Amendment__00002_0002.pdf

(x)

75N95024R00077 x x

1 copies of the amendment; (b) By acknowledging receipt of this amendment on each copy of the offer submitted ; or (c) By separate letter or electronic communication which includes a reference to the solicitation and amendment numbers. FAILURE OF YOUR ACKNOWLEDGEMENT TO BE

RECEIVED AT THE PLACE DESIGNATED FOR THE RECEIPT OF OFFERS PRIOR TO THE HOUR AND DATE SPECIFIED MAY RESULT IN REJECTION OF YOUR

OFFER. If by virtue of this amendment you desire to change an offer already submitted , such change may be made by letter or electronic communication, provided each letter or electronic communication makes reference to the solicitation and this amendment, and is received prior to the opening hour and date specified.

x

NIDA

Bethesda, MD 20892-7511 National Institute on Drug Abuse National Institutes of Health

NIDA-EXEC

Bethesda, MD 20892-7511 National Institute on Drug Abuse National Institutes of Health

07/05/20240002

13. THIS ITEM ONLY APPLIES TO MODIFICATION OF CONTRACTS/ORDERS. IT MODIFIES THE CONTRACT/ORDER NO. AS DESCRIBED IN ITEM 14.

12. ACCOUNTING AND APPROPRIATION DATA (If required) is not extended.is extended, Items 8 and 15, and returning

Offers must acknowledge receipt of this amendment prior to the hour and date specified in the solicitation or as amended , by one of the following methods: (a) By completing

The above numbered solicitation is amended as set forth in Item 14. The hour and date specified for receipt of Offers

11. THIS ITEM ONLY APPLIES TO AMENDMENTS OF SOLICITATIONS

FACILITY CODE CODE

10B. DATED (SEE ITEM 13)

10A. MODIFICATION OF CONTRACT/ORDER NO.

9B. DATED (SEE ITEM 11)

9A. AMENDMENT OF SOLICITATION NO.

CODE

8. NAME AND ADDRESS OF CONTRACTOR (No., street, county, State and ZIP Code)

7. ADMINISTERED BY (If other than Item 6)CODE 6. ISSUED BY

PAGE OF PAGES

4. REQUISITION/PURCHASE REQ. NO.3. EFFECTIVE DATE2. AMENDMENT/MODIFICATION NO. 5. PROJECT NO. (If applicable)

1. CONTRACT ID CODE

AMENDMENT OF SOLICITATION/MODIFICATION OF CONTRACT

06/07/2024

CHECK ONE A. THIS CHANGE ORDER IS ISSUED PURSUANT TO: (Specify authority) THE CHANGES SET FORTH IN ITEM 14 ARE MADE IN THE CONTRACT

B. THE ABOVE NUMBERED CONTRACT/ORDER IS MODIFIED TO REFLECT THE ADMINISTRATIVE CHANGES (such as changes in paying office, C. THIS SUPPLEMENTAL AGREEMENT IS ENTERED INTO PURSUANT TO AUTHORITY OF:

D. OTHER (Specify type of modification and authority) appropriation data, etc.) SET FORTH IN ITEM 14, PURSUANT TO THE AUTHORITY OF FAR 43.103(b).

E. IMPORTANT: Contractor is not is required to sign this document and return __________________ copies to the issuing office.

ORDER NO. IN ITEM 10A.

14. DESCRIPTION OF AMENDMENT/MODIFICATION (Organized by UCF section headings, including solicitation/contract subject matter where feasible.)

The PURPOSE of this Amendment #00002 is to A) provide answers to the questions submitted in response to Request for Proposals (RFP) No. 75N95024R00077 and B) make changes to the RFP as described in the following pages.

Amendment #00002 replaces Amendment #000001 in its entirety because the Amendment #000001 attachment did not upload to sam.gov.

16A. NAME AND TITLE OF CONTRACTING OFFICER (Type or print)15A. NAME AND TITLE OF SIGNER (Type or print)

15C. DATE SIGNED 16B. UNITED STATES OF AMERICA 15B. CONTRACTOR/OFFEROR 16C. DATE SIGNED

(Signature of person authorized to sign) (Signature of Contracting Officer)

RIEKA N. PLUGGE

STANDARD FORM 30 (REV. 11/2016)

Prescribed by GSA FAR (48 CFR) 53.243

Previous edition unusable

Except as provided herein, all terms and conditions of the document referenced in Item 9 A or 10A, as heretofore changed, remains unchanged and in full force and effect .

SF-30 CONTINUATION SHEET

AMENDMENT #00002

NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

REQUEST FOR PROPOSALS (RFP) NUMBER: 75N95024R00077

PROJECT TITLE: Drug Manufacturing and Formulation Program (DMFP)

AMENDMENT NUMBER: 00002

DATE OF ISSUANCE: July 5, 2024

The above numbered RFP is amended as set forth below. The hour and the date specified for receipt of proposals remains unchanged. Offerors must acknowledge receipt of the amendment prior to the hour and the date specified in the RFP or as amended, by one of the following methods:

I. By acknowledging receipt of this amendment on each copy of the proposal submitted.

Please note that this is the preferred method.

II. By separate email which includes a reference to the RFP and amendment number.

FAILURE OF YOUR ACKNOWLEDGMENT TO BE RECEIVED AT THE PLACE DESIGNATED

FOR THE RECEIPT OF PROPOSALS PRIOR TO THE HOUR AND DATE SPECIFIED MAY

RESULT IN REJECTION OF YOUR PROPOSAL. If by virtue of this amendment you desire to change a proposal already submitted, such change may be made by email, provided each email makes reference to the RFP and this amendment, and is received prior to the opening hour and date specified.

The Purpose of this Amendment, issued on 7/05/2024, is to A) provide answers in response to to questions received in response to RFP No. 75N95024R00077 and B) make changes to RFP No.

75N95024R00077.

The hour and the date specified for receipt of proposals remains unchanged.

A. This amendment provides responses to questions received concerning the above numbered RFP as stated below.

INTERESTED OFFEROR QUESTIONS GOVERNMENT ANSWERS TO INTERESTED OFFEROR

QUESTIONS

QUESTION #1:

Is it accurate to say that the resulting proposal for this RFP is a fully detailed technical proposal based on Sample Task Order #0001 including identifying by name all personnel anticipated to be performing work?

GOVERNMENT ANSWER TO QUESTION #1:

Yes. The Offeror needs to include a fully detailed technical proposal for Sample Task Order #00001 and Statement of Work. As part of its proposal, the Offeror must provide a completed Breakdown of Proposed Costs (Attachment 9 to

RFP).

QUESTION #2: GOVERNMENT ANSWER TO QUESTION #2:

milgramm2 Highlight

INTERESTED OFFEROR QUESTIONS GOVERNMENT ANSWERS TO INTERESTED OFFEROR

QUESTIONS

Will all responses to RFI’s be communicated to all prospective Offerors?

Yes. Answers to all questions and requests for information (RFI) will be provided in Amendment number 00002 to the RFP. All RFP amendments will be published on www.sam.gov under RFP number/Notice ID 75N94024R00077.

QUESTION #3:

Does the Offeror need to possess the skills to provide all DMFP services? For example, can the offeror bid solely on API synthesis and scale-up related work

GOVERNMENT ANSWER TO QUESTION #3:

Offeror may opt to include URL’s in its proposal submission.

However, Offerors shall refer to SECTION L of the RFP for all proposal instructions concerning the submission of the Small Business Subcontracting Plan (2.c.6.), Travel Policy (2.c.14.), Total Compensation Plan (2.c.9.), and Proposer’s Annual Financial Report (2.c.13.).

QUESTION #4:

Does the bidder need to be a US based company, or can a company utilize a non-US associated company to complete part of the contracted services? Specifically, can the Offeror provide the formulation development outside of the US using a non-US affiliated company?

GOVERNMENT ANSWER TO QUESTION #4:

All work performed under a resultant contract will be subject to any applicable restrictions in the Federal Acquisition Regulations (FAR), including any restrictions in FAR Part 25.7

– Prohibited Sources. Additionally, any resultant contract shall comply with the requirements in NIH Manual Chapter 6325- 1 - Clearance of Foreign Contracts, Foreign Subcontracts, and Domestic Contracts or Subcontracts with a Foreign Component.

QUESTION #5:

A5 - TECHNICAL PROPOSAL COST

INFORMATION/SUMMARY OF LABOR AND

DIRECT COSTS – Is this table to be filled out based on the sample task order 00001? Is it considered non-binding since the scope is not fully detailed?

GOVERNMENT ANSWER TO QUESTION #5:

Yes, Attachment 5 - Technical Proposal Cost Summary is to be completed based on Sample Task Order #0001 and Statement of Work (Attachment 18 to RFP). Per page 86 of the RFP, the “technical proposal must include direct cost and resources information, such as labor hours and categories and applicable rates, materials subcontracts, travel, etc., and associated costs so that the offeror's understanding of the project may be evaluated (See SECTION J Attachment 5 entitled TECHNICAL PROPOSAL COST SUMMARY.) However, the technical proposal should not include pricing data relating to individual salary information, indirect cost rates or amounts, fee amounts (if any), and total costs.”

Although any cost estimate is non-binding prior to the Offeror being awarded a contract, the Government reserves the right to award a task order that is based on an offeror’s technical proposal cost summary.

QUESTION #6: GOVERNMENT ANSWER TO QUESTION #6:

http://www.sam.gov/ http://www.acquisition.gov/far/subpart-25.7 http://www.acquisition.gov/far/subpart-25.7

INTERESTED OFFEROR QUESTIONS GOVERNMENT ANSWERS TO INTERESTED OFFEROR

QUESTIONS

Is it a requirement that all personnel that may be involved in providing these services be named in the response to this RFP so that a conflict-of-interest screening can be conducted? If so, are there provisions to add newly named personnel in response to future task orders?

Yes. All personnel that may be involved in providing the DMFP services should be named in the Offeror’s proposal.

Refer to sections “4. Personnel” and “5. Resumes” on page 100 of the RFP.

Yes, offerors will be permitted to add new personnel in their response to task order requests for proposals.

QUESTION #7:

Will all Task Orders be awarded on a cost-plus fixed fee basis? If so, is it accurate to say the A9_Breakdown is a non-binding estimate of costs?

GOVERNMENT ANSWER TO QUESTION #7:

As stated in Section L of the RFP (page 87 of RFP), with the exception of a firm-fixed price task order to be awarded for Performance Activity 1 at the time of contract award, it is anticipated that all other task orders will be awarded on a cost-plus fixed fee basis.

Although a cost estimate is non-binding prior to the Offeror receiving a contract award, the Government reserves the right to award a task order that is based on an offeror’s technical proposal cost summary.

QUESTION #8:

Is it a requirement that subcontracting must include some level of Small, Small Disadvantaged, Women-Owned, HUBZone, Veteran-Owned, and Service Disabled Veteran-Owned Small Business Concerns as subcontractors

GOVERNMENT ANSWER TO QUESTION #8:

Yes. Refer to section “f. Small Business Subcontracting Plan” of the RFP (pages 107-111 of RFP) and “Section M – Evaluation Factors for Award” of the RFP (pages 125-134 of

RFP).

QUESTION #9:

Attachment A7 “Additional Technical Proposal Instructions” states “Only proposals from prospective offerors who demonstrate the capability to perform all aspects of the performance activities in the SOW will be considered for contract award.” Does this mean all aspects of the performance activities must be conducted in-house or can some aspects be performed by subcontractors?

GOVERNMENT ANSWER TO QUESTION #9:

Offeror should propose the approach it believes would best meet the requirements stated in Attachment 18 - Sample Task Order #0001 and Statement of Work. Some aspects of the performance activities may be subcontracted.

QUESTION #10:

Attachment A18 “Sample Task Order #0001” references multiple potential drug product formulations. For example, paragraph 2 on page 1 references “manufactured as API in capsules (10 mg, 50mg and 200 mg

GOVERNMENT ANSWER TO QUESTION #10:

The Offeror should only consider API in capsule as the first option and consider injectable USP solution with same strengths as a secondary option. Yes, the Offeror may consider sterilized solution in vials for injectable USP solution (secondary option). Please see section “E.

INTERESTED OFFEROR QUESTIONS GOVERNMENT ANSWERS TO INTERESTED OFFEROR

QUESTIONS

strengths) and injectable USP solution” while Section E under Campaign 2 references prototype formulations including API in Capsule, Blend in Capsule and Liquid in Capsule and the Technical Requirements list “dosage form in press tablets, packaged in blister packs and sterilized solution in vials.”.

How should Section E of Campaign 3 be quoted? Should the offeror include effort for sterilized solution in vials and press tablets, packaged in blister packs?

Formulation studies” in revised Attachment 18 – Revised Task Order #00001 and SOW, dated 07/05/2024 and included at the end of this amendment.

QUESTION #11:

What details can be shared on the handling of the Compound? Is an MSDS, OEL/OEB or LD50 available? If not, what assumptions should be made around Compound handling requirements?

GOVERNMENT ANSWER TO QUESTION #11:

Assume for the purpose of the proposal that this compound is not considered high potency nor is it considered extremely toxic. It is anticipated that this compound will be entering GLP tox and human clinical trials testing.

QUESTION #12:

Attachment A18 “Sample Task Order #0001” references Ref: Med. Chem. Lett. 2011, 2, 929-932. This paper includes similar compounds to the one shown in Attachment A18 but not the exact compound. Is there a separate reference showing a medicinal chemistry route to the target compound?

GOVERNMENT ANSWER TO QUESTION #12:

No. The reference was provided as a starting point and does not exactly reflect the proposed compound. It is up to the Offeror to propose a process chemistry strategy that leads to the indicated compound.

QUESTION #13:

Is this notice intended to support one or multiple drug substance and drug product development programs, if so how many could we anticipate in a calendar year

GOVERNMENT ANSWER TO QUESTION #13:

The DMFP contracts resulting from the subject RFP are intended to support multiple DMFP drug substance and drug product development programs. It is anticipated that task order requests for proposals will be issued during the ordering period as needs arise, up to the estimated maximum of $49,999,999. (RFP, page 2.)

QUESTION #14:

Is there flexibility in the location of the manufacturing facility, or are US facilities preferred?

GOVERNMENT ANSWER TO QUESTION #14:

Refer to Government answer to question #4 (above).

QUESTION #15: GOVERNMENT ANSWER TO QUESTION #15:

Refer to Government answer to question #4 (above).

INTERESTED OFFEROR QUESTIONS GOVERNMENT ANSWERS TO INTERESTED OFFEROR

QUESTIONS

In the same vein could laboratory research work be carried out ex-US or must it be carried out in the US only

QUESTION #16:

If ex-US facilities are permitted, are facilities in China acceptable or not

GOVERNMENT ANSWER TO QUESTION #16:

Refer to Government answer to question #4 (above).

QUESTION #17:

Attachment 18, Paragraph A, Scope. This paragraph states that studies shall evaluate preformulation and formulation of the compound listed above to be manufactured as API in capsules (10 mg, 50mg and 200 mg strengths) and injectable USP solution. Should an injectable USP solution also be considered for formulation development, or should we focus only on API in capsules? The Sample Task Order SOW requirements for Campaign No. 2 mention only capsules, not an injectable. However, the Scope section of the SOW includes an injectable.

GOVERNMENT ANSWER TO QUESTION #17:

Refer to Government answer to question #10 (above).

QUESTION #18:

Are there any restrictions on where a material is manufactured

GOVERNMENT ANSWER TO QUESTION #18:

Refer to Government answer to question #4 (above).

QUESTION #19:

Would the restrictions be different for non- GMP material vs. GMP material? Or is it required to have GMP material made only in

US?

GOVERNMENT ANSWER TO QUESTION #19:

Refer to Government answer to question #4 (above).

QUESTION #20:

Are there any countries being banned where we cannot have contractual relationships with any companies in those countries?

GOVERNMENT ANSWER TO QUESTION #20:

Refer to Government answer to question #4 (above).

QUESTION #21:

Is there a specific Period of Performance that should be used for the Sample

GOVERNMENT ANSWER TO QUESTION #21:

The Offeror may select the period of performance it deems the most appropriate so long as the period of performance allows for the completion of all the performance activities

INTERESTED OFFEROR QUESTIONS GOVERNMENT ANSWERS TO INTERESTED OFFEROR

QUESTIONS

Task/Campaigns, or are we free to choose dates for estimation purposes?

outlined in Attachment 18 - Sample Task Order #0001 Statement of Work. Offeror’s proposal should clearly indicate when the materials are ready for release.

QUESTION #22:

Are there any page limitations for the Technical or the Business Volume or for the sample Task Orders?

GOVERNMENT ANSWER TO QUESTION #22:

There are page limitations. Please refer to Part B of this Amendment.

QUESTION #23:

Article 14 on page 39 “Confidentiality of Information” ends at “The following information is covered by this article:” with no subsequent details. Was this an inadvertent omission, or is NIDA waiting until award to definitize the information that will be confidential?

GOVERNMENT ANSWER TO QUESTION #23:

Article 14 “CONFIDENTIALITY OF INFORMATION” is deleted in its entirety.

QUESTION #24:

Regarding section e. on page 12-13 of the

SOW

Is the reference to API in this section a typo? Should this say drug product? This will change whether ICON can execute or if a subcontractor is required.

GOVERNMENT ANSWER TO QUESTION #24:

Yes, the reference to API is a typo. Please refer to amended Attachment 3 – Revised Contract Statement of Work, which replaces original Attachment 3 – Contract Statement of Work in its entirety to account for this change on page 13.

(End of Answers to Questions to the RFP)

B. This amendment revises the above numbered RFP as stated below.

1. In “SECTION L” of the RFP, the following paragraph is added under “b. Authorized Official and Submission of Proposal” (pages 85-86 of RFP):

“IV. PAGE AND FORMATTING LIMITATIONS

The Technical Proposal shall not exceed 30 single-sided pages. This page limitation does not include the cover sheet, abstract, table of contents, personnel resumes, facilities, equipment and resources, other considerations, schedule, other support, cost information, and literature cited. Appendices shall not exceed a total of 40 single-sided pages. Pages in excess of the limitation will be deleted and will be neither read nor evaluated. Each page of the technical proposal must be numbered sequentially. Offerors are encouraged to limit the overall size of the technical proposal, inclusive of appendices, attachments, etc. Although no page limit has been placed on the business proposal, offerors are encouraged to limit its content to only those documents necessary to provide adequate support for the proposed costs.

Font size must be 11 or 12 points. Page margins must be no less than 1/2 inch around, exclusive of headers and footers.”

2. In Attachment 7 - Additional Technical Proposal Instructions, the text below the section titled “Performance Activity 1 (PA1) – Kickoff Meeting” is replaced in its entirety with the following:

“The contractor shall ensure and participate in a one-day contract initiation meeting. The meeting will be scheduled by the contracting officer’s representative (COR) and will take place within two months following the effective date of the base contract award. For additional details, please see Attachment 3 – Contract Statement of Work.”

3. Attachment 3 – Contract Statement of Work is replaced in its entirety with a revised Attachment 3 – Revised Contract Statement of Work, dated 7/05/2023 and included in this amendment (below).

4. Attachment 18 - Sample Task Order 0001 and Statement of Work (SOW) is replaced in its entirety with a revised Attachment 18 – Revised Sample Task Order #0001 and SOW, dated 7/05/2024 and included in this amendment (below).

5. Section “5. ADVANCE UNDERSTANDINGS” of the RFP is amended by the addition of the following paragraph:

“e. Confidential Treatment of Sensitive Information

“The Contractor shall guarantee strict confidentiality of the information/data that is provided by the Government during the performance of the contract. The Government has determined that the information/data that the Contractor will be provided during the performance of the contract is of a sensitive nature. Disclosure of the information/data, in whole or in part, by the Contractor can only be made after the Contractor receives prior written approval from the Contracting Officer. Whenever the Contractor is uncertain with regard to the proper handling of information/data under the contract, the Contractor shall obtain a written determination from the Contracting Officer.”

6. “SECTION J - List of Documents, Exhibits and Other Attachments” in the RFP is replaced in its entirety as follows:

Attachment Number

Title Date Number of Pages

1 Packaging and Delivery of Proposals for Use with the NIH eCPS website

03/12/2018 2

2 Proposal Intent Response Form N/A 1 3 Revised Contract Statement of Work 07/05/2024 24

(End of Summary of Changes to the RFP)

4 Section K - Representations, Certifications, and Other Statements of Offerors

06/07/2024 6

5 Technical Proposal Cost Summary N/A 1 6 Summary of Related Activities N/A 1 7 Additional Technical Proposal Instructions 06/07/2024 2 8 Proposal Summary and Data Record, NIH-2043 N/A 1 9 Breakdown of Proposed Estimated Costs (plus fee) 06/07/2024 1 10 Offeror’s Points of Contact N/A 1 11 Wage Determination 04/28/2024 11 12 Disclosure of Lobbying Activities, OMB Form SF-LLL N/A 1 13 Invoice/Financing Request Instructions-CR-NIH(RC)-1 N/A 1 14 NIDA Supplemental Billing Instructions N/A 1

15 Commitment to Protect Non-Public Information Contractor Agreement

N/A 2

16 Employee Separation Checklist N/A 1

17 Declaration of Exceptional Circumstances Acknowledgment

06/07/2024 1

18 Revised Sample Task Order #0001 and Statement of Work 07/05/2024 19

Attachment 3: Revised Contract Statement of Work, 07/05/2024, 16 pages

REVISED CONTRACT STATEMENT OF WORK

A. BACKGROUND INFORMATION AND OBJECTIVES

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

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

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

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

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

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

Date: 07/05/2024

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

(TORFP).

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

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

B. SCOPE AND PERFORMANCE ACTIVITIES

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

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

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

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

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

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

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

Manufacture/ Analytical Methods Development and Stability Testing

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

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

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

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

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

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

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

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

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

B.2.2.3 Analytical Methods Development and Stability Testing:

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

C. TECHNICAL REQUIREMENTS

C.1 SPECIFIC REQUIREMENTS AND SCHEDULE OF WORK

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

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

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

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

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

C.1.1 REQUIREMENTS FOR PERFORMANCE ACTIVITY 1: KICKOFF MEETING

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

C.1.2 REQUIREMENTS FOR PERFORMANCE ACTIVITY 2:

C.1.2.1 REQUIREMENTS FOR PERFORMANCE ACTIVITY 2A – GENERAL

ADMINSITRATION AND TECHNICAL SUPPORT

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

C.1.2.1.1 SCOPE

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

C.1.2.1.2 TECHNICAL REQUIREMENTS

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

C. 1.2.1.2.1 PROJECT MANAGEMENT

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

C. 1.2.1.2.2 MEETINGS

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

C. 1.2.1.2.3 TRANSITION PLANS

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

C. 1.2.1.2.4 Final Transition

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

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

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

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

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

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

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

MANUFACTURE/ FORMULATION AND DOSAGE FORM MANUFACTURE/

ANALYTICAL MRTHODS DEVELOPMENT AND STABILITY TESTING

C.1.3.1 SCOPE

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

PA2B.

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

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

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

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

C.1.3.2 TECHNICAL REQUIREMENTS:

C.1.3.2.1 API SCALE UP AND MANUFACTURE

a. Chemistry Technology Transfer:

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

1. Communicating with small scale chemistry vendor

2. Participating in LDT meetings/conferences

3. Creating and sharing electronic files securely

4. Receiving and storing samples under controlled conditions

5. Performing analytical and physicochemical testing to fully characterize samples

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

b. Process Development:

Perform process development to establish synthetic methodologies and processes amenable to scale up and quality control. The effort will consist of activities, including but not limited to, sourcing raw material and intermediates, evaluating critical process issues, establishing in-process controls, conducting stress tests, performing safety evaluations, engineering controls, evaluating timelines, improving yields, improving purities, improving efficiency, improving cost of goods, and instituting regulatory compliance. The development shall result in a synthetic methodology that considers linear and convergent chemical syntheses, as well as stages at which regulatory requirements are critical. The development will consider a variety of purification and isolation methodologies that are critical to scalability, impurity identification and isolation, and cost. Process development will incrementally evaluate scalability and manufacturing to assess and verify improvements.

c. Chemical Synthesis:

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

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

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

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

d. Analytical Method Development:

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

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

Provide a summary plan for storage conditions and packaging for all final compounds and intermediates. Each sample will be appropriately packaged and labeled according to a protocol that has been reviewed and approved by the COR. The Contractor shall have capability to ship samples in accordance to established material transfer agreements and provide storage for samples for the length of the individual task order.

Additional storage beyond the length of the task order may be requested by the COR in special circumstances. No samples should be discarded or destroyed without explicit written approval of the COR. The Contractor shall retain all samples and records throughout the life of contract.

f. Non-standard/Exploratory Studies:

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

C.1.3.2.2 FORMULATION AND DOSAGE FORM MANUFACTURE

a. Preformulation Studies API Characterization:

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

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

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

i. Organoleptic

ii. Microscopic: Morphology, birefringence and particle size.

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

Additional tests can be performed if requested

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

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

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

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

b. Preclinical Prototype Formulations:

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

The formulation enabling studies should encompass the following considerations:

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

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

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

c. Preformulation Studies:

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

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

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

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

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

d. Clinical Formulation:

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

Activities include, but are not limited to:

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

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

iii. Optimization of the prototype formulations if needed.

iv. Selection of…