A-2_SOW.pdf

STATEMENT OF WORK

TITLE: Procurement of ultrahigh pressure liquid chromatograph tandem quadrupole time-of-flight mass spectrometer (UHPLC-QTOF MS)

LAB REQUESTING SERVICE: Material Measurement Laboratory

I. BACKGROUND INFORMATION

The National Institute of Standards and Technology (NIST) operates a laboratory at the Institute for Bioscience and Biotechnology Research (IBBR) in Rockville, MD that develops fundamental measurement science, standards, and reference data to enable more accurate and confident characterization of key attributes of protein drugs. The group at IBBR is responsible for monoclonal antibody reference materials (RMs) and related therapeutic protein RMs to be made available to the biopharmaceutical industry. The group recently released RM 8671, a monoclonal antibody reference material, and are now developing additional reference methods to be added to the Report of Investigation, performing interlaboratory harmonization studies, and beginning work on additional candidate RMs. Such materials are a highly micro-heterogeneous mixture of proteins with the same amino acid sequence but with various post-translational modifications, N-glycosylation variation, and low abundance sequence variants. It is imperative that stakeholders are provided with accurate and thorough data and information regarding the composition and structures of the RM. A large proportion of the data collected on the RMs will utilize mass spectrometric techniques, which, given the complex nature of the modifications of interest, require specific and well-designed companion analytical software.

Ultrahigh pressure liquid chromatography tandem quadrupole time-of-flight mass spectrometry (UHPLC-QTOF MS) is required for product characterization, comparability and similarity, and process improvement. The system will be used to measure the protein in its intact form, moderate sized subunits (e.g. middle down mass spectrometry), and following complete enzymatic digestion to smaller peptides (e.g. trypsin cleavage). Glycans, comprised of sugar subunits, may also be present and analyzed using UHPLC-MS workflows. Glycans are often specifically released from the protein of interest, further processed via labeling chemistry to prepare them for mass spectrometry, and then analyzed using UHPLC-MS. Significant drivers for providing increased product understanding have also begun to accelerate exploration of these and other mass spectrometry-based techniques for Quality Control applications. Translation of a characterization method to QC is a main driver for IBBR that aims to develop novel methods while also improving understanding of accuracy, precision, and robustness as it relates to method performance. Acquisition of the proposed UHPLC-QTOF is required to provide NIST the ability to characterize and value-assign NIST Reference Materials of critical significance to the biopharmaceutical industry.

II. SCOPE OF WORK

GENERAL REQUIREMENTS

The contractor shall provide a turn-key system composed of an Ultra-high-performance liquid chromatograph (UHPLC, used for analyte separation) coupled to a hybrid quadrupole time-of-flight mass spectrometer (QTOF, for analyte detection and identification) equipped with a heated electrospray (HESI) ionization source. The UHPLC shall consist of a multisampler, UHPLC pump with degassing capabilities, column oven, fluorescence detector, and variable wavelength UV detector that seamlessly connects in-line to the mass spectrometer. The mass spectrometer shall be a benchtop high resolution LCMS QTOF instrument. The data system, for instrument control and data analysis, shall also be included with the liquid chromatography and mass spectrometry instruments. To provide the greatest functionality and ease of use, both the UHPLC and QTOF shall be controlled via software specifically designed for the concerted system.

Additionally, the system must be directly compatible with current IBBR technologies developed for the NISTmAb RM 8671. Specific instrument components and specifications that will provide this functionality are described in more detail in Section II.

III. MINIMUM SPECIFICATIONS

The UHPLC and MS system meet or exceed the minimum requirements identified below. All items must be new. Used or remanufactured equipment will not be considered for award.

Experimental, prototype, or custom items will not be considered. The use of “gray market” components not authorized for sale in the U.S. by the Contractor is not acceptable. All line items shall be shipped in the original manufacturer’s packaging and include all original documentation and software, when applicable.

Brand-Name Only The following equipment components must be manufactured brand-name from:

Agilent Technologies, Inc.

2850 Centerville Rd Wilmington, DE 19808-1610

Contract Line Item Number (CLIN) 0001: The Contractor shall provide an Agilent UHPLC-QTOF MS that meets the following minimum specifications:

UHPLC-QTOF MS General

The system must be a new benchtop UHPLC QTOF MS system with components and specifications as described below.

The UHPLC and MS shall be operated by the same software without the use of third party device drivers.

The system shall include the following components:

o UHPLC o Mass Spectrometer (MS) o Nitrogen Generator o UPS System o Software and Control System

UHPLC

The UHPLC system must be a new benchtop.

The UHPLC shall consist of a multisampler, UHPLC pump with degassing capabilities, column oven, fluorescence detector, and variable wavelength UV detector that seamlessly connects in-line to the mass spectrometer.

Must include a stackable, self-contained modular UHPLC with solvent resistant material used in all areas which may have contact with the mobile phase.

UHPLC system must have a pH range 1.0 — 12.5.

UHPLC system must have operating pressure range up to 130 MPa (1300 bar) up to 2 ml/min, 80 MPa (800 bar) at 5 ml/min to ensure capability with HPLC and UHPLC methods and optimally support all column dimensions.

UHPLC Pump o Must have settable flow range of 0.001-5mL, in 0.001 mL/min increments.

o Must deliver a flow rate of up to 5mL/min in high pressure binary mixing.

o Must have as low as possible gradient delay volume of 10 µL or less.

o Must have flow precision of ≤0.07% RSD or ≤0.005 min SD, whatever is greater, for the best retention time precision and identification confidence.

o Must have composition precision of ≤0.15% RSD or ≤0.01 min SD, whatever is greater, for the best retention time precision and identification confidence.

o Must have composition accuracy of ± 0.35% absolute.

o Must have dual pistons in series hydraulic system for highest robustness and reliability.

o Must have integrated 2-channel degassing unit.

UHPLC multisampler o Must have cooling capabilities down to 4 oC.

o Mustcome equipped with two or more injection plates capable of holding 54 or more standard HPLC vials each. The injector must also be scalable to include additional drawers and injection plates all within the LC-stack footprint.

o Musthave outer needle wash and seat backflush for carryover reduction with up to 3 different solvents.

o Musthave carryover specification of 9 ppm or less.

o Musthave injection volume range of 0.1 to 20µL in 0.1 µL increments.

o Must have precision of ≤0.15% RSD or SD ≤10nL, whatever is greater.

UHPLC column oven o Must support columns of up to 30cm length.

o Must be dual, independent Peltier-element thermostatted with solvent pre-heating for reduction of chromatographic brand-broadening under UHPLC-conditions o Must have temperature range from 20°C below ambient to 110°C.

o Must be ± 0.8 °C or ± 0.5 °C with calibration o Must be ± 0.05 °C.

o Must have an integrated 2Pos/6Port valve with the same pressure range as of the pump. The valve shall be user-exchangeable. The valve shall have pull-out mounting to bring the capillary connections into a position where they are unhindered and accessible. Valves must be in close proximity to columns.

o UHPLC pump flow will be firmware controlled and reduced before a valve will be switched.

UHPLC Variable Wavelength UV Detector o Must be capable of single and dual (or more) wavelength detection at acquisition rates of 240 Hz and 2.5 Hz, respectively o UHPLC VWD detector must have a wavelength range of at least 190 to 600 nm o UHPLC VWD detector must have linearity ≥ 2.5 AU (upper limit).

o Must have a flow cell of 2 µL volume or less.

o Must be ≤± 0.15 x10-5 AU at 230 nm using single wavelength detection.

o Must have sampling rate of up to 240Hz (single wavelength acquisition).

o Must be ≤ 1 x 10-4 AU/h at 230 nm.

o Must have wavelength accuracy of ± 1 nm, and wavelength precision of ≤ ± 0.1 nm.

UHPLC Fluorescence Detector o Must be able to acquire spectra (excitation or emission) during the analysis (no stop flow needed).

o Must have in single wavelength mode a Raman signal-to-noise of ≥3000, with Ex 350nm and Em 397nm and using the dark value at 450nm as reference point, water filled standard flow cell.

o Must have in dual wavelength mode a Raman signal-to-noise of ≥300, with Ex 350 nm/Em 397 nm and Ex 350 nm/Em 450 nm, water filled standard flow cell.

o Must have Excitation wavelength range must be at least 200 – 1200 nm, Emission wavelength range must be at least 280 – 1200 nm.

o Must be Xenon flash lamp, normal mode (20 W), economy mode (5 W), and lifetime 4000 hours.

o Must have flash lamp technology that can be switched on directly before the analysis and doesn’t require warm up time.

o Must have option for a bio-inert flow cell available.

Mass Spectrometer (MS)

Be a benchtop LCMS QTOF instrument.

MS shall have a resolution of at least 50,000 FWHM at (m/z = 2,722) obtained without signal losses and obtained through an automatic tuning procedure.

MS shall have a mass range of at least 50-30,000 amu to be compatible with the wide range of samples that are required to be analyzed.

MS shall have capability to collect MS/MS data in both data dependent and data-independent modes.

MS shall have the capability perform iterative MS/MS acquisition.

Have a mass accuracy in MS mode of better than 0.8 ppm [(M+H)+ ion of reserpine (m/z

609.2807)] and better than 2 ppm in MS/MS mode (product ion m/z 397 for reserpine) to enable accurate compound identification.

For electrospray running at 400 uL/min, an on-column injection of 1 pg of reserpine must yield a signal-to-noise of 500:1 RMS for the (M+H)+ at m/z 609.2807 while the instrument maintains a resolution of 50,000 FWHM resolution.

In MS/MS mode, detect 1 pg of reserpine with a S:N ratio of 1,500:1 RMS while the instrument maintains a resolution of 50,000 FWHM, ensuring high sensitivity to detect even low level analytes.

The instrument must use a dual-spray source design to introduce calibrant and analyte simultaneously. Must have an integrated calibrant solution for automated delivery of calibrant for tuning and mass calibration.

The source must use thermal focusing to collimate the ion beam prior to entry into the mass spectrometer. This ensures the highest level of sensitivity and assists with ion desolvation.

Have a positive to negative cycle switching time of 1.5 seconds or less.

Must include a vent-free capillary removal for easy maintenance/minimal downtime – allows source and sampling capillary maintenance while maintaining system vacuum.

To quantify over a large range of sample concentration, the Q-TOF detector must offer a minimum five decades in-spectrum dynamic range without data manipulation. The instrument must have an in-scan dynamic range of 5 decades on co-eluting components.

It must have an analog-to-digital conversion (ADC )-based detector system capable of sampling at a rate of 4 GHz, ensuring a broad linear dynamic range.

The QTOF system must feature ion beam compression technology that enables simultaneous maximum sensitivity and mass resolution performance without having to change mass resolution modes to achieve the specification requested in this specification.

To minimize mass error which is introduced by room temperature variation, the flight tube material must contain low thermal expansion rate material. The mass error cannot be more than 1 ppm per 1 degree C.

The instrument must include an automated tuning algorithm that incorporates a multi-dimensional optimization algorithm to find the optimum sensitivity. This tuning algorithm must be a flexible and robust multidimensional optimization algorithm that can optimize up to 21 parameters simultaneously– even when no initial signal is present.

This tuning algorithm must avoid getting trapped in local optima. This tuning algorithm must optimize elements for a target resolution, level of fragmentation, or for maximum sensitivity with a simple start tune button. The tuning algorithm must also include an autotune specific for large molecules (proteins) and small/labile molecule analysis to prevent loss of fragile ions when requested by the operator.

Nitrogen Generator

The system shall include a nitrogen generator capable of producing required nitrogen for heated electrospray source (e.g. drying gas and nebulizer gas).

UPS System

The system shall include an uninterruptable power supply (UPS) system to protect the Mass spectrometer and nitrogen generator during an unforeseen power outage for a period of no less than 10 minutes.

Software and Control

The system must come with an appropriate computer system (CPU, monitor, keyboard, mouse).

Software must allow complete integration of the UHPLC with the mass spectrometer.

Data acquisition software must simultaneously control all hardware components without the use of third party device drivers.

Include a data extraction algorithm capable of automatically de-noising spectra and finding compounds and their associated multiply charged peaks and adducts to speed and simplify data processing.

Must include automated data analysis for the following workflows: Intact Protein Analysis, Peptide Sequence Mapping and Glycan Profiling. Guided Workflow enabled software for Intact Protein analysis with automated zero charge deconvolution.

Must include full Walk-up LCMS Acquisition and data analysis software with ability to automate drug-to-antibody ration calculations for antibody drug conjugate analysis

Must include stand-alone drug-to-antibody ratio software for antibody drug conjugate analysis.

Must include peptide mapping analysis with interactive MS/MS acquisition feature (allows for more comprehensive MS/MS analysis with no user intervention). Data Analysis must be able to add results from multiple enzyme digestions in a single table and report with no cut/paste required.

For n-Glycan analysis must include a glycan library for automated labeling and reporting.

Software must support common glycan labeling including 2AB, Instant AB, Instant PC among others to accommodate current analytical method pipeline.

The Contractor shall be responsible for contacting and notifying the COR of all software updates released not later than 60 days after any such update is released for the duration of the period of performance.

Warranty The contractor shall warrant the entire system for a period of a minimum of one (1) year after receipt of the equipment and shall be in accordance with terms in FAR 52.212-4. The warranty shall also include the following:

1. Provide one (1) preventive maintenance visit as specified in the manufacturer’s operations and maintenance manual at time of award of this requirement.

2. Dispatch of a technician for service when the instrument becomes inoperable or fails to perform to specifications due to a failure in the instrument.

3. Replacement of defective parts with certified replacement parts.

CLIN 0002: Installation and training The system shall be installed by the Contractor and meet contract specifications no later than 120 days after receipt of a purchase order. Installation, at a minimum, shall include uncrating/unpackaging of all equipment, rigging, set-up and hook-up of the system, demonstration of all specifications, and removal of trash. Onsite installation and demonstration shall be done at the place of performance identified below.

The contractor shall conduct a training session for up to three (3) users at NIST. The training shall provide a thorough demonstration of all system/solution functions, basic system maintenance, data administration, and basic troubleshooting. The training may be completed at NIST immediately after installation/set-up and on-site measurements demonstrating that no damage or misalignment issues arose during transportation and installation, but shall be completed no later than 120 days after receipt of a purchase order.

OPTION LINE ITEMS: THE FOLLOWING SERVICES AND SUPPLIES ARE OPTION

LINE ITEMS. PRICES QUOTED SHALL BE EFFECTIVE FOR A PERIOD OF ONE

YEAR FROM THE DATE OF AWARD. AWARD OF OPTION LINE ITEMS IS AT THE

SOLE DISCRETION OF THE GOVERNMENT IN ACCORDANCE WITH FAR 52.217-

9.

OPTION CLIN 0003: The Contractor shall provide twelve (12) months maintenance for the UHPLC-QTOF MS described in CLIN 0001 to include the following services:

1. All services performed shall be provided by personnel who are trained and authorized by the manufacturer to perform maintenance and repair services.

2. All parts shall be approved for use with the instrument by the manufacturer.

3. At least a 90 day to 1-year warranty shall apply to all repairs and OEM parts.

4. The Contractor shall respond to all service calls Monday through Friday, between

8:00 am and 5:30: pm Eastern Time. The Contractor shall provide a service technician/engineer on-site at IBBR, Rockville MD, within one week after the service call is placed by the Government. No weekend service visits shall be required.

5. In the event that the Contractor is unable to resolve the problem during the service call, the Contractor shall provide telephone support and on-site support as needed to expedite a solution for IBBR.

6. The Contractor is responsible to obtain all parts required for all repairs and maintenance. The Contractor shall make a commercially reasonable effort to secure parts within one week after identifying the need for a replacement part for the covered equipment. Parts requiring a lead time of longer than two weeks shall be identified by the Contractor in writing to the COR and a plan submitted detailing a temporary solution that would allow the equipment to continue working while the part is sourced.

7. All repairs must result in the instruments meeting manufacturer’s specifications.

8. Any parts or components removed for replacement shall become the property of the

Contractor unless otherwise agreed to by the parties. The Contractor shall remove the parts from the IBBR campus at the time of the service call and that no shipping charges will be incurred by the Government. The Contractor shall assume liability for all parts removed from the IBBR campus.

9. Provide one (1) preventive maintenance visit during each period of performance as specified in the manufacturer’s operations and maintenance manual at time of award of this requirement for each instrument. Should the preventative maintenance schedule in future be reduced, from the current maintenance schedule, the contractor shall receive approval of the reduction of preventative maintenance from the COR prior to implementing the revised procedures. At least 30 days prior to the need for preventative maintenance, the Contractor shall contact the IBBR TPOC to schedule the time and date of preventative maintenance services.

Service Tickets The Contractor shall submit a service ticket prior to departure from IBBR on any given service call for maintenance or repairs. The service ticket shall include the following:

a. Date and time of arrival to IBBR.

b. Description of service performed.

c. Name and quantity of any parts that were repaired.

d. Name and quantity of any parts that were replaced.

e. Date and time of departure from IBBR.

f. Diagnostic test results or narrative summary demonstrating that the instrument and/or accessories are meeting the performance standards.

g. Any comments or recommendations.

h. Signature of Contractor’s service person

i. Signature block for IBBR personnel accepting the services rendered.

OPTION

CLIN 0004:

The Contractor shall perform all tasks listed under CLIN 0003 for a period of twelve (12) months after the completion of CLIN 0003’s period of performance with execution of a modification to exercise the option.

OPTION

CLIN 0005:

The Contractor shall perform all tasks listed under CLIN 0004 for a period of twelve (12) months after the completion of CLIN 0004’s period of performance with execution of a modification to exercise the option.

IV. PERIOD OF PERFORMANCE

The period of performance shall be as follows:

Delivery shall be FOB Destination and shall occur within ninety (90) days of purchase order issuance.

FOB Destination means: The contractor shall pack and mark the shipment in conformance with carrier requirements, deliver the shipment in good order and condition to the point of delivery specified in the purchase order, be responsible for any loss of and/or damage to the goods occurring before receipt and acceptance of the shipment by the consignee at the delivery point specified in the purchase order; and pay all charges to the specified point of delivery.

Installation and training: 120 days after receipt of award (ARO).

Warranty: 12 months from the date of acceptance of the instrument

Options for Maintenance Services:

Option Year 1: To commence upon warranty expiration and extend for a period of 12 months after exercise of the option Option Year 2: To commence upon exercise of the option and extend for a period of 12 months after exercise of the option Option Year 3: To commence upon exercise of the option and extend for a period of 12 months after exercise of the option

V. PLACE OF PERFORMANCE

Installation, training and maintenance services shall be accomplished at IBBR, 9600 Gudelsky Dr., Rockville, Maryland. Normal duty hours are Monday through Friday, 8:30 a.m. to 5:00 p.m.

with the exception of Federal holidays. Work will be coordinated with the Technical Point of Contact (TPOC).

VI. DELIVERABLES

Description Quantity Due Date

Delivery of instrument One (1) 90 days after award of this requirement.

Installation and Familiarization Training One (1) 120 days after award of this requirement

VII. ACCEPTANCE CRITERIA AND PAYMENT

Formal acceptance of the system will be given at the time the Contractor demonstrates that all performance standards in this statement of work have been met.

Cost of shipping shall be included in the price of the acquisition.

Advance payment is not authorized. Payment will be made upon receipt and acceptance of the required deliverables. Partial payments are authorized, provided the deliverables being invoices have been accepted by IBBR. Proposed payment schedules shall be submitted with vendor’s response to the RFQ for consideration.

VIII. GENERAL INFORMATION

Safety: The Contractor employee shall be responsible for knowing and complying with IBBR installation safety prevention regulations. Such regulations include, but are not limited to, general safety, fire prevention, and waste disposal.

Security: IBBR is a restricted campus. An identification badge is required for access for entry into buildings and also is shown to the Security Guard when entering the building. Contractors will be escorted at all times by TPOC.