A3_Contract_Statement_of_Work.pdf

STATEMENT OF WORK

A. BACKGROUND INFORMATION AND OBJECTIVES

The National Institutes of Health (NIH) established the Blueprint Neurotherapeutics Network (BPN) to bridge the gap in drug development between academic and industry research (http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm). The BPN supports, through grants and contracts, every step of the drug development process from validated hits through Phase I clinical trials. The Drug Manufacturing and Formulation Program (DMFP), a component of the BPN, will conduct the active pharmaceutical ingredient (API) synthesis and development and manufacture of dosage forms of small molecule drug candidates suitable for administration in preclinical efficacy studies, Investigational New Drug (IND) enabling studies, and clinical trials. As detailed in this Statement of Work (SOW), the National Institute of Neurological Disorders and Stroke (NINDS) anticipates awarding multiple Indefinite Delivery/Indefinite Quantity (ID/IQ) contracts to contractors that, together, will constitute the DMFP. Said Contractors will conduct process development and preparation of active pharmaceutical ingredients (API), pre-formulation and formulation studies, analytical method development and validation, stability studies, drug product manufacturing, packaging, storage, and distribution of the API and drug products. The work will be conducted in accordance with Current Good Manufacturing Practices (cGMP) regulations as required and as appropriate Good Laboratory Practice (GLP) regulations. Data and documentation will be prepared for all chemistry, manufacturing, and controls (CMC) regulatory documents in a form acceptable to the Food and Drug Administration (FDA) for inclusion in a Drug Master File (DMF), IND application, or New Drug Application (NDA).

The DMFP will interact with other components of the BPN, as indicated:

1. Neuroscience researchers who initiated the project (Contributors) will provide the DMFP with small-scale medicinal chemistry synthetic routes and analytical standards to serve as the starting point for DMFP activities.

The Contributors’ compounds will be provided to contractor as samples with protocols and limited physical/chemical characterizations.

2. NIH Staff, the Contracting Officer (CO) and Contracting Officer’s Representative (COR), will oversee the execution of the DMFP contract.

The COR will offer suggestions and provide feedback to the contractor on various activities including process development, formulation, and project design, with advice from NINDS-hired consultants (see below). The COR will provide information on the scope of work required (i.e., the entry and exit stages), the desired dosage form, materials and information required for effective technology transfer within a Task Order Request for Proposal

Date: 06/07/2024

PROJECT TITLE: Drug Manufacturing and Formulation Program (DMFP) http://neuroscienceblueprint.nih.gov/bpdrugs/index.htm

(TORFP).

3. Lead Development Team (LDT). The NINDS will hire consultants to assist the COR in reviewing proposals, reports, and data produced by the contractor and contributors. The COR, consultants, contributor, and contractor leaders will form the LDT. The LDT will serve as the leadership team for the development work for the project. The LDT will meet approximately every 2 weeks by teleconference and ad-hoc when requested to discuss strategies and review data.

4. Other BPN contractors. The contractor will communicate and collaborate with other BPN vendors to arrange technology transfer or shipment of materials.

B. SCOPE AND PERFORMANCE ACTIVITIES

The National Institute of Neurological Disorders and Stroke (NINDS) anticipates awarding multiple Indefinite Delivery/Indefinite Quantity (ID/IQ) contracts to contract research organizations that are found to best meet the overall qualifications needed to fulfill the technical requirements of this SOW.

The goal of the DMFP contract is to initiate and complete API scale up and manufacture, formulation, and dosage form manufacture, analytical methods development, stability testing and included but not limited to documentation, fill and finish, packaging, and labeling to enable BPN candidate molecules or other NIH drug discovery projects to enter clinical stage development. All activities under the DMFP contract are executed in accordance with current Good Manufacturing Practices (cGMP) regulations as required and as appropriate Good Laboratory Practice (GLP) regulations. It is the responsibility of the contractor to establish quality assurance and quality control systems in line with current FDA and ICH guidelines.

Independently and not as an agent of the Government, contractors shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities, to perform the activities outlined in each of the following Performance Activities:

B.1 Performance Activity 1 (PA1) – Kickoff Meeting:

The contractor shall ensure and participate in a one-day contract initiation meeting.

The meeting will be scheduled by the contracting officer’s representative (COR) and will take place within two months following the effective date of the base contract award. For additional details, please see Attachment 3 – Sample Task Order #0001 Statement of Work (SOW).

B.2 Performance Activity 2 (PA2)– General Administration and Technical Support/ API Scale Up and Manufacture/ Formulation and Dosage Form

Manufacture/ Analytical Methods Development and Stability Testing

Performance Activity 2 encompasses two major activities: Performance Activity 2A (P2A) which include general administration and technical support and Performance Activity 2B (P2B), which covers API Scale Up and Manufacture/ Formulation and Dosage Form Manufacture/ Analytical Methods Development and Stability Testing.

B.2.1 Performance Activity 2A – General Project Administration and Technical Support:

Work under Performance Activity 2A, the contractor (Project manager/ principal investigator) shall provide general administration, coordination, and management of contract activities, participate in LDT, ad hoc meetings and teleconferences (for example pre-IND meeting, IND meetings, and additional FDA updates); prepare and submit reports as required by the terms of the contract or specified timeframes to the COR and CO and provide the necessary technical support for information technology and information systems security staff and timely submission of information systems reports as required.

B.2.2 Performance Activity 2B – API Scale Up and Manufacture/ Formulation and Dosage Form Manufacture/ Analytical Methods Development and Stability Testing:

PA2B shall incorporate one or more but not limited to the following activities:

B.2.2.1 API Scale Up and Manufacture: The contractor shall have adequate infrastructure to perform scale up and manufacturing of API from approximately small scale (≈25 g) up to typically 1-2 kg but large scale (10 kg) should be accessible as needed. API scale up and manufacture shall support preclinical studies, IND enabling studies, and clinical studies, which will be performed by other components of the BPN. The contractor should have the ability to conduct API manufacturing and qualification under cGMP/GLP conditions as appropriate on request. The contractor shall also provide chemistry expertise to perform process development to transition from medicinal chemistry routes to establish synthetic methodologies and processes amenable to scale up, and quality control. The contractor will be required to have adequate personnel, equipment, and space to perform approximately 1-2 API scale up and manufacture campaigns simultaneously. The contractor must have the capability to ship samples and provide adequate facilities for the storage of raw, intermediates, final materials, and products according to regulatory requirements, and including controlled substances for the length of the individual task order.

B.2.2.2 Formulation and Dosage Form Manufacture: The contractor shall conduct studies to support the development of suitable formulations and dosage forms manufacture of potential therapeutics for clinical testing (typically for Phase I testing). Targeted formulations may include, and are not limited to, oral (through the mouth), parenteral (intravenous or intramuscular or subcutaneous), topical (skin) forms (cream, ointment, gel, paste or powder), intraocular, transmucosal (intravitreal, nasal, buccal/sublingual, vaginal, and rectal), inhalation, and others.

The contractor shall also package, label, store, and ship materials intended for evaluation in preclinical studies, IND enabling studies, and clinical studies.

Activities shall be performed in compliance with cGMP/GLP guidelines as necessary. Formulations shall be manufactured as sterile products as necessary.

B.2.2.3 Analytical Methods Development and Stability Testing:

The contractor shall conduct suitable analytical methods development in a stage appropriate fashion to provide qualification and if required validation studies to support API and dosage form manufacture of potential therapeutics. The studies shall support documentation of the identity, strength, quality, purity, potency and stability of drug substances and drug products. The contractor shall have capabilities in assembling information, submitting samples, and presenting data to support analytical methodologies for drug substances and drug products in a form acceptable to the FDA for an IND or NDA submission. The contractor shall also conduct stability studies to collect up to 5-year stability data to ensure product stability during preclinical/clinical studies. The stability studies will be conducted under long-term (usually 60 months), accelerated (6 months), intermediate (12 months), and/ or under photo-stability conditions.

C. TECHNICAL REQUIREMENTS

C.1 SPECIFIC REQUIREMENTS AND SCHEDULE OF WORK

NINDS intends to award a Multiple-Award ID/IQ Contract having a period of performance of 10 years. As necessary, NINDS will issue Task Orders under which the Contractor will perform any or all the Performance Activities listed below.

The NINDS intends to issue Task Order #001 for Performance Activity 1 –Kickoff Meeting concurrent with the Base Contract Award. Task Order #001 will be a onetime payment for a base performance period of 10 years.

Task Orders under Performance Activity 2 will be awarded following the issuance of and response to a Task Order Request for Proposal (TORFP) which will describe a DMFP project. TORFPs will be issued as the need arises. It is anticipated that these Task Orders will be non-severable, cost-reimbursement, completion-type task orders and have variable periods of performance. NINDS anticipates issuing 1-2 TORFPs for Performance Activity 2 during each year of the base contract. The amount of work required for each Task Order will depend upon the needs of NINDS and the availability of funds. The amount of work may vary from year to year. Due to changes in priorities within NINDS, the projected workload cannot be precisely described for each year.

The following is a more detailed description of the performance activities that the

NINDS may assign to the contractor via issuance of a Task Order under the contract, although all activities may not be carried out necessarily in every year or in every Task Order. The contractor shall not perform any work for the NINDS unless authorized in an appropriately awarded Task Order:

C.1.1 REQUIREMENTS FOR PERFORMANCE ACTIVITY 1: KICKOFF MEETING

The contractor shall ensure and participate in a one-day contract initiation meeting to be held at the contractor’s facility. The meeting will be scheduled by the contracting officer’s representative (COR) and will take place within two months following the effective date of the base contract, and shall be attended by the Principal Investigator/ Project manager and other relevant key contractor technical and business staff, the contracting officer (CO), and the COR. The purpose of the meeting shall be to introduce contractor and NINDS staff, review the terms and conditions of the base contract and to go over the contractor and subcontractor(s)’ capabilities and facilities.

C.1.2 REQUIREMENTS FOR PERFORMANCE ACTIVITY 2:

C.1.2.1 REQUIREMENTS FOR PERFORMANCE ACTIVITY 2A – GENERAL

ADMINSITRATION AND TECHNICAL SUPPORT

Work under this performance activity will require the principal investigator/ project manager to consult with the project COR (it is expected that weekly consultations will be necessary based on experience from the current contracts), attend and participate in all meetings and teleconferences; and approve/sign-off on all contract deliverables. As part of Performance Activity 2A, the contractor (Project manager/ principal investigator) shall also provide general administration, coordination, and management of contract activities, participate in LDT, ad hoc meetings and teleconferences (for example pre-IND meeting, IND meetings, and additional FDA updates); prepare and submit reports as required by the terms of the contract or specified time frames to the COR and CO and provide the necessary information technology and information systems security staff and timely submission of information systems reports as required.

C.1.2.1.1 SCOPE

General administration and technical support shall be conducted on a recurring basis to support all Task Orders Request for Proposals awarded under the DMFP contract.

C.1.2.1.2 TECHNICAL REQUIREMENTS

Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary administrative services to perform all activities outlined in the Statement of Work. Specifically, the contractor shall provide:

C. 1.2.1.2.1 PROJECT MANAGEMENT

The contractor (Principal Investigator/ Project manager) shall plan, initiate, implement, manage, and coordinate the activities of this Contract. Provide administrative and technical support for the evaluation of new Task Order Request for Proposal (TORFP) and for all planning activities associated with Task Orders prior to their award. Coordinate the management of all awarded Task Orders and monitor overall progress within each Task Order. Task Order-specific project management activities will be incorporated into the Statements of Work for each individual Task Order.

C. 1.2.1.2.2 MEETINGS

Convene standing and ad hoc meetings/teleconferences between contract personnel, NINDS staff, and Lead Development Team (LDT) approximately every 1-2 weeks to review and discuss status of ongoing Task Orders and any technical problems or issues requiring resolution. Provide meeting minutes to the COR and the LDT within 48 hours of the conclusion of the meeting.

C. 1.2.1.2.3 TRANSITION PLANS

Provide an orderly, secure, and efficient transition of contract activities and contract-related data, documents, and other materials in the event transition between contractors is required.

C. 1.2.1.2.4 Final Transition

a) Three (3) months prior to the expiration date of the Task order activities, the

Contractor shall submit to the CO and COR for approval a Final Transition Plan providing for an orderly transition of unfinished work to a successor Contractor or to the Government. The Final Transition Plan shall include:

1) A list of performance activities anticipated to be unfinished on the expiration date of the incumbent’s contract and the remaining steps needed for a successor contractor to complete the Task Orders.

2) Plans for transportation of Task Order-related materials and data necessary for completing any activities anticipated to be unfinished on the completion date of the incumbent’s contract.

3) A timeline of proposed activities required to complete the transition and proposed personnel and their level of effort.

4) The Contractor shall implement and complete the Final Transition prior to the expiration date of the Task Order.

C.1.3 REQUIREMENTS FOR PERFORMANCE ACTIVITY 2B – API SCALE UP AND

MANUFACTURE/ FORMULATION AND DOSAGE FORM MANUFACTURE/

ANALYTICAL MRTHODS DEVELOPMENT AND STABILITY TESTING

C.1.3.1 SCOPE

Independently, and not as an agent of the Government, the contractor shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities as needed to successfully perform activities defined under performance Activity 2B which includes all technical activities related to API scale up and manufacture, formulation and dosage form manufacture, analytical methods development, and stability testing. The contractor (Project manager/ Principal investigator) will be responsible with the overall administration and implementation of all work under

PA2B.

To mitigate potential early termination of drug development projects and to better manage the DMFP contract budget, technical activities falling under PA 2B can be divided into three major campaigns (Sample Task Order-Attachment # 3):

A. Feasibility studies (Campaign #1) includes but not limited to the following performance activities: chemistry technology transfer, route familiarization and process development, chemical synthesis of demonstration batch, analytical method development and qualification, salt polymorph screen, characterization of API and related substances, synthesis of labelled reference standard, annual certification of reference standards and supply chain management.

2) Clinical trial readiness (Campaign#2) includes but not limited to the following performance activities: chemical synthesis and scale up of toxicology batch, ICH stability on toxicology batch, analytical methods development, pre-formulation studies, formulation development studies and supply chain management of the toxicology batch.

3) Clinical trial material (Campaign #3) includes but not limited to the following performance activities: manufacture of GMP API, ICH stability on GMP API, preparation of drug product, analytical methods development, ICH stability on drug product, packaging, labelling and distribution of drug product.

C.1.3.2 TECHNICAL REQUIREMENTS:

C.1.3.2.1 API SCALE UP AND MANUFACTURE

a. Chemistry Technology Transfer:

Perform chemistry technology transfer within 30 days of Task Order award. These activities will include, but are not limited to:

1. Communicating with small scale chemistry vendor

2. Participating in LDT meetings/conferences

3. Creating and sharing electronic files securely

4. Receiving and storing samples under controlled conditions

5. Performing analytical and physicochemical testing to fully characterize samples

6. Reporting final characterization of received samples and completed technology transfer

b. Process Development:

Perform process development to establish synthetic 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 shall result in a synthetic methodology that considers linear and convergent chemical syntheses, as well as stages at which regulatory requirements are critical. 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.

c. Chemical Synthesis:

Conduct scale up chemical synthesis and manufacture in accordance with GLP and cGMP guidelines as required. The optimal goal is to move purity levels of greater than 99%, while identifying and characterizing impurities according to the ICH guidelines outlined in the following Table.

Independently synthesize and characterize certain impurities and related compounds as requested.

Establish, communicate, and update lead times for a variety of batch sizes but not limited to 25g to 10kg.

Standard operating procedures (SOP) shall be established and approved by the COR in advance of initiating chemical synthesis. All batches above 50 grams should follow SOPs and undergo full quality control review by the Contractor. The Contractor shall always make available to the COR the quality control and assurance documents and batch records via secure site provided by the NINDS. The purity levels for individual batches should be fully characterized and reported. Later stage batches that would go into preclinical toxicology and clinical studies shall be accompanied by full chemistry write up and follow FDA mandated GMP/GLP guidelines. Any deviation from the guidelines and standard operating procedures must be communicated with the COR upon discovery. Additional batch records shall be available as requested.

d. Analytical Method Development:

Fully characterize all intermediates and final compounds resulting from approved studies including, but not limited to, NMR, HPLC, HPLC/MS, and elemental analysis. Characterize the final compounds for stability and morphology studies including, but not limited to, stability studies according to the International Conference on Harmonization (ICH) guidelines, crystallinity, melting properties, and various isolation strategies to yield the final product. Additional studies may be required such as salt screen, solubility, density, storage conditions, packaging, solvent content, impurities, and compatibilities.

e. Supply Management (Package, Label, Storage, and Distribution):

Provide a summary plan for storage conditions and packaging for all final compounds and intermediates. 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 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.

f. Non-standard/Exploratory Studies:

If API scale up and manufacture require non-standard/exploratory studies or tests as required by the FDA or requested by the COR, the contractor shall obtain the necessary resources and staff to perform such studies.

C.1.3.2.2 FORMULATION AND DOSAGE FORM MANUFACTURE

a. Preformulation Studies API Characterization:

Preformulation is defined as a stage of development during which the physicochemical properties of the drug substance is characterized and established. A complete knowledge of the relevant therapeutic and physicochemical properties of the drug enables determination of its proper formulation and delivery method.

The Contractor shall perform and validate physical and chemical characterization of API to determine the properties as described below.

Emphasis shall be on obtaining preliminary information for early identification of problems with the API under study. Preformulation studies can include determining and assessing the solid-state properties of the API such as: crystallinity, hygroscopicity, particle size, shape, surface area, and moisture/solvent content. Additional studies can include polymorph studies for example, identification, characterization and synthesis of the most stable polymorph. Additional studies may include solid and solution state chemical stability, biopharmaceutical profiling including: pKa and LogP determination, pH-solubility profile, permeability and BCS classification, solubility in pharmaceutical solvents and physiological buffers. Additional processing of the API may be required such as micronization, spray dried dispersion etc. in order to have acceptable PK of the API. The following properties may be determined, but are not limited to:

i. Organoleptic

ii. Microscopic: Morphology, birefringence and particle size.

Characteristic tests may include powder x-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), microscopy, Raman spectroscopy, and Karl Fischer moisture analysis.

Additional tests can be performed if requested

iii. Physical: Hygroscopicity, melting point, thermal analysis and polymorphism

iv. Solution: pKa, partition coefficient and solubility in various solvent systems such as water and buffers (pH 1-2, 4.8 and pH 7.4). If necessary, surfactant solutions, cyclodextrin solutions, non-aqueous solvents, and mixed solvents may be used for solubility

v. Stability: Solid and solution stability including photo-stability under accelerated and/or long-term storage conditions including room temperature and refrigeration conditions using thermal analysis, spectroscopy techniques and/or other methods available

All studies shall be performed using standard operating procedures in accordance with FDA and ICH guidelines as requested by the COR.

b. Preclinical Prototype Formulations:

Preparation of species-tolerated/compatible prototype formulation(s) to enable in-vivo pharmacokinetic, efficacy, dose-range finding and IND enabling toxicology/GLP safety studies. Preclinical prototype formulations to be evaluated should include oral along with intravenous bolus/ infusion, subcutaneous, intraperitoneal, nasal, intra-ocular, and intrathecal routes of administration.

The formulation enabling studies should encompass the following considerations:

i. Solubility screening studies in biorelevant media which may include the use of biocompatible buffer systems, and may also encompass the use of surfactants, cosolvents, oils/lipids, and/or complexation agents

ii. Preclinical formulation development should accommodate a dose-range varying from about 50 to 500 mg/kg either as a solution, emulsion, or suspension dosage form

iii. Preclinical chemical and physical formulation stability studies at ambient and physiological relevant temperatures.

c. Preformulation Studies:

Perform and validate studies with emphasis on physical and chemical stability of drug-excipients mixtures either in solid or solution state under accelerated and/or long-term storage conditions. Activities included, but not limited to, are as follows:

i. Physical characteristics of bulk drugs: Density, surface Activity, static charge, flow properties, compressibility, dissolution rates at pHs 1-2, 4.8 and 7.4 and pH-solubility profiles.

ii. Drug-excipients compatibility in solid state: Physical mixtures of drug and commonly used excipients for tablets and capsules will be evaluated for physical and chemical stability under accelerated and/or long-term storage conditions. Dissolution rates of the drug-excipients mixtures will be measured at pHs 1-2 (stomach), 4.8 (intestines) and 7.4 (blood).

iii. Drug-excipients compatibility in solution state: Physical and chemical stability of drug solutions in aqueous vehicles containing commonly used excipients such as antioxidants, buffers, antimicrobial agents, non-aqueous solvents, or solubilizing agents will be evaluated under accelerated and/or long-term storage conditions.

iv. Analytical methods development to evaluate the stability of the drug-excipients mixtures in solid and solution states for screening purposes.

d. Clinical Formulation:

Perform and validate formulation studies with emphasis on dosage form development for Phase I and II clinical trials. Evaluate physical and chemical stability of candidate formulations including solid such as tablets and capsules, liquid (solution, emulsion, and suspension) and semi-solid under accelerated and/or long-term storage conditions. Submit manufacturing procedures and product specifications to COR on request.

Activities include, but are not limited to:

i. Preparation of prototype formulations for preclinical, Phases I and II based on the preformulation data.

ii. Determine physical and chemical stability studies of the prototype formulations under accelerated and/or long-term storage conditions.

iii. Optimization of the prototype formulations if needed.

iv. Selection of packaging/closure system based on the stability study for moisture-sensitive dosage forms and on the compatibility study especially for liquid dosage forms.

v. Stability studies on the optimized/selected formulations if needed.

vi. Establishment of a final formulation based on the stability data.

vii. Establishment of a placebo formulation.

viii. Provide Pharmacy Manual with step-by-step instruction to enable manufacturing of the dug product and placebo on-site at the Phase I unit.

ix. Establishment of manufacturing procedures for a batch size of up to but not limited to 1,000 units for active and placebo drug product.

x. Establishment of test methods for active and placebo in accordance with USP and FDA/ICH guidelines.

xi. Establishment of tentative product specifications for active and placebo in accordance with USP and FDA/ICH guidelines.

e. Manufacture:

Manufacture under cGMP a batch of nonclinical or clinical trial material (CTM) and matching placebo at pre-determined and agreed upon strengths. The strengths will be based on the formulation and the manufacturing procedures developed under formulation studies or based on the data provided by the COR in case the product had been manufactured elsewhere and the information on formulation, manufacturing procedures, test methods, and product specifications are available. The typical batch size approximately falls within <1,000 and >100-unit doses including tablets, capsules, vials, etc. The batches may be manufactured manually or automated. Activities include, but are not limited to:

i. Manufacture of a batch of API and matching placebo under cGMP for each of requested (approximately 2-5) strengths. In-process control on blend uniformity, tablets or capsules weight variation, and content uniformity should be closely monitored for solid dosage forms.

ii. Packaging and labeling in accordance with Federal Regulations for Investigational New Drugs.

iii. Testing for release of the product based on release specifications.

iv. Store the drug product under appropriate conditions for stability.

Products containing controlled substances should be handled for security in accordance with Drug Enforcement Agency (DEA) regulations.

v. Secure shipment of the drug product to clinical study sites or a location designated by COR for distribution to preclinical/clinical investigators.

vi. Develop and perform stability-indicating methods for release of the products and stability testing in accordance with FDA regulations/ ICH guidelines.

vii. Alternatively, CTM can be in form of an API in the bottle.

f. Stability Studies:

Conduct Stability Studies to collect up to 5-year stability data to ensure product stability during preclinical/clinical studies. The stability studies will be conducted under long-term (usually 60 months), accelerated (6 months), intermediate (12 months), and photo-stability conditions. FDA regulations and ICH guidance on stability studies on drug products should be consulted. Activities include, but are not limited to:

i. Prepare a stability study protocol for long-term (usually 36 months), accelerated (6 months), intermediate (12 months), and photostability conditions in accordance with FDA and ICH guidelines on stability.

ii. Store the drug product under appropriate conditions for stability.

Products containing controlled substances should be handled for security in accordance with DEA regulations.

iii. Recommended sampling schedules are as follows:

a. Long-term study: 0, 3, 6, 9, 12, 24, 36 months

b. Accelerated study: 1, 2, 3, 6 months

c. Intermediate study: 2, 4, 6, 9, 12 months

iv. The storage conditions and sampling schedules will vary depending on the stability of drug and the dosage form under study.

g. Supply Management (Package, Label, Storage, and Distribution):

A summary plan shall be provided for packaging, label, and storage conditions for all final products and intermediates in compliance with the World Health Organization (WHO) and FDA technical reports and guidelines. Final products and intermediates shall be appropriately packaged and labeled according to a protocol that has been reviewed and approved by the COR. The Contractor shall have capability to distribute samples and provide storage for samples for the length of individual task order in accordance to standard operating procedures and established material transfer agreements. All samples and records shall be securely retained throughout the life of contract. No samples should be discarded or destroyed without explicit written approval of the COR.

Packaging: Pharmaceutical packaging materials and systems must be subject to the same quality assurance requirements as pharmaceutical products. The appropriate system of quality assurance for the manufacture of pharmaceutical products should therefore follow the WHO guidelines for GMP.

The suitability of packaging or packaging material for any particular requirements and conditions shall be ascertained through detailed packaging and stability studies on the product concerned. The packaging shall include but not be limited to ampules, bags, blister, bottle, cartridge, injectable needle, injectable syringe, single dose container, strip, tube, and vial.

Packaging may be defined as the collection of different components (e.g.

bottle, vial, closure, cap, ampoule, and blister) which surround the pharmaceutical product from the time of production until its use. The aspects of packaging to be considered include, but not limited to, are:

— The functions of packaging

— The selection of a packaging material

— The testing of the material selected

— Filling and assembling

— Sterilization

— Storage and stability

The quality of the packaging of pharmaceutical products plays a very important role in the quality of such products and shall:

— Protect against all adverse external influences that can alter the properties of the product, e.g. moisture, light, oxygen and temperature variations

— Protect against biological contamination

— Protect against physical damage

— Carry the correct information and identification of the product

Packaging may be referred to as primary or secondary, depending on whether they are for immediate use after production of the finished product or not. The capabilities shall include single-dose and multi-dose containers. Containers may be well-closed, tightly closed, hermetically closed or light-resistant. Packaging process consists of the following stages:

— Filling and assembling;

— Sterilization in the final container, if applicable;

— Placing labels on the container;

— Storage at the manufacturing and shipping sites.

Packaging documentation shall include aspects related to:

— Specifications and quality control, including batch records;

— Labels, inks and adhesive materials (e.g. glue);

— Package inserts for patients.

Packaging materials also include printed material employed in the packaging of a pharmaceutical product, but not any outer packaging used for transportation or shipment. A distinction must be made between primary and secondary packaging components. The choice of primary and/or secondary packaging materials will depend on the degree of protection required, compatibility with the contents, the filling method and cost, and the convenience of the packaging for the user (e.g. size, weight, method of opening/ reclosing (if appropriate), legibility of printing).

Label: All finished drug products shall be identified by labeling, as required by the FDA, bearing at least the following information:

— The name of the drug product;

— A list of the active ingredients (if applicable, with the International

Nonproprietary Names (INNs)), showing the amount of each present, and a statement of the net contents, e.g. number of dosage units, mass or volume

— The batch number assigned by the manufacturer

— The expiration date in an uncoded form (if available)

— Any special storage conditions or handling precautions that may be necessary

— The directions for use, and any warnings and precautions that may be necessary

— The name and address of the manufacturer or the company or person responsible for placing the product in use

Storage: Good storage practices (GSP) shall be applicable in all circumstances where pharmaceutical products are stored and throughout the distribution process. General principles of storage of pharmaceutical products shall be implemented and followed according to the WHO guide to good storage practices for pharmaceuticals. The facilities shall be available for the storage of all final products and intermediates under appropriate conditions (e.g. environmentally controlled when necessary).

Records should be maintained of these conditions if they are critical for the maintenance of the characteristics of the pharmaceutical product stored.

Distribution: Distribution of final products and intermediates shall be compliant with the WHO and FDA guidelines (World Health Organization WHO Technical Report Series, No. 957, 2010). The distribution shall ensure the quality and identity of pharmaceutical products during all aspects of the distribution process including, but not limited to, procurement, purchasing, storage, distribution, transportation, repackaging, relabeling, documentation and record-keeping practices for example shipping with temperature sensor or other monitors.

C.1.3.2.3 ANALYTICAL METHODS DEVELOPMENT AND STABILITY TESTING

The contractor shall develop and execute parameters for validation including but not limited to accuracy, detection limit, quantitation limit, linearity, precision, range, recovery, robustness, sample solution stability, specificity/selectivity, and system suitability specifications/tests. The contractor shall stability studies as described above to collect up to 5-year stability data to ensure product stability during preclinical/clinical studies. A summary plan addressing analytical methods development and stability studies shall be provided according to the national and international guidelines (e.g., FDA guidelines and ICH documents).

D. REPORTING REQUIREMENTS AND DELIVERABLES

D.1 REPORTING REQUIREMENTS AND DELIVERABLES FOR PERFORMANCE

ACTIVITY 2A

D.1.1 Technical Reports

In addition to those reports required by the other terms of this Task Order, the contractor shall prepare and submit all reports required for information technology and information systems security. Submission of information systems reports as required herein shall be submitted to the contracting officer (CO) and contracting officer’s representative (COR) in electronic format on a quarterly, or as needed basis.

D.1.2 LDT Summaries:

a) The contractor (Principal Investigator/ Project manager) to participate in LDT, ad hoc meetings and teleconferences (for example pre-IND meeting, IND meetings, and additional FDA updates);

b) The contractor (Principal Investigator/ Project manager) shall be required to generate and deliver summaries of all LDT meetings conducted in performance of work under the contract. The summary shall consist of a bulleted list of decisions made and action items identified on the web-enabled meetings. These summaries shall be deposited on NIH SharePoint site and a link to them sent via e-mail to all participants within 48 hours of each call. The exact number and timing for such calls will depend on the specifics and circumstances surrounding each individual project.

D.1.3 Quality Assurance and Quality control systems:

The contractor to provide quality assurance/quality control oversight of all Task Order activities requiring compliance with GLP and cGMP guidelines. All documentation required for regulatory filings (e.g. IND-filing with appropriate QA/QC sign off to fully enable the CMC section filing to the FDA to enable clinical testing. This includes but is not limited to Reports listed below.

D.1.4 Quarterly Progress Reports:

The contractor to prepare and submit reports as required by the terms of the contract or specified timeframes to the COR and CO. The contractor shall be required to submit Quarterly Progress Reports due within 5 business days of the end of the reporting period and shall describe all contract-related work accomplished during the preceding 3 months. Reports shall summarize progress made on active Task Orders, describe activities planned for the ensuing reporting period, identify deviations from prior plans, provide updated timelines, and describe technical or administrative problems encountered and their resolution or proposed corrective action. Quarterly Progress Reports shall include a cover page listing:

• Base contract title and contract number

• Task Order title and number

• Type of report and period of performance being reported

• Contractor’s name and address

• Date of submission

D.1.5 Task Order Final Reports:

A Task Order Final Reports are due within 30 calendar days of completion of the Task

Order and shall describe the work accomplished under the Task Order. All reports considered for inclusion in an IND application should conform/ comply with the electronic common technical document (eCTD) file format. The contractor shall provide this report to the COR and CO as specified in the Statement of Work.

1. Final Chemistry Technology Transfer Report:

This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The material safety and data sheet (MSDS) shall be drafted and provided as part of this final report. The Contractor shall provide this report to the COR and CO as specified in Section D.1.5.

2. Final Process Development Report:

Provide written comparisons of initial process proposed and the final accepted process for each scale up task ordered by COR. This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The assessment of the final component shall include discussion on the purity, yield, synthesis efficiency, time, cost, environmental savings, and a proposed timeline for scale up. The Contractor shall provide this report to the COR and CO as specified in D.1.5.

3. Final Chemical Synthesis Report:

Provide written comparisons of initial chemistry proposed and the final accepted chemical synthesis for each scale up task ordered by COR. This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The report shall also include the certificate of analysis, the partial DMF for chemical synthesis and a summary of modifications required to optimize yield and efficiency. The Contractor shall provide this report to the COR and as specified in Section D.1.5.

4. Final Analytical Methods Development Reports:

data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The report shall also include standard operating procedures, analytical documents, and documentation of accordance to GLP guidelines pertaining to the compound developed. The Contractor shall provide this report to the COR and CO as specified in Section D.1.5.

5. Final Preformulation Studies (API) Reports:

data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the improvements made in drug ability, physical properties and chemical properties of the candidate molecule. The Contractor shall provide this report to the COR and CO as specified in D.1.5.

6. Final Preformulation Studies (Excipients) Reports:

Contractor’s assessment of the improvements made in drug ability, physical properties, and chemical properties of the candidate molecule. The Contractor shall provide this report to the COR and CO as specified in Section D.1.5.

7. Final Formulation Studies Reports:

Contractor’s assessment of the improvements made in drug ability, physical properties, chemical properties, and compatibility for manufacturing of the candidate molecule. The Contractor shall provide this report to the COR and CO as specified in Section D.1.5.

8. Final Manufacturing Reports:

data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the manufacturing suitability of the candidate molecule. Additional reports estimated cost of goods and documents such as Chemical Manufacturing Control (CMC) documents as part of the IND package should be delivered to the COR upon request. The Contractor shall provide this report to the COR and as specified in Section D.1.5. Additional documents can be requested as part of IND documents and FDA reporting requirements.

9. Final Stability Studies Reports:

Contractor’s assessment of the suitability of the stable candidate molecule.

Additional reports and documents such as CMC documents as part of the IND package should be delivered to the COR upon request. The Contractor shall provide this report to the COR and CO as specified in Section D.1.5.

10. Final Storage, Package, Label, Distribution Reports:

data produced, and (2) the Contractor’s assessment of the standard operating procedures. The report shall also include the standard operating procedure for storage, documentation that compound integrity was maintained, guidelines for distribution that ensures safety, protocols for dispensing, after use handling instructions, final MSDS and transportation records. The

11. Task Order Final Report:

A Task Order Report is due within 30 calendar days of completion of the Task Order and shall describe the work accomplished under the Task Order. The

12. Contract Transition Plan:

During the final year of the contract, the COR will provide guidance to the Contractor regarding the relocation/disposition of all compounds generated under the contract. The Contractor shall submit a Contract Transition Plan for review and approval to the CO and COR three (3) months prior to the completion date of the contract, as specified in Section D.1.5. The Contract Transition Plan shall address relocation/disposition of all compounds generated under the contract. The Contract Transition Plan shall also include a timeline of proposed activities and completion of the transition. The Contractor shall implement the approved Contract Transition Plan to achieve a complete, timely, and orderly transition of contract activities and resources.

13. Final Report:

On or before the expiration/termination date of the contract, the contractor shall submit a comprehensive final report to the CO and COR that also summarizes the number of projects initiated over the course of the contract and their outcomes. This final report should also summarize lessons learned that may be applicable to future NIH drug development initiatives.

E. SPECIAL REQUIREMENTS

Data Transfer Requirements

Upon execution of this contract and in addition to providing all the outlined reports under section D; independently, and not as an agent of the federal government, the contractor shall hereby commit to transfer during and at the completion of each task order of all Task order-related data to a designated federal government secured SharePoint. At the completion of the Task order, the Contractor shall transfer to the recipient (Government and/or Principal Investigator/Contributor) all right, title and interest in and to all data and information in its possession, custody, or control. It is also the responsibility of the Contractor to maintain regulatory GMP compliance or otherwise relating to stability, retests, storage, shipping, and any of the foregoing task-order related activities. To the extent permitted by law, the Contractor and recipient (Principal Investigator/ Contributor) agrees to treat in confidence, for a period determined in the material transfer agreement (MTA) of any written information and data about the Material that is stamped confidential.

Confidentiality

All data provided to the Contractor and developed by the Contractor under this contract must be treated confidentially. The data to be treated confidentially is associated not only with the certain “discreet” compounds which are not available to the public, but with all agents submitted for testing through the program. Under no circumstances are chemicals or drugs or any information associated with these chemicals or drugs, including the data generated under this contract, to be released or divulged without prior written approval of the NINDS COR.

The Government requires that all data accumulated under the projected contract be immediately available for its review and that provisions are made to maintain confidentiality of all data. Authority to release data may be granted only by the Contracting Officer together with the COR and must be in writing.

The Contractor shall use compounds supplied by investigators under this contract only for contract-related research. The Contractor shall not publish any data generated from investigators’ compounds submitted for testing under the contract, without written approval of the COR and Contributor. Toxicity and safety data for compounds shall be disclosed only to the COR and may only be disclosed to other parties at the direction of the COR.

Invention Reporting Requirement

All reports and documentation required by FAR CLAUSE 52.227-11 - (Deviation) Patent Rights-Ownership by the Contractor and FAR Clause 52.227-13, Patent Rights-Ownership by the Government, including, but not limited to, the invention disclosure report, the confirmatory license, and the government support certification, shall be directed to the Division of…