Att1-SOW_NOI_75N91024Q00089.pdf

STATEMENT OF WORK

1.0 TITLE

Acquisition of Services for the Manufacture of Clinical Grade Lentiviral Vector Encoding

GPC2-CAR

2.0 BACKGROUND

The Laboratory of Molecular Biology (LMB) and the Pediatric Oncology Branch (POB) at the National Institutes of Health (NIH), National Cancer Institute (NCI), Center for Cancer Research (CCR), require services for the production and subsequent stability testing of Good Manufacturing Practice (GMP) grade lentiviral (LV) vector, pWPT-CT3-EGFRt.

Neuroblastoma accounts for 8–10% of all childhood cancers and 15% of all pediatric cancer mortality. Glypican-2 (GPC2) is a cell surface protein that is expressed in nearly half of neuroblastoma cases. High GPC2 expression correlates with poor overall survival. It modulates N-myc, an oncogenic driver of neuroblatoma tumorigenesis, through Wnt signaling. Thus, GPC2 is a promising target for adoptive T-cell therapy. In this approach, T cells are taken from the patient, engineered in the laboratory into chimeric antigen receptor- (CAR-) T cells, and reapplied to the patient to fight cancer cells.

The manufactured product under this acquisition will be used to engineer T-cells of neuroblastoma patients into CAR-T cells with the ability to specifically target GPC2-expressing tumor cells. Ultimately, this product will be used in a phase I clinical trial in the Pediatric Oncology Branch at NCI under IRB001812 entitled Phase I/II Study Glypican-2–targeted Autologous Genetically Modified CT3.CD28HTM.BBζ Chimeric Antigen Receptor (GPC2CAR)- T-cell Therapy in Children and Young Adults with Recurrent or Refractory Neuroblastoma. The protocol is being submitted to the Office of Sponsor and Regulatory Oversight (OSRO)) for review and in preparation for the Investigational New Drug Application (IND) package for submission to the Federal Drug Administration (FDA).

3.0 SCOPE

This acquisition includes services to prepare cGMP (clinical) grade transfer plasmid from a transfer plasmid provided by the Government; to obtain one (1) batch of purified, GMP grade lentiviral vector, of 250 ml in total; and to perform stability studies on the lentiviral vector product.

Note: The CCR prepared and validated the transfer plasmid pWPT-CT3-EGFRt, which also acts as lentiviral vector.

4.0 CONTRACT REQUIREMENTS

Independently and not as an agent of the Government, the Contractor shall provide all labor, materials, and equipment required to perform the following tasks:

1. Task #1, Production and Product Release:

a. The Contractor shall use the Government’s construct pWPT-CT3-EGFRt as transfer plasmid and for lentiviral vector production.

b. The turn-around time shall be no more than six (6) months from the date of award.

c. The clinical grade product shall be manufactured in full compliance with FDA cGMP regulations.

d. Staff must by highly trained and experienced in cGMP manufacturing.

e. Staff must use Quality-Assurance issued Batch Records.

f. cGMP manufacturing must take place inside ISO Class 7 cleanrooms.

g. Personnel training, Quality Assurance, and document management compliance shall be managed through a validated electronic Quality Management System.

h. The vector used for manufacture must be generated in HEK-293T cells from a certified Master Cell Bank and Working Cell Bank (MWCB).

i. The Fetal Bovine Serum (FBS) supplement in the Dulbecco’s Modified Eagle Medium (DMEM) must originate from the USA or from Canada.

j. Residual DNA in the product must be digested with Benzonase, and the product must be further purified using anion exchange membrane chromatography, concentrated, and diafiltered.

k. NCI will determine the final product formulation buffer.

2. Task #2, Stability Testing:

Stability testing shall be in accordance with the Guidance for Industry, “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)”, published by the FDA in January 2020.

a. Environmental factors shall include environmental factors (temperature, humidity, light) and product-related factors (packaging materials, container, expidients).

b. Storage and testing shall be performed under GMP conditions.

c. Samples shall be stored in appropriate, monitored environmental chambers.

d. Sample analysis shall be done under actual storage conditions.

e. The stability data must meet the requirements for compliance to:

i. 21 Code of Federal Regulations (CFR) 207.1, 207.3, 210.3(b)(7), 210.3, 211.166, 312.23;

ii. International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q1A (R2) - Stability Testing of New Drug Substances and Drug Products;

iii. ICH Q1B, Photostability Testing of New Drug Substances and Drug Products;

iv. ICH Q1C, Stability Testing for New Dosage Forms;

v. ICH Q1E, Evaluation for Stability Data;

vi. ICH Q3A, Impurities in New Drug Substances;

vii. ICH Q5C, Stability Testing of Biotechnological/Biological Products;

viii. ICH Q6A, Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances;

ix. ICH Q6B, Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Biotechnological/Biological Products;

x. ICH Q7, Good Manufacturing Practice for Active Pharmaceutical Ingredients;

xi. ICH Annex 10, Stability testing of active pharmaceutical ingredients and finished pharmaceutical products.

5.0 TASK #1: PRODUCTION AND PRODUCT RELEASE

1. Within ten (10) business days of award, the Contractor shall begin with the manufacture of GMP grade transfer plasmid from the Government’s transfer plasmid pWPT-CT3- EGFRt. The amounts shall be sufficient for the production of the lentiviral vector, see below.

2. Upon completion, the Contractor shall notify the Contracting Officer’s Representative (COR) and COR Alternate; and provide the Certificate of Analysis for the GMP-grade pWPT-CT3-EGFRt transfer plasmid.

3. The Contractor shall manufacture a minimum of 250 ml concentrated, GMP grade pWPT-CT3-EGFRt lentiviral vector (LV).

4. The Contractor shall test the pWPT-CT3-EGFRt LV product for GMP compliance.

5. The Contractor shall ship the product (pWPT-CT3-EGFRt lentiviral vector), as 0.5 ml aliquotes, on dry ice, in one (1) shipment, to the Center for Cellular Engineering (address provided in Section 10.0 below), together with the Certificate of Testing (see table below).

6. The Contractor shall provide electronic versions of the Certificate of Testing to the COR and the COR Alternate.

The Certificate of Testing for the released GMP pWPT-CT3-EGFRt LV product shall include:

Test Method Sequence identification / confirmation Sanger sequencing (100% match)

Appearance Inspection for visible particulates Bovine serum albumin (BSA) Immunoassay (report results)

Residual benzonase Immunoassay (<100 ng/mL)

Isolator sterility Direct inoculation (to be free from viable bacterial and fungal contamination within 14 days)

Suitability of isolator sterility method Direct inoculation (to be free from viable bacterial and fungal contamination within 14 days) pH pH measurement (pH 7.0 – 7.5)

Residual host cell DNA and SV40 Quantitative polymerase chain reaction (qPCR)

(report results) Residual plasmid DNA qPCR (report results)

Viruses 28 day in vitro virus assay on three cell lines

(report results)

Replication-Competent Lentivirus (RCL) C8166 detector cell-line for both supernatant and cells (RCL not detected)

Amebocytes Limulus Amebocyte Lysate (LAL) assay, quantitative chromogenic method

Mycoplasma Agar cultivation in accordance with

USP/EP/PTC/JP requirements

Mycoplasma Non-Agar cultivation in accordance with USP, EP, and 1993 PTC requirements Physical titer

(lentiviral coat protein p24) Enzyme-linked immunosorbent assay (ELISA)

(report results) Infectious titer qPCR (report results)

6.0 TASK #2: PRODUCT STABILITY TESTING

1. The Contractor shall conduct product stability studies on the GMP pWPT-CT3-EGFRt LV product at the following time points after production release:

3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 36 months, and 48 months.

2. At each time point, the Contractor shall test the product for sterility, endotoxins, and potency; its p24 physical titer by ELISA; for its infectious titer by qPCR; and for product identity.

3. The Contractor shall provide a final GMP pWPT-CT3-EGFRt lentivirus stability report;

which shall include storage conditions, test methods, all test results, deviations from the protocol, unexpected results, and bilateral amendments to the protocol.

7.0 TYPE OF ORDER

This shall be a firm fixed-price purchase order.

8.0 PERIOD OF PERFORMANCE

The estimated Period of Performance shall be 9/1/1024 – 8/31/2029.

9.0 PLACE OF PERFORMANCE

All work shall be performed at the Contractor’s facilities.

10.0 REPORTS/DELIVERABLES AND DELIVERY SCHEDULE

The Contractor shall provide an estimated delivery timeframe for the final GMP grade lentiviral product, give immediate notice upon setbacks that may impact this timeframe, and provide tracking information to anticipate delivery to the best extent possible.

The final GMP grade lentiviral product shall be delivered to:

(Address TBD upon award)

Deliverable Description Due Date

Certificate of Analysis for GMP transfer plasmid

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within 10 weeks of award

GMP grade vector supernatant

One batch of 60 Liter of viral vector will be concentrated to a final product volume of 250 mL GMP grade lentiviral vector supernatant

(pWPT-CT3-EGFRt); to be delivered on dry ice to the Center for Cellular Engineering at the

NIH Clinical Center; as 0.5 ml aliquots (n=500).

Within six (6) months of award

Certificate of Testing for GMP grade vector supernatant

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within six (6) months of award

Stability test result #1

T=3M GMP Lentivirus Stability Test Result.

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within four (4) months of GMP LV production

Stability test result #2

T=6M GMP Lentivirus Stability Test Result.

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within seven (7) months of GMP LV production

Stability test result #3

T=9M GMP Lentivirus Stability Test Result.

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within ten (10) months of GMP LV production

Stability test result #4

T=12M GMP Lentivirus Stability Test Result.

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within thirteen (13) months of GMP LV production

Stability test result #5

T=18M GMP Lentivirus Stability Test Result.

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within nineteen (19) months GMP of LV production

Stability test result #6

T=24M GMP Lentivirus Stability Test Result.

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within twenty-five (25) months of GMP LV production

Stability test result #7

T=36M GMP Lentivirus Stability Test Result.

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within thirty-seven (37) months of GMP LV production

Stability test result #8

T=48M GMP Lentivirus Stability Test Result.

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within forty-nine (49) months of GMP LV production

Final GMP Lentivirus Stability Report

Final GMP Lentivirus Stability Study Report.

Comprehensive overview; to include storage conditions, test methods, all test results, deviations from the protocol, unexpected results, and bilateral amendments to the protocol.

To be delivered by email as electronic PDF file to the COR and the COR Alternate.

Within forty-nine (49) months of production

11.0 CONTRACTING OFFICER’S REPRESENTATIVE

The Contracting Officer’s Representative (COR) will serve as the Governments primary point of contact for coordination of all required efforts covered under the scope of the purchase order. Additionally, all services shall be delivered to the COR for final inspection and acceptance upon completion. All deliverables will have been deemed accepted fifteen

(15) calendar days after date of delivery, except as otherwise specified in this purchase order if written approval or disapproval has not been given within such period.

The following individual shall be the Contracting Officer’s Representative (COR) for this purchase order:

Name: TBD Upon award Email:

Phone:

The COR Alternate is:

Name: TBD Upon award Email:

Phone:

The COR role is limited to the authorities specified herein. The COR does not have the authority to issue directions that:

1) Constitutes a change of assignment or additional work outside the statement of work;

2) Constitutes a change as defined in clause 52.212-4 (c) "Changes";

3) In any manner causes an increase or decrease in the purchase order price, or the time required for performance.

4) Changes any of the terms, conditions, or requirements of the purchase order;

5) Interferes with the Contractor's right to perform under the terms and conditions of the purchase order; or

6) Directs, supervises, or otherwise controls the actions of the Contractor's employees.

If at any time the Contractor feels that such direction listed above has been given, they must contact the Contracting Officer immediately.

12.0 INSPECTION AND ACCEPTANCE

Pursuant to FAR clause 52.212-4, all work described in the SOW to be delivered under this purchase order is subject to final inspection and acceptance by an authorized representative of the Government. The authorized representative of the Government is the NCI Contracting Officer’s Representative (COR) who is responsible for inspection and acceptance of all services, materials, or supplies to be provided by the Contractor.

Regardless of format, all digital content or communications materials produced as a deliverable under this purchase order, shall conform to HHSAR 352.239-79 Information and

Communication Technology Accessibility (FEB 2024) (Deviation). See attached terms and conditions for additional details.

All written drafts and final deliverable products shall be submitted as an electronic copy in draft format for review, comment, and approval by the COR. Final copies of approved drafts shall be delivered to the COR within 3 business days after receipt of the Government’s comments. If requested, final deliverable products shall be submitted in an electronic format. Other quantities and formats may be submitted after prior approval from the COR. All deliverables shall be sent electronically as; Microsoft Excel 2013, Microsoft Excel, or Adobe Portable Document Format (PFD), unless otherwise approved by the COR.

The NIH shall have 30 days in which to review and accept the deliverables provided by the Contractor. If no comments or request for revisions are provided within 30 days, the deliverables shall be considered acceptable.

13.0 PAYMENT SCHEDULE

Payment shall be made in accordance with the payment schedule below:

Item Description Price

1 Shall be invoiced in full upon delivery/acceptance of Certificate of Analysis for the clinical grade transfer plasmid (pWPT-CT3-EGFRt) by the Government.

2 Shall be invoiced in full upon completion of GMP lentiviral production (pWPT-CT3-EGFRt), product release testing, product shipment, product acceptance, and Certificate of Analysis delivery/acceptance by the Government.

3 Shall be invoiced in full upon delivery/acceptance of the 3M stability test results of the pWPT-CT3-EGFRt LV product by the Government.

4 Shall be invoiced in full upon delivery/acceptance of the 6M stability

5 Shall be invoiced in full upon delivery/acceptance of the 9M stability

6 Shall be invoiced in full upon delivery/acceptance of the 12M stability test results of the pWPT-CT3-EGFRt LV product by the

Government.

7 Shall be invoiced in full upon delivery/acceptance of the 18M

8 Shall be invoiced in full upon delivery/acceptance of the 24M

9 Shall be invoiced in full upon delivery/acceptance of the 36M

10 Shall be invoiced in full upon delivery/acceptance of the 48M stability test results of the pWPT-CT3-EGFRt LV product and the

Final Stability Report by the Government.

Grand Total: