D-75N95023R00037 RFP_w_Attachments.pdf

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PROPOSAL INTENT RESPONSE FORM

RFP No:

RFP Title:

Please review the Request for Proposal (RFP). Furnish the information requested below and return this page to the Contracting Officer/Contract Specialist identified on Section A-Solicitation/Contract Form by

Your expression of intent is not binding but will greatly assist us in planning for proposal evaluation.

Choose one of the following Options:

Do intend to submit a proposal Do Not intend to submit a proposal

If you are not responding to this RFP, please provide your reason(s):

Please provide the following contact information:

Name (First, Middle Initial, Last):

Title:

Organization:

E-mail:

the following date:

Attachment 2

Exhibit A to NIH(RC)-1 NIDA Supplemental Billing Instructions

In addition to the requirements of the NIH(RC)-1, the Contractor agrees to include the following supplemental information on each invoice for the cost categories shown below:

i. DIRECT LABOR

(1) Position Category

(2) Employee Identification Number or Name

(3) Hours Expended

(4) Hourly Rate

ii. TRAVEL

(1) Detail what travel is for (i.e., seminar, course, site visit, etc.)

(2) Dates and duration of travel

(3) Point of departure and destination

(4) Names of individuals

(5) Per diem rate (broken down by lodging and M&IE)

(6) Travel costs (airfare, car rental (including mileage), taxis, etc.)

iii. MATERIALS OR EQUIPMENT (RENTAL OR PURCHASE)

(1) Description, quantity, and amount of each item

(2) COA letter number, if applicable

iv. SUBCONTRACT COSTS

Breakdown identical in format and detail as required of the Prime Contractor

v. REIMBURSEMENT OF TRAVEL AND HONORARIA

Monthly invoices must include a summation of all unpaid travel and honoraria reimbursements, with explanation for all obligations outstanding over 30 days.

vi. INDIRECT COST – ADJUSTMENTS

Annual negotiated indirect cost rate adjustments applied to billings of indirect costs shall be submitted on a separate invoice/financing request.

Monthly invoices must include the cumulative total expenses to date, adjusted (as applicable) to show any amounts suspended by the Government.

The Contractor agrees to immediately notify the Contracting Officer in writing if there is an anticipated overrun (any amount) or unexpended balance (greater than 10 percent) of the amount allotted to the contract, and the reasons for the variance. Also, refer to the requirements of the Limitations of Funds and Limitations of Cost Clauses in the contract.

NIH(RC)-1 Exhibit A Rev. 3/2021

Attachment 20

NIH(RC)-2

Revised 3/2021

Format: Submit payment requests on Standard Form 1034, Public Voucher for Purchases and Services Other Than Personal, or the Contractor’s self-generated form provided it contains all of the information prescribed herein. DO NOT include a cover letter with the payment request.

Number of Copies: Submit payment requests in the quantity specified in the Invoice Submission Instructions in Section G of the Contract Schedule.

Frequency: Submit payment requests upon delivery and acceptance of goods or services unless otherwise authorized by the Contracting Officer.

Currency: All NIH contracts are expressed in United States dollars. When the Government pays in a currency other than United States dollars, billings shall be expressed, and payment by the Government shall be made, in that other currency at amounts coincident with actual costs incurred.

Currency fluctuations may not be a basis of gain or loss to the Contractor. Notwithstanding the above, the total of all invoices paid under this contract may not exceed the United States dollars authorized.

Preparation and Itemization of the Payment Request: Prepare payment requests as follows:

Note: All information must be legible or the invoice will be considered improper and returned to the Contractor.

(a) Designated Billing Office Name and Address: Enter the designated billing office name and address, as identified in the Invoice Submission Instructions in Section G of the Contract Schedule.

(b) Contractor's Name, Address, Point of Contact, TIN, and DUNS or DUNS+4 Number: Show the Contractor's name and address exactly as they appear in the contract. Any invoice identified as improper will be sent to this address. Also include the name, title, phone number, and e-mail address of the Point of Contact in case of questions. If the remittance name differs from the legal business name, both names must appear on the invoice. Provide the Contractor’s Federal Taxpayer Identification Number (TIN) and Data Universal Numbering System (DUNS) or DUNS+4 number. The DUNS number must identify the Contractor’s name and address exactly as stated in the contract, and as registered in the System for Acquisition Management (SAM) database.

When an approved assignment of claims has been executed, the Contractor shall provide the same information for the assignee as is required for the Contractor (i.e., name, address, point of contact, TIN, and DUNS number), with the remittance information clearly identified as such.

(c) Invoice/Voucher Number: Identify each payment request by a unique invoice number, which can only be used one time regardless of the number of contracts or orders held by an organization. For example, if a Contractor has already submitted invoice number 05 on one of its contracts or orders, it cannot use that same invoice number on any other contract or order.

Attachment 21

INVOICE INSTRUCTIONS FOR NIH FIXED-PRICE CONTRACTS, NIH(RC)-2

Payment requests with duplicate invoice numbers will be considered improper and returned to the Contractor.

The NIH does not prescribe a particular numbering format but suggests using a job or account number for each contract and order followed by a sequential invoice number (example:

8675309-05). Invoice numbers are limited to 30 characters. There are no restrictions on the use of special characters, such as colons, dashes, forward slashes, or parentheses.

If all or part of an invoice is suspended and the Contractor chooses to reclaim those costs on a supplemental invoice, the Contractor may use the same unique invoice number followed by an alpha character, such as “R” for revised (example: 8675309-05R).

(d) Date Invoice/Voucher Prepared: Insert the date the payment request is prepared.

(e) Contract Number and Order Number (if applicable): Insert the contract number and order number (as applicable).

(f) Contract Title: Insert the contract title listed on the cover page of the contract and/or Section G of the Contract Schedule.

(g) Current Contract Period of Performance: Insert the contract start date/effective date through the current completion date of the contract.

(h) Total Fixed-Price of Contract/Order: Insert the total fixed-price of the contract/order.

(i) Two-Way/Three-Way Match: Identify whether payment is to be made using a two-way or three-way match. To determine required payment method, refer to the Invoice Submission Instructions in Section G of the Contract Schedule.

(j) Office of Acquisitions: Insert the name of the Office of Acquisitions, as identified in the Invoice Submission Instructions in Section G of the Contract Schedule.

(k) Central Point of Distribution: Identify the Central Point of Distribution, as specified in the Invoice Submission Instructions in Section G of the Contract Schedule.

(l) Billing Period: Insert the beginning and ending dates (month, day, and year) of the period in which costs were incurred and for which reimbursement is claimed.

(m) Description of Supplies or Services: Provide a description of the supplies or services, by line item (if applicable), quantity, unit price (where appropriate), and total amount. The item description, unit of measure, and unit price must match those specified in the contract. For example, if the contract specifies 1 box of hypodermic needles (100/box) with a unit price of $50.00, then the invoice must state 1 box, hypodermic needles (100/box), $50.00, not 100 syringes at $0.50 each.

Invoices that do not match the line item pricing in the contract will be considered improper and will be returned to the Contractor.

(n) Amount Billed - Current Period: Insert the amount claimed for the current billing period, including any adjustments, if applicable. If the Contract Schedule contains separately priced line items, identify the contract line item(s) on the payment request.

(o) Amount Billed - Cumulative: Insert the cumulative amounts claimed to date, including any adjustments as applicable. If the Contract Schedule contains separately priced line items, identify the contract line item(s) on the payment request.

(p) Freight or Delivery Charges: Identify all charges for freight or express shipments, other than f.o.b. destination, as a separate line item on the invoice. (If shipped by freight or express, and charges are more than $25, attach prepaid bill.)

(q) Government Property: If the contract authorizes the purchase of any item of Government Property (e.g., equipment), the invoice must list each item for which reimbursement is requested. Include reference to the following (as applicable):

- item number for the specific piece of equipment listed in the Property Schedule, and

- Contracting Officer Authorization (COA) Number, if the equipment is not covered by the

Property Schedule.

Quality Agreement National Institutes of Health Clinical Center Pharmacy Investigational Drug Outsourcing Unit

Address: Building 10, Room 1C230, MSC 10 Center Drive Bethesda, MD 20892-1196

Contract Manufacturer:

Address:

Approvals

National Institutes of Health

Contract Manufacturer

Attachment 22

Quality Agreement: NIH Clinical Center Pharmacy Outsourcing Unit and Contract Manufacturer

PART 1 – QUALITY AGREEMENT

Background

The National Institutes of Health Clinical Center (NIH/CC), America's research hospital, is located on the NIH campus in Bethesda, MD. Through clinical research, clinician-investigators translate laboratory discoveries into better treatments, therapies and interventions to improve the nation's health. Studies include clinical trials, which often are the first tests of new drugs and therapies in people. The clinical trials at the NIH Clinical Center are predominantly Phase I and Phase II, often first-in-human to test safety and efficacy.

The Pharmacy Department’s Investigational Drug Management Research Section (IDMRS) manages the investigational drug supply that is used for patients enrolled in trials at the Clinical Center. This includes, for some studies, the procurement of a uniquely formulated or packaged investigational drug.

The Outsourcing Unit (OU), part of the IDMRS group, is tasked with working, on behalf of a Principal Study Investigator, with a qualified contract manufacturing facility to ensure that a drug meeting study design is manufactured, packaged, tested and released, shipped, stored, and distributed in a manner that meets requirements of 21 CRF 211 Current Good Manufacturing Practice For Finished Pharmaceuticals. As such, the OU represents “the owner” of the drug and is ultimately responsible for approving and rejecting drug product manufactured by the contract manufacturer.

The OU procures manufacturing services from a qualified contract manufacturing facility operated in full compliance with these regulations as appropriate to the Phase of the investigational study drug under contract. The contract manufacturer is referred to as ‘CM’ and the NIH/CC/Pharmacy/OU group is referred to as ‘IDOU’ in this agreement.

Purpose

This Quality Agreement establishes the expectations that the IDOU has for contract manufacturers in performing manufacturing activities that support NIH/CC clinical trials. The Contract Manufacturer must possess systems and conduct activities in compliance with various laws and regulations including, but not limited to

• 21 CFR 210 / 211: Good Manufacturing Practice Regulations

• 22 CFR 600, 601, 610: Biologics Regulations, where applicable

• 21 CFR 11: Electronic Records and Signature Regulations

• Applicable Chapters of USP

This Quality Agreement is additionally written to include principles and recommendations of the FDA Guidance for Industry, Contract Manufacturing Arrangements for Drugs: Quality Agreements May 2013.

Scope

This Quality Agreement covers required responsibilities between the Contract Manufacturer and IDOU. The IDOU is defined as the Outsourcing Group (OU) of the Pharmacy Department at the NIH Clinical Center. This agreement applies to the manufacturing of all investigational drug products procured by the IDOU from the Contract Manufacturer.

This agreement additionally outlines provisions for a project specific agreement to be made between the Contract Manufacturer and IDOU at the time of contracting for a specific batch of investigational drug product. Project specific agreements are necessary due to the varying nature of products utilized in various clinical studies at the NIH. Potentially products may include non-sterile or sterile dosages via varying formulations and routes of administration. The source of the API may also differ between projects (i.e. whether Contract Manufacturer procures API or whether IDOU supplies API), and responsibilities for product testing may vary between projects in method source and validation requirements and who will perform testing.

These variations make each contracted investigational product unique. The project specific agreements are intended to capture these details and responsibilities and will be the basis for preparing project quotes and contracts. They are prepared at the time of contracting a specific product and prior to manufacture of the drug product.

Communications

This table identifies the expected timeframes for communication of specified events between the Contract Manufacturer and IDOU. Technical and quality discussions take place, as needed, through development, execution, and following completion of a project. Communications should be initiated by the points of contacts listed in this quality agreement who will coordinate discussions between other personnel as needed. Both Contract Manufacturer and IDOU will retain records of communications.

Event Timeframe IDOU CM Issuance of warning letter (e.g., FDA-483), or notice of other regulatory actions to the Contract Manufacturer

Within 5-business days X

Events that would impact Contract Manufacturers ability to conduct contracted activities in the agreed upon timeframe days X X

Errors or deviations from approved procedures during contracted activities

Within 3-business day X

Product quality issues, such as an OOS test result obtained prior to initial release of product

Within 3- business days or confirmation of the quality issue and prior to taking corrective action

X X

Product quality issues discovered following product release day X X

Deviations or errors noted during review of records associated with contracted activities

Changes to the listed contacts on this quality agreement or project specific contacts

Notification of intent to destroy records associated with contracted activities

At least 30 days prior to destruction X

Manufacturing Activities and Responsibilities

1. Contract Manufacturer Quality Organization

Responsibilities IDOU CM

1.1 Contract Manufacturer must have a current and quality approved Quality

Systems Manual (QSM) that describes the design of the CM’s quality system to ensure all applicable sections of 21 CFR Part 210/211 Current Good Manufacturing Practices are met in the manufacture, testing, and release of investigational drug products. This manual must be made available to the IDOU for review upon request.

X

1.2 Maintains a Quality Unit that is independent of the Production Unit. The Quality Unit has the responsibility and authority to approve or reject API, excipients, components, or finished products if any part of the product does not meet requirements for current Good Manufacturing Practices (cGMPs).

1.3 The Quality Unit is involved in all quality related matters and reviews and approves all quality critical related documents including, but not limited to Certificates of Analysis, validation reports, records related to material testing and release, production batch records, deviation and investigation reports.

1.4 Operates in compliance with applicable environmental, occupational health and safety laws and regulations including where required specifically for the purpose of handling or testing drugs classified as hazardous

1.5 Maintains a list of all Standard Operating Procedures that are used in support of the manufacturing of investigational drug products for the IDOU. SOPs are provided to the IDOU for reference upon request.

1.6 Maintains an internal GMP auditing program and provides IDOU the ability to verify this program is functioning, but Contract Manufacturer is not required to share internal audit reports with IDOU

1.7 Maintains an external GMP auditing program for subcontractors and a supplier qualification program for suppliers of API, raw materials and components.

1.8 This quality agreement is accepted and approved by the Contract Manufacturer’s Quality Unit. X

2. IDOU Quality Organization

2.1 This quality agreement is accepted and approved by the IDOU’s Quality

Unit. X

2.2 The IDOU’s quality unit reviews all completed documentation provided by the Contract Manufacturer per this agreement in support of release of the drug product from the NIH/CC/IDCU.

2.3 The quality unit oversees the functions allocated by this quality agreement to the IDOU (i.e. project details, consultation, gaining agreement, review and approval of any specified tasks, or review of completed tasks).

2.4

The quality unit will direct questions or concerns about batch manufacturing or testing/release documentation to the Contract Manufacturer as indicated in the dispute resolution of this agreement

3. Personnel

3.1 Contract Manufacturer ensures that personnel have the education, training, and experience to properly perform their assigned functions in compliance with cGMPs and administers a comprehensive training program for all employees involved in cGMP activities. Training records will be readily retrievable and available to NIH for review upon request.

3.2 Ensures appropriate staffing levels are maintained to ensure all agreed to project requirements are met in a timely manner and that there are sufficient personnel to execute projects according to the defined GMP quality system. Maintains a current organization chart available to NIH upon request.

3.3 Maintains a current organizational chart that identifies the positions supporting cGMP manufacturing of IDOU’s products. The organization chart must be made available to the IDOU for review upon request.

Notifies the IDOU of any changes in organizational structure or key personnel that may impact the production of IDOU products.

3.4 Ensures that individuals are properly trained and qualified to execute all manufacturing steps of the IDOU’s approved batch records and to meet provisions of this quality agreement.

4. Documentation and Records

4.1 Ensures that any computerized systems used in the production or support of GMP activities to collect or analyze raw data are validated appropriately and controlled to ensure compliance with 21 CFR Part 11.

Systems will have sufficient controls to prevent unauthorized access or changes to the data, systems capture changes to original data in audit trails including the date and identity of the individual making the change, and systems ensure that data integrity is maintained in the event of a system failure and prevents permanent loss of electronic records.

4.2 Maintains systems to document the control, receipt and use of API, excipients, and components in manufacturing batch records to ensure approved materials are used, that materials are not expired, and to ensure traceability throughout the manufacturing and testing process

4.3 Maintains a written, approved procedure for the issuance of part and lot numbers that are used in cGMP documentation so that materials are uniquely identified and traceable

4.4 All documentation during manufacturing must be made in accordance with Contract Manufacturer’s SOPs and good documentation practice principles of GMP including real-time documentation of critical manufacturing data, second person verifications where required, proper notation and correction techniques, and retention of all raw data.

4.5 Documents are retained in accordance with a document retention policy that meets Contract Manufacturer, IDOU, and regulatory requirements X X

4.6 Maintains a controlled documentation system that assures all documents supporting GMP activities are initiated, reviewed, revised using version control, approved, and made obsolete in a controlled manner.

5. IDOU Right to Audit

5.1 Agrees that the IDOU retains the right to audit Contract Manufacturer as part of the IDOU’s external auditing program to qualify the Contract Manufacturer to perform manufacturing, testing, and release of IDOU’s investigational drug products. Details of the audit will be agreed to between the Contract Manufacturer and IDOU.

5.2 The IDOU retains the right to request and Contract Manufacturer must provide any SOPs related to the quality system supporting the cGMP manufacturing, testing, and release of IDOU’s products.

5.3 Agrees to allow on-site visits by the IDOU (and/or designated representatives) at a time prearranged between the Contract Manufacturer and IDOU. The IDOU will provide an audit agenda in advance of scheduling.

5.4 Agrees to address concerns of the IDOU’s quality unit as they relate to the manufacturing, testing, or release of drug product through discussions, providing documentation for review, and evidence of GMP compliance.

5.5 Ensures that NIH retains the right to request or audit procedures, investigation reports, or documentation relating to the drug product manufacturing or testing conducted at CM’s subcontractor facilities.

6. Regulatory Filings, Inspections, and Exchanges

6.1 IDOU is responsible for determining the regulatory filing requirements and process. Contract Manufacturer shall provide information and documentation to facilitate regulatory filings.

6.2 Responsible for communicating to the other party approvals, deficiencies or rejections of the study drug by regulatory agencies regarding X X submissions, amendments or updates for regulatory filings (e.g. CMC sections, INDs)

6.3 IDOU shall provide Contract Manufacturer with the following information regarding the use of the product including, but not limited to

• Clinical phase of development of the drug product or drug substance that product is used in and any change regarding this status

• Intended use of the drug product or drug substance in which that

Product is used

• Regulatory agencies with which the drug product or drug substance is filed and if product is included in the filing.

6.4 Provides information to the IDOU necessary to include in investigational drug IND filings, including as applicable to the CMC section X

6.5 Notify Contract Manufacturer if CM will be named in any governmental filing prior to such filing being made. X X

7. Complaints and Recalls

7.1 IDOU will notify Contract Manufacturer regarding any quality related issues of a manufactured drug product X

7.2 Conducts an investigation when a product complaint indicates a drug quality issue impacting the safety, identity, strength, purity or quality (SISPQ) of the drug product

7.3 IDOU will assist investigations regarding the drug product SISPQ with respect to any IDOU responsible activities in the manufacturing, testing or release of the drug product

7.4 Maintains procedures to facilitate the recall of any drug product as necessary due to product quality issues, or when retesting data (stability) does not support continued use of the drug product

8. Facilities (General)

8.1 Manufacture and store drug products using facilities that are designed and maintained to meet cGMPs appropriate for the type of drug product (i.e. sterile or nonsterile).

8.2 Facilities must be of adequate size and design to prevent the mix-up or cross-contamination of drug products and components and must be appropriately qualified for use.

8.3 Procedures are in place to ensure that

• personnel, raw materials, equipment, and waste flows are controlled to prevent cross contamination

• perform area clearance and changeover between products

• ensure manufacturing and testing facilities are controlled from unauthorized access

8.4 Facilities are supported by a comprehensive pest management program X

8.5 Maintains a preventive maintenance program for facilities and critical systems including X

• monitoring and trending of all systems and utilities that could impact product quality

• investigation of out of tolerance conditions to determine impact to manufactured product

• maintenance of documentation including a record of the type, frequency, and details of the service.

8.6 Maintains a facility cleaning program appropriate for the classification and use of the facility that includes responsibilities, schedules, list of qualified disinfectants, and documentation requirements

9. Facilities (Hazardous)

9.1 Handle and manufacture any drug listed as Hazardous (NIOSH) in accordance with the USP <800> regulations set to become effective on December 1, 2019. All facility and engineering controls, procedures for deactivating, decontaminating, and cleaning, spill control, and documentation and other related processes must be in place and effective by the effective date of USP<800>.

9.2 Compliance with the Globally Harmonized System of Classification and Labeling of Chemicals (GHS), as implemented by the United Nations:

(http://www.unece.org/trans/danger/publi/ghs/ghs_welcome_e.html)

9.3 Ensures that any subcontractors testing or handling the investigational drug product meet the requirements stated in 9.1 and 9.2 X

10. Facilities (Aseptic)

10.1 Facilities that support aseptic filling operations must be of appropriate design and ISO Classification and be fully validated, controlled and monitored to support ongoing aseptic operations.

10.2 Maintains plans in place to take down facilities and return facilities to use if there is a disruption (i.e. loss of control) in the controlled environment. X

10.3 Maintains a comprehensive cleaning program that is effective at microbial contamination control including for molds and objectionable organisms. X

10.4 Maintains a comprehensive environmental monitoring program for non-viable and viable air sampling and viable surface sampling. The program must include personnel monitoring, reporting and trending of results, and responses to alert and action level results.

10.5 Facility HEPA filters are maintained under a filter certification program that routinely tests filter integrity. X

10.6 Primary engineering controls, such Laminar Flow Hoods are tested and certified to meet guidelines established by ISO 14644 and manufacturer’s specifications on a routine schedule.

10.7 Areas of aseptic processing (i.e. rooms or primary engineering controls) are qualified through air flow visualization studies for the manufacturing operation or processes used to manufacture IDOU’s drug products.

http://www.unece.org/trans/danger/publi/ghs/ghs_welcome_e.html

11. Aseptic Processing Personnel Qualifications

11.1 All personnel working in ISO controlled areas are subject to strict gowning requirements based on room classification. X

11.2 Maintains a qualification program for personnel performing aseptic operations that includes initial qualification and routine evaluation and testing of personnel to ensure ongoing proper gowning practices are followed.

11.3 Maintains a qualification program for personnel to ensure the development of and adherence to proper aseptic techniques during the conduct of aseptic processing activities. Personnel must be periodically sampled as part of the ongoing environmental monitoring program.

12. Change Control

12.1 Maintains written procedures for control of changes impacting the

Product including manufacturing components or process, computer hardware/software, Product specifications, test methods, vendors, and subcontractors, if applicable.

12.2 Notifies and gains approval from IDOU of the intent to make changes that could impact the identity, strength, safety, potency, stability, purity, or regulatory status of IDOU’s drug product prior to implementation of the change.

12.3 Issues a written evaluation of the change including change justification so that IDOU can determine the impact of use of the drug product in the applicable study protocol, and to notify regulatory authorities of any changes to an IND or CMC protocol section

13. Validation/Qualification

13.1 Validated processes are in place to ensure no cross-contamination occurs between product batches that utilize shared equipment. Equipment cleaning procedures remove prior active ingredients and excipients, eliminates endotoxin and microbial contamination, and removes the residual cleaning agent(s).

13.2 Products manufactured in an aseptic environment (i.e. sterile products) are produced using processes that have been validated through media fill testing. The media fill validation evaluates the entire process from bulk non-sterile through final fill/finish. Media Fills are performed in triplicate.

14. Production and Process Controls

14.1 Contract Manufacturer shall generate and both parties must approve the master batch production record, labeling, packaging procedures, acceptance specifications, and test methods for the manufacture and release of the Product based on the information supplied by IDOU.

14.2 Any changes to the master batch production record, labeling and packaging procedures for the manufacture of the Product shall go through Contract Manufacturer change control system and shall be approved by IDOU.

14.3 Contract Manufacturer’s change control system will include maintenance of a revision history file and justification for changes initiated by both parties. IDOU shall provide justification for changes initiated by IDOU.

14.4 Contract Manufacturer will notify IDOU of any deviations that occur during the manufacturing process and will document and investigate for impact to the production batch. Contract Manufacturer’s quality unit will communicate with IDOU’s quality unit throughout the investigation to ensure agreement on the outcome. IDOU will be supplied with a completed, quality approved deviation report.

14.5 Unless otherwise specified in the project agreement, the Contract Manufacturer will procure all excipients in accordance with the company’s Standard Operating Procedures for selection, receipt, testing, and release of raw materials.

14.6 Unless otherwise specified in the project agreement, the Contract Manufacturer will procure the study drug API in accordance with the company’s Standard Operating Procedures for selection, receipt, testing, and release of APIs.

14.7 Contract Manufacturer maintains a supplier qualification program to ensure that purchased excipients and API comply with cGMPs including, but not limited to

a. BSE/TSE statement, as applicable

b. Residual solvent statement

c. Impurity Profiles

d. USP Tests, as applicable including

14.8 For any IDOU supplied API, excipient, or component, Contract Manufacturer will provide guidance to IDOU to ensure that any IDOU provided material meets cGMP quality standards and must be accepted by Contract Manufacturer.

14.9 IDOU will comply with requests for information from Contract Manufacturer regarding any IDOU provided project material. X

14.10 Unless otherwise agreed to in the project plan, Contract Manufacturer will perform the quality release of the API, raw materials, or components provided by IDOU.

15. Laboratory Controls

15.1 Maintains a program for qualification, calibration, and preventive maintenance of all analytical equipment. Out of Tolerance (OOT) conditions will be investigated for impact and records of all maintenance and calibration activities retained. IDOU will be notified if an OOT condition impacted the testing and release of IDOU products.

15.2 Performs analytical method development, qualification, and or method transfer, as appropriate and defined by the specific project agreement.

Method development, validation, and transfer reports, as applicable, will be approved by the quality unit and made available to the IDOU upon request.

15.3 Method transfer protocols between the Contract Manufacturer and IDOU will be approved by the quality units of both. Method transfer protocols between the IDOU and a 3rd party (subcontractor of the Contract Manufacturer), will be approved between the quality units of the IDOU, Contract Manufacturer, and subcontractor. Project quality agreements will delineate quality responsibilities in this arrangement.

15.4 Ensures that subcontractor for analytical or microbiological testing are qualified through the Contract Manufacturer’s qualification program for subcontractors. All subcontractors must also adhere to applicable portions of this quality agreement as applied to the testing of IDOU’s drug product.

15.5 Methods, specification, and subcontractors will be stated and agreed to in the project agreement between the Contract Manufacturer and IDOU. X X

15.6 Maintains written procedures for sample management, testing, approval, disposition, recording, storage, retention and disposal of laboratory data. X

15.7 Maintains written procedures and appropriately document the preparation, use and management of reagents, solutions, and standards. X

15.8 The Contract Manufacturer will test the API, drug product, or components, as applicable, in accordance with approved validated or qualified methods and specifications using calibrated equipment. Test methods must be available upon request.

15.9 The Contract Manufacturer will assist in determining appropriate product acceptance criteria based on appropriate specifications and test procedures for the product which are consistent with the applicable approved filing and/or compendial monograph. Specifications will be agreed to between Contract Manufacturer and IDOU or between Contract Manufacturer, IDOU and subcontractor.

16. Deviations and OOS

16.1 Contract Manufacturer will have procedures for the identification, investigation, and reporting of deviations and Out-of-Specification (OOS) results that occur during the manufacture and testing of the Product.

• Perform root cause analysis

• Extend the investigation to other lots that may have been associated with the failure as appropriate

• Include preventive actions and track these to completion

• Contract Manufacturer’s quality unit will approve all deviation, OOS, and exception reports.

16.2 Contract Manufacturer will inform IDOU regarding OOS results or other product deviations or quality events. Contract Manufacturer and IDOU will communicate on the conduct of the investigation and reach an agreement on the outcomes and conclusions.

16.3 The Contract Manufacturer will provide a written, quality approved report to the IDOU. X

17. Project Deliverables

16.4 The Certificate of Analysis (COA) for the API will be made available to the

IDOU for suppler sourced API. X

16.5 For IDOU supplied API, the Certificate of Analysis (COA) for the API will be made provided to the Contract Manufacturer. X

16.6 The Contract Manufacturer must follow procedures for accepting and releasing IDOU supplied API. If deficiencies exist that prevent the Contract Manufacturer from accepting the API, Contract Manufacturer and IDOU will work together to resolve deficiencies up to and including Contract Manufacturer testing of the API.

16.7 Contract Manufacturer will provide the following documents for each lot of manufactured drug product: Complete Certificate of Analysis for the Product, containing "at minimum" the following information:

• Contract Manufacturer Product number

• Contract Manufacturer lot/batch number

• Name of Product

• Name of the test

• Specification limit

• Expiration or retest date, if applicable

• Test results (as a numerical value, unless designated Pass/Fail in the specification limit

• Quality Assurance approval and date

• Manufacturing Date

• COA Issuance Date

18. Stability (If applicable per Project Agreement)

18.1 If stability studies are indicated as a contractor responsibility in the project agreement, then contractor will perform studies in accordance with the requirements of FDA Guidance Q1A (R2) Stability Testing of New Drug Substances and Products.

18.2 Stability chambers will be qualified and monitored. Any events compromising the stated storage conditions of the drug product will be reported to the IDOU.

18.3 Drug products will remain in their original packaging configuration, at the specified stability storage condition until the time of testing. Sufficient samples should be allocated for stability to allow for testing of an unopened sample at each planned stability time point.

18.4 Stability studies will be conducted under a stability protocol, approved by the Quality Units of both the Contract Manufacturer and IDOU. The protocol will specify the storage conditions, testing intervals, tests to be performed at each interval, and information regarding appropriate windows for pulling samples and obtaining results.

Development of Project Agreements

Due to the varied nature of the investigational drug products procured by the NIH Clinical Center IDOU group, it is necessary to have project specific agreements in place in order to obtain accurate quotes and to ensure that each individual project’s GMP needs are satisfied. These are the responsibilities in creating project agreements.

1 IDOU will provide Contract Manufacturer with the study drug information that is necessary to determine an appropriate formulation and packaging configuration. This includes, but is not limited to API, route of administration, potency, volume, and quantity of product required for study, planned duration of study

2 Where IDOU is requesting the manufacturing of an existing drug in an ongoing study, or for use of an existing or similar drug in a new study, the IDOU will provide any applicable background information regarding formulation, manufacturing, packaging, or testing of previously manufactured study drugs.

3 Contract Manufacturer will make recommendations and the CM and IDOU will agree on

• the requirements for process validation appropriate for the dosage form and phase of study (i.e. media fills for aseptic processes, test batches)

• in-process testing controls (i.e. bulk bioburden testing, content uniformity testing)

• quality controls for the product configuration (i.e. container closure integrity studies)

4 Contract Manufacturer will make recommendations on the applicability of USP microbial testing and the Contract Manufacturer and IDOU will agree on the testing necessary to support the GMP compliance of the product including, but not limited to

• Antimicrobial Effectiveness Testing <51>

• Microbiological Examination of Nonsterile Products: Microbial

Enumeration Tests <61>

• Microbiological Examination of Nonsterile Products: Tests for Specified

Organisms <62>

• Sterility Tests <71>

• Bacterial Endotoxins Test <85>

5 Contract Manufacturer will make recommendations on the applicability of the analytical tests necessary to support acceptance of the API and release of the drug product. IDOU and Contract Manufacturer will agree on tests required to ensure compliance with cGMPs including, but not limited to

• Drug Substance Characterization

• Reference Standard Qualification

• Assay and Related Substances

• Extractables and Leachables

• Solubility and Solution Stability Studies

• Stability Indicating Assays

• Dissolution Testing

• Physical Methods

• Drug Excipient Compatibility Studies

• Impurities

6 A project plan will be created for each drug product or similar grouping of drug products produced by Contract Manufacturer for IDOU. Project plans are subject to all the requirements of this quality agreement, and list specific details for each product as referenced in this section. The project plan will be jointly approved by IDOU and Contract Manufacturer, including each entity’s quality unit prior to the start of manufacturing.

PART 2 – PROJECT PLAN AGREEMENT

PROJECT PLAN AGREEMENT

PURPOSE

The project plan agreement is a supplement to a previously signed Quality Agreement between the NIH Clinical Center Pharmacy Outsourcing Group and the Contract Manufacturer for the manufacturing of an investigational drug product to be used at the NIH Clinical Center in clinical study.

This agreement identifies the drug product, materials, methods, and testing required for the manufacture and release of the study drug.

SCOPE

This agreement specifies details for the manufacture of the following investigational drug product.

Product Name:

Potency:

Volume:

Configuration:

Count:

Storage Conditions:

Product Description:

Special Product Requirements (i.e. protect from light)

CONTRACT MANUFACTURER

This section identifies the location of manufacturing activities and the contact information of key personnel related to this project.

Company Name:

Address Location of Manufacturing Facility:

Primary Contact:

Quality Unit Contact:

INVESTIGATIONAL PRODUCT and TRIAL INFORMATION

This section will detail the phase of study, the intended use of the drug, the anticipated quantity of drug needed (batch size) and number of batches, information on previous formulations of drug product (if applicable and if intended to be provided to contractor as a basis for formulation), information on prior analytical testing (if applicable and intended to be transferred).

MANUFACTURING PROCESS REQUIREMENTS

This section provides an overview of the manufacturing process to be used, validation requirements, in-process testing requirements (such as bioburden testing for sterile products, blend uniformity testing for solid oral dosage forms), and provides a calculation of batch size that includes the intended number of units to be used for study plus a specified number of samples for testing, for retention to meet regulatory requirements, and for stability purposes.

Attachment 1 specifies the API, raw materials, and components to be used in the manufacturing and packaging of the drug product.

Also included in this section are requirements for container-closure integrity studies or justification if not applicable.

FINISHED PRODUCT TESTING REQUIREMENTS

This section lists tests and specifications that are required to support release of the investigational drug product and assigns responsibility for testing (i.e. sterility, LAL, endotoxin, particulates, assay, dissolution, content uniformity, impurities, etc.). Release responsibilities will be stated and any initial expiration (or retest) date as applicable.

This section lists subcontractors, for tests that will not be performed by contractor at the manufacturing site.

Also included in this section are requirements for method validation or transfer.

LABELLING

Investigational product labelling requirements will be established.

FINISHED PRODUCT SHIPPING REQUIREMENTS

This section will detail any storage, shipping and handling requirements. Addresses for shipments and any special conditions will be noted.

STABILITY PROGRAM REQUIREMENTS

This section will establish responsibility for stability monitoring of the investigational drug product.

The stability protocol will be established here to include the number of samples and the storage condition. If stability is outsourced, the name of the subcontractor is stated here. Provisions for transferring stability product to and from the testing location will be established and detailed or referenced here. This section will also indicate retest dating requirements.

This section establishes Date Corresponding to Time Point 0 (Initial):

PROJECT PLAN APPROVALS

This section will contain approvals of key individuals and Quality Unit representation for both the contract manufacturer and IDOU.

ATTACHMENT 1: RAW MATERIAL AND COMPONENT IDENTIFICATION

Material Name Material Type (i.e. API, Excipient, Component)

Material Grade Contract Manufacturer Name

Responsibility1 Contractor NIH

1 1=Purchased by Contractor, 2= Purchased by NIH, 3 = Released by Contractor, 4= Released by NIH

Quality Agreement

National Institutes of Health

National Institutes of Health

Background

1. Contract Manufacturer Quality Organization

2. IDOU Quality Organization

3. Personnel

4. Documentation and Records

5. IDOU Right to Audit

6. Regulatory Filings, Inspections, and Exchanges

7. Complaints and Recalls

8. Facilities (General)

9. Facilities (Hazardous)

10. Facilities (Aseptic)

11. Aseptic Processing Personnel Qualifications

12. Change Control

13. Validation/Qualification

14. Production and Process Controls

15. Laboratory Controls

16. Deviations and OOS

17. Project Deliverables

18. Stability (If applicable per Project Agreement)

Clinical phase of development of the drug product or drug substance that product is used in and any change regarding this status

Intended use of the drug product or drug substance in which that Product is used

Regulatory agencies with which the drug product or drug substance is filed and if product is included in the filing.

personnel, raw materials, equipment, and waste flows are controlled to prevent cross contamination monitoring and trending of all systems and utilities that could impact product quality investigation of out of tolerance conditions to determine impact to manufactured product maintenance of documentation including a record of the type, frequency, and details of the service.

Perform root cause analysis

Extend the investigation to other lots that may have been associated with the failure as appropriate

Include preventive actions and track these to completion

Contract Manufacturer’s quality unit will approve all deviation, OOS, and exception reports.

Contract Manufacturer Product number

Contract Manufacturer lot/batch number

Name of Product

Name of the test

Specification limit

Expiration or retest date, if applicable

Test results (as a numerical value, unless designated Pass/Fail in the specification limit

Quality Assurance approval and date

Manufacturing Date

COA Issuance Date

Development of Project Agreements the requirements for process validation appropriate for the dosage form and phase of study (i.e. media fills for aseptic processes, test batches) in-process testing controls (i.e. bulk bioburden testing, content uniformity testing) quality controls for the product configuration (i.e. container closure integrity studies)

Antimicrobial Effectiveness Testing <51>

Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests <61>

Microbiological Examination of Nonsterile Products: Tests for Specified Organisms <62>

Sterility Tests <71>

Bacterial Endotoxins Test <85>

Drug Substance Characterization

Reference Standard Qualification

Assay and Related Substances

Extractables and Leachables

Solubility and Solution Stability Studies

Stability Indicating Assays

Dissolution Testing

Physical Methods

Drug Excipient Compatibility Studies

Impurities

NIH Supplier Audit Questionnaire

It is the purpose of this questionnaire to facilitate National Institutes of Health (NIH) in gathering information for the approval of your materials/products/services. All information provided in this questionnaire will be treated strictly confidential. In case of any question or comment concerning this questionnaire please contact:

Name: TBD Email: TBD Tel: TBD

This questionnaire may be completed electronically (preferred) or hand written.

Please return the completed questionnaire to the person listed above along with all additional, applicable information/documentation.

Company Name

Name (printed) Signature (Quality Unit person responsible for completing this questionnaire)

Title Location Date

Attachment 23

COMPANY INFORMATION:

Date Form Completed:

Type of product(s) subject to this audit (please check all that apply):

Drug Substance API Excipient Packaging Component Intermediate Drug Product Name of Product(s) Subject to this audit (include dosage forms/services if applicable):

Company Name:

Company Corporate Address:

Company Internet Address:

Key Personnel:

a) Contact Person Name:

Position/Title:

Telephone Number:

Cellular/Mobile Number:

Facsimile Number:

Email Address:

b) Person Responsible for Manufacturing/Production Name:

Position/Title:

Qualifications:

Experience:

c) Persons Responsible for Quality (QA/QC) Name:

Position/Title:

Qualifications:

Experience:

Does your company have a U.S. Agent or U.S.-based Corporate Office that may operate in the U.S. on your company’s behalf? Yes No N/A If applicable, please provide the contact information of US Agent:

Company Name:

Contact Person Name:

Position/Title:

Address:

Telephone Number:

Facsimile Number:

Email Address:

What is the native language at this facility?

If not English, what is the level of English understanding of the contact person (s) named above?

None Little Intermediate Fluent Will English translated documents be available for review? Yes No N/A Does your company manufacture products under cGMPs? Yes No N/A Can you provide a cGMP certification (please attached)? Yes No Can you provide a Debarment certification (please attached)? Yes No Is your company ISO certified? Yes No N/A If yes, please list type of ISO Certification:

Is the company licensed or certified under any other GMP/Quality Scheme? Yes No If yes, please provide brief details):

What is your FDA establishment number (if applicable):

PRODUCT INFORMATION

GENERAL

Do you have a DMF (US) or EDMF (EU) filed for this product? Yes No Please provide DMF #: and Country:

Date the DMF was filed/last updated:

Has this DMF been reviewed by the FDA? Yes No N/A If there is no DMF on file, does your company plan on filing a DMF in the future? Yes No If yes, provide date of planned filing:

What is the batch size for development batches?

What is the price for developmental quantities?

What is the batch size for commercial batches?

What is the capacity per year?

Is there additional capacity planned? Yes No INTELLECTUAL PROPERTY (if not applicable, check box and skip this section) N/A Will you be handling the customs clearance?