Attachment6 - Sample TO_Area3_4.17.23 Biologics.pdf

1 | P a g e Department of Health and Human Services Acquisition Plan (AP) CMC Drug Product - Sample Task Order for Technical Area 3 (Biopharmaceuticals)

Contractor: TBD STO Title: Manufacture and stability studies of

NCATS-AAVx-001, an adeno associated virus (AAV)-based gene therapy candidate, for intravenous administration

Contract No.: TBD

NCATS Ref. No.: Contracted Technical Area(s): Technical Area 3

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

(Completion/Non-Severable)

STO 3 – 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 3 of the Statement of Work.

The task involves the development, of NCATS-AAVx-001, an AAV-based gene therapy vector intended for intravenous administration, for treatment of a rare, hereditary condition. The objective of this SOW is to conduct the chemistry, manufacturing, and controls (CMC) development and manufacturing tasks necessary to enable regulatory filing and clinical studies of NCATS-AAVx-001.

Task 1. Manufacture of NCATS-AAVx-001 to support preclinical and clinical studies

• Generate not less than 1E14 vg of lab scale (10L) NCATS-AAVx-001 material.

• Perform an engineering run to demonstrate the scalability of the process to generate material to support IND-enabling toxicology studies and clinical trials.

• Develop final formulation buffer for drug product that is compatible for clinical use.

• Develop and qualify payload-specific analytical methods for product release specifications and stability indication.

• Generate and release plasmid master cell banks for the gene of interest plasmid, Rep-Cap and AAV Helper plasmids.

• Generate not less than 2E15 vg of manufacturing scale (200L or greater) non-GMP material for toxicology

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CMC Drug Product - Sample Task Order for Technical Area 3 (Biopharmaceuticals) studies and reference standard using GMP grade raw materials. Develop and qualify all related release assays.

• Generate not less than 1.5E16 vg of cGMP material (100 vials at 1.5E14 vg/ml) for clinical studies using GMP-ready plasmids in a cGMP facility.

• Perform accelerated stability studies on the reference standard.

• Perform standard stability studies on the cGMP material up to 36 M under ICH procedures at 2-8oC, negative 20oC and negative 70oC.

• Provide all manufacturing related documentation for regulatory filings in eCTD format.

Task 2. Development and qualification of analytical methods and performance of release testing

Stage: End of cell culture

1. Bioburden (spread plate)

2. USP and EP mycoplasma culture with mycoplasmastasis

3. In vitro adventitious agents (28-day method) using MRC-5, Vero, and HEK293

Stage: Bulk Drug Substance

1. Genomic titer (gene-specific qPCR for release, ddPCR for FIO)

2. Capsid titer (ELISA)

3. Genome sequencing of viral product (Sanger or NGS; can be on BDS or DP)

4. Empty/full particles analysis (cryo-TEM)

5. Residual host cell protein (ELISA)

6. Residual host cell DNA (qPCR)

7. Residual benzonase (ELISA)

8. Residual E1A DNA (qPCR)

9. Residual plasmid DNA (qPCR against nptII and aphA1 kanamycin genes)

10. Residual Tween-20 (UV/Vis Spectrophotometry—QL is 0.02 mg/mL; HPLC is a possible option if greater sensitivity needed but would need to be qualified)

11. Residual PEI (HPLC)

12. Vector purity (SDS-PAGE and Silver Staining)

13. Endotoxin (LAL/chromogenic method)

14. Bioburden (spread plate)

15. Replication competent AAV (culture/qPCR; can be on BDS or DP)

Stage: Drug Product

1. Appearance (visual inspection)

2. Genomic titer (gene-specific qPCR for release, ddPCR for FIO)

3. Endotoxin (LAL/chromogenic method)

4. Vector purity (SDS-PAGE and Silver Staining)

5. Osmolality (USP <785>)

6. pH (USP <791>)

7. Subvisible particle analysis (USP <787> or USP <788> depending on how product is being delivered to patients)

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8. Sterility (USP <71> direct immersion method)

9. Bacteriostasis/fungistasis (USP <71>; must do as part of sterility—can substitute this test on final formulation buffer instead of sacrificing more drug product)

10. Aggregation

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.

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.

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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• 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. Assay Method Development and Qualification Report

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

2. Manufacture of a Clinical Batch of Drug Product

The Contractor shall deliver not less than 100 vials at 1.5E14 vg/ml, 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 due within 210 calendar days following the effective date of the TO.

3. Executed Batch Records Documentation in eCTD Format

All of the tasks conducted in support of release of the clinical batch will be documented. The contractor’s Quality Assurance Department will issue a certificate of analysis/compliance confirming that the batch was manufactured under cGMPs and all deviations have been satisfactorily addressed. This is to be provided within 30 calendar days following the manufacture of the clinical batch.

4. Characterization and Short-Term Stability Data

Characterization report and short-term stability study report are due within 60 days after all the components are available to begin the study.

5. Stability Protocol

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

6. 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.

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CMC Drug Product - Sample Task Order for Technical Area 3 (Biopharmaceuticals)

7. 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.

8. Out of Specification Report The Contractor shall notify the COR within 24 hours after any unexpected event that occurs during any planned activity. Investigation should be initiated in a reasonable time and Corrective Action and Preventive Action (CAPA) should be included in the OOS Report. The final report must be reviewed and approved within 7 days after the completion of the report.

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.

Study Deliverables and Reporting Requirements Item Description Delivery Delivery Schedule

1 Assay Method Development and Qualification Report

Electronically to CO & COR

Within 90 calendar days following the effective date of the TO

2 Manufacturing of Clinical Batch Electronically to CO & COR

Within 210 calendar days following the effective date of the TO

3 Executed Batch Records Documentation in CTD Format

Electronically to CO & COR

Within 30 calendar days following the manufacture of the plasmid injectable

4 Characterization and Short-Term Stability Study

Electronically to CO & COR

Within 60 calendar days following all the components are available for testing

5 Stability Protocol Electronically to CO & COR

15 calendar days prior to initiating the stability study

6 Interim Stability Study Reports in CTD format

Electronically to CO & COR

Within 30 calendar days after each pull date

7 Final Stability Study Report in CTD format

Electronically to CO & COR

Within 30 calendar days after completion of the stability study

8 Out of Specification Report Electronically to CO & COR

Notification within 24 hours, and final report with 7 days after completion of CAPA

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