of sufficient detail to include in a regulatory submission to the FDA.

7. Manufacture of a Clinical Batch of Lyophilized Drug Product

The Contractor shall manufacture not less than 2000 usable vials of lyophilized SPDC injectable product. The drug product shall be manufactured and documented according to cGMP criteria, all applicable institutional standard operating procedures, and the specifications described above as mutually agreed upon after completion of development/technology transfer work.

This task is to be completed within 330 calendar days following the effective date of the TO, or 60 days after exercise of the option, whichever is later.

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CMC Drug Product - Sample Task Order for Technical Area 2 (Peptides and Oligos)

8. Executed Batch Records Documentation in eCTD Format

All tasks conducted in support of release of the clinical batch of SPDC injectable product will be documented and provided to the Government within 60 days after manufacture. The Contractor’s Quality Assurance Department will issue a certificate of analysis/compliance confirming that the batch was manufactured under cGMP and that all deviations have been satisfactorily addressed.

9. 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.

Deliverable Delivery Due Date

Stability Indicating Method Development and Qualification Report

Electronically to CO & COR Within 90 calendar days of TO award

2 Formulation Development Report

Electronically to CO & COR Within 120 calendar days of TO award

3 Pilot Batch Report and Short- Term Stability Data

Electronically to CO & COR Within 270 calendar days of TO award

4 Stability Protocol Electronically to CO & COR

15 calendar days prior to initiating the stability study

5 Interim Stability Study Reports Electronically to CO & COR

Within 30 calendar days after each pull date

6 Final Stability Study Report Electronically to CO & COR

Within 30 calendar days after completion of the stability study

7 Manufacture of Clinical Batch As directed by the COR Within 330 calendar days of TO award

8 Executed Batch Records Electronically to CO & COR

Within 60 calendar days following the manufacture of the clinical batch

9 Final Report Electronically to CO & COR On or before expiration of the TO