A18_Sample_Task_Order_0001_and_SOW.pdf

SAMPLE TASK ORDER #0001

STATEMENT OF WORK

A. SCOPE

Studies conducted under this Sample Task Order shall be used to conduct process development, identify a chemical synthesis amenable for GMP scale up, and perform manufacturing of the compound listed below.

Ref: Med. Chem. Lett. 2011, 2, 929-932

The 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. The proposal should take into consideration packaging, label, storage, and shipping.

B. TECHNICAL REQUIREMENTS

Independently, and not as an agent of the Government, the Contractor shall furnish all the necessary services, qualified personnel, materials, equipment, and facilities, not otherwise provided by the Government as needed to perform the activities below.

Background: The compound above is a test compound. It was originally designed as a potent agonist of a GPCR lacking activity against a closely related GPCR family member activity.

Specifically, the Contractor shall:

1. Plan, initiate, implement, manage, and coordinate the activities associated with this Task Order.

2. Conduct technology transfer from a Medicinal Chemistry program.

3. Propose and perform process development to enable manufacturing of the API

O

N

CH3

CH3F

H

H at 10 kg scale while adhering to the GMP guidelines.

4. Propose and perform preformulation studies to deliver GMP material (0.5-1.0 Kg) for preclinical and IND enabling studies. The proposal should include specific packaging, label, storage, and distribution plans.

5. Propose and perform manufacture and formulation of dosage form in press tablets, packaged in blister packs and sterilized solution in vials.

6. In the event of a catastrophic event, follow the documented emergency contingency plan that has been reviewed and approved by the COR to protect the work produced under this contract.

C. REPORTING REQUIREMENTS AND DELIVERABLES FOR SAMPLE TASK

ORDER #0001

C.1 Technical Reports:

In addition to those reports required by the other terms of this Task Order, the Contractor shall prepare and submit the following reports in the manner stated below (section C.1.1).

All reports required herein shall be submitted to the Contracting Officer (CO) and Contracting Officer’s Representative (COR) in electronic format.

C.1.1 Task Order Final Report

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

a. A cover page listing:

• Base contract and Task Order titles and numbers

• Type of report

• Contractor’s name and address

• Date of submission

b. A table of contents

c. An introduction describing the goals of the Task Order

d. A detailed description of methodology of techniques used

e. Results and a discussion of their significance

f. A description of problems encountered and their solution

g. Representative spectra, chromatograms, and other charts/tracings from analytical instrumentation

[End of Statement of Work]

Sample Task Order #0001

Campaign No. 1- Feasibility Studies

Base Award Performance Requirements:

• API Technology transfer

• Route Familiarization/ Process development

• Synthesis of demo batch

• ICH-Stability study on Demo batch (Up to 2 year)

• Analytical Method Development and Qualification

• Salt & Polymorph Screen/Characterization of API and related substances

Work Plan Specifications:

Technology Transfer & Process Development

A. Manufacture of 200g demonstration (Demo) batch B. Analytical methods development: CRO will develop and qualify the analytical methods required to support the manufacture of API (demo and Toxicology batches). This work should include the following:

• Development and qualification of a chemical purity method (weight percent) suitable for API release with estimation of impurities by Activity-% normalization

• Development and qualification of forced degradation conditions for the API (targeting 5% to 20% degradation of API in acid, base, peroxide, heat, and light) to demonstrate the stability-indicating nature of the chemical purity method for the API.

• Development and qualification of a residual solvents limit test method for API for solvents used in the process.

• Development of laser light scattering method for the particle size distribution for API

• Development and qualification of ICP-MS method for

USP<232>/<233>.

• Development and qualification of microbial analysis

Specifications for the demo and toxicology batch are represented in the following table:

Analyses

Appearance ID by FTIR ID by 1H-NMR Potency by calculation (weight %) Purity/impurities by HPLC-96-97% Water content by Karl Fischer Residual solvents content

ROI

LC-MS analysis for specific impurities Elemental Impurities USP <233>

DSC

XRPD

Particle size distribution Elemental (CHN) Melting point

C. Characterization of API and Related Substances/ Polymorph and Salt

Screening Studies:

• Characterize material as supplied with regard to solid state properties

• Conduct polymorph screening on free form to identify the most stable, anhydrous non-solvated sold form. In the event the solid form identified is not suitable for development, conduct salt screening / co-crystal screening as applicable

D. Perform ICH Stability Study on 200g Demonstration Batch

• 2 years

• Conditions

i. 25ºC/60%RH

ii. 30ºC/65%RH – intermediate: test only if failure at 40ºC/75%RH

iii. 40ºC/75%RH

• Time points

i. Accelerated: 1, 3 and 6 mo.

ii. Intermediate 1, 3, 6, 9 and 12 mo.

iii. Real time: 0, 1, 3, 6, 9, 12, 18, and 24 mo.

• Stability Attributes

i. Appearance

ii. Assay, Purity (including chiral purity), and Impurities

iii. Water Content

iv. XRPD

v. DSC

vi. Microbiology

E. Any Shipping or Storage Requirements

F. Any work not specifically called for in A-E above that Vendor deems necessary for successful campaign execution should be included in the budget as separate item and highlighted in the work plan.

Campaign No. 1 Deliverables:

1. LDT Summaries

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

2. All documentation required for regulatory filings (e.g. IND-filing with appropriate QA/QC sign off to fully enable the CMC section filing to the FDA to enable clinical testing. This includes but is not limited to the following Reports:

a. Final Chemistry Technology Transfer Report for Campaign #1

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

b. Final Process Development Report for Campaign #1

Provide written comparisons of initial process proposed and the final accepted process for each scale up task ordered by COR. This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule.

The assessment of the final component shall include discussion on the purity, yield, synthesis efficiency, time, cost, environmental savings, and a proposed timeline for scale up. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

c. Final Chemical Synthesis Report for Campaign #1

Provide written comparisons of initial chemistry proposed and the final accepted chemical synthesis for each scale up task ordered by COR.

This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The report shall also include the certificate of analysis, the partial DMF for chemical synthesis and a summary of modifications required to optimize yield and efficiency. The Contractor shall provide this report to the COR and as specified in Section F (Deliverables).

d. Final Analytical Method Development Reports for Campaign #1 reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The report shall also include standard operating procedures, analytical documents and documentation of accordance to GLP guidelines pertaining to the compound developed. The Contractor shall provide this report to the COR and CO as specified in Section F

e. Interim and Final Stability Studies Reports for Campaign #1 reports, and (2) the Contractor’s assessment of the suitability of the stable candidate molecule. Additional reports and documents such as CMC documents as part of the IND package should be delivered to the COR upon request. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

Quantity Option: Campaign No. 2 - Clinical Trial Readiness

Campaign No. 2- Performance Sub-activities:

• Chemical synthesis and scale up of Toxicology batch & Issuance of CoA

• ICH Stability study on Toxicology batch

• Pre-formulation Studies

• Analytical Method Development and Qualification for drug substance/product

• Formulation development studies

• Supply chain management for bulk API

Work Plan Specifications:

A. Manufacture of 1 kg of API for GLP Toxicology Studies (Toxicology Batch)

• Acceptance and use testing of starting materials

• Synthesis of API according to specifications

• Release testing

• Issue of CoA

A. Perform ICH stability assessment

• 2 years

• Conditions

i. 25°C/60%RH

ii. 30°C/65%RH - intermediate: test only if failure at 40°C/75%RH

iii. 40°C/75%RH

• Time points

i. Accelerated: 1, 3 and 6 month

ii. Intermediate: 1, 3, 6, 9 and 12 month.

iii. Real time: 1, 3, 6, 9, 12, 18, and 24 month

• Performing and reissuing of CoA for API after first retest date as needed (based on stability data if sufficient or retesting if required for retest date extension)

B. Prepare and characterize reference standard - Manufacture 50g of reference standard with supporting documentation:

• Proof of structure on the reference standard (1H and 13C-NMR with peak assignments, 2D-NMR, UV, MS, IR with main peak assignments.

• Single crystal X-ray structure (if not performed during polymorph screening)

C. Manufacture of 500 mg of Labelled-Drug candidate - Manufacture of 500 mg of labelled bioanalytical standard with supporting CoA documentation in GLP Toxicology studies and clinical PK studies. Molecule should contain >3 deuterium atoms and/or 13C atoms and >98% purity (≥98% of mass + 3 vs natural abundance material).

D. Pre-formulation Studies - Determination of API’s solid state and physical properties.

• Develop suitable formulation to enable toxicological studies as required.

E. Formulation studies: Develop suitable formulations for Phase 1 clinical studies suitable for use at the clinical pharmacy where the clinical pharmacy will make the actual doses up.

• Compatibility Studies: Excipient compatibility as appropriate for the formulation(s) under consideration

• Evaluation of Prototype Formulations: Phase 1 will employ API in liquid, however other possibilities include:

• API in Capsule

• Blend in Capsule

• Liquid in capsule

• Assess feasibility for an API in liquid drug product configuration based on based on solubility and stability as a function of pH and dissolution.

• Assess feasibility for a blend or API in capsule drug product configuration based on excipient compatibility studies, dissolution of neat API and dissolution as a function of particle size.

• Feasibility evaluation to bracket low and high fill weights in single capsule size as required.

• Capsule size will be selected based on adequate filling of the higher weight

Considerations:

• pH dependent solubility and stability in solution

• Effect of particle size on dissolution of the API

• Excipient compatibility studies

• Effect of excipients on dissolution of API

• Assumes adequate bioavailability when applicable and necessary, in vivo confirmation of dosage form performance (in vivo studies to be performed by a separate NIH vendor and not as part of this contract).

• Short-term stability studies on prototype formulations (14 days stability assessment)

• Assume 4 strengths:

o Conditions

- 25°C/60%RH

- 40°C/75%RH

o Time Points

- T=0

- Accelerated: 1 and 2 weeks

- Real time: 1 and 2 weeks o Attributes

- Appearance

- Dissolution

- Stability

» Assay, purity, related substances » Enantiomeric purity

- Water Content

- Average weight of 10 capsules

• Manufacture of non-GMP Experimental Batches of Drug Product o Prepare and coordinate with vendor to ship API/drug product (3-4 strengths) for PK Study if required

F. Storage and required shipment and handling

• The proposal shall include a detailed plan, timeline and cost estimate for storage and supply chain activities including primary packaging and labeling, secondary packaging and labeling for shipping.

Campaign No. 2 Deliverables:

summary shall consist of a bulleted list of decisions made and action items identified on the web-enabled meetings. These summaries shall be deposited on NIH SharePoint site and a link to them sent via e-mail to all participants within 48 hours of each call. The exact number and timing for appropriate QA/QC sign off to fully enable the CMC section filing to the FDA to enable clinical testing. This includes but is not limited to the following Reports:

a. Final (Updated) Process Development Report for Campaign #2 accepted process for each scale up task ordered by COR. This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and

(2) the Contractor’s assessment of the suitability of the candidate molecule. The assessment of the final component shall include discussion on the purity, yield, synthesis efficiency, time, cost, environmental savings, and a proposed timeline for scale up. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

b. Final Chemical Synthesis Report for Campaign #2 accepted chemical synthesis for each scale up task ordered by COR.

This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The report shall also include the certificate of analysis, the partial DMF for chemical synthesis and a summary of modifications required to optimize yield and efficiency. The Contractor shall provide this report to the COR and as specified in Section F

c. Final Analytical Method Development Reports for Campaign #2 reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The report shall also include standard operating procedures, analytical documents and documentation of accordance to GLP guidelines pertaining to the compound developed. The

d. Final Stability Studies Reports for Campaign #2 reports, and (2) the Contractor’s assessment of the suitability of the stable candidate molecule. Additional reports and documents such as CMC documents as part of the IND package should be delivered to the COR upon request. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

e. Final Preformulation Studies (API) Reports for Campaign #2 reports, and (2) the Contractor’s assessment of the improvements made in drug ability, physical properties and chemical properties of the candidate molecule. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

f. Final Preformulation Studies (Excipients) Reports for Campaign #2 reports, and (2) the Contractor’s assessment of the improvements made in drug ability, physical properties and chemical properties of the candidate molecule. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

g. Final Formulation Studies Reports for Campaign #2 reports, and (2) the Contractor’s assessment of the improvements made in drug ability, physical properties, chemical properties, and compatibility for manufacturing of the candidate molecule. The

h. Final Manufacturing Reports for Campaign #2 reports, and (2) the Contractor’s assessment of the manufacturing suitability of the candidate molecule. Additional reports estimated cost of goods and documents such as Chemical Manufacturing Control (CMC) documents as part of the IND package should be delivered to the COR upon request. The Contractor shall provide this report to the COR and as specified in Section F (Deliverables). Additional documents can be requested as part of IND documents and FDA reporting requirements.

i. Interim and Final Stability Studies Reports for Campaign #2 reports, and (2) the Contractor’s assessment of the suitability of the stable candidate molecule. Additional reports and documents such as CMC documents as part of the IND package should be delivered to the COR upon request. The Contractor shall provide this report to the

j. Final Storage, Package, Label, Distribution Reports for Campaign #2 and the data produced, and (2) the Contractor’s assessment of the standard operating procedures. The report shall also include the standard operating procedure for storage, documentation that compound integrity was maintained, guidelines for distribution that ensures safety, protocols for dispensing, after use handling instructions, final MSDS and transportation records. The Contractor shall provide this report to the COR and CO as specified in Section F

Quantity Option: Campaign No. 3- GMP Campaign/Clinical Trial Materials

Campaign No. 3- Performance Sub-activities:

• Analytical method development and qualification for cGMP

• Manufacture of 500 g GMP API

• ICH Stability studies on GMP API

• Preparation of GMP Drug Product & ICH stability on drug product

• Supply Chain Management (GMP API)

• Annual retest and certification of reference standard, Toxicology and GMP batches

(12 & 24 month)

Work Plan Specifications:

A. Analytical method development and qualification for cGMP - CRO will develop and qualify any analytical method not already developed and qualified under the demo/Toxicology campaign 1 and 2 that are required to support the GMP manufacture of API including:

• Development and qualification (evaluation of specificity, quantitation limit (“QL”), detection limit (“DL”), and solution stability) of chemical purity methods for release of any isolated intermediates.

• Development and qualification of in-process control method for all the chemical transformations.

• Characterization of all starting materials, intermediates of the API as identification standard.

B. Manufacture of 500g GMP API

• Use test starting materials

• Synthesis of GMP according to specifications

• Release testing

• Issue of CoA summarizing the results of the following analyses:

Analyses Appearance ID by FTIR ID by 1H-NMR Potency by calculation (weight %) Purity/impurities by HPLC-96-97% Water content by Karl Fischer Residual solvents content

ROI

LC-MS analysis for specific impurities Elemental Impurities USP <233>

DSC

XRPD

Particle size distribution Elemental (CHN) Melting point Microbiology

C. Perform ICH stability assessment

• 2 years

• Conditions o 25ºC/60%RH o 30ºC/65%RH – intermediate: test only if failure at 40ºC/75%RH o 40ºC/75%RH

• Time points o Accelerated: 1, 3 and 6 months o Intermediate: 1, 3, 6, 9 and 12 months o Real time: 1, 3, 6, 9, 12, 18, and 24 months

D. Performing and reissuing of COA for GMP API after first retest date as needed (based on stability data if sufficient or retesting if required for retest date extension).

E. Drug Product:

• Development of the Manufacturing Process

• Preparation of GMP drug product

• Release testing and issuing a CoA.

• Determine the quantity of each placebo for the corresponding CTM strength required to ensure that CMC IND filing requirements are met, both the SAD and MAD studies can be completed and include a 20% overage in the calculation.

• Manufacturing the GMP placebo product, release testing and issuing a CoA

• ICH stability on GMP drug product

F. GMP storage, required shipments and handling - The proposal shall include a detailed plan, timeline and cost estimate for supply chain activities including primary packaging and labeling, secondary packaging and labeling for shipping.

G. Perform any work not specifically called for in A-F above that vendor deems necessary for successful campaign execution should be included in the budget as separate item and highlighted in the work plan

GMP-API Specifications:

Example of specification that will be required:

Test Targeted Acceptance Criteria

Appearance Report results

Identification IR spectra consistent with structure

1H- and 13C-NMR spectra consistent with structure

Purity (% of total peak Activitys) NLT 98%

Impurities (Drug Related) Report all ≥ LOQ (target LOQ is 0.05%)

Individual Impurities ≤ 0.5%

Total Impurities ≤ 2.0%

Chiral Purity (% of total peak Activitys) NLT 98%

Optical Roatation Report result

Residual Solvents NMT or Report results

All the Solvents used throughout the GMP synthesis Limit defined by ICH Q3C guideline

Water Content (Karl Fisher Analysis) Report results

Crystallinity and Morphology (XRPD) a Report results

Heavy Metals NMT or Report results

As (Class 1) 1.5 μg/g

Cd (Class 1) 0.5 μg/g

Hg (Class 1) 3 μg/g

Test Targeted Acceptance Criteria

Pb (Class 1) 0.5 μg/g

Co (Class 2A) 5 μg/g

V (Class 2A) 10 μg/g

Ni (Class 2A) 20 μg/g

Other metals used in the GMP synthesis ICH Q3D

Residue on Ignition Report results

Thermal Properties (DSC and TGA) a Report results

Particle Size Distribution Report results

Microbial Enumeration Tests:

Total Aerobic Count

Total Yeast and Mold Count

Absence of Specified Microorganisms

Salmonella

Escherichia coli

Staphyloccus aureus

Pseudomonas aeruginosa

Report Results

Report Results

Absent

Campaign No. 3 Deliverables:

summary shall consist of a bulleted list of decisions made and action items identified on the web-enabled meetings. These summaries shall be deposited on NIH SharePoint site and a link to them sent via e-mail to all participants within 48 hours of each call. The exact number and timing for appropriate QA/QC sign off to fully enable the CMC section filing to the FDA to enable clinical testing. This includes but is not limited to following

Reports:

a. Final (Updated) Process Development Report for Campaign #3 accepted process for each scale up task ordered by COR. This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The assessment of the final component shall include discussion on the purity, yield, synthesis efficiency, time, cost, environmental savings, and a proposed timeline for scale up. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).

b. Final Chemical Synthesis Report for Campaign #3 accepted chemical synthesis for each scale up task ordered by COR. This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule. The report shall also include the certificate of analysis, the partial DMF for chemical synthesis and a summary of modifications required to optimize yield and efficiency. The Contractor shall provide this report to the COR and as specified in Section F (Deliverables).

c. Final Analytical Method Development Reports for Campaign #3

This report shall include (1) a summary of the experiments performed and the data produced with appropriate certifications and quality reports, and (2) the Contractor’s assessment of the suitability of the candidate molecule.

The report shall also include standard operating procedures, analytical documents and documentation of accordance to GLP guidelines pertaining to the compound developed. The Contractor shall provide this report to the

d. Final Stability Studies Reports for Campaign #3 the Contractor’s assessment of the suitability of the stable candidate molecule. Additional reports and documents such as CMC documents as part of the IND package should be delivered to the COR upon request. The

e. Final Preformulation Studies (API) Reports for Campaign #3 the Contractor’s assessment of the improvements made in drug ability, physical properties and chemical properties of the candidate molecule. The

f. Final Preformulation Studies (Excipients) Reports for Campaign #3 the Contractor’s assessment of the improvements made in drug ability, physical properties and chemical properties of the candidate molecule. The

g. Final Formulation Studies Reports for Campaign #3 the Contractor’s assessment of the improvements made in drug ability, physical properties, chemical properties, and compatibility for manufacturing of the candidate molecule. The Contractor shall provide this report to the

h. Final Manufacturing Reports for Campaign #3 the Contractor’s assessment of the manufacturing suitability of the candidate molecule. Additional reports estimated cost of goods and documents such as Chemical Manufacturing Control (CMC) documents as part of the IND package should be delivered to the COR upon request. The Contractor shall provide this report to the COR and as specified in Section F (Deliverables). Additional documents can be requested as part of IND documents and FDA reporting requirements.

i. Interim and Final Stability Studies Reports for Campaign #3 the Contractor’s assessment of the suitability of the stable candidate molecule. Additional reports and documents such as CMC documents as part of the IND package should be delivered to the COR upon request. The

j. Final Storage, Package, Label, Distribution Reports for Campaign #3 the data produced, and (2) the Contractor’s assessment of the standard operating procedures. The report shall also include the standard operating procedure for storage, documentation that compound integrity was maintained, guidelines for distribution that ensures safety, protocols for dispensing, after use handling instructions, final MSDS and transportation records. The Contractor shall provide this report to the COR and CO as specified in Section F (Deliverables).