Attachment 1- Statement of Requirement.pdf

STATEMENT OF REQUIREMENT

TITLE: Manufacturing of a Monoclonal Antibody Reference Material from NISTCHO

Cell Line

LAB REQUESTING SERVICE: Material Measurement Laboratory, Biomolecular

Measurement Division, Biomolecular Structure and Function Group

I. BACKGROUND INFORMATION

The Biomolecular Structure and Function (BSF) group in the Biomolecular Measurement Division of the Materials Measurement Laboratory at the National Institute of Standards and Technology

(NIST) (1) advances novel measurement methods and models for the determination and analysis of the structure and function of biological macromolecules, including lipids, deoxyribonucleic acid

(DNA), ribonucleic acid (RNA), and proteins and macromolecular complexes and assemblies formed by these molecules; (2) advances methods to determine the physical and chemical factors which determine the specific interactions of macromolecules with cofactors and ligands; (3) studies the relationships between biomolecule structure, dynamics, function, and energetics using computational, biophysical and biochemical techniques; (4) develops reference databases for these properties; and (5) advances measurement methods for engineering complex biological systems.

The BSF group intends to develop a monoclonal antibody expressed from the National Institute of Standards and Technology Chinese Hamster Ovary (NISTCHO) reference cell line as a NIST

Reference Material (NIST RM). The material is intended to be highly representative of Chinese

Hamster Ovary (CHO)-expressed monoclonal antibodies used as biopharmaceuticals. This reference material is planned to be a companion molecule to both the NISTmAb (RM 8671) monoclonal antibody reference material (reference product) and the NISTCHO (RM 8675) cell line reference material (non-originator expressing cell line). As such, the BSF group intends to contract the manufacturing of a monoclonal antibody expressed from the NISTCHO cell to an organization capable of performing such manufacture and characterization to include key features of GMP (Good Manufacturing Practice) manufacturing to enable a comparable production process and similar quality attributes (commonly referred to as “GMP-like”). This material will be released with quantitative data traceable to fundamental units of measurement and is expected to be utilized as a system suitability tool in the biopharmaceutical industry.

II. SPECIFICATIONS

General Qualifications of the Manufacturer

Contractor shall have experience with manufacturing large quantities (minimum 200L scale) of biopharmaceutical products such as monoclonal antibodies from CHO cell lines.

The contract manufacturer’s platform shall contain production unit operations and process controls representative of biopharmaceutical production.

The Contractor’s manufacturing workflow is not required to be GMP, however, it must incorporate key features of GMP manufacturing to enable a comparable production process and similar quality attributes to include:

- Document Management and Traceability

- Raw Material Sourcing

- Manufacturing Process

NIST Contracting Officer’s Representative (COR), Subject Matter Expert (SME), and NIST authorized personnel shall visit the Contractor’s site after award of contract and prior or at the start of production to observe product/process conformance.

Kick-off Meeting

The contractor shall attend a kick-off meeting, via phone or video conference, no later than 10 calendar days after award of the contract. The NIST SME, COR, and other authorized NIST personnel shall be in attendance. The Contractor’s team (project manager, chief scientist and/or technical lead, additional personnel suggested by Contractor) must be present. The meeting will be utilized to review all contract requirements and deliverables.

Status Meetings and Reports

The Contractor shall participate in status meetings on a reoccurring basis (minimum bi-weekly) to obtain updates on Contractor progress for contract deliverables.

During these meetings, the Contractor shall advise the SME and COR of any anticipated problems or issues that may have arisen or may further delay receipt of the product. Status meetings shall be conducted via conference call.

Status meetings will include recent project developments and if any issues were encountered, a list of corrective actions taken.

A summary report of each status meeting shall be prepared by the Contractor and submitted to the COR within 7 calendar days of each meeting.

Step One: Replicate NIST Process at Lab Scale (Pilot Run)

The NIST BSF group or the storage facility responsible for storage of the Master Cell Bank

(MCB) material shall provide cells from the MCB to the Contractor within 30 calendar days of the kick-off meeting. The NIST Contracting Officer’s Representative (COR) shall notify the

Contractor at least 14 calendar days prior to shipment of the MCB to the Contractor. The COR shall also provide documented MCB media requirements, manipulation protocols, to the

Contractor within 30 calendar days of the kick-off meeting. The Contractor shall agree to use the MCB and its product for only the scope of work governed by this contract. The Contractor shall agree not to grant material access to the MCB, its product, or any documentation concerning the MCB or its product to any party other than those parties listed in this contract, a

Subcontractor engaged to perform activities within the Scope of Work described herein, or a party declared to the Contractor by the COR.

- After award, the Contractor shall accept into their facility the NISTCHO cell line in the form of a Master Cell Bank (MCB) provided by the NIST BSF group or by the storage facility responsible for storage of the MCB material.

- The Contractor shall accept the MCB on the basis of documentation showing that

NISTCHO has been developed using processes free of animal-derived cell culture and/or media components.

- After award, NIST shall deliver their current batch bioprocess (2L bioprocess) to the

Contractor including technical protocols as outlined in Appendix A.

- Contractor shall initiate replicate(s) bioreactor run at lab scale within 60 calendar days of protocol/document delivery from NIST. Run shall incorporate all salient features of the

NIST-delivered or equivalent baseline process for monoclonal antibody manufacturing.

- Contractor may propose lab scale process as alternative to NIST-delivered process. NIST will review process and NIST COR will provide email confirmation of acceptance of procedure prior to initiation of the run.

- NIST will provide supplementary information for the NIST-delivered process as outlined in Appendix A. The Contractor shall collect measurements a minimum of every 24 hours once cells have been revived.

- Contractor shall review and deliver documentation for specifications outlined above with

NIST in status meeting(s) before progression to part B is approved.

- Contractor shall have no more than two attempts to successfully complete and demonstrate replication of pilot run. If unable to successfully replicate the pilot run within two attempts, the contract will be terminated.

- Contractor shall deliver materials to NIST for testing at the completion of the run for evaluation of product quality and attributes as described in Appendix B. Delivery shall be

FOB DESTINATION. Material shall be delivered to NIST on dry ice. Material shall remain frozen and packed with sufficient dry ice to maintain a frozen state throughout shipment. Material must be received frozen and temperature shall be monitored throughout shipment process.

- Contractor shall deliver all product material to NIST upon completion of run or provide documentation material was successfully destroyed, whichever is agreed upon by NIST

COR and Contractor.

- Deliverable: Pilot run must meet or exceed performance acceptable ranges (PAR) outlined in Appendix A/B before transitioning to step 2 of Statement of Requirement.

- Deliverable: Copies of reports and documentation for pilot manufacturing process and acceptable performance ranges from pilot run (electronic pdf document) within 10 calendar days of completion of run.

Step Two: Scale-Up and Production

- Upon completion of Part A and approval by COR, Contractor shall perform scale-up of the lab scale process to a pilot scale process of no less than 200L volumetric capacity.

- Contractor shall perform bioreactor run(s) to meet an equivalent volume of no less than

1000L capacity. If the government determines it necessary, replicate bioreactor runs may be performed (i.e. 2 x 500L, or 5 x 200L)

- Minimally acceptable batch conditions include:

o If multiple production runs are required, each batch shall be frozen at 100 mg/ml

± 5 mg/mL in specified formulation buffer o Contractor shall deliver retain materials to NIST for testing at the completion each run for evaluation and demonstration of product quality attributes as outlined in

Appendix B.

o NIST will evaluate within 30 calendar days of receipt of material and provide acceptance on batches for final homogenization. Any batches that do not receive government acceptance shall be excluded from the final homogenization.

- Each government accepted batch shall be frozen and stored at -80 degrees C at the

Contractor’s site until manufacturing of all batches is complete. Contractor shall be responsible for maintaining and monitoring the temperature of the storage units until approval by the COR for proceeding to step three.

- Contractor shall have no more than two attempts to successfully complete each batch run.

Contractor shall deliver all product material to NIST upon completion of run or provide documentation material was successfully destroyed, whichever is agreed upon by NIST

COR and Contractor.

- Deliverable: Retains (minimum 1 milliliter volume, concentration 100 mg/mL ± 5 mg/mL) of each batch shall be provided to NIST within 10 calendar days of the completion of each run for evaluation of product quality attributes as outlined in

Appendix B. Delivery shall be FOB DESTINATION. Material shall be delivered to NIST on dry ice. Material shall remain frozen and packed with sufficient dry ice to maintain a frozen state throughout shipment. Material must be received frozen and temperature shall be monitored throughout shipment process.

- Deliverable: Copies of reports and documentation for each batch manufacturing process and acceptable performance ranges from each batch run (electronic pdf document) within

10 calendar days of completion of each run (if applicable).

Step Three: Homogenization of Contractor Produced Batches (If applicable)

- If the Contractor produces multiple batches of monoclonal antibody, the Contractor shall produce a “homogenized bulk” material using all previously produced frozen batches that received government acceptance.

- The homogenized bulk concentration shall be 100 mg/mL ± 5 mg/mL

- Concentration pre- and post-homogenization shall be determined by UV-VIS absorption.

Absorbance readings along with standard deviation for concentration determination shall be reported.

- The Homogenous Bulk shall be dispensed into 1 L containers, with each containing 800

±10 mL of Homogeneous Bulk.

- The Contractor shall store the 1L containers frozen at -80 degrees C and remain at -80 degrees C until delivery to NIST.

- A maximum of one thaw/freeze cycle shall be used for the Homogenized Bulk material.

Undue mechanical stress (stirring and agitation) should be minimized in order to reduce risk of aggregation or other product related attributes.

- Thaw of material shall be performed at no greater than 25 degrees C (room temperature) and the material shall not exceed a temperature above 30 degrees C at any time. The time from thaw to refreeze in homogenized bulk should be less than 48 hours, and no additional freeze/thaw may be performed.

- Contractor shall deliver sample material to NIST for testing at the completion of the homogenization protocol for evaluation of product quality attributes as outline in

Appendix B.

- The 1L frozen containers shall be delivered to NIST on dry ice. Material shall remain frozen and packed with sufficient dry ice to maintain a frozen state throughout shipment.

Material must be received frozen and temperature shall be monitored throughout shipment process.

- 1L homogenized bulk containers shall be affixed with a label appropriate for cold storage at -80 degrees C in a formatted template provided by NIST.

- Deliverable: One (1) homogenized bulk sample (minimum 1 milliliter volume, concentration 100 mg/mL ± 10 mg/mL) shall be delivered to NIST within 10 calendar days of the completion of the homogenization run for evaluation of product quality attributes as outlined in Appendix B

- Deliverable: Labeled Homogenized bulk containers containing monoclonal antibody filled at 800mL (± 10). Delivery shall be FOB DESTINATION.

- Deliverable: Copies of reports and documentation for the homogenization process

(electronic pdf document) within 10 calendar days of completion of the process (if applicable).

III. Final Product SPECIFICATIONS

Requirements for the Performance of the Statement of Requirement

1. The Contractor shall deliver an electronic PDF document to the COR/SME that is a compiled report of analysis for the pilot and scale up run(s) to include batch records and performance acceptable ranges as outlined in Appendix A/B.

Acceptance by the Government of the monoclonal antibody homogenized bulk material

2. The Contractor shall deliver retains of each batch for evaluation of product quality by NIST.

Product quality must meet the specifications provided by NIST and outlined in Appendix B.

3. Contractor shall deliver an electronic PDF document to the COR that is a compiled report of analysis for each batch of monoclonal antibody product, within 30 calendar days after the completion of each batch.

4. The Contractor shall deliver a sample from the homogenized bulk material for evaluation of product quality to NIST within 10 calendar days after the completion of the homogenization protocol. Product quality must meet specifications provided by NIST and outlined in

Appendix B.

5. Contractor shall deliver an electronic PDF document to the COR that is a compiled report of analysis for the homogenized bulk material within 30 calendar days of protocol completion.

Delivery of Materials and Documentation from the Contractor to NIST

6. Contractor shall deliver the homogenized monoclonal antibody at a nominal net weight of one kilogram. The minimum acceptable weight is 850 grams and contractor is not restricted on product maximum weight.

7. The Contractor shall arrange for appropriate transportation and/or shipping of the labeled monoclonal antibody homogenized bulk 1L containers, which maintains the units under appropriate dry ice storage conditions (≤ -80 °C), to the NIST Office of Reference Materials

(ORM). The Contractor will maintain responsibility for the quality of the monoclonal antibody homogenized bulk units. Acceptance will occur by NIST after inspection to include (package integrity, temperature stability, etc.)

8. The contractor shall notify NIST at least 48 hours prior to shipment of bulk material to NIST.

9. The Contractor shall deliver, as (an) electronic PDF document(s), to the COR that is a compiled report of analysis of the homogenized bulk units upon shipment to NIST.

10. All homogenized bulk monoclonal antibody deliverable units will be delivered to the NIST

Office of Reference Materials storage facility with mailing/delivery address of Office of

Reference Materials, NIST, 100 Bureau Drive, Gaithersburg, MD 20899. Delivery shall take place on Tuesday, Wednesday or Thursday between 8:30 a.m. to 4:00 p.m. EST.

IV. PERIOD OF PERFORMANCE

The period of performance shall be 18 months from date of award.

V. GOVERNMENT FURNISHED PROPERTY

The NIST Biomolecular Structure and Function Group will provide the Contractor with the Master

Cell Bank (MCB) comprised of up to ten (10) vials, as described in the specifications. The MCB will be conveyed directly to the Contractor from Eurofins Lancaster Laboratories, 2430 New

Holland Pike Suite C100, Lancaster PA, 17601. The COR will provide documentation as to

NISTCHO media requirements and protocols as outlined in Appendix A and B within 30 calendar days of the kickoff meeting. The COR will also provide, as an electronic document, the design of the labels to be applied to the homogenized bulk units as described in the Specifications.

VI. DELIVERABLES

Description Quantity Due Date

Progress reports from status meetings x

(x = total # of status meetings)

Every two (2) weeks starting from date of award.

Description Quantity Due Date

Step One, deliverable 1: Completion of pilot run(s) using NIST delivered or equivalent baseline process. Demonstrated acceptable performance and quality attribute ranges provided by NIST

1 Within 14 calendar days of completion of run and per contract period of performance

Step One, deliverable 2: Copies of reports and documentation for acceptable performance and quality attribute ranges from pilot run (electronic pdf document)

1 Within 30 calendar days of completion of run and per contract period of performance

Step Two, deliverable 1: Scale-Up and production retains provided to NIST for each batch (if applicable). Retains demonstrate performance acceptable and quality attribute ranges that meet or exceed

NIST historical knowledge

X

(x = # of batches)

Within 14 calendar days of completion of run and per contract period of performance

Step Two, deliverable 2: Copies of reports and documentation for performance acceptable and quality attribute ranges from scale up and production batch(s)

(electronic pdf document)

X

(x = # of batches)

Within 30 calendar days of completion of run and per contract period of performance

Step Three, deliverable 1: Homogenized bulk retains demonstrating quality attribute ranges

X

(x = TBD # of containers)

Within 14 calendar days of completion of run and per contract period of performance Step Three, deliverable 2: Labeled

Homogenized bulk containers containing monoclonal antibody filled at 800mL (±

10) 1L

X

(x = TBD # of containers)

Within 30 calendar days of government acceptance of deliverable 1 in step 3 and per contract period of performance

Step Three, deliverable 3: Copies of reports and documentation for homogenized bulk material (electronic pdf)

1 Within 30 calendar days of completion of homogenization and per contract period of performance

VII. ACCEPTANCE REQUIREMENT SUMMARY

1. Monoclonal antibody production report of analysis will be accepted once it has been received by the COR and/or SME to verify the findings listed. This review shall be completed within

15 calendar days of receiving the monoclonal antibody production report of analysis.

VIII. GENERAL INFORMATION

Patent Rights: The Government retains a Government use license to all inventions arising from this work.

Security: NIST and the NIST/IBBR maintain restricted campuses. An identification badge is required for access for entry into buildings and may be obtained from the security desk upon arrival.

Identification Badges: Contractor employees shall comply with NIST identification and access requirements. The Contractor employee is responsible for absences due to expired identification and access documents. Each Contractor employee entering the NIST Campus shall wear a visible identification badge provided by the NIST Office of Security. The badge must show the full name, title, and if required by NIST, the words “Contractor” in front. The Contractor employee shall turn in the NIST identification badge to the COR or Contracting Officer (CO) upon termination of their services under this contract.

Media Inquiries: The Contractor employee shall not respond to any media inquiries. Any inquiries from the media shall be immediately relayed to the COR and CO. There shall be no interviews, comments, or any other response without the knowledge and approval of the NIST

Director.

Appendix A

Upstream and Downstream Supplementary Information

Media: EX-CELL Advanced CHO (MilliporeSigma)

NIST shall deliver their current batch bioprocess (2L bioprocess) to the contractor including SOPs for the following processes including:

• Cell thaw and handling, seed train, and bioreactor inoculation

• Upstream: equipment, set points and proven acceptable ranges

• Harvest – Clarification

• Downstream: equipment and conditions

NIST will provide historical process knowledge related to the following process analytical technology

(PAT):

• Cell density/viability

• Titer

• Additional PAT if available/requested

Downstream to include 3 step purification process, with viral inactivation and filtration steps representative of typical monoclonal antibody manufacturing:

• Protein A

• Anion Exchange Chromatography

• Cation Exchange Chromatography

Performance Acceptable Ranges:

• Titer ≥ 2 g/L

• Cell viability on day of harvest: ≥70%

• Downstream recovery: ≥60%

Appendix B

Final Product Evaluation Attributes

The product should be representative of a typical biopharmaceutical monoclonal antibody. The product quality must meet the specifications provided by NIST upon award for the following attributes.

• Concentration: 100 mg/mL ± 5mg/mL

• Identity Confirmation

• Size Heterogeneity

• Charge Heterogeneity

• Particle Content

• Host Cell Protein content

Minimally Viable Product Specifications:

• Monomeric Purity: ≥ 95%

• Host Cell Protein (HCP) Content: ≤ 500 ppm

• Sub-Visible particle content:

o >=10μm: 6000 o >=25μm: 600