Attch 1- Statement of Work.docx

Attachment 1- STATEMENT OF WORK Title: Monoclonal Antibody Reference Material Vialing

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, DNA, 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 has an IgG1k monoclonal antibody that was developed into a reference material (NISTmAb, RM 8671) and released in 2016. This reference material has an associated in-house IgG1k monoclonal antibody serving as an internal standard known as PS 8670 (Primary Sample 8670). NISTmAb, RM 8671 was released with physicochemical and quantitative data and is utilized by the biopharmaceutical community as a system suitability and analytical method development tool. Additionally, NIST is developing a monoclonal antibody expressed from the NISTCHO reference cell line as a NIST Reference Material (cNISTmAb, RM 8672). The material is intended to be highly representative of CHO-expressed monoclonal antibodies used as biopharmaceuticals. This NIST RM 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 vial each of these monoclonal antibody RMs to produce several lots of both NISTmAb RM 8671 and cNISTmAb RM 8672. These RM lots will be released with quantitative data traceable to fundamental units of measurement and are expected to be utilized as a system suitability tools in the biopharmaceutical industry.

II. PURPOSE

Using government-furnished material in the form of multiple lots of monoclonal antibody, the Contractor shall vial monoclonal antibody RMs to produce several lots of NISTmAb PS 8670/RM 8671 and cNISTmAb RM 8672. Contractor shall be responsible for providing all other necessary materials to include vials, racks, and labels.

PLACE OF PERFORMANCE

All work shall be completed at the Contractor’s facility. All units of monoclonal antibody deliverable units will be transferred to the NIST Office of Reference Materials storage facility with the mailing/delivery address:

NIST – Office of Reference Materials (Storage Facility) 100 Bureau Drive Gaithersburg, MD 20899

The Government intends to visit

Regular Business Hours Regular business hours are Monday through Friday, 8:30 am to 5:00 pm Eastern Time, excluding Federal holidays and NIST closures.

PERIOD OF PERFORMANCE

Period of performance will be 18 months after Receipt of Order (ARO).

III. SPECIFIC REQUIREMENTS

General Qualifications of the Manufacturer Contractor shall have experience handling and processing protein therapeutics. The techniques and handling utilized throughout must maintain the sterility of the final product at a level equal to that of the stock material.

Potential contractors shall provide details of the content of a standard data package informing on the vialing process in the proposal.

Potential contactors shall provide details of production timelines and delivery of final product.

Task 1 – Monoclonal Antibody a Vialing (NISTmAb PS 8670/RM 8671)

1. One 1L container labeled as PS 8670 Humanized Monoclonal Antibody and Three 1L containers labeled as RM 8671 Humanized Monoclonal Antibody homogenized bulk will be transferred to the contractor under frozen (dry ice) conditions, not to exceed -20 degrees C and shall be stored at -80 degrees C upon arrival and until thaw.

2. Each individual 1L bulk container shall be thawed at no greater than 25 degrees C (room temperature) and the material shall not exceed a temperature above 30 degrees C at any time. A maximum of one freeze/thaw cycle shall be used for generation of vialed material.

3. Each 1L container shall be individually diluted to 10 mg/mL in 12.5 mM L-histidine, 12.5mM L-histidine hydrochloride pH 6.0. Both materials shall be USP grade.

4. The contractor shall confirm concentration at 10 mg/mL (± 0.5 mg/mL) using UV-VIS before proceeding to aliquoting. The contractor shall provide documentation of the UV-VIS results to the COR/SME as part of the documentation for each lot.

5. Each container shall be labeled with a label provided by NIST. Each rack of 96 containers shall be labeled with a label provided by NIST.

6. Each individual diluted homogenized bulk container will be aliquoted into 10,000 (±300) units of 800 µL each, for a total of 40,000 (±1000) units of 800 µL (± 25 µL) each.

7. Containers shall be immediately frozen at -80 degrees C.

8. The time from thaw to refreeze in final vial shall be less than 48 hours, and no additional freeze/thaw may be performed. The material shall not exceed a temperature of 30 degrees C.

9. The container used shall be compatible with -80°C storage and have a sealed lid (not a vial intended for clinical use). The closure shall be screw-top containing 800 (±50) μL of material per vial. Thermo matrix vial and rack system (Product number 3741) shall be used. Required colors for the caps each of the vials:

a. PS 8670: Clear

b. RM 8671: Yellow

10. Documentation will be recorded to trace vials originating from each specific 1L container. Vial to vial reproducibility of both homogeneity and volume are of critical importance. Documentation shall include at a minimum:

a. Lot identification

b. Rack Identification (x of xxx)

c. Fill sequence both of the rack and within the rack

d. Date/time of fill

e. Cap color

f. NIST Label for rack

g. NIST label for vial

11. The Contractor shall provide a final report with a detailed explanation of the steps involved in material preparation. The explanation shall include all of the following, at a minimum:

a. Transportation of material to and from NIST.

b. Estimated time of each step including estimated temperature of each step.

c. Methodology and instrumentation used for dilution, fill, freeze, and storage

d. Methodology and instrumentation used for analytical testing and product specifications

Deliverable 1: 30,000 labeled vials of 10 mg/mL NISTmAb RM 8671 monoclonal antibody separated into 3 lots of 10,000 vials each.

Deliverable 2: 10,000 labeled vials of 10 mg/mL NISTmAb PS 8670 monoclonal antibody in one lot of 10,000 vials each.

Deliverable 3: Copies of reports and documentation for all steps of material preparation as outlined in step 11 above.

Task 2 – Monoclonal Antibody B Vialing (cNISTmAb RM 8672)

1. Three 1L containers labeled as RM 8672 cNISTmAb, Monoclonal Antibody homogenized bulk will be transferred to the contractor under frozen (dry ice) conditions, not to exceed -20 degrees C and must be stored at -80 degrees C upon arrival and until thaw.

2. Each individual 1L homogenized bulk container shall be thawed at no greater than 25 degrees C (room temperature) and the material shall not exceed a temperature above 30 degrees C at any time. A maximum of one freeze/thaw cycle shall be used for generation of vialed material.

3. Each 1L container shall be individually diluted to 10 mg/mL in 12.5 mM L-histidine, 12.5mM L-histidine hydrochloride pH 6.0. Both materials must be USP grade.

4. The contractor shall confirm concentration at 10 mg/mL (± 0.5 mg/mL) using UV-VIS before proceeding to aliquoting. The contractor shall provide documentation of the UV-VIS results to the COR/SME within 10 calendar days of the testing

5. Each container shall be labeled with a label provided by NIST. Each rack of 96 containers shall be labeled with a label provided by NIST.

6. Each individual diluted homogenized bulk container will be aliquoted into 10,000 (±300) units of 800 µL each, for a total of 30,000 (±1000) units of 800 µL (± 25 µL) each.

7. Containers shall be immediately frozen at -80 degrees C.

8. The time from thaw to refreeze in final vial should be less than 48 hours, and no additional freeze/thaw may be performed. The material shall not exceed a temperature of 30 degrees C.

9. The container used should be compatible with -80°C storage, have a sealed lid (not a vial intended for clinical use). The closure shall be screw-top containing 800 (±50) μL of material per vial. Thermo matrix vial and rack system (Product number 3741) must be used. Required colors for the caps each of the vials:

a. RM 8672: Blue

10. Documentation will be recorded to trace vials originating from each specific homogenized bulk container. Vial to vial reproducibility of both homogeneity and volume are of critical importance. Documentation shall include at a minimum:

a. Lot identification

b. Rack Identification (x of xxx)

c. Fill sequence both of the rack and within the rack

d. Date/time of fill

e. Cap color

f. NIST Label for rack

g. NIST label for vial

11. The Contractor shall provide a final report with a detailed explanation of the steps involved in material preparation. The explanation shall include all the following, at a minimum:

a. Transportation of material to and from NIST.

b. Estimated time of each step including estimated temperature of each step.

c. Methodology and instrumentation used for dilution, fill, freeze, and storage

d. Methodology and instrumentation used for analytical testing and product specifications

e. Identification of 10 sample vials tested for concentration

f. Identification of vials tested for monomeric purity, minimum 3 Deliverable 1: 30,000 labeled vials of 10 mg/mL monoclonal antibody separated into 3 lots of 10,000 vials each.

Deliverable 2: Copies of reports and documentation for all steps of material preparation as outlined in step 11 above.

IV. GENERAL REQUIREMENTS

Include all requirements that are not specific tasks but are applicable to the overall contract and the work that will be performed. For example, IT Security, Government Property, Public Affairs Clearance, OMB clearance, printing, data rights, etc.

Government Responsibilities The Government will:

1. Provide the government-furnished material to the Contractor for vialing. All other materials required (vials, racks, labels, etc.) shall be provided by the Contractor.

2. Participate in status meetings and the kick-off meeting. Provide technical information useful in the accomplishment of contract objectives.

3. Perform a Contractor-site visit by the NIST SME and NIST authorized personnel after contract award and prior to or at the start of production to ensure product/process conformance.

4. Perform documentation review and acceptance testing to ensure product/process conformance.

Government Furnished Material The NIST Biomolecular Structure and Function Group will provide the contractor with:

1. The Homogenized bulk monoclonal antibody 1L units as described in the specific requirements.

2. As an electronic document, the design of the labels to be applied to the individual vialed units as described in the Specifications.

All property, data and information provided by the Government in the performance of this task remains the property of the Government and shall be surrendered to the government upon completion or termination of this requirement. Likewise, all deliverables generated under this requirement remain the property of the Government.

Inspection & Acceptance In addition to the inspection and acceptance terms articulated in the specific FAR clause that allows the Government reserves the right to perform such performance tests and evaluations as defined below to verify specified system performance. Such tests and evaluations, if performed, shall be conducted within the environment that the system is to be operated. The Contractor has the right to be present during the tests and evaluations, if performed, at the Contractor’s expense.

Government Site Visit NIST SME and NIST authorized personnel will visit the contractor’s site after award of contract and prior or at the start of production to ensure product/process conformance.

Contractor Site:

Performance Tests Tasks 1 and 2:

Bulk Testing:

1. When thawed, the solution should be in the form of a clear, colorless liquid. No precipitates or turbidity shall be present.

2. Concentration:

a. The protein concentration shall be ± 0.5 mg/mL of the 10 mg/mL target concentration as determined by UV-Vis absorption using an extinction coefficient of 1.42 mL · mg−1 · cm−1 at A280.

Vial Testing per lot:

1. When thawed, the solution should be in the form of a clear, colorless liquid. No precipitates or turbidity shall be present. Vials shall be free of damage including striations, cracks, or visible leakage.

2. Concentration:

a. The vial-to-vial reproducibility should be reported by performing UV-Vis on ten vials of the vialed material chosen by the contractor at random with only one sample coming from any single rack (10 racks total).

b. The protein concentration shall be ± 0.5 mg/mL of the 10 mg/mL target concentration as determined by UV- Vis absorption using an extinction coefficient of 1.42 mL · mg−1 · cm−1 at A280.

c. The vial-to-vial precision shall be no more than 5 % coefficient of variation.

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

e. Contractor shall destroy any remaining material not utilized in vial testing. Vial location in rack will be left vacant.

3. Monomeric Purity:

a. The purity of the monomeric molecule shall be ≥95% and demonstrated through high-performance size exclusion chromatography.

b. Contractor must provide testing on at least three samples of each lot of 10,000 vials.

c. Contractor shall destroy any remaining material not utilized in vial testing. Vial location in rack will be left vacant.

NIST Site:

All vials shall be delivered as frozen protein solution. When thawed, the solution should be in the form of a clear, colorless liquid. No precipitates or turbidity shall be present. Vials shall be free of damage including striations, cracks, or visible leakage.

Performance Tests Tasks 1 and 2:

1. When thawed, the solution should be in the form of a clear, colorless liquid. No precipitates or turbidity shall be present.

1. The protein concentration should be ± 0.5 mg/mL of the 10 mg/mL target concentration as demonstrated by UV-Vis absorption on 3 vials from each lot.

1. The purity of the monomeric molecule shall be ≥95% and demonstrated through high-performance size exclusion chromatography on 3 vials from each lot.

A visual inspection of the deliverables will be performed by the NIST POC to identify surface defects or any form of indication that any deliverable was damaged during transport to NIST. The Government shall have sole discretion to require repair or replacement of damaged and/or nonconforming supplies at no cost to the Government. The Government at any time prior to acceptance shall reject the deliverables due to defects and/or nonconformance. The vendor is responsible for latent defects discovered any time after final inspection.

Ownership of the deliverables shall transfer to NIST upon acceptance by the Government.

The Government will test, inspect, and accept or reject the deliverables within 14 days of the receipt of the product unless otherwise indicated above. The Government reserves the right to conduct quality assurance testing to confirm that a given products(s) meets the manufacturer’s and/or the Government’s performance specifications.

V. SCHEDULE OF DELIVERABLES

(pdf, word, etc.)

Per Contract

Kick-off Meeting The contractor shall attend a kick-off meeting, via phone or video conference, no later than 14 days after the award of the contract. The NIST subject matter expert (SME), contract officer’s representative (COR) and other authorized NIST personnel shall be in attendance. The contractor’s team must be present, and the meeting will be utilized to review all contract requirements and deliverables.

Status Meetings The contractor shall participate in status meetings on a reoccurring basis (minimum monthly but to be decided between contractor and SME and COR) to obtain an update on the intended delivery date of the Government furnished product.

During these meetings, the contractor shall inform the SME and COR of any anticipated problems or issues that may have arisen or may further delay work upon receipt of the product. Status meetings shall be conducted via conference call. The contractor and NIST SME and COR shall establish a meeting schedule.

The contractor shall be responsible for maintaining the meeting agenda and tracking issues. A summary report of each status meeting shall be prepared by the Contractor and submitted to the COR and SME within 7 calendar days of each meeting.

VI. PAYMENT SCHEDULE

Partial payments are allowed. Contractor may invoice for individual lots upon notification of government acceptance.

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