DFMC_Final.pdf

STATEMENT OF WORK FOR

DRUG FORMULATION AND MANUFACTURING CONTRACTS

22 February 2019

1. BACKGROUND INFORMATION AND OBJECTIVES

The National Institutes of Health (NIH) Category Management, Strategic Sourcing, and Data Analysis Branch (CMSSDA) mission is to advance the Category Management and Strategic Sourcing initiatives at NIH to deliver better value in acquisition. The NIH Clinical Center (CC), Pharmacy Department, Investigational Drug Management and Research Service (IDMRS) is responsible for the procurement and management of investigational drugs for Phase I, Phase II, and Phase III clinical studies. The IDMRS can help investigators identify Contract Manufacturing Organizations (CMO) to outsource sterile and non-sterile material production for a clinical trial.

Formed as part of an initiative intended to inculcate a culture and practice of safety and quality and improve oversight and compliance, the Office of Research Support and Compliance (ORSC) is responsible for maintaining the highest levels of compliance with research regulations and standards at NIH. ORSC requires insight into the outsourcing of drug manufacturing and quality agreements between the Government and outsourcing contractors.

ORSC, IDMRS, and CMSSDA are partnering to establish a suite of multiple award Indefinite Delivery/Indefinite Quantity (ID/IQ) contracts that, together, will constitute the Drug Formulation and Manufacturing (DFMC). The DFMC will allow NIH ICs to hire contractors to conduct the 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. These contractors will conduct the 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. The work will be conducted in accordance with Current Good Manufacturing Practices (cGMP) regulations. Data and documentation will be prepared 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).

2. DEFINITIONS

“Clinical Trial Material” (CTM) - GMP drug product for use in clinical trials and/or use in associated non-clinical studies is collectively referred to as Clinical Trial Material. The term CTM will be used throughout this document as a term to represent all GMP drug products unless specified otherwise.

“Institute/Center” (IC) – an entity within NIH which focuses on a specific disease state or body system.

Each institute or center has its own research agenda.

3. SCOPE

The goal of the contract is to complete all the manufacturing, documentation, formulation, fill and finish, packaging, and labeling required for investigational drug products. Throughout the period of performance of the contract, the contractor must maintain the technical capabilities, minimum resources and organizational compliances with which to successfully conduct any awarded contract activity. Additionally, unless otherwise requested, any assigned research must be performed in compliance with all current FDA, World Health Organization (WHO), and International Committee on Harmonization (ICH) policies, practices, procedures, guidelines and regulations specific to current good manufacturing practices (cGMP) as may be applicable.

4. PERFORMANCE ACTIVITIES

As necessary, the NIH will issue task orders for the contractor to perform any or all of the performance activities listed below. Independently and not as an agent of the Government, the contractor shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the Government, as needed, for conduct of these performance activities. The following is a detailed description of possible performance activities under this contract.

The performance descriptions include a significant amount of detail regarding examples of performance activities. NIH Customers may, at the task order level, relax or strengthen the specific thresholds, timelines, requirements, etc. outlined in the performance descriptions below. However, the following requirements may not be relaxed without the express consent of the IDIQ contracting officer:

• Product manufacture and documentation should be according to GMP practice.

The Government has the right to update this listing by unilateral modification of the contract.

4.1 Performance Activity 1: Technical Support

The Contractor shall provide technical expertise and support related to finished drug product development, cGMP standard operating procedures, and other areas within the subject matter of this contract. This technical support tasking may include, but is not limited to, input in terms of manufacturing investigational drug product for clinical study with the support from Government projects/programs, customizing protocol development, analyzing manufacturing processes, reviewing and analyzing data regarding manufactured products, and participating in project planning.

4.2 Performance Activity 2 – Drug Product Formulation and Manufacture

The contractor shall conduct preformulation studies, formulation development, process development, scale-up, and GMP manufacture of CTM. The contractor will discuss with sponsor to establish specifications, acceptance criteria, and select the test procedures for both the in-process manufacture and release testing of the drug product in accordance with the ICH Quality Guideline Q6A. Additionally, the contractor will qualify the analytical methods to be used for release testing the CTM and in the absence of existing methods will develop and validate phase-appropriate drug product analytical procedures to include but not limited to assay, related impurities, dissolution, residual solvents and elemental impurities in accordance with the ICH Quality Guidelines Q2(R1), Q3B(R2), Q3C(R5) and Q3D.

The Contractor will conduct formal stability assessment of the drug product in accordance with the ICH Quality Guidelines Q1A(R2), Q1B, Q1C, Q1D, Q1E and Q1F. The contractor will also perform other stability studies that may be required beyond what is covered in the guidelines after discussion and approval by the COR. The contractor will provide comprehensive supply chain activities including, but not limited to, the manufacture of experimental and GMP batches of drug product, package and label development, CTM packaging, labeling, storing, and shipping to clinical sites and to other sites as needed. Targeted drug products include, but are not limited to, solid- and liquid-oral (by mouth), parenteral (sterile injection), transdermal (across skin), transmucosal (across mucous membranes), topical (on skin), nasal (applied in nose) and inhalation (lung delivery) while the type of dosage form may include, but not be limited to tablets, capsules, powder-in-capsule, powder-in-bottle, creams, ointments, gels, pastes, sachets, lyophilized powder in a vial, sterile or preserved liquids in a vial, suspensions, and suppositories. Activities shall be performed in compliance with cGMP as listed in 21 CFR, FDA Guidance, and ICH Quality Guidelines.

The principles as laid out in ICH Quality Guidelines Q8(R2) and Q9 for pharmaceutical development and quality risk management shall be followed to as a reasonable degree as possible during development of the drug product.

Performance Activity 4 incorporates the following activities which may or may not be required for any given project evaluation:

4.2.1 Preformulation Studies

Preformulation studies provide a roadmap of the physicochemical properties of a drug that guide the development of the formulation and processes used to manufacture a stable dosage form that delivers the drug to the site of action.

The contractor may perform preformulation studies as listed below in order to identify problems with the API early in development and rapidly develop ways to overcome or minimize them in the formulation. Preformulation studies may include, but not be limited to the following:

1) Intrinsic Stability/Solubility Properties: solid state stability in the presence of heat, humidity, light, and oxidizers; stability in solution as a function of pH and in pharmaceutically acceptable solvent systems. Equipment used to conduct these studies include, but are not limited to: HPLC, LC/MS/MS, GC, UV/VIS, XRD, DSC, and TGA.

2) Biopharmaceutical Properties: solubility as a function of pH and in pharmaceutically acceptable solvents, complexation, partition coefficient, pKa, permeability, and Biopharmaceutics Classification System (BCS) classification. Equipment used to conduct these studies include, but are not limited to: auto-titrators, HPLC, GC, UV/VIS, cell lines such as CACO-2 and MDCK.

All studies shall be performed following the most current ICH guidelines, the Contractor’s SOPs and cGMP guidelines in accordance with FDA requirements.

4.2.2 Analytical Method Development, Qualification andValidation

The analytical method can be transferred from API manufactuer or client, or new method should be developed. The contractor shall qualify the transferred method or develop a new method and validate phase-appropriatel HPLC methods for assay, purity, identification and dissolution test and other assays required to demonstrate content purity and related substances as may be required to demonstrate purity (e.g. enantiomeric purity) or the performance of the dosage form (e.g.

dissolution) for the drug product in accordance with the ICH Quality Guideline Q2(R1) along with Q4 and appropriate Annex. Validation will be conducted under protocols developed by the Client, API manufacturer or Contractor and approved by the COR. Once methods are validated a validation report will be issued by the Contractor. Phase-appropriate validation must be complete prior to the release of any drug product intended to be used in clinicaltrials.

The Contractor shall validate the most suitable (either provided or alternative) method for linearity, accuracy, precision, limit of quantitation, and limit of detection as described in Table 1 of the USP General Chapter (<1225>). The Contractor shall also evaluate the stability indicating properties of the most suitable (either provided or alternative) HPLC method by performing forced degradation studies that include exposure of the oral liquid formulation to acid, base, heat, light, and oxidation.

4.2.3 Formulation Development Studies

The contractor shall perform studies that will guide the selection and amount of excipients used in a formulation and guide the mechanical processes to be used during manufacture of the dosage form only if the dosage form is not determined by the client at the beginning of the development stage.

The contractor shall manufacture prototype dosage forms to choose the optimum formulation for the dosage form, manufacture prototype dosage forms to select the optimum equipment train for use in the manufacturing process, and manufacture prototype batches to select the optimum processing to be used during manufacture.

The Contractor shall perform formulation development studies for a number of different types of dosage forms each having its own particular requirement that will also vary based on the physicochemical properties of the API. As a generalization, in the development of most dosage forms, the formulation development studies conducted by the contractor may include, but are not limited to the following:

4.2.3.1 Compatibility Studies

The Contractor shall design and perform excipient compatibility studies in the solid state with either physical mixtures or compacts to evaluate physical drug-excipient interactions and chemical stability of the API in the presence of various excipients or additives to the potential formulation to cover the majority of solid-oral dosage forms. During this early development work, samples may be placed on stability at conditions that are guided by the intrinsic stability of the API. Conditions that are outside of those directed by the ICH Quality Guidelines will be discussed and approved by the COR. Evaluation of the excipient compatibility samples will normally involve HPLC methods for assay and related substances, moisture content by Loss on Drying (LOD) or Karl Fischer and other thermal and spectroscopic methodologies.

The contractor shall design and perform excipient compatibility studies either as solutions or suspensions to cover dosage forms such as parenterals, liquid-oral, dispersed systems (e.g.

suspensions, emulsions, creams, etc.), transdermals and others. The Contractor will also consider the need for a preservative system as part of the dosage form and include it as part of the compatibility evaluation. During this early development work, samples may be placed on stability at conditions that are guided by the API stability as a function of pH, solubility as a function of pH, or solubility in pharmaceutically relevant solvents determined as part of the preformulation studies. The stability conditions are likely to be outside of those suggested by the ICH Quality Guidelines and will be discussed and approved by the COR. Evaluation of the excipient compatibility samples should involve HPLC for assay and related substances, microscopy, particle size analysis, and other methodologies.

4.2.3.2 Evaluation of Prototype Formulations

Prepare prototype formulations for the target dosage form that are guided by the results from the excipient compatibility studies. In the case for a sterile dosage form, the Contractor will identify the method of sterilization to be used and initiate qualification of the compendial method for sterility and endotoxin testing. Like the excipient compatibility studies, the physical and chemical stability of the prototype formulations need to be assessed expeditiously and stability studies may involve conditions and sampling points that are outside of the ICH Quality Guidelines, which will be discussed and approved by the COR. In any stability study, the HPLC method for assay and related substances are two key attributes for any dosage form that require testing. Testing of other attributes will be dependent on the type of dosage form.

4.2.3.3 Development of the Manufacturing Process

Once the formulation for the dosage form of interest is identified through the evaluation of prototypes, the Contractor will develop the manufacturing process for the specified drug product that may include, but are not limited to: the evaluation of the type of processing equipment necessary to manufacture the dosage form; the identification and evaluation of processing parameters critical to the manufacturing process (e.g. time, speed, temperatures, etc.); and the determination of the order of addition of the API relative to any solvents or excipients used in the formulation. Stability studies are sometimes necessary to determine differences when samples are generated in these studies but it is likely that differences are either obvious or involve the analysis of fresh samples. If stability testing is required, conditions may be needed that are outside of those listed in the ICH Quality Guidelines and will be discussed and approved by the COR.

4.2.3.4 Manufacture of non-GMP Experimental Batches of Drug Product

Based on the composition of the lead and one or more backup (if needed) prototype formulations of the drug product, the Contractor will manufacture one or more experimental batches of the prototypes according to the manufacturing process identified during initial development. The expected batch size may range from 100 -3,000 units. The Contractor will manufacture additional experimental batches to make small formulation changes, changes to the manufacturing equipment, process parameter changes or changes to the order of addition deemed necessary to finalize the formulation and manufacturing process prior to the preparation and manufacture of clinical trial material (CTM) or other cGMP drug product batch.

The Contractor will determine any testing to be done during the manufacture of experimental drug product batches that help ensure the correctness of the formulation or how the manufacturing process is working (in-process testing). The type of testing will vary depending on the dosage form. The testing and results from experimental batches will be for information and data gathering only and may form the basis of formal in-process specifications.

The Contractor will identify a suitable primary packaging system (e.g. vial, stopper, crimp seal and flip-off for a sterile parenteral or bottle, cap and induction seal for solid- oral drug products) that will physically and chemically safeguard the drug product to the extent possible based on known and/or assumed issues with either the API or drug product. The Contractor will package experimental drug product batches using the selected primary packaging system, which will be placed on stability in accordance with the ICH Quality Guidelines Q1A(R2), Q1B, Q1C, Q1D, and Q1E. Should additional conditions outside those of the ICH Quality Guidelines be required to provide rapid information to aid in a rapid selection of closure or packaging system, the possibility will be discussed with and approved by the COR.

The stability protocol will be developed by the Contractor including specifications and storage conditions. The testing time points will be 0, 1, 3 and 6 months.

If the aggregate of stability data generated on the API or prototype/experimental drug product identifies a stability concern where a suitably identified formulation or primary packaging system is uncertain the Contractor will evaluate another formulation or primary packaging configuration, manufacture another experimental batch of drug product and put on stability as the same schedule. Should additional conditions outside those of the ICH Quality Guidelines be required to provide information more rapidly to aid in the selection of formulation, a closure or packaging system, the possibility will be discussed with and approved by the COR.

The Contractor will test the experimental drug product batches for assay and related substances by HPLC in addition to other testing that is dosage form appropriate.

4.2.3.5 Placebo Development

If required, the Contractor will develop a placebo to match the drug product as closely as possible, including matching the taste for oral dosage forms.

4.2.4 Manufacture of GMP Drug Product

Clinical Trial Material (CTM) will be manufactured to the standards set forth in 21 CFR, FDA Guidelines and ICH Quality Guidelines or as directed by the COR. The contractor will have written Standard Operating Procedures (SOPs) consistent with the highest standards of cGMP manufacturing that include, but are not limited to SOPs for receiving, sampling, release testing, managing retained samples, storing and dispensing of raw materials, chemicals and solvents;

writing, reviewing, approving, executing, and reconciling batch records; developing formal release specifications, performing release testingof manufactured product against specifications and issuing a Certificate of Analysis (CoA); managing a retain program; and for packaging, storing, and shipping of CTM and other manufactured products with temperature monitoring and controlled shipping.

Batch records, specifications, CoAs, stability data and other Quality related documents shall be made available to the COR at all times via a secure site provided by the NIH. Each batch will be fully characterized by testing against release specifications followed by the issuance of a CoA. Any deviation from GMP guidelines and/or the Contractor’s SOPs must be communicated with the COR upon discovery. Additional information shall be made available as requested.

4.2.4.1 Manufacture Preparations

The amount of CTM required to be manufactured by the Contractor will range between 100 and 20,000 individual units of the active and matching placebo (if required)dosage forms. The manufacturing process may be fully automated, manual, or a combination of both depending on the unit operations required in themanufacture.

The number of dosage strengths will be determined and agreed upon during the formulation development activities with at least one non-GMP experimental pilot batch of each strength manufactured by the Contractor as part of the formulation development process.

The CTM will be based on the strengths and manufacturing processes developed as part of the formulation development studies performed by the Contractor. In the case of CTM development and/or manufacture occurring by third party, the COR will supply all available information and data if available to the Contractor within 30 days of the award of the contract to include but not limited to the following: formulation development reports, manufacturing batch records, testing methodologies, specifications for release testing, etc. Additionally, a formal technology transfer will most probably be required between the third party from where the information is being transferred to the Contractor to whom the information is being transferred. The technology transfer will be conducted by protocol and designed in such a way to show equivalence for each validated or qualified analytical method and equivalence between drug product manufactured by both Contractors. A formal technology transfer including protocol development, analysis of samples, comparison of manufactured product, and final report will be done within 60 days from when the contractor receives all pertinent information and data from the COR.

The Contractor will write individual batch records for each strength of CTM and matching placebo to be manufactured based on the manufacturing process development studies and batch records for the manufacture of experimental batches. Batch records will be reviewed and approved prior to the manufacture of CTM by the COR.

Prior to the manufacture of CTM or placebo, the Contractor will develop in-process testing specifications for the check and testing methods that will be used during the manufacture in accordance with ICH Quality Guideline Q6A. When appropriate, the checks and testing methods will be qualified or phase-appropriately validated with reports complete prior to the manufacture of CTM or placebo in accordance with ICH Quality Guideline Q2(R1).

Prior to the manufacture of CTM or placebo, the Contractor will develop a set of phase-appropriate specifications for each strength of CTM and for each matching placebo that will be used to release the CTM before it may be shipped or used in the clinic. The specifications and acceptance criteria will be based on the results of testing the same attributes of identical prototype drug product and experimental drug product batches in accordance with ICH Quality Guideline Q6A. The release specifications and acceptance limits will be reviewed and approved by the COR.

The Contractor will have the appropriate controls and SOPs for receiving, sampling, testing, storing (including retains) and dispensing API received from other vendors as well as raw materials and solvents that will be used to manufacture the CTM (see paragraph 2 and 3 of the introduction to 2.4 Manufacture of GMP Drug Product).

4.2.4.2 Manufacture of CTM

The Contractor will manufacture batches of CTM and matching placebo in accordance with cGMP regulations contained in Section 21 of the CFR, FDA Guidance and ICH Quality Guidelines.

Once the manufacture is complete, the Contractor will place the CTM and placebo in bulk storage containers in accordance with the FDA Guidance on Container Closures and store the materials in quarantine under appropriate storage conditions.

The Contractor will perform the cleaning and cleaning verification of their GMP equipment using validated cleaning methodologies.

The Contractor will perform a reconciliation for each batch record. The batch records will be reviewed by the COR for review and comment.

The Contractor will also perform release testing on each batch of CTM and placebo according to the release specifications for the material by testing against each attribute in the specification in accordance with ICH Quality Guideline Q6A. Testing will use the analytical methods developed and validated as part of the formulation development process for each attribute in the specification.

Once the testing is complete, the data will be reviewed for Quality against the acceptance criteria for each attribute and Quality will issue a Certificate of Analysis (CoA) for each batch of CTM and placebo.

The CTM and placebo are considered released after the Quality personnel approve the batch records and issue the Certificate of Analysis. Once the CTM is released, itis removed from quarantine and stored as released material.

4.2.4.3 Packaging the CTM

Unless the primary packing of the CTM is part of the manufacturing process (e.g. powder in a bottle), the Contractor will package the CTM with the same primary packing components as used to package the experimental batches of the lead drug product formulation in accordance with the FDA Guidance Container Closure Systems for Packaging Human Drugs and Biologics. Packaging the CTM and placebo may be done “at risk”, meaning before the product is released. The CTM and placebo packaged in its primary packing is then stored under quarantine at the appropriate storage condition until it is released.

4.2.4.4 CTM Stability Studies

The Contractor will place all batches of CTM on formal stability in accordance with the ICH Quality Guidelines Q1A(R2), Q1B, Q1C, Q1D, Q1E, and Q1F. Durations for the stability studies will range from as little as the time to cover the conduct of the clinical trial up to a maximum of 3 years during early development and up to 5 years as the drug product matures in later stage clinical studies. The duration for the stability studies will be discussed and approved by the COR and may or may not be as recommended in the ICH Quality Guidelines especially for early clinical trials. The Contractor will develop the stability protocol, which will be reviewed and approved by the COR. The sample pull date from the stability chamber as well as the time frame for the start date of testing will also be in accordance with the ICH Quality Guidelines mentioned above. If additional pull dates or storage conditions are required that are different from the ICH Quality Guidelines these will be discussed and approved by the COR.

4.2.4.5 Supply Chain Management (Package, Label, Storage, andDistribution)

The Contractor will provide comprehensive supply chain activities in accordance with regulations for the packaging, labeling, kitting, and distributing of CTM.

4.2.4.5.1 Packaging

For general guidance regarding the container closure system for Phase 1 studies refer to the FDA guidance for industry Content and Format of investigational New Drug Applications(INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products. For general guidance regarding the container closure system for Phase 2 and Phase 3 studies, refer to the FDA guidance for industry INDs for Phase 2 and 3 Studies of Drugs, Including Specified Therapeutic Biotechnology-Derived Products, Chemistry, Manufacturing, and Controls Content and Format.

The primary packaging for the drug product is dependent on the type of dosage form, so there are many permutations and combinations of primary packaging. However, the suitability of the primary packaging for its intended use is important for any dosage form. This includes protection from alteration, contamination, and damage during storage, handling and shipping. The primary packaging must also be safe and not leach undesirable amounts of substances to which a patient is exposed, be compatible with the dosage form and provide performance to allow delivery of the drug product.

If primary packaging is not performed directly as part of the manufacturing process, the contractor will package unit dosage forms (e.g. tablets, capsules, etc.) in bulk packaging. Since the bulk packaging is somewhat akin to a temporary primary package, it must be suitable for its intended use with regard to protection, safety and compatibility.

Secondary packaging does not come in direct contact with the product but may offer some physical (e.g. during shipping) or chemical (e.g. protect from light) protection to the CTM. Secondary packing used for clinical trials is most often cartons or boxes used in the assembly of patient kits for clinical trials and contain the drug product, placebo, or both, and possibly other items that help the patient with administration.

Also important is the quality and control for each component including, release testing and acceptance criteria, dimensional drawing and performance criteria, and methods to monitor consistency in composition. The Contractor will have SOPs in place to ensure the quality of all packaging components including bulk, primary, secondary and tertiary. The contractor will write a batch record that will be approved by QA prior to the packing run. Once the primary packaging run is complete (e.g. tablets into bottles, capsules into blister packs), a reconciliation is done and the batch record is reviewed and approved by QA.

4.2.4.5.2 Labeling

The Contractor will, in consultation with the COR, develop label content that will be placed on each unit of packaging material (i.e. primary, secondary, tertiary). Once the label content is agreed upon, the Contractor will have the appropriate SOPs in place for label design, layout, in-house printing, and will provide 100% inspection of all labels. Usually, randomization will be handled by NIH IDMRS.

The Contractor may provide randomization and bar coding services as well as have the capability to print multi-lingual booklets or wrap-around labels and the ability to print complex clinical trial labels. Labels may be as simple as ink-jet printing a batch number onto a primary packaged drug product or as complex as an automated label application for a double-blind, placebo-controlled clinical study with a coded key to unblind the study. Each unit of packaging material must be labeled in some manner to ensure easy traceability and prevent mixups with the following information: the product name, quantity, batch number, expiry or retest date, warnings, storage conditions and the name of the manufacturer.

4.2.4.5.3 Assembly of CTM Patient Kits

The contractor will develop batch records for the assembly of CTM patient kits, only if it’s indicated by the protocol and as required by the task order, that will be approved by QA. Similarly, to other processes, SOPs must be in place to ensure that the CTM, packing materials, and labels are correct for the study that will take place. The use of appropriate means (e.g. segregation, label reconciliation, verification of operations by a second individual, confirmatory laboratory testing of the packaged and labeled product and review by the Quality organization) will be used to achieve effective control especially in situations where the potential for mix-ups is more likely to occur (e.g.

use of placebo, blinded trials, multiple strengths).

4.2.4.5.4 Distribution

The contractor will handle CTM in accordance with labeled conditions (e.g. temperature) to ensure retention of the quality of the drug product. This may include specialized shipping at controlled temperatures (cold chain for refrigerated and frozen CTM). If specialized temperature shipping is required, the Contractor will ensure that there is a reliable and validated process that allows real-time temperature monitoring of the CTM such that if a temperature excursion happens, the correct decisions can be made to the fate of that specific CTM. The contractor will maintain a distribution record of each batch of CTM that is sufficiently detailed to allow traceability and facilitate recall of the drug product if necessary. The contractor will also have SOPs in place for the return and disposal of unused CTM.

4.2.4.5.5 Storage

The contractor shall provide a summary plan for storage conditions and packaging for all final compounds and intermediates. GMP qualified storage with temperature monitoring record is required. 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.

4.2.4.6 Non-standard/Exploratory Studies

Should that need arise, the COR will determine what additional studies are required and discuss the additional work required with the Contractor.

4.2.4.7 Quality Assurance

The contractor shall be required to accommodate annual audits performed NIH Pharmacy Quality assurance staff. NIH staff will perform annual audits of the CMO using the following criteria:

• A brief history of the contractor or CC production facility including mission statement and a list of leadership positions and qualifications

• Detailed assessment of the company/facility history

• An organization chart

• Facilities Diagrams and material/personnel or process flow diagrams

• Personnel Education, Training and Experience

• List of SOPs

• Regulatory history and accreditation, licensure, or registration with appropriate agencies

(FDA, State licensure boards, DEA, NRC)

• Client List (if willing to provide)

• Quality Manual (if available)

• Addresses of manufacturing sites and a site history

• Capacity, including average number of products produced per type

• Project lead time, On-time delivery ability and average project completion times

• Process for handling deviations

• Example master batch records

• Example quality agreements

• Personnel qualifications and experience, and length of time employed with the company

• Discussion of key quality systems including employee training, internal auditing and CAPA

In addition, the NIH staff will participate in drafting, processing and ensuring approval of the Quality Agreement. The contractor shall uphold the terms of the agreement and achieve favorable results on the annual audits in order to be eligible for the award of new task orders.

5. ELECTRONIC AND INFORMATION TECHNOLOGY ACCESSIBILITY (SECTION 508)

Pursuant to Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794d), as amended by the Workforce Investment Act of 1998, all electronic and information technology (EIT) products and services developed, acquired, maintained, and/or used under this contract must comply with the “Electronic and Information Technology Accessibility Provisions” set forth by the Architectural and Transportation Barriers Compliance Board (also referred to as the “Access Board”) in 36 CFR Part 1194. The Section 508 standards applicable to this contract are as follows:

All reports delivered electronically (e.g., via e-mail) must meet the requirements of Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794d). Section 508 governs electronic information and requires that:

Federal employees with disabilities to have access to and use information and data that is comparable to the access and use of information and data by Federal employees who are not individuals with disabilities; and

Members of the public with disabilities seeking information or services from a Federal agency to have access to and use of information and data that is comparable to the access and use of information and data by members of the public who are not individuals with disabilities.

Compliance with Section 508 of the Rehabilitation Act of 1973

Section 508 of the Rehabilitation Act of 1973 (29 U.S.C. 794d) requires Federal agencies to purchase electronic and information technologies (EIT) that meet specific accessibility standards. This law helps to ensure that federal employees with disabilities have access to, and use of, the information and data they need to do their jobs. Furthermore, this law ensures that members of the public with disabilities have the ability to access government information and services.

There are three regulations addressing the requirements detailed in Section 508. The Section 508 technical and functional standards are codified at 36 CFR Part 1194 and may be accessed through the Access Board’s Web site at http://www.access-board.gov. The second regulation issued to implement Section 508 is the Federal Acquisition Regulation (FAR). FAR Part 39.2 requires that agency acquisitions of Electronic and Information Technology (EIT) comply with the Access Board’s standards. The entire FAR is found at Chapter 1 of the Code of Federal Register (CFR) Title 48, located at http://www.acquisition.gov. The FAR rule implementing Section 508 can be found at http://www.section508.gov. The third applicable regulation is the HHS Acquisition Regulation (HHSAR).

Regardless of format, all Web content or communications materials produced for publication on or delivery via HHS Web sites - including text, audio or video - must conform to applicable Section 508 standards to allow federal employees and members of the public with disabilities to access information that is comparable to information provided to persons without disabilities. All contractors (including subcontractors) or consultants responsible for preparing or posting content intended for use on an HHS-funded or HHS-managed Web site must comply with applicable Section 508 accessibility standards, and where applicable, those set forth in the referenced policy or standards documents below. Remediation of any materials that do not comply with the applicable provisions of 36 CFR Part 1194 as set forth in the SOW or PWS, shall be the responsibility of the contractor or consultant retained to produce the Web-suitable content or communicationsmaterial.

The following Section 508 provisions apply to the content or communications material identified in this SOW. See Guidelines and Standards at http://www.access- board.gov/sec508/standards.htm

References:

HHS Policy for Section 508 Electronic and Information Technology (E&IT) (January 2005):

http://www.hhs.gov/od/Final_Section_508_Policy.html HHS Section 508 Web site: http://508.hhs.gov/ HHS ASPA Web Communications Division Web site: http://www.hhs.gov/web/policies/index.html US General Services Administration (GSA) Section 508 Web site: http://www.section508.gov/index.cfm

6. TECHNICAL REPORTING REQUIREMENTS/DELIVERABLES

In addition to those reports required by the other terms of this contract, the Contractor shall prepare and submit the following reports in the manner stated below and in accordance with the DELIVERIES http://www.access-board.gov/ http://www.acquisition.gov/ http://www.section508.gov/ http://www.access-board.gov/sec508/standards.htm http://www.access-board.gov/sec508/standards.htm http://www.hhs.gov/od/Final_Section_508_Policy.html http://508.hhs.gov/ http://www.hhs.gov/web/policies/index.html http://www.section508.gov/index.cfm

Article in SECTION F of this contract:

[Note: Beginning May 25, 2008, the Contractor shall include, in any technical progress report submitted, the applicable PubMed Central (PMC) or NIH Manuscript Submission reference number when citing publications that arise from its NIH funded research.]

All paper/hardcopy documents/reports submitted under this contract shall be printed or copied, double-sided, on at least 30 percent post-consumer fiber paper, whenever practicable, in accordance with FAR 4.302(b). The Contractor shall be required to prepare and deliver the following reports as part of their performance responsibilities under the contract as follows:

6.1 Technical Reports:

a. Conference Call Summaries

The Contractor shall be required to generate and deliver summaries of all conference calls 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 call. These summaries shall be sent via secure 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.

b. Quarterly Reports

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.

c. Drug Product Reports

1) Final Preformulation Report

This report shall include pertinent data and a summary for each test or study that was performed to gain an understanding of the API to determine a way forward develop the API into a drug product (e.g. crystallinity, hygroscopicity, excipient compatibility, etc.). The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

2) Final Drug Product Analytical Method Validation Reports

For each drug product analytical method that was validated (e.g. assay for purity, assay for related substances, cleaning assay, etc.) this report shall include a copy of the analytical method and a detailed summary and supporting data for each of the attributes the method was validated against as well as a statistical analysis demonstrating the validation was successful for each attribute. The Contractor shall provide these reports to the COR and CO as specified in Section F (Deliverables).

3) Final Drug Product Qualification Report

For each drug product analytical procedure that was qualified (e.g., water content, hygroscopicity, XRD, DSC, etc.) the report shall contain the specific written procedure that was used for the drug product or API and data (e.g. from a standard) that corroborates the procedure and instrumentation were functioning properly. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

4) Final Formulation Development Report

This report shall summarize all of the studies performed that guided the development of the formulation, selection of formulation components, and manufacturing process for the drug product.

The report will include all associated stability assessments including a summary table of all stability data generated on prototype and experimental batches as well as a summary of how the stability data guided the formulation and process studies. Additionally, justification for the manufacturing equipment train chased to make the drug product and rationalization in the selection of the processing parameters for the manufacture of CTM. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

5) Final CTM Manufacturing Report

This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, (2) the Contractor’s assessment of the manufacturing suitability of the candidate molecule and (3) the Batch Records for each batch of CTM manufactured.

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 F (Deliverables).

6) Final Experimental Batch Report

All of the development work completed in support of formulation development will be documented in a report. The most suitable formulation and/or package system used for experimental batch production will have stability study for 6 months.

7) Final CTM Stability Reports

These reports shall include a copy of the stability protocols used to assess the stability of each batch of CTM, a list of the CTM attributes that were tested at each time point with reference to the analytical procedure used to test each attribute, a summary table for each batch of CTM of all the data generated for each attribute at each time point that was evaluated, and an overall written assessment of the general stability behavior of the CTM. 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 F (Deliverables).

8) Final Supply Management Report

This report shall include a summary of all packaging, labeling (including samples of labels), storage conditions, shipping records, and final disposition and reconciliation of CTM for each batch of CTM and placebo used in a clinical trial. The report shall also include the standard operating procedure for storage, detail description of the intermediate and final compound handling controls, documentation the compound integrity was maintained, guidelines for distribution that ensures safety, and transportation records. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

9) Task Order Final Report

A Task Order Report is due on or before the completion date of the Task Order and shall describe the work accomplished under the Task Order. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

d. 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.

6.2 Other Reports/Deliverables:

a. IT Security Plan (IT-SP)

In accordance with HHSAR Clause 352.239-72, Security Requirements For Federal Information Technology Resources, the contractor shall submit the IT-SP within thirty (30) days after the first drug compound task order. The IT-SP shall be consistent with, and further detail the approach to, IT security contained in the Contractor's bid or proposal that resulted in the award of this contract. The IT-SP shall describe the processes and procedures that the Contractor will follow to ensure appropriate security of IT resources that are developed, processed, or used under this contract. If the IT-SP only applies to a portion of the contract, the Contractor shall specify those parts of the contract to which the IT-SP applies.

The Contractor shall review and update the IT-SP in accordance with NIST SP 800- 53A, Guide for Assessing the Security Controls in Federal Information Systems and Organizations, on an annual basis.

b. Contractor – Employee Non-Disclosure Agreement(s)

The contractor shall complete and submit a signed and witnessed “Commitment to Protect Non-Public Information – Contractor Agreement” form for each contractor and subcontractor employee who may have access to non-public Department information under this contract. This form is located at:

http://ocio.nih.gov/docs/public/Nondisclosure.pdf .

c. Section 508 Annual Report

The Contractor shall deliver to the CO and COR a Section 508 Annual Report at the completion of this contract. The report shall be delivered via-email, as outlined in Section “H” of the resultant contract.

7. SPECIAL REQUIREMENTS

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 COR.

The Government requires that all data accumulated under the projected contract be immediately available for its review and that provision 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 NIH Office of Technology Transfer http://ocio.nih.gov/docs/public/Nondisclosure.pdf

6011 Executive Boulevard, Suite 325 Rockville, Maryland 20852

Telephone: (301) 496-7057 Fax: (301) 496-9056

In addition, one copy of an annual utilization report, and a copy of the final invention statement, shall be submitted to the Contracting Officer. The final invention statement (see FAR 27.303(b)(2)(ii)) shall be submitted to the Task Order Contracting Officer

To assist contractors in complying with invention reporting requirements of the clause, the NIH has developed "Interagency Edison," an electronic invention reporting system. Use of Interagency Edison is encouraged as it streamlines the reporting process and greatly reduces paperwork.