3 - Ramp-On - TRND 3 - SOW - CMC DP 8_23_24.pdf

Statement of Work 1

DRAFT STATEMENT OF WORK

Chemistry, Manufacturing and Controls and Related Services for Development of Drug Products

Revised August 23, 2024

I. Introduction/Background

The Therapeutic Development Branch (TDB) within the Division of Preclinical Innovation (DPI) at the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), conducts translational research on human therapeutics development by moving small molecule and biologic drug candidates forward in the drug development pipeline. Upon reaching predetermined milestones, TDB hands off clinical candidates to external partners to bring these novel therapies to patients. In addition to developing new candidate drugs, TDB seeks to advance the entire field of drug discovery and development by encouraging scientific and technological innovations aimed at improving success rates in the crucial preclinical stage of drug development. The TDB model is to operate as a comprehensive small molecule and biologics drug development organization, moving therapeutic candidates through each phase of the preclinical development process until an Investigational New Drug (IND) application is filed with the US Food and Drug Administration (FDA). For certain drug development campaigns, TDB will support studies up to human Phase IIb. TDB conducts drug development through collaborations, with therapeutic candidates originating from academia, industry, non-profit foundations, or internally from NCATS and other NIH institutes. TDB’s operational strategy is to combine the capabilities of in-house staff and collaborative partners, who may be the drug originators, with complementary support from contract research organizations (CROs). Each development program operates in a multi-disciplinary matrix team environment, with a DPI project officer (PO) responsible for overall planning, execution, and reporting.

II. Scope and Objectives

The scope of this Statement of Work is Chemistry, Manufacturing, and Control (CMC) services for Drug Products. The objective is to ensure receipt of formulated Drug Product (DP) of sufficient quality and quantity to support preclinical, IND-enabling, and clinical studies.

The Contractor shall provide support for a broad range of preclinical services required for the design, development, manufacture, and release of DP as Clinical Trial Material (CTM) and all required testing.

Ancillary products (e.g., placebos, diluents, adjuvants, master cell banks, testing standards, reference materials) and other materials manufactured or purchased to support clinical trials or CMC activities may also be required. All activities preliminary to manufacturing in accordance with current Good Manufacturing Practice (cGMP) may be required (e.g., development or engineering lots, formulation studies), even without an associated cGMP manufacturing task. All activities required to maintain material in a usable state, including storage, shipping, testing (in process, release, stability, and quality actions), and preparation of documents to support regulatory submissions may also be required.

Product formats may include small molecules, short oligomeric compounds, biological (large) molecules, quaternary molecular assemblies (homogenous or heterogenous), vectors for gene therapy, nanoparticles, and any of the above modified genetically, biologically, or chemically. Novel formats identified after this draft might also be needed. Formats could also include Devices or Combination Products.

The breadth of this Statement of Work (SOW) includes capabilities to support a range of activities differing in size, complexity, and duration.

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III. General Requirements

The below General Requirements apply to each Task Order issued under this indefinite-delivery, indefinite-quantity (IDIQ) contract and will be supplemented by additional details as needed for each Task Order.

Contract Administration

The Contractor shall perform activities related to the overall administration of the contract. This includes fulfilling administrative reporting and deliverable requirements, ensuring contract terms and conditions are adhered to, and communicating with the Contracting Officer’s Representative (COR) and Contracting Officer (CO) as needed.

Project Management

The Contractor shall provide project management for their own core team to ensure effective project planning, execution, delivery of reports, and accurate and timely communication with the COR, CO, and other stakeholders. The Contractor shall provide and implement overall project management to coordinate and integrate activities for each Task Order. The Contractor shall provide sufficient project management staff to ensure management and monitoring of all Task Order activities and shall identify for each Task Order a lead individual who will serve as a primary point of contact for the Government.

The Contractor shall provide qualified multidisciplinary staff to fulfill the requirements of each Task Order award. For each discipline, the staff shall have all the required and customary training, experience, and licensure or certification needed to fulfill their assigned role.

Collaboration and Communications

The Contractor shall provide effective collaboration and communication with the COR, CO, and other stakeholders as needed to support successful Task Order performance and project outcomes. This includes providing status updates and technical information when requested and providing information as needed to ensure the Government is sufficiently informed in accordance with the needs of the project. This also includes collaboration on deliverables, technical approaches, or other areas.

The Contractor shall participate in regularly-scheduled and ad hoc meetings with the Government and other stakeholders as needed. The Contractor will generally be required to provide meeting support such as logistics and arrangements, facilitation, graphics and video support, materials preparation and distribution, and translation, as well as meeting notes, minutes, summaries and/or summary reports. Such meetings may include:

• Task Order Initiation / Kick-Off Meetings. These meetings are to review the applicable requirements and timelines, discuss technical plans/Project Management Plan and approaches, and identify any anticipated problems/obstacles to completing the requirements.

• Progress Review Meetings. These meetings are to review and discuss ongoing and planned activities, protocols and associated data; timelines for task initiation and completion, submission of data and other information; any problems or deficiencies identified with respect to the accuracy, timeliness, and completeness of research, trials and studies, including outcomes such as data submission; and any other matters relevant to the Task Order performance or administration.

• Ad Hoc Meetings. These meetings may be required to address issues or questions that arise related to performance or administration. They may also include investigator, protocol, working group, strategic

Statement of Work 3 planning, and network meetings.

Quality Management

The Contractor shall ensure that all work performed under this contract, including by any subcontractors, meets the highest levels of quality, as appropriate for the task. All management and operational systems used must be sufficient to monitor, maintain, and document quality.

One or more domestic or international regulations may apply to Task Orders issued under this IDIQ. These include, but are not limited to, US FDA current Good Manufacturing Practice (cGMP), Good Laboratory Practice (GLP) and Good Clinical Practice (GCP) regulations, and/or International Council for Harmonisation (ICH) and International Organization for Standardization (ISO) regulations. When one or more regulations apply, the Contractor shall:

• Provide a Quality Assurance Unit (QAU) that is independent of other operations of the Contractor to assure that all products and services meet quality requirements and comply with international, federal, state and local government regulations, as applicable.

• Provide a Quality Assurance/Quality Control (QA/QC) infrastructure for the awarded Contract including SOPs for establishing and maintaining the QA/QC processes and approaches/methods to document, identify the source(s) of and address any problems and deviations as they occur, as well as provide recommendations for the resolution of problems and correction of deviations. The Contractor shall have a Quality Management Plan (QMP) that shall include management responsibilities, resources, assessment and training, oversight of outsourced operations, defined metrics, and accountability for identification and remediation of errors as well as communication processes and timelines.

• Arrange and/or accommodate independent audits of any Contractor or subcontractor sites. The Government may require an independent audit of any Contractor and/or subcontractor sites to ensure that all facilities satisfy the quality requirements set forth for successful performance of the work. During such an audit, the Contractor shall ensure that staff, facilities, and relevant documentation are available. The Contractor shall prepare updates to the QMP and provide updated plans including corrective actions and preventative actions (CAPA) as needed.

Facilities, Equipment and Other Resource Management

The Contractor shall provide and maintain facilities, equipment, space, and other resources as needed that comply with all local, domestic, in-country, state, federal and NIH regulations. The Contractor shall maintain QA documentation to support adherence to these areas. This includes submitting a floor plan of the relevant facilities, including details of the water quality systems, and providing safe and secure operation of / access to facilities; establishing processes and procedures limiting access to only approved and qualified staff to physical sites, systems, equipment, technology, internet, and/or data; and providing biohazard, environmental and occupational health safety, emergency management/preparedness, security, transportation and logistics services. All work with hazardous biological materials shall comply with all local, domestic, in-country, state, federal and NIH regulations. Contingency and catastrophic event plans shall be developed and documented to protect project-related work.

The Contractor shall provide for overall management and conduct of the receipt, storage, retrieval, custom clearance, packaging and shipping of materials, including obtaining appropriate licenses and permits and developing SOPs for processes and procedures. All storage, packaging, and shipping shall comply with all local laws and all applicable regulations. As appropriate, material shall be inventoried and tracked to ensure chain of custody. Plans shall be developed and documented to identify and mitigate against supply chain or other delays to ensure steady access to critical resources.

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Data Access and Technology Transfer

The Contractor shall fully support submission of technology transfer packages to the Government or a designated third party when directed by the COR and/or at the completion of the Task Order. Technology transfer packages will include information, technology, and documentation created with sufficient detail, clarity, and completeness to enable the receiving party to fully understand, and if needed, repeat activities of the Task Order. In certain cases, the Contractor may be required to provide training to the Government or designated third parties to utilize or operate a subject technology. The Contractor will support NCATS regulatory affairs processes by providing authorization to the Government and/or any relevant third parties identified by the Government to access and cross reference relevant prior data generated by the Contractor, including but not limited to, drug master files (DMFs) or other previous regulatory filings, as needed.

Site Visits

The Contractor shall arrange and/or accommodate site visits and independent audits as needed. Site visits may be necessary to ensure that all required equipment is available and in good working order and to review the training records of all key technical staff, as available. Audits may be needed to assure Contractor and subcontractor facilities and all planned procedures meet regulatory (e.g., GMP, GLP) standards. The 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 data generated by the Contractor to support manufacture of cGMP material shall have a strict quality system review of raw data and transcription, technical supervisor approval, and quality assurance (QA) release.

Project Closeout

The Contractor shall ensure an orderly, secure, and efficient transition at the conclusion of each Task Order.

This may include preparing and submitting a Transition Plan; transferring and/or disposing of contract-related materials, supplies, and information / data; and retaining documents in secure storage (up to five years).

IV. Technical Requirements

Independently and not as an agent of the Government, the Contractor shall be required to furnish all the necessary services, qualified personnel, materials, equipment, and facilities not otherwise provided by the Government to provide the services described in this Statement of Work and subsequent Task Orders. Task Orders will include tasks and activities that fall under one or more of the below technical areas.

Technical Area 1: Formulation Development, Manufacture and Analysis of Small Molecule Drug Products

I. The Contractor shall perform activities related to the formulation development, manufacture and analysis of small molecule drug products.

II. Anticipated activities related to the formulation development and manufacture of small molecule drug product include, but are not limited to, the following:

a. Perform technology transfer from the Government or its collaborators, and route familiarization.

b. Perform formulation development studies and define final formulation.

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c. Perform pre-formulation studies based on the targeted dosage form.

d. Conduct formulation development studies based on the targeted dosage form.

e. Determine critical/key process parameters and optimize final formulation using Design of

Experiments (DoE)

f. Perform process demonstration runs.

g. Perform cost analysis.

h. Manufacture non-GMP DP of sufficient quality and in quantities necessary to meet the needs of preclinical studies, typically 500 to 5,000 units.

i. Manufacture DP under cGMP, of sufficient quality and in quantities to support clinical studies, typically 1,000 to 10,000 units.

III. Anticipated activities related to the analysis of small molecule drug products include, but are not limited to, the following:

a. Develop necessary in process control (IPC) methods for manufacture of DP.

b. Validate analytical and stability-indicating, dosage-specific analytical methods (e.g., dissolution method for capsule dosage form).

c. Identify, isolate, and characterize impurities and degradation products.

d. Develop release specifications.

e. Perform all tests necessary to release DP for clinical use, including issuing a certificate of analysis (COA).

f. Establish stability protocols with proper specifications for DP and perform stability studies up to 24 months (minimum) per guidelines published by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

g. Perform clinical simulation studies of the intended administration of DP to humans.

IV. Anticipated activities considered ancillary to the formulation development, manufacture and analysis of small molecule drug products include, but are not limited to, the following:

a. Deliver study reports, including but not limited to weekly status update reports, summary development reports, analytical methods development and qualification/validation protocols and reports, Master Batch report, GMP campaign report, and CMC report in the common technical document (CTD) format utilized for regulatory submissions to the FDA.

b. Conduct bi-weekly or weekly (as required) project update teleconferences.

c. Perform technology transfer from/to a third party when required.

d. Store non-GMP and GMP lots of Reference Standard (RS), Drug Substance (DS) and DP.

e. Ensure compliance with cGMP.

f. Maintain quality systems to support cGMP activities.

g. Provide quarterly cost schedule and performance reports.

Technical Area 2: Formulation Development, Manufacture and Analysis of Synthetic Peptides, Oligonucleotides, and Related Drug Products and analysis of synthetic peptides, oligonucleotides, and related drug products.

II. Anticipated activities related to the formulation development and manufacture of synthetic peptides, oligonucleotides, and related substances include, but are not limited to, the following:

a. Perform technology transfer from the Government or its collaborators, and route familiarization.

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b. Perform pre-formulation studies based on the targeted dosage form.

c. Conduct formulation development studies based on the targeted dosage form.

d. Perform formulation development studies and define final formulation.

e. Determine critical/key process parameters and optimize final formulation using Design of

Experiments (DoE)

f. Perform process demonstration runs.

g. Perform cost analysis.

h. Manufacture non-GMP DP of sufficient quality and in quantities necessary to meet the needs of preclinical studies, typically 500 to 5,000 units.

i. Manufacture DP under cGMP, of sufficient quality and in quantities to support clinical studies, typically 1,000 to 10,000 units.

III. Anticipated activities related to the analysis of synthetic peptides, oligonucleotides, and related substances include, but are not limited to, the following:

a. Validate analytical and stability-indicating methods.

b. Perform forced degradation studies.

c. Identify, isolate, and characterize impurities and degradation products.

d. Develop release specifications.

e. Perform all tests necessary to release DP for clinical use, including issuing a COA.

f. Establish stability protocols with proper specifications for DP and perform stability studies up to 24 months (minimum) per ICH guidelines.

g. Perform clinical simulation studies of the intended administration of DP to humans.

IV. Anticipated activities considered ancillary to the manufacture and analysis of synthetic peptides, oligonucleotides, and related substances include, but are not limited to, the following:

a. Deliver study reports, including but not limited to weekly status update reports, summary development reports, analytical methods development and qualification/validation protocols and reports, forced degradation study protocols and reports, Master Batch reports, GMP campaign reports, and CMC report in CTD format.

b. Conduct bi-weekly or weekly (as required) project update teleconferences.

c. Perform technology transfer from/to a third party when required.

d. Store non-GMP and GMP lots of RS, DS and DP.

e. Ensure compliance with cGMP.

Technical Area 3: Formulation Development, Manufacture and Analysis of Biopharmaceutical and Gene Therapy Drug Products and analysis of biopharmaceutical and gene therapy drug products.

II. Anticipated activities related to the manufacture and analysis of biopharmaceuticals and gene therapies include, but are not limited to, the following:

a. Analytical method development:

Statement of Work 7 o Develop, qualify and/or validate analytical methods, per ICH guidelines.

o Perform characterization of Drug Substance (DS) and Drug Product (DP) for identity, content, purity, potency and safety.

o Develop release specifications.

b. Formulation development studies:

o Perform excipient screening, optimize, and develop final formulation buffer for liquid formulation and lyophilization protocol for lyophilized DP.

o Perform accelerated stability studies.

o Define container closure and fill finish strategy.

c. Manufacturing under current Good Manufacturing Practices (cGMP):

o Manufacture Master Cell Banks and perform cryo-storage (expected to be not less than

300 vials per candidate).

o Conduct viral clearance validation studies.

o Manufacture cGMP lots of DP (including fill finish, in amounts determined per TO) to support clinical studies, typically 1,000 to 10,000 units.

o Perform all tests necessary to release DP for clinical use, including issuing a COA.

o Perform stability evaluation of DP, per ICH guidelines.

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

a. Deliver study reports, including but not limited to weekly status update reports, summary development reports, analytical methods development and qualification/validation reports, executed cGMP batch records, a CMC report in CTD format.

b. Conduct bi-weekly or weekly (as required) project update teleconferences.

c. Perform technology transfer from/to a third party when required.

d. Store non-GMP and GMP lots of RS, DS and DP.

e. Ensure compliance with cGMP.