A28 - STO 2 - AAV Manufacturing Task Order.pdf

Sample Task Order #2- Statement of Work

AAV9 Manufacturing Support for NINDS Ultra-Rare Neurological Genetic Disease Gene Therapy Project

Background The Ultra-Rare Gene Therapy (URGenT) program (https://www.ninds.nih.gov/Current- Research/Research-Funded-NINDS/Translational-Research/urgent-network) has been established by the National Institute of Neurological Disorders and Stroke (NINDS) to support the development and clinical evaluation of therapeutics to address ultra-rare genetically based neurological disorders. The network will provide neuroscience researchers with funding and access to a full range of industry-style biologics development services and expertise. The program is intended to rapidly advance patient-customized therapeutics through manufacturing, preclinical toxicology testing and evaluation in Phase 1b/2a clinical studies. Each project will be directed by a Lead Development Team (LDT) comprised of the NIH grant recipient (Principal Investigator (PI)), industry consultants contracted by NIH, and NIH staff. These teams map out research strategy, including program milestones and oversee product development activities. The NIH Contracting Officer’s Representative (COR) oversees manufacturing and nonclinical study services provided by Contract Manufacturing Organizations (CMOs) and/or Contract Research Organizations (CROs). Manufacturing, pharmacological studies, efficacy studies, and other services may be supported through a grant to the PI or may be provided without cost to the PI through NIH contracts.

Objectives The objective of this Task Order (TO) is for the Contractor and/or Subcontractor(s) to conduct all technology transfer, chemistry, manufacturing, and controls (CMC) development and manufacturing tasks required to support execution of IND-enabling nonclinical studies, regulatory filings and clinical trial study evaluation for an adeno-associated virus. For the purposes of proposal development assume AAV serotype 9 (AAV9) based gene therapy product will be manufactured to treat a genetically based ultra-rare neurological disorder, in a small number of subjects (1-5 subjects).

The main objective has two sub-objectives divided into a Base Task and an Optional Task for this TO:

a) Base Task: Delivery of preclinical Good Laboratory Practice (GLP) lots and associated data packages to support Investigational New Drug (IND) submission and enable clinical trials

b) Optional Task: Delivery of clinical current Good Manufacturing Practices (cGMP) lots and associated data packages to support IND submission and enable clinical trials

Separate costing should be provided for the Base Task and Optional Task

Manufacturing services for both the Base Task and Optional Task include, but are not limited to:

(1) Technology-transfer of an R&D laboratory scale process from a research facility to the

CMO

(2) Biological therapeutics manufacturing process development

Attachment #28 https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/urgent-network https://www.ninds.nih.gov/Current-Research/Research-Funded-NINDS/Translational-Research/urgent-network

(3) CMC development

(4) Small-scale manufacture, scale-up, engineering runs (as needed), and full-scale manufacturing of sufficient quality and in quantities under cGMP to support IND-enabling nonclinical studies and clinical studies

(5) Fill-finish, release testing, validation, stability testing, and other associated tasks

(6) CMC study report documentation that will enable regulatory filings and evaluation of biological therapeutics in clinical trials for these NIH programs

(7) Development of robust and scalable process for manufacture of AAV9 gene vectors, with IP freedom to operate

(8) Participate in NIH organized team meetings and present oral and written reports.

The two sub-objectives may be addressed separately and in parallel, e.g., initial clinical lots may not necessarily be manufactured using IP-free or optimized technology, with technology development continuing while initial lots are manufactured using currently available methods.

The COR will notify the Contractor when the Optional Task will be exercised. The Optional Task will only be exercised if the biologic meets milestones set by the LDT. The Optional Task may be exercised and run concurrently with the Base Task if the LDT determines that the biologic has met required milestones. The Optional Task may also be exercised and run subsequent to Base Task activities if required. The Contractor should be prepared for both possibilities, and the activities required to accomplish the Base Task and the Optional Task may overlap, as is common with drug development and manufacturing projects.

General Requirements for Base Task and Optional Task

(1) Independently and not as an agent of the Government, Contractor shall be required to furnish all the necessary services, qualified personnel, materials, equipment, and facilities not otherwise provided by the Government as needed to provide the services described in this Statement of Work and subsequent TOs.

(2) All work under this TO shall be monitored by the Government COR, whose position is defined in Section G of the contract.

(3) Contractor shall, at the direction of the COR, submit any Standard Operating Procedures (SOPs), method descriptions, and references to be used in the implementation of the studies. Contractor SOPs will be treated as confidential, and how much detail is revealed, and at what time, can be discussed.

(4) Contractor shall provide project management for its own core team to ensure project planning, execution, delivery of reports, and accurate and timely communication with the COR, Contracting Officer (CO), and other stakeholders. The Contractor’s core team leader shall attend program team meetings on an as needed basis (no more than one meeting per week) either in person or via teleconferencing. During these meetings, the Contractor shall report project progress and provide input and feedback to the program team. The Contractor shall send the materials needed for these meetings to the COR at least 24-hours in advance of the meeting. The material needed shall include a status update on all ongoing studies, plans for the next reporting period, data generated and interpretations of data, any quality control issues, and the status of the budget when requested.

(5) Contractor shall arrange for site visits and independent audits, as requested by the COR. Audits may be requested to assure Contractor and subcontractor facilities and all planned procedures meet U.S. Food and Drug Administration (FDA)-required drug development (GMP and GLP) standards. Contractor shall ensure all contractor and subcontractor records and staff are available in response to site visits or study-specific audits, and provide interim and final audit reports to the COR. All information generated by the Contractor to support manufacture of cGMP drug product shall have 100% quality system review of raw data and transcription.

(6) The Contractor shall immediately contact the COR if there are any adverse or problematic research results or difficulties with studies that would impact the development success of the project or endanger the timeline. The communications shall include proposed solutions according to the Contractor’s risk mitigation plan.

(7) Within 45 days of task order expiration, the Contractor shall provide the COR with a proposed Transition Plan for an orderly and complete transition/relocation of the task order resources to a successor Contractor or to the Government. The plan shall include details on the relocation/disposition of unused materials and supplies; manuals and directories developed by the Contractor; and all other government property not listed.

Upon written direction by the Government, the Contractor shall transfer all Government property as directed, and fully cooperate with any successor Contractor and the Government to ensure an efficient transfer.

Base Task Specific Requirements

This Base Task in the TO will cover Manufacturing and other related activities for delivery of preclinical GLP lots for a single project under the URGenT program. Other NINDS programs may require similar services. The specific scope for this Base Task includes:

(1) Technology transfer specific to AAV9 containing gene insert production methodology from the developer to the CMO facility, to be initiated within 30 days of Task Order award. These activities will include, but are not limited to:

(a) Communicating with small scale vendor or research group

(b) Participating in development team meetings/conferences and provide updates

(c) Creating and sharing electronic files securely

(d) Receiving and storing samples under controlled conditions

(e) Performing analytical and physicochemical testing to fully characterize samples

(f) Other activities required for successful technology transfer

(g) Reporting final characterization of received samples and completed technology transfer

(2) Manufacture sufficient quantities of reagents required to support small-scale and/or clinical scale AAV production including but not limited to:

a. cGMP plasmid DNAs required for recovering recombinant AAV9 production from cell culture; Provide DNA support services including but not limited to plasmid purification, structure and sequence analysis and next generation sequencing (NGS), and/or

b. Generation of a Development Cell Bank (DCB) or cGMP Master Cell Bank

(MCB) for manufacture of preclinical and clinical grade AAV vector, in accordance with GLP and applicable State and Federal regulations, for use by CROs approved by the NINDS. Associated activities include but are not limited to:

i. Perform production of DCB

ii. Perform production of cGMP MCB

iii. Perform production of Working Cell Bank (WCB)

iv. Characterize cell banks per ICH guidelines and other applicable regulatory guidelines (the offeror shall provide examples of typical MCB characterization plans)

v. Perform cell culture media and feed optimization

vi. Develop robust upstream processes

vii. Develop scalable downstream purification processes

viii. Determine critical process parameters

Separate costing should be provided for the Manufacture of Reagents activities.

(3) Perform process development to establish manufacturing methodologies and processes amenable to scale-up and quality control. These activities need to be sufficient for producing a small-scale lot to be used for IND-enabling studies and will be amenable to future scale-up activities outlined in the Option section below. The effort will consist of activities, including but not limited to, sourcing raw material and intermediates, evaluating critical process issues, establishing in-process controls, conducting stress tests, performing safety evaluations, engineering controls, evaluating timelines, improving yields, improving purities, improving efficiency, improving cost of goods, and instituting regulatory compliance. The development will consider a variety of purification and isolation methodologies that are critical to scalability, impurity identification and isolation, and cost. Process development will incrementally evaluate scalability and manufacturing to assess and verify improvements.

(4) Manufacture of the AAV9 vectors at scales requested by the NIH, including small-scale to support nonclinical studies (e.g. 1E+14 genome copies per prep or greater) with the future goal of being able to scale-up to clinical scale production (e.g. 5E+15 GC per prep or greater) using a scalable method and a characterized cell bank. This may include AAV vector serotypes 1 through 9, as well as additional serotypes that could become available in the future and be of interest to the NIH investigators. For the purposes of proposal development assume AAV9. Note: if, as a result of development studies, delivery of 5xE15 GC batch for clinical studies and toxicology (for each gene vector) will be determined not feasible, the NIH and Contractor will have a joint discussion on a path forward. The NIH can potentially adjust toxicology material requirements based on manufacturing feasibility. Delivery of separate batches for toxicology and clinical studies may also be acceptable.

(5) Employ and maintain state-of-the-art vector production technology for small- and large-scale productions. This may require the contractor to develop or refine such technology (or technologies).

(6) Provide a range of analytics for the characterization and release of the manufactured small-scale AAV lot, including but not limited to:

a. genome sequence determination

b. genome titer determination

c. infectious titer determination

d. amount of empty and full virus capsids

e. endotoxin detection

f. mycoplasma detection

g. purity

h. bioburden and/or sterility

i. host cell DNA

j. host cell protein

k. virus aggregation

l. particle content analysis

m. replication competent adeno-associated virus (rcAAV) assay

n. serotype identity

o. genome identity

p. potency

q. provide a rationale for conducting characterization and release assays according to project designation (i.e. discovery or IND-enabling)

r. development of analytical methods, including stability‐indicating methods per

ICH guidelines

s. qualification or validation of analytical methods, per ICH guidelines

t. development and qualification of potency assays

u. development and qualification of other relevant assays that may be required by regulatory agencies, including the FDA

(7) Development of assays for improved characterization of the small-scale lot, including the development of product-specific release and in vitro potency assays as needed to support late-stage preclinical studies.

(8) Supply Management (Package, Label, Storage, and Distribution). Provide aseptic fill finish of drug product and a summary plan for storage conditions and packaging for all final products. Each sample will be appropriately packaged and labeled according to a protocol that has been reviewed and approved by the COR. The Contractor shall have capability to ship samples in accordance with established material transfer agreements and to provide storage for samples for the length of the individual task order. Additional storage beyond the length of the task order may be requested by the COR under special circumstances. No samples should be discarded or destroyed without explicit written approval of the COR. The Contractor shall retain all samples and records throughout the life of contract.

(9) Use of SOPs and batch record forms for all production and quality control steps

Optional Task Specific Requirements

This Optional Task in the TO will cover Manufacturing and other related activities for delivery of clinical cGMP lots for a single project under the URGenT program. This Optional Task follows from the Base Task and may occur concurrently. The specific scope for this Optional Task may include the following as necessary to create the clinical cGMP lots. The Contractor will work with the LDT and PI to identify steps that need to be repeated or adjusted, or steps that are not needed again.

(1) Manufacture sufficient quantities of reagents required to support clinical scale AAV9 production including but not limited to:

a. cGMP plasmid DNAs required for recovering recombinant AAV9 production from cell culture; Provide DNA support services including but not limited to plasmid purification, structure and sequence analysis and next generation sequencing (NGS).

b. Generation of a DCB or cGMP MCB for manufacture of preclinical and/or clinical grade AAV vector, in accordance with GLP and applicable State and Federal regulations, for use by CROs approved by the NINDS. Associated activities include but are not limited to:

i. Perform production of DCB

ii. Perform production of cGMP MCB

iii. Perform production of WCB

iv. Characterize cell banks per ICH guidelines and other applicable regulatory guidelines (the offeror shall provide examples of typical MCB characterization plans)

v. Perform cell culture media and feed optimization

vi. Develop robust upstream processes

vii. Develop scalable downstream purification processes

viii. Determine critical process parameters

Separate costing should be provided for the Manufacture of Reagents activities.

(2) Perform additional process development as needed to establish manufacturing methodologies and processes amenable to scale-up and quality control. The effort will consist of activities, including but not limited to, sourcing raw material and intermediates, evaluating critical process issues, establishing in-process controls, conducting stress tests, performing safety evaluations, engineering controls, evaluating timelines, improving yields, improving purities, improving efficiency, improving cost of goods, and instituting regulatory compliance. The development will consider a variety of purification and isolation methodologies that are critical to scalability, impurity identification and isolation, and cost. Process development will incrementally evaluate scalability and manufacturing to assess and verify improvements.

(3) Manufacture of the AAV9 vectors at scales requested by the NIH, including sufficient material at large scale to support clinical studies (e.g. 5E+15 genome copies per prep or other depending on the specific needs of the program ) using a scalable method and a characterized cell bank. This may include AAV vector serotypes 1 through 9, as well as additional serotypes that could become available in the future and be of interest to the NIH investigators. For the purposes of proposal development assume AAV9. Note:

if, as a result of development studies, delivery of 5xE15 GC batch for clinical studies and toxicology (for each gene vector) will be determined not feasible, the NIH and Contractor will have a joint discussion on a path forward. The NIH can potentially adjust toxicology material requirements based on manufacturing feasibility. Delivery of separate batches for toxicology and clinical studies may also be acceptable.

(4) Employ and maintain state-of-the-art vector production technology for small- and large-scale productions. This may require the contractor to develop or refine such technology (or technologies).

(5) Provide a range of analytics for the characterization and release of the clinical scale manufactured AAV, including but not limited to:

a. genome sequence determination

b. genome titer determination

c. infectious titer determination

d. amount of empty and full virus capsids

e. endotoxin detection

f. mycoplasma detection

g. purity

h. bioburden and/or sterility

i. host cell DNA

j. host cell protein

k. virus aggregation

l. particle content analysis

m. replication competent adeno-associated virus (rcAAV) assay

n. serotype identity

o. genome identity

p. potency

q. provide a rationale for conducting characterization and release assays according to project designation (i.e. discovery or IND-enabling)

r. development of analytical methods, including stability‐indicating methods per

ICH guidelines

s. qualification or validation of analytical methods, per ICH guidelines

t. development and qualification of potency assays

u. development and qualification of other relevant assays that may be required by regulatory agencies, including the FDA

(6) Development of assays for improved characterization of vectors, including the development of product-specific in vitro potency assays to support late-stage preclinical and clinical studies

(7) Supply Management (Package, Label, Storage, and Distribution). Provide aseptic fill finish of drug product and a summary plan for storage conditions and packaging for all final products. Each sample will be appropriately packaged and labeled according to a protocol that has been reviewed and approved by the COR. The Contractor shall have capability to ship samples in accordance to established material transfer agreements and to provide storage for samples for the length of the individual task order. Additional storage beyond the length of the task order may be requested by the COR in special circumstances. No samples should be discarded or destroyed without explicit written approval of the COR. The Contractor shall retain all samples and records throughout the life of contract.

(8) Use of SOPs and batch record forms for all production and quality control steps

Deliverables and Reporting Requirements for the Base Task and Optional Task

(1) Biweekly Project Team Meeting updates (typically teleconferences) to review available experimental results and plan for the next period’s work. Minutes of project team meetings held during the month are due by the 15th of the following month.

(2) Monthly (or biweekly as necessary) Periodic Project Status Reports, due 24 hours before each Project Team Meeting.

(3) Development reports for each process development phase, due after completion of each phase.

(4) Study reports for each analytical method development, due after completion of each method development.

(5) Study protocols and study reports for each analytical method qualification. Reports due after completion of each method qualification.

(6) Executed batch records for manufacturing campaigns

(7) Certificates of Analyses. Due at the delivery of each small-scale, engineering run, and/or cGMP batch

(8) MSDS CMC reports in CTD and/or eCTD format. Due 2 months after delivery of cGMP batch for each product

(9) Non-GMP small-scale lots of AAV9 gene vectors. Specifications to be agreed on by NIH and Contractor based on product quality requirements and development data

(10) cGMP lots of AAV9 gene vectors suitable for clinical use

(11) Stability study protocols and stability study reports. Protocols due before start of stability studies. Stability study reports due no later than 2 months after each sample pull

Anticipated activities considered ancillary to the manufacture and analysis of biopharmaceuticals include, but are not limited to, the following:

(1) Deliver study reports, including but not limited to weekly status update reports, summary development reports, analytical methods development and qualification/validation reports, CMC report in CTD and/or eCTD format;

(2) Organize/conduct/participate in bi-weekly or weekly (as required) project update teleconferences;

(3) Perform technology transfer from/to a third party when required;

(4) Store non-GMP and GMP lots of BDS and BDP, and vialed material;

(5) Ensure compliance with cGMP; and

(6) Sustain Quality systems to support GLP and cGMP activities as evidenced by maintaining SOPs and Quality Audit records