Attachment4 - Sample TO_Area1_Small Molecule 4.17.23.pdf

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

CMC Drug Product -Sample Task Order for Technical Area 1 (Small Molecule)

Contractor: TBD STO Title: Development, manufacturing and stability studies of a non-sterile dosage form of Compound 310 (small molecule)

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: 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 1 of the Statement of Work.

The task involves the development, manufacture and stability studies of an immediate release capsule formulation of an antifungal agent (molecular weight – 310) 40 mg and 320 mg/capsule plus a placebo.

Formulation Development of Compound 310 as 40 mg and 320 mg capsules and a 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 drug product. Forced degradation studies shall be performed under acid, base, oxidation, heat and light. Offerors are to evaluate at a minimum for: system suitability, linearity (50-150% of injection concentration), accuracy, precision, limits of detection, and limits of quantitation.

2. The contractor shall carry out excipient compatibility studies with the drug substance. Offerors are to evaluate up to 10 excipients (at least 2 from the following categories: bulking agents, lubricants, disintegrants, and glidants. Three powder blend formulas are also to be included. The active pharmaceutical ingredient (API) itself and API in a capsule are to be used as controls. Studies are to be carried out at 50 °C, 40 °C/75% RH and 25°C/60% RH at 0, 2, 4, 8 and 12 weeks for assay and impurities. Offerors are to propose the weight ratio of API to excipient to be evaluated as well as any other parameters to be studied.

3. The contractor shall develop a suitable dissolution test for the drug substance in the drug product using USP apparatus II including the selection of dissolution media and stability of the formulation in the media. Offerors are to assume the solubility of compound 310 is ≥ 1 mg/ml. A validated dissolution test method will be used as a release test and on stability study.

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4. The contractor shall develop manufacturing processes for each of two capsule formulations at two strengths based on data from the excipient compatibility studies as non-GMP pilot batches. Each batch (total of four, excluding placebo) is to yield about 300 capsules. Prior to filling drug product formulas into capsules the contractor is to demonstrate that the powder blend is uniform. For evaluation purposes the offeror is to assume product strengths will be 40 and 320 mg/capsule. Offerors are to assume that the drug substance will not require particle size reduction or modification of bulk density.

5. The contractor shall carry out short term stability studies at a minimum of two temperature/humidity conditions over 6 months (0, 1, 2, 3 and 6 months) (total four capsule products). At a minimum, products are to be tested for assay, impurities, appearance and dissolution.

6. The contactor shall develop a placebo formulation of the drug product including preparation of a placebo batch and evaluation by the HPLC method for absence of active.

7. The contractor shall develop a method to assess cleaning of multiple-use equipment used in manufacture of drug product. For proposal purposes, offerors are to assume three different surfaces are to be evaluated using the swab recovery approach.

8. Within one month after data are obtained on the two trial formulation compositions (both strengths) at 3 months of stability testing, the contractor shall provide a report of the work carried out to develop the drug products and the manufacturing process. The report is to include data obtained in: 1) excipient compatibility study, 2) manufacturing process development, 3) stability studies on the drug products through 3 months, 4) composition of and manufacturing process for the placebo formulation and 5) cleaning assessment of surfaces representative of all product contact equipment proposed for use in the manufacturing process. The contractor shall draft the dissolution method and provide that document to the COR as an attachment to the development report. Based on the data obtained in the development of the drug product, the contractor shall propose to the COR the drug products to be manufactured, the quantitative composition of the formula and the rationale for selection of the formula(s). The stability data at 6 months on the trial formulations will be reported as an addendum to the development report.

GMP Manufacture of Compound 310 at 40 mg/capsule and 320 mg/capsule and a placebo formulation 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 active drug products (two strengths) and the 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. If requested by the COR, the contractor may also propose specifications for the drug products and the placebo. 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 all “in process” testing to demonstrate blend uniformity and control of capsule fill weight.

Testing of both strengths of final product (assay, impurities, uniformity of dosage units, appearance and dissolution) and of placebo formulations (absence of active ingredient and appearance) is to be carried out according to tests and specifications in Table 1 and Table 2, respectively.

2. For proposal purposes, offerors are to assume batch sizes of 2400 each of capsules of 310: 40 mg/capsule, 320

3 | P a g e mg/capsule and of placebo. Contractor is responsible for release testing of drug products and placebo, packaging capsules with a desiccant pack in child-proof, tamper evident, high density polypropylene container and labeling of the packaged drug products. Batches of active and placebo formulations will be labeled as to contents. Randomization will be performed at the clinical site pharmacy. Coded labeling at the drug product manufacturing site is not requested.

Table 1: Representative tests and specifications for solid oral dosage forms (Active)

Table 2. Representative tests and specifications for solid oral dosage forms (Placebo)

Tests Specification Appearance of intact dosage form Report result

Identity by HPLC retention time is within 3% of a reference lot of API

Uniformity of dosage units meets requirements of current USP

Strength Assay (HPLC-UV) 92.0 – 108.0% of label – assay of composite of twenty dosage units

Impurities (individual) report % and RRT of each impurity ≥ LOQ not in placebo

Dissolution USP <711> apparatus II mean not less than 70% at 30 minutes (n=6), plus report results at 15, 45, and 60 min

Microbial enumeration USP <61> TAMC <10E3 cfu/g, TYMC <10E2 cfu/g

Specific Organism USP <62> Absence of E. coli

Moisture content USP <921> Report value

Tests Specification Appearance of intact dosage form Report result

Appearance of contents of dosage form Report result

Assay Absence of active by HPLC/UV method

Microbial enumeration USP <61> TAMC <10E3 cfu/g, TYMC <10E2 cfu/g

Specific Organism USP <62> Absence of E. coli

Uniformity of dosage units by weight Meets requirements of current USP

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Stability Studies

The contractor shall carry out stability studies of compound 310, 40 mg/capsule and 320 mg/capsule and of placebo capsules under ICH procedures. Stability studies are to be initiated soon after drug manufacture to ensure that final product testing can be used for the zero time stability time point. Test intervals are 1, 3, 6, 9, 12, 18, 24 and 36 months at 25°/60% relative humidity (RH); 1, 3, 6, 9 and 12 months at 30°C/65% RH; and 1, 3, and 6 months at 40°C/75% RH. Stability testing is to consist of: appearance, assay and impurities/degradation products plus dissolution by HPLC-UV for compound 310. Placebo capsules are to be evaluated for appearance at each time point.

In addition, microbial testing (USP <61> and <62>) is to be carried out on the samples stored at 25°C/60% RH annually.

Other

Offerors are to 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 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.

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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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

• 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 in capsules. 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

6 | P a g e 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

The Contractor shall manufacture not less than 2400 capsules of each strength of drug product and placebo. 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.

8. Executed Batch Records Documentation in eCTD Format

All tasks conducted in support of release of the clinical batch 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 Within 30 calendar days after

7 | P a g e to CO & COR 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