SOW - Lot Production.docx

STATEMENT OF WORK

ARRA H1N1 Influenza Project – Preparation and Testing of Influenza Challenge Viruses

I. General Requirements:

A. The Contractor shall be required to prepare, at the request of the Contracting Officer Technical Representative (COTR), suspensions of viruses that are needed for evaluation in pathogenesis studies.

During the performance of the contract, the Government shall request eight (8) virus suspensions to be grown in Vero cells or special pathogen free (SPF) eggs.

The virus suspensions that will be made are predominantly for clinical pathogenesis studies, therefore, the traditional method of preparing Master and Working Virus Seed Banks will not be followed. Nevertheless, the cell lines and virus suspensions, which are intended for evaluation in human volunteers by the NIAID, shall be prepared using methods and facilities which meet all FDA and cGMP standards for preparation of live virus vaccine candidates as described in the most current Code of Federal Regulations; specifically 21CFR58; 21CFR210; 21CFR211; 21CFR600, and 21CFR610 (See http://www.gpoaccess.gov/cfr/index.html). When applicable, animal-derived raw materials and virus suspensions shall be tested for bovine and porcine viruses as described in 9CFR113.46, 9CFR113.47, and 9CFR113.53. Further, these virus suspensions and cell lines shall be safety-tested to determine freedom from adventitious agents by procedures acceptable to the Center for Biologics Evaluation and Research (CBER), FDA, using the CFR sections indicated above as guidelines. The Contractor should be familiar with the following sources of information and how they pertain to the cGMP production of vaccine lots for use in Phase I and II clinical studies in humans:

· Points to Consider in the Characterization of Cell Lines Used to Produce Biologicals, CBER (7/93), http://www.fda.gov/cber/gdlns/ptccell.pdf

· ICH Harmonized Tripartite Guideline Q5A: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin. Federal Register, Vol 63; No.185 51074-51084 (9/24/1998) or http://www.fda.gov/cber/gdlns/virsafe.pdf

· ICH Guideline Q5D: Derivation and Characterization of Cell Substrates Used for the Production of Biotechnological/Biological Products. Federal Register, Vol 63; No.182 50244-50249 (9/21/1998) or http://www.fda.gov/cber/gdlns/qualbiot.pdf

· Guidance for Industry: Content and Format of Chemistry, Manufacturing and Controls Information and Establishment Description for a Vaccine or Related Product. http://www.fda.gov/cber/gdlns/cmcvacc.pdf

· ICH Final Guidelines on Stability Testing of Biotechnology/Biological Products, Federal Register, Vol. 61, No. 133 36466-36469, (7/10/1996) or http://www.fda.gov/cber/gdlns/ichq5c071096.pdf

· ICH Guideline Q6B: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products, Federal Register, Vol 63, No. 110 31056-31513 (6/9/1998) or http://www.fda.gov/cder/guidance/Q6Bfnl.pdf

· Guidance for Industry: Revised Preventive Measures to Reduce the Possible Risk of Transmission of Creutzfeldt-Jakob Disease (CJD) and Variant Creutzfeldt-Jakob Disease (vCJD) by Blood and Blood Products. 2002. http://www.fda.gov/cber/gdlns/cjdvcjd.pdf

Note: All policies and guidelines for products used in human Phase I and II clinical studies are subject to periodic review by the FDA, and may change over the course of contract performance. Additionally, the U.S. Government may require additional testing to be performed to ensure that virus suspensions and cell lines meet all sterility and efficacy standards in accordance with NIH protocols and FDA guidance. The Contractor shall be required to produce all virus suspensions and cell lines in accordance with the most current standards as required by the U.S. Government.

B. The COTR will provide the Contractor with sufficient seed virus to inoculate the substrate (e.g., Vero cells or SPF eggs) used for virus lot production. The Contractor shall confirm microbial sterility of material provided by the COTR before initiating virus production. Each of the virus suspensions (candidate virus lot) will be produced, processed, filled, and qualified by the Contractor as directed by the COTR. As required by the Contractor, the COTR will supply sufficient quantities of antiserum directed against the virus for use in the in vitro tests performed to detect the presence of adventitious viral agents in the virus suspension.

II. Specific Requirements A. Production of Virus Suspensions in Vero Cells

1. Virus Preparations

The preparation of the virus suspensions will be performed at Biosafety Level 2 by the Contractor.

The Contractor shall prepare virus suspensions that meet current FDA requirements of Good Manufacturing Practices. All steps of the manufacturing process will be performed according to a fully executed and approved batch production record.

Notwithstanding any additional instructions noted for any specific virus type, virus preparations shall be filled into screw-cap vials containing 0.6 - 1.0 mL of virus suspension. Filled vials are multi-dose and are intended for dilution at the clinical site prior to administration. The Contractor shall prepare 0.5-2 liters (approximately 500 to 2500 vials) for each of the lots made in Vero cells. Vials shall be filled, flash frozen, and handled in a manner that maintains even and consistent potency throughout the entire fill process.

The U.S. Government will supply the Contractor with qualified Vero cells from their Working Cell Bank for production of the virus suspensions. The suspensions are produced and processed as directed by the COTR with harvest and filling performed on the same day, if possible.

The virus suspensions should be prepared without serum or antibiotics. Additionally, the Contractor shall take every possible precaution to avoid the use of animal derived materials.

Virus suspensions are conditionally acceptable based on sterility, virus titer, and nucleotide sequence. The Contractor will provide sample vials to the NIAID who will perform virus titer, nucleotide sequence analysis and testing to determine if the candidate challenge viruses retain their genotype. The lots that meet titer, sequence, and sterility requirements are then subjected to the complete series of lot release and safety tests.

Preparations will include, the production of influenza viruses. These viruses include influenza A viruses belonging to hemagglutinin subtypes H1 and H3, and neuraminidase subtypes N1 and N2, or to other subtypes if they appear in humans. Influenza viruses will be grown in qualified Vero cells when such viruses replicate poorly in eggs or when Vero cell production is preferred.

Seed virus will be provided by the COTR.

The viruses will have been approved for work at Biosafety Level 2 by the NIH Biosafety Office prior to transfer to the Contractor.

The Contractor shall produce and test these viruses as described above and ensure that they have a consistent final vial potency of greater than 107 TCID50/mL measured on MDCK cell culture monolayers in the presence of ~1 µg of trypsin per mL.

Note: Laboratory workers who handle these viruses should be immunized with currently licensed influenza A virus vaccines.

2. Lot Release / Safety Test procedures

The Contractor will perform lot release/safety test procedures as specified in the approved batch production record for in-process samples and final vials.

All testing should be conducted in compliance with Good Laboratory Practice regulations (21CFR58) using validated procedures.

Required testing may include any of the following: Microbial sterility test (21CFR610.12) with Bacteriostasis and Fungistasis determination; Mycoplasma sterility (cultivatable and non-cultivatable) (21CFR610.30); Mycobacterium ssp. sterility; In vivo tissue culture safety test; Detection of adventitious viruses by inoculation into guinea pigs, mice, and embryonated chicken eggs (In vivo safety test); General safety test (21CFR610.11); Assay to detect viral reverse transcriptases (PCR based); Endotoxin determination (Limulus ameobocyte lysate assay); Concentration of residual DNA determination; Size of residual DNA determination; Concentration of residual endonuclease (Benzonase) determination; Residual intact cell assay; pH determination; Sucrose concentration.

The type, quantity, and sequence of required testing is not limited to the above referenced. Additional testing, as determined by either the COTR and/or the Contractor, may be required for specific virus products.

Potency testing (virus titer), virus identity, and genome sequence testing will be performed by the NIAID.

3. Storage and Shipping

Virus suspensions are to be stored by the Contractor at -70C or below in a monitored freezer according to cGMP guidelines. It is expected that the virus will maintain its titer during this storage period. Upon release, virus suspensions will be transferred by the Contractor to a long-term cGMP storage facility designated by the COTR.

B. Production of Influenza A Virus Suspensions in the Allantoic Cavity of Embryonated Eggs

1. Preparation

Preparations will include, the production of influenza A viruses. These viruses include influenza A viruses belonging to hemagglutinin subtypes H1 and H3, and neuraminidase subtypes N1 and N2, or to other subtypes if they appear in humans. Seed viruses will be provided by the COTR.

The Contractor shall prepare virus suspensions that meet current FDA requirements of Good Manufacturing Practices. All steps of the manufacturing process will be performed according to a fully executed and approved batch production record. The preparation of the virus suspensions will be performed at Biosafety Level 2 by the Contractor and all viruses will have been approved for work at Biosafety Level 2 by the NIH Biosafety Office prior to transfer to the Contractor.

The Contractor will prepare virus suspensions of 500ml - 2 liters (500 - 2000 vials) of influenza virus in embryonated chicken eggs obtained from specific-pathogen-free (SPF) flocks and safety test these suspensions. Vials shall be filled, flash frozen, and handled in a manner that maintains even and consistent potency throughout the entire fill process.

The suspensions shall be grown in SPF avian leucosis virus-free embryonated eggs. The final virus suspension shall be tested for freedom from avian leucosis virus and other adventitious microbial agents.

The viral suspensions shall have a consistent final vial potency of 107.3 to 108.0 TCID50/mL measured on MDCK cell culture monolayers in the presence of ~1 µg of trypsin per mL.

Virus suspensions are conditionally acceptable based on sterility, virus titer, and nucleotide sequence. The Contractor will provide sample vials to the NIAID who will perform virus titer, nucleotide sequence analysis and testing to determine if the candidate challenge virus retain their genotype. The lots that meet titer, sequence, and sterility requirements are then subjected to the complete series of lot release and safety tests.

Note: Laboratory workers who handle these viruses should be immunized with currently licensed influenza A virus vaccines.

2. Lot Release and Safety Test Procedures

The Contractor will perform lot release/safety test procedures as specified in the approved batch production record for in-process samples and final vials.

All testing should be conducted in compliance with Good Laboratory Practice regulations (21CFR58) using validated procedures.

Required testing may include any of the following: Microbial sterility test (21CFR610.12) with Bacteriostasis and Fungistasis determination; Mycoplasma sterility (cultivatable and non-cultivatable) (21CFR610.30); Mycobacterium ssp. sterility; In vivo tissue culture safety test; Detection of adventitious viruses by inoculation into guinea pigs, mice, and embryonated chicken eggs (In vivo safety test); General safety test (21CFR610.11); Avian leucosis virus assay; Assay to detect viral reverse transcriptases (PCR based).

The type, quantity, and sequence of required testing is not limited to the above referenced. Additional testing, as determined by either the COTR and/or the Contractor, may be required for specific virus products.

Potency testing (virus titer), virus identity, and genome sequence testing will be performed by the NIAID.

3. Storage and Shipping

Virus suspensions are to be stored by the Contractor at -70C or below in a monitored freezer according to cGMP guidelines. It is expected that the virus will maintain its titer during this storage period. Upon release, virus suspensions will be transferred by the Contractor to a long-term cGMP storage facility designated by the COTR.

C. Process Development.

During the course of contract performance, the Contractor may be asked to assist with basic process development as directed by the COTR.

These requirements will include the development of improved manufacturing methods designed to: (a) increase challenge virus potency (titer); (b) determine optimal day of virus harvest, (c) improve challenge virus stability; and (d) increase challenge virus purity by the reduction of undesirable contaminants such as cellular DNA, serum, and animal derived proteins.

D. Qualification of other challenge virus components.

As directed by the COTR, the Contractor may be asked to safety test materials intended for use as challenge virus components or study materials. Such materials may include virus excipients, diluents, and placebo fluids. In general, these filled materials are purchased by the COTR from commercial sources and qualified for human use by additional safety testing, which can include: Microbial sterility test (21CFR610.12) with Bacteriostasis and Fungistasis determination; Mycoplasma sterility (cultivatable and non-cultivatable) (21CFR610.30); General safety test (21CFR610.11); pH determination; Assay for amino acid composition.

III. Deliverables and Reporting Requirements:

All virus suspensions and reports produced by the Contractor and all cell lines produced and qualified for use under this contract will be considered U.S. Government-owned materials.

In order to accomplish the goals of this contract, virus suspensions are expected to be delivered within six months of the date that a suitable seed virus is made available to the Contractor.

For all contract facilities located outside of the United States of America, the Contractor will be responsible for ensuring the timely import and export of virus seed lots and all deliverables.

Contract deliverables include, but are not limited to:

(a) Manufactured virus suspensions or cell lines;

(b) Technical reports

(c) Clinical Lot Release / Safety Test Reports;

(d) Production and Manufacturing batch records, including all reports of deviations;

(e) Compilation of raw material including Certificates of Analysis and Certificates of Origin (for animal-derived raw materials).

1. Reporting Requirements

Quarterly progress reports shall be required.

For all progress reports, the Contractor shall be required to deliver one (1) electronic copy to the COTR and one (1) hard copy to the Contracting Officer or other designated Contracting Official.

The quarterly progress report shall contain all of the following:

i. A summary of the results for each task in progress and/or completed during the quarter;

ii. Identification of any problems incurred during the quarter and whether they have an impact on delivery or completion. If the problems are anticipated to impact delivery or completion, new delivery dates should be noted;

iii. The percent of funds expended and the percent of work completed for each task order on a quarterly and year-to-date basis.

2. Delivery Schedule

The Contractor shall adhere to the following delivery schedule: