A -- NIH INITIATIVE FOR THE PRODUCTION OF ADENOVIRAL VECTORS (ADENOVECTORS) CONTAINING HIV-1 GENES SUPPLIED BY THE NIH FOR THE USE IN HIV VACCINE CLINICAL TRIALS

Notice Date

August 28, 2001

Contracting Office

NCI Frederick Cancer Research and Development Center (NCI-FCRDC), P.O. Box B, Frederick, Maryland 21702-1201

ZIP Code

21702-1201

Solicitation Number

S01-073

Response Due

October 1, 2001

Point of Contact

Patricia L. Getzandanner, Sr. Contract Specialist, 301-846-1721, Contracting Officer -- Dennis J. Dougherty, 301-846-1087

E-Mail Address

Patricia L. Getzandanner, Sr. Contract Specialist (pgetzandanner@mail.ncifcrf.gov)

Description

Introduction: R&D Request for Proposal, SAIC,NIH,NIAID, Introduction to procurement officials at SAIC, P O Box B, Frederick, MD 21702-1201. The National Institute of Allergy and Infectious Diseases (NIAID) is initiating the following: BACKGROUND There are three main pieces of work: 1. providing a packaging cell line for adenoviral vectors, 2. adenoviral vector construction, 3. and cGMP production and testing of these materials. These three main pieces of work are expanded in the Statement of Work (SOW) below into five detailed Milestones, which together constitute the entire requirement. The five Milestones, each representing the critical phases of the overall Request for Proposal (RFP), are listed in the approximate chronological order in which they are to be executed. Offerors must respond to the RFP as one contract, which addresses all five Milestones. Offerors may subcontract portions of the Milestones, although Offerors must submit a detailed plan specifying the subcontractor(s). Execution of later Milestones will be dependant on successful completion of previous Milestones and success of vectors of in pre-clinical/clinical studies. STATEMENT OF WORK (SOW) MILESTONE NUMBER 1 PRODUCTION OF ADENOVIRAL VECTORS FOR PRE-CLINICAL TOXICOLOGY TESTING A. 1. Produce Specific Vaccine Products as Directed by the COTR Produce, scale-up characterize and formulate specific vaccine products as directed by the COTR. This requirement is to develop and produce four lots of at least 1 x 1013 particles of adenoviral vectors containing four separate HIV-1 genes in suitable packaging cell line and purity for pre-clinical toxicology testing. These lots will be used in the support of production of material suitable for Phase I clinical testing. SAIC Frederick will maintain Quality oversight and conduct audits of all operations associated with this project. Task I: Construct adenoviral vectors and verify sequence is correct using genes provided by the Vaccine Research Center (VRC), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes Health (NIH). This will include insertion of HIV genes into shuttle plasmid, plasmid conversion to adenovector, expansion of vector seed stock, and certification of vector to ensure sequences are correct. Task II: Produce four (4) lots of Ad vectors using qualified packaging cell line consisting of at least 1 x 1013 particles: The Contractor will produce a Master Virus Bank from which sufficient quantities of purified vialed virus of at least 1 x 1013 particles is achieved. Task III: Test each production lot bulk cell harvest for pre-clinical toxicology testing. The tests will include, but are not limited to the following: (1) sterility testing on cell harvest (as per 21 CFR 610.12) (2) cultivatable and non-cultivatable mycoplasma assay (as per FDA PTC, 1993) (3) in vitro assay for adventitious viral contaminants (4) bovine viral assay in cell lysates (5) porcine parvovirus detection in cell lysates (6) RT-PCR assay for Hepatitis C (7) Replication competent adenoviruses (RCA) using A549 cells (8) The following PCR-based assays for the detection of a. Adeno-Associated viruses b. B-19 parvovirus c. HIV-1 and 2 d. HTLV-I/II e. Hepatitis B f. CMV g. EBV The above listed tests may be modified during the duration of this contract based on regulatory developments within the adenoviral vector vaccine field. Any changes to the above tests will be forwarded to the SAIC Frederick Contracting Officer. The following guidelines shall apply to the production of the lots for toxicology testing: a) Where applicable, obtain starting materials from product inventory/supplier. Complete a material transfer agreement and confidentiality agreement, if needed. b) Develop detailed production plan, timeline and budget for manufacture of lots of candidate vaccine products. c) Where applicable, purchase or otherwise acquire, products and materials necessary for production of stated vaccine product. Ensure all raw materials and reagents conform to current requirements by FDA on TSE risk, where possible, remove all materials of animal origin from processes. d) Scale-up production to required capacity. e) Produce vaccine product in a form suitable for use in pre-clinical toxicology testing (including characterization, formulation, vialing, labeling, packaging and storage). These products shall be prepared under appropriate quality conditions and provide no possibility of replication competent adenoviral particles. f) Maintain an inventory of test and pilot lots of vaccine products that have been produced. Periodically, as required by the technical officer, examine titer or potency of vaccine products. g) Ship the manufactured, packaged, and labeled dosage forms utilizing shipping procedures and materials to maximize product stability. h) Manage and account for intellectual property rights that pre-exist or may develop through the activities of the Contractor, including maintenance of security of confidential and/or proprietary data. i) Where applicable and as directed by the COTR, produce reagents necessary for the testing or evaluation of immune responses to the vaccine product. [NOTE #1 TO OFFERER. The four HIV-1 genes will be provided by the Vaccine Research Center, NIH. The inserts are genes for HIV proteins. The material does not contain enough of the viral genome to cause infection. The government will supply the DNA sequence and approximately 1 mcg of the DNA plasmid.] 2. Provide Facilities, Equipment and Resources a) Provide and/or contract facilities and equipment suitable for pre-clinical production of vaccine product. b) Manage the receipt, storage and manipulation of biohazardous materials and maintain their viability in facilities that provide aseptic and/or sterile conditions as appropriate (as per CDC (Center for Disease Control)/NIH Biosafety in Microbiological and Biomedical Laboratories, U.S. Department of Health and Human Services.) c) Contract and/or maintain and operate controlled storage of samples at appropriate temperatures with appropriate monitoring for failure (controlled room temperature through -90C, liquid nitrogen storage may be required for some products). d) Contract and/or provide protective garments, equipment and sufficient monitoring to assure safe handling of potentially hazardous materials, including radioactive materials, for the safety and protection of workers. e) Conduct work under the contract in accordance with all applicable and current Federal, State, and Local laws, codes ordinances and regulations, as well as all PHS Safety and Health Provisions. [NOTE #2 TO OFFEROR: The technical proposal should include a detailed production plan with timeline and specific tasks. The Offeror should propose production, purification and characterization methods and a timeline for obtaining completion of each lot. Potential pitfalls and back-up plans should be included. Also, include cost estimates in the form of a detailed budget proposal for performing the activities listed in the Milestone above. Include cost documentation for proposal personnel.] 3. Perform Vaccine Lot Characterization Tests Task IV: The following tests will be performed on the final product: At various steps during the manufacture of a vaccine, the product must be characterized. Prior to the use of a vaccine in pre-clinical studies that will support clinical studies, the manufactured vaccine will need to undergo final lot release testing. As described in the regulations for General Biological Product Standards (21 CFR 610) the following tests must be performed for each lot of vaccine. a) Test for Potency. A test for potency (21 CFR 610.10) will evaluate in an in vitro or in vivo test the specific ability of the vaccine to affect a given response, such as an immune response in mice, which should be supportive of the efficacy of the vaccine in humans. In the case of viral vaccines constructs, potency may be evidenced by the production of the pertinent antigen in a transfected cell line. This test will be developed and performed in conjunction with the VRC/NIAID/NIH. b) Test for General Safety. The general safety test (21 CFR 610.11) must be performed in mice and guinea pigs on each lot of vaccine to detect extraneous toxic contaminants potentially introduced during manufacture. c) Test for Sterility. A test for sterility (21 CFR 610.12) must be performed as described in the regulations. In additional, bacteriostasis/fungistasis testing will also be performed. d) Test for Purity. A test for purity (21 CFR 610.13) must be performed on each lot to ensure that the product is free from extraneous material except for that which is unavoidable due to the manufacturing process. e) Test for Identity. The test for identity (21 CFR 610.14) is generally a physical or chemical test performed to establish the identity of the material in the final container. f) Test for Quantity. A measure of the amount of material present is imperative for calculating the dilution of the bulk material required for the final container fill. g) All other tests as may be required for specific vaccine types. Develop and validate procedures as needed. 4. Perform Stability Testing Initiate and maintain appropriate stability tests that are required for further development of product to clinical trials. Maintain stability program as directed by the Contracting Officer's Technical Representative, SAIC Frederick. Stability will be continued per FDA discussion between contractor, VRC/NIAID/NIH and SAIC Frederick. [NOTE #3 TO OFFEROR: Stability testing will be required at various points during the production process. There is no single stability-indicating assay or parameter for all biological products. Therefore, manufacturers should propose on a case-by-case basis stability-indicating profiles for their products which provide assurance that changes in identity, purity and potency of the product will be detected.] 5. Deliverables a) Production of four (4) pre-clinical lots composed of separate HIV genes containing a total of at least 1.0 x 1013 particles per lot. Material packaging/labeling for pre-clinical toxicology testing will be specified by the SAIC Frederick Contracting Officer's Technical Representative. b) Contractor will provide the requisite documentation of the pre-clinical production, review of the Batch Production Records, along with the results of all bulk and final product release tests, to the SAIC Frederick COTR. MILESTONE NUMBER 2 MASTER CELL BANK AND WORKING CELL BANK CONSTRUCTION OF PACKAGING CELL LINE(S) FOR ADENOVIRAL VECTORS B. 1. Produce Specific Cell Banks as Directed by the COTR Produce Master Cell Bank (MCB) and Master Working Cell Banks (WCB) for the production of adenoviral vectors suitable for use in Phase I through Phase III clinical studies and licensed vaccine production. A suitable adenoviral vector system complementing the cell line must also be available. This packaging cell-line / vector system should provide no possibility of generation of replication competent adenoviral (RCA) particles. SAIC Frederick will maintain Quality oversight and conduct audits of all operations associated with this project. a) Where applicable, obtain starting materials from product inventory/supplier. Complete a material transfer agreement and confidentiality agreement, if needed. b) Develop detailed production plan, timeline and budget for manufacture of lots of candidate vaccine products. c) Where applicable, purchase or otherwise acquire, products and materials necessary for production of stated vaccine product. Ensure all raw materials and reagents conform to current requirements by FDA on TSE risk, where possible, remove all materials of animal origin from processes. d) Produce MCB/WCB in a form suitable for use in Phase I III human clinical studies (including characterization, vialing, labeling, packaging and storage). These vials shall be prepared under cGMP conditions, and conform to all FDA guidelines and policies concerning the production of adenoviral vectors. There should be no possibility of generation of RCA utilizing the proposed packaging cell line and vector system. e) Manage and account for intellectual property rights that pre-exist or may develop through the activities of the Contractor, including maintenance of security of confidential and/or proprietary data. [NOTE #1 TO OFFERER. These Master and Working cell banks will be used by the Vaccine Research Center, NIH for production of HIV-1 adenoviral vector candidate products. The inserts for the adenoviral vectors will be genes for HIV-1 proteins. The material does not contain enough of the genome to cause infection.] 2. Provide Facilities, Equipment and Resources a) Provide and/or contract facilities and equipment suitable for cGMP production of MCB/WCB. b) Manage the receipt, storage and manipulation of biohazardous materials and maintain their viability in facilities that provide aseptic and/or sterile conditions as appropriate (as per CDC (Center for Disease Control)/NIH Biosafety in Microbiological and Biomedical Laboratories, U.S. Department of Health and Human Services.) c) Contract and/or maintain and operate controlled storage of samples at appropriate temperatures with appropriate monitoring for failure (controlled room temperature through -90C, liquid nitrogen storage may be required for some products). d) Contract and/or provide protective garments, equipment and sufficient monitoring to assure safe handling of potentially hazardous materials, including radioactive materials, for the safety and protection of workers. e) Conduct work under the contract in accordance with all applicable and current Federal, State, and Local laws, codes ordinances and regulations, as well as all PHS Safety and Health Provisions. [NOTE #2 TO OFFEROR: The technical proposal should include a detailed production plan with timeline and specific milestones. The Offeror should propose production characterization methods and a timeline for obtaining completion of each cell bank. Potential pitfalls and back-up plans should be included. Also, include cost estimates in the form of a detailed budget proposal for performing the activities listed in the Milestone above. Include cost documentation for proposal personnel.] 3. Perform Stability Testing Initiate and maintain appropriate stability tests that are required for further development of product to clinical trials. Maintain stability program as directed by the Contracting Officer's Technical Representative, SAIC Frederick. Stability will be continued per FDA discussion between contractor, VRC/NIAID/NIH and SAIC Frederick. [NOTE #3 TO OFFEROR: Stability testing will be required at various points during the production process. There is no single stability-indicating assay or parameter for all biological products. Therefore, manufacturers should propose on a case-by-case basis stability-indicating profiles for their products which provide assurance that changes in identity, purity and potency of the product will be detected.] 4. Deliverables a) Production of MCB/WCB of packaging cell line. b) Contractor will provide the requisite documentation of the cGMP clinical production, review of the Batch Production Records, along with the results of all bulk and final product release tests, to the SAIC Frederick COTR. MILESTONE NUMBER 3 EXPEDITIOUS PHASE I PRODUCTION OF ADENOVIRAL VECTORS C. 1. Produce Specific Vaccine Products as Directed by the COTR Produce, scale-up, characterize and formulate specific vaccine products as directed by the COTR. Develop and produce two (2) lots of at least 1 x 1013 particles of clinical grade (cGMP) adenoviral vectors containing two separate HIV-1 genes in suitable packaging cell line and purity for clinical human vaccine trials. SAIC Frederick will maintain Quality oversight and conduct audits of all operations associated with this project. Task I: Production of two (2) lots of at least 1 x 1013 particles of clinical grade (cGMP) adenoviral vectors. The master virus bank and working cell bank of the packaging cell line will be provided under a separate requirement. The bulk cell harvests will be tested for use in clinical trials. These tests will include, but are not limited to the following: (1) sterility testing on cell harvest (as per 21 CFR 610.12) (2) cultivatable and non-cultivatable mycoplasma assay (as per FDA PTC, 1993) (3) in vitro assay for adventitious viral contaminants (4) bovine viral assay in cell lysates (5) porcine parvovirus detection in cell lysates (6) RT-PCR assay for Hepatitis C (7) Replication competent adenoviruses (RCA) using A549 cells (8) The following PCR-based assays for the detection of a. Adeno-Associated viruses b. B-19 parvovirus c. HIV-1 and 2 d. HTLV-I/II e. Hepatitis B f. CMV g. EBV The above listed tests may be modified during the duration of this contract based on regulatory developments within the adenoviral vector vaccine field. Any changes to the above tests will be forwarded to the SAIC Frederick Contracting Officer. The following guidelines shall apply to the production of the lots for Phase I Clinical Lot testing: a) Where applicable, obtain starting materials from product inventory/supplier. Complete a material transfer agreement and confidentiality agreement, if needed. b) Where applicable, purchase or otherwise acquire, products and materials necessary for production of stated vaccine product. Ensure all raw materials and reagents conform to current requirements by FDA on TSE risk, where possible, remove all materials of animal origin from processes. d) Scale-up production to required capacity. e) Produce vaccine product in a form suitable for use in human clinical studies (including characterization, formulation, vialing, labeling, packaging and storage). These products shall be prepared under cGMP conditions and provide no possibility of replication competent adenoviral particles. f) Maintain an inventory of test and pilot lots of vaccine products that have been produced. Periodically, as required by the technical officer, examine titer or potency of vaccine products. g) Ship the manufactured, packaged, and labeled dosage forms utilizing shipping procedures and materials to maximize product stability. h) Manage and account for intellectual property rights that pre-exist or may develop through the activities of the Contractor, including maintenance of security of confidential and/or proprietary data. i) Where applicable and as directed by the COTR, produce reagents necessary for the testing or evaluation of immune responses to the vaccine product. [NOTE #1 TO OFFERER. The two (2) HIV-1 genes in the form of working virus banks will be provided by the Vaccine Research Center, NIH under a separate requirement. The inserts are genes for HIV proteins. The material does not contain enough of the viral genome to cause infection. The government will supply the working virus banks.] 2. Provide Facilities, Equipment and Resources The following shall apply to the production of the cGMP lots for clinical trials: a) Provide and/or contract facilities and equipment suitable for cGMP production of vaccine product. b) Manage the receipt, storage and manipulation of biohazardous materials and maintain their viability in facilities that provide aseptic and/or sterile conditions as appropriate (as per CDC (Center for Disease Control)/NIH Biosafety in Microbiological and Biomedical Laboratories, U.S. Department of Health and Human Services.) c) Contract and/or maintain and operate controlled stora

Record

Loren Data Corp. 20010830/ASOL003.HTM (W-240 SN50W168)