Technical_Annex_FINAL.docx

TECHNICAL ANNEX

Section I: Regulatory requirements, Documentation, and Information Outlines of production The Contractor shall submit two outlines of production: one outline for the production of the vaccine antigen concentrate (VAC) and one outline for the finishing of the VAC to a usable vaccine. All outlines of production must conform to Title 9, Code of Federal Regulations (9 CFR), Part 114.9 (d). Laws, regulations, and guidance related to all aspects and requirements for the use of veterinary vaccines in the United States are available through the USDA-APHIS Center for Veterinary Biologics (CVB) webpage.

Requirements for product license and permitting The Contractor shall comply with the standards set forth by the Virus-Serum-Toxin Act (21 U.S.C.151-159) and the regulations promulgated from this Act as listed in 9 CFR Parts 101-123. These regulations were promulgated to ensure that all biologic products offered for sale or use in the United States meets all requirements for purity, safety, potency, and efficacy.

Vaccines should be eligible for a product license or a permit for distribution and sale in the United States, Canada and Mexico. The Contractor should designate representatives in the United States, Mexico and Canada for licensing/permitting purposes. The Contractor shall provide data to support product eligibility for regulatory approval. Outlines of production; labels; master seed virus and propagation cell line; and test results on vaccine purity, safety, potency, and efficacy should be submitted to the NAFMDVB and to the USDA/APHIS/VS/CVB the Canadian Food Inspection Agency (CFIA) and Mexico’s Secretaría de Agricultura, Ganadería, Desarrollo Rural, Pesca, y Alimentación (SAGARPA).

Ingredients of animal origin The contractor certifies that all materials of animal origin that are used in the production of FMD VACs and vaccines are sourced exclusively from countries whose BSE status is either no risk or low risk as defined by the USDA/APHIS/VS National Center for Import-Export (NCIE) and 9CFR Part 94.18.

Personnel requirements The Contractor should have adequately trained personnel, sufficient production equipment and instrumentation for quality control, and possess the production capacity necessary to meet the needs of the NAFMDVB in the vaccine manufacturing facility to consistently prepare and formulate high quality products. A list of Key personnel should be filed with the NAFMDVB and changes in key personnel should be reported.

Section II: Testing by the Manufacturer

Identification and Purity of the Master Seed Virus Strain Strain identity and purity of the master seed virus (MSV) must be verified by acceptable procedures. MSV should be neutralized by a reference antiserum produced with a strain of virus of the same subtype as the master seed virus, but with passage, origin, and/or production history different than that of the MSV.

Extraneous agents in Master Seed Virus and Master Cell Stocks MSVs should be tested for extraneous agents as described in 9 CFR 113.55 or by alternate methods according to EU regulations and approved by APHIS. The Contractor will provide extraneous agents testing worksheets for the MSVs used in the production of the VACs included in this contract.

Master Cell Stock (MCS) used in the propagation of antigens should be tested according to the requirements of 9 CFR 113.52, or by alternate methods according to EU regulations and approved by APHIS. The Contractor will provide extraneous agents testing worksheets for the MCSs used in the production of the VACs included in this contract.

Sterility Testing MSVs and MCSs must be tested by the contractor for extraneous viruses, bacteria (including Mycoplasmas), and fungi according to the filed outlines of production for both MSVs and MCSs.

Prior to inactivation, harvest fluids should be tested for extraneous viruses, bacteria (including Mycoplasmas), and fungi according to 9 CFR 113.27 and 113.28, for virus identity according to 9 CFR 113.300(c) or tested by analogous European Pharmacopoeia or Monograph. Alternate testing methods may be approved by agreement between APHIS and the contractor.

Inactivation Kinetics and Innocuity Testing The harvested culture fluids should be inactivated by the addition of the first order reaction inactivant. Samples should be taken at regular intervals for the purpose of determining the inactivation kinetics for each of the sub serials. A linear regression correlation coefficient of R2-value ≥ 0.95 must be obtained to indicate that inactivation was linear and that the data are significantly supportive of the inactivation. Extrapolation of the line must indicate that there would be less than one infectious particle per 10,000 liters of harvested culture fluid at the end of the inactivation period. If the extrapolation fails to reach this limit the harvested culture fluid is not satisfactory.

Tests for inactivation (innocuity test) shall be conducted on the VAC by the contractor using a sample of bulk harvest fluids taken after the inactivation period. The protocol for this test is to inoculate three tissue culture flasks of BHK cells with a proportion of the batch of bulk antigen representing at least 200 dose-equivalents of the original harvest fluids taken immediately after inactivation. Examine cultures at 48 hours for cytopathic effect (CPE) and, if negative, perform two successive subcultures with 50 ml per culture of harvested fluid from the preceding culture, and re-examine at 48 hours after each subculture. The same test will be performed by the NAFMDVB on samples of the final VAC. Observing CPE for any reason designates a failure of the innocuity testing.

Quantification of 146S FMD Capsids and VAC inferred Stability Testing The concentration (in μg/ml) of 146S FMD viral particles in each VAC will be determined by the contractor and reported to the NAFMDVB. The 146S antigen content of the VAC should be sufficient for the manufacture of the number of doses stipulated in the contract at the µg/dose of 146S described in the outline of production for each of the serotypes.

Each year, the contractor shall determine the stability of the VAC by measuring the 146S concentration in density gradients or other validated methods accepted by the NAFMDVB. The in vitro tests shall result in a report detailing the 146S content of the VACs in samples tubes stored with the VACs.

In Vivo Potency Testing The contractor will perform an in vivo potency test by vaccinating at least five head of cattle with a vaccine trial blend using the VAC in question and titrating antibody levels by a Virus Neutralization Test (VNT) with serum taken from the test cattle at 21 days post-vaccination. The potency of the vaccine will be determined by VNT and relational potency tables before VAC batch release (T0).

Subsequent in vivo inferred stability and potency tests shall be performed at T0+2.5 years and T0+5 years of VAC storage. This testing will provide results on the inferred stability of the VAC(s) and the potency of the VAC(s) by means of inoculation with a trial blend vaccine prepared from the accessory VAC samples in four (4) head of cattle performing VNTs using serum taken 21 days post-vaccination for each group. Theses latter testing results will be compared with those obtained from the initial potency test (T0). In the case of a VNT showing unsatisfactory results, the contractor shall propose a suitable remedy to ensure compliance with the guarantee given such as replacement of the VAC at no cost to APHIS. The NAFMDVB may also conduct parallel potency testing using the PD50 strategy to compare with the VNT potency results.

Testing reports – Documentation of the VAC Documentation of the testing procedures, results, and certificate(s) of analysis for the VAC will be provided to the USDA.

The record sheets for the inactivation kinetics for all the lots used in the preparation of the VAC and for the innocuity test, as well as the manufacturers test performed for the VAC release should be e-mailed to the NAFMDVB the day of the transfer of the VAC into long-term storage at the manufacturer.

Results of the annual determination of the antigenic mass 146S, and the virus neutralization titers at Time (T)0, T+2.5 & T+5 years, should be reported to the NAFMDVB within two months of the completion of the tests.

Section III: Testing Completed by the North American FMD Vaccine Bank (NAFMDVB)

Extraneous Agents testing The NAFMDVB will perform testing for the detection of extraneous agents in Master Seed Virus samples provided by the manufacturer according to 9 CFR § 113.55, § 9 CFR 113.46, and 9 CFR § 113.47.

Nucleotide Sequencing The NAFMDVB may choose to characterize the vaccine virus master seed, the challenge virus, the VAC, and trial blend vaccine preparations by nucleotide sequencing. The sequence information derived from these samples (except for the challenge virus) will be considered to be proprietary and therefore Confidential Business Information (CBI), and will not be disclosed by the NAFMDVB Bank Manager or any USDA officer to other parties (including NAFMDVB partners) without the consent of the contractor. The sequence information generated from the master seed virus will be used to verify the identity of the VAC strain and as a guide for antigen selection along with serological vaccine matching.

Materials to be supplied by the Manufacturer for Nucleotide Sequencing

· An aliquot of Master Seed Virus

· An aliquot of Challenge Virus

· An aliquot of the VAC

· A Trial Blend Vaccine

Innocuity Testing The NAFMDVB will perform an innocuity test on VAC samples to confirm virus inactivation. For this test, 200 dose- equivalents of raw VAC will be inoculated onto monolayers of BHK (or other susceptible cells). Inoculated cells are observed for 48-72 hours for cytopathic effect (CPE) followed by transfer of the media to fresh monolayers of BHK cells in a secondary inoculation container and replenishing the media in the primary inoculation container. The process is repeated for a third time with a tertiary inoculation container with inoculation by media from the secondary inoculation container and observed for 48-72 hours for CPE. If no CPE is observed in any container, the VAC will be considered to have successfully passed the innocuity test.

Materials to be supplied by the Manufacturer for Innocuity Testing (Refer to Section IV):

· An aliquot of VAC Safety Testing in Cattle The NAFMDVB may perform a safety test on each VAC for the purpose of confirming virus inactivation. For this test, 0.1 ml of the raw VAC is inoculated via an intradermolingual route into 20 separate sites of each tongue of three (3) susceptible cows. The inoculated cattle will be observed for 21 days. If lesions consistent with FMD are observed (e.g. vesicle formation), the VAC is considered unsatisfactory. Sera will be collected from each cow prior to inoculation, and also 21 days after inoculation and then analyzed for FMD antibodies to non-structural proteins (NSP) using a validated ELISA test.

Materials to be supplied by the Manufacturer for Safety Testing (Refer to Section IV):

· An aliquot of VAC Sterility Testing The NAFMDVB may perform a sterility test on the master-seed virus, challenge virus, VAC samples, and trial blend vaccine.

Quantification of 146S Antigen Content of the VAC The manufacturer will be required to perform 146S testing annually on the VAC(s) held by the NAFMDVB as described in Section II.

The NAFMDVB may repeat the 146S test on additional auxiliary VAC samples for quality control verification as follows: 1.0 ml of a 1:2 dilution of clarified VAC will be layered on top of a 55%/15% sucrose gradient in an ultracentrifuge tube, and then centrifuged at 41,000 rpm for 2.5 hours. The concentrated viral fractions will appear as bands inside the density gradient, these viral band fractions will be collected from the gradient and placed into cuvettes where the 146S full virions are detected by spectrophotometry at 259 nanometers and antigen concentration calculated based on the extinction coefficient for FMD.

The 146S concentration of the VAC should be stable for the 5-year guarantee period and any variance in testing results should be within expected tolerance limits. If however during the 5-year storage period there is significant variation in the testing results that are consistently outside the tolerance limits; or there is a decline in the 146S concentration of the VAC resulting in insufficient antigenic mass to finish the contracted number of doses at the concentration and potency determined in the outline of production, then the manufacturer must replace the VAC at no cost to USDA.

Materials to be supplied by the Manufacturer for 146S Content of the VAC (Refer to Section IV):

· An aliquot of VAC In Vivo Potency Testing - Protective Dose 50% (PD50) in Cattle The potency of the VAC will be determined by a PD50 study. The PD50 will be performed by testing a trial blend of vaccine prepared by the contractor using auxiliary samples of the VAC that have been stored together with the bulk VAC and prepared in a manner identical to the finished vaccine described within this contract. The VAC may be tested at any time during the 5-year guarantee storage period.

All animals used for this test are susceptible cattle meeting the following criteria:

· are at least 5 months of age and weigh a minimum of 400 pounds (181 kg);

· sourced from herds known to be free of FMD;

· have not been vaccinated for or exposed to FMD;

· and are free of topotype-specific FMD antibodies at the final 1:10 dilution in a virus neutralization test using 50 to 300 TCID50 of virus.

There will be a total of 17 animals in the study with 15 animals divided into three groups of five that will be vaccinated with graduated doses of vaccine per group, and a group of two cows that will be sham vaccinated to serve as control animals. The amount of antigen each group of 5 cows receives will vary by administering different volumes of vaccine. The vaccine will be administered via the intramuscular route and the injection scheme is as follows:

· 5 cows will receive 2.0 ml of vaccine;

· 5 cows will receive 0.5 ml of vaccine;

· 5 cows will receive 0.125 ml of vaccine;

· and the 2 sham-vaccinated control cows will receive 2.0 ml of sterile water.

Blood samples will be collected from each of the groups on day 0, 7, 14, and 21 post-vaccination.

Twenty one days post vaccination, the 15 animals vaccinated for FMD and the 2 sham vaccinated control animals will be challenged with the homologous virulent FMD virus corresponding to the VAC being tested, but having a different passage history than the virus used to manufacture the vaccine thus retaining wild-type virulence. The challenge virus will be given by the intradermolingual route at four (4) sites on the tongue with a total of 10,000 LFU50 (50% lesion forming units, as determined previously by cattle titration). Vaccinates and controls must be observed for 8 days post challenge and examined for lesions of FMD. The group of animals vaccinated with 1/16 dose (0.125 ml) will be transferred to a separate room immediately prior to challenge for the 8 day observation period. At 8 days post challenge, a final blood sample will be taken from all groups of cattle and subjected to a DIVA ELISA test.

This in vivo titration of the vaccine will ascertain its potency by determining the titer of virus-neutralizing antibodies to the strain of FMD virus in the trial-blend vaccine. For a valid test, both sham vaccinated control animals must develop generalized signs of FMD with lesions on at least three of the feet.

Unprotected animals must show lesions at sites other than the tongue. From the number of protected and unprotected animals in each group, the 50% protective dose (PD50) for the trial blend is calculated. To qualify as a successful test, the vaccine should contain at least 6 PD50 per 2 ml dose, otherwise the VAC is unsatisfactory and the manufacturer must replace the VAC at no cost to USDA.

A validated DIVA test for antibody to 3ABC or other diagnostically relevant NSPs must be negative at 21 days post vaccination. If antibodies to FMD neutralizing antigens or extraneous antibodies generated by FMD antigens other than 3D are found in the sera of cattle 21 days after vaccination, the VAC is considered as unsatisfactory.

The cost for PD50 testing for any VAC that fails this potency test must be reimbursed by the manufacturer to USDA via monetary remuneration or by extension of a credit on any subsequent purchase of VAC. USDA will notify the manufacturer of the results of the test and provide test data and an invoice of testing costs to the manufacturer no more than 30 days after the failure of the potency test. The manufacturer will then have 90 days from the time of notification to review the results or conduct independent testing to verify VAC potency, but the test will still be repeated by the NAFMDVB before accepting the VAC. After the 90 day review period, the manufacturer must issue a written credit (an email sent from the appropriate financial officer is acceptable) to the NAFMDVB for future use. If the VAC fails two consecutive potency tests performed by the NAFMDVB, the manufacturer must automatically reimburse testing costs and replace the VAC or its antigenic equivalent at no cost to USDA. If the NAFMDVB does not purchase subsequent VAC, the credit(s) must be reimbursed to USDA in the form of monetary compensation.

Materials to be supplied by the Manufacturer for Potency Testing (Refer to Section IV):

· An aliquot of Challenge Virus

· A Trial Blend Vaccine Test for Antibodies to Non Structural Protein (NSP) A test for antibodies against NSPs will be conducted on serum from cattle at the end of the safety test (21 dpi) and in the potency tests at 21 days post vaccination, by using a FADDL validated DIVA test. If antibody to NSP is found in the sera of cattle after inoculation of the VAC, or in animals vaccinated with a corresponding trial blend vaccine prior to challenge, the VAC is unsatisfactory. If a VAC fails to meet the requirements and results in animals seroconverting and demonstrating the NSPs specified in the validated DIVA test, the contractor shall replace the VAC and reimburse the NAFMDVB for the cost of testing.

Challenge Virus The NAFMDVB may choose to characterize the challenge virus preparation provided by the contractor by nucleotide sequencing and titration of infectivity in bovine tongue and cell cultures. If unsatisfactory results are found such as non-viable virus, failure to produce generalized foot lesions in at least three feet, or challenge virus which is not homologous to the corresponding VAC, then the contractor will be required to furnish another shipment of the challenge virus. If the manufacturer cannot to provide a bovine harvested challenge virus preparation then a low passage original field virus homologous to the vaccine strain can be supplied for propagation and titration in cattle.

Materials to be supplied by the Manufacturer for Challenge Virus evaluation (Refer to Section IV):

· An aliquot of Challenge Virus Section IV: Samples provided by Manufacturer to NAFMDVB

VAC and Sample identification Each cryopreservation vessel shall be clearly identified with a NAFMDVB label; and labels affixed to the individual VAC-containers should bear the following identifying information:

· the serotype/subtype of virus;

· the serial number of the batch;

· and the date the VAC was released.

Identifying labels must be affixed to the VAC container which are permanent, indelible, and also impervious to the effects of moisture and the conditions of ultra-cold storage, such as an etched or stamped metal tag bearing the required identifying information as designated above and attached to the VAC container by a metal wire encircling the bottle collar.

Trial Blend The following information regarding the formulation of trial blend must be provided by email at the time of shipping to the NAFMDVB:

· the volume and concentration in micrograms/ml (based on the results of the 146S testing) of the antigen;

· the volume and type of buffers;

· and the volume of mineral oil and emulsifying agents.

The trial blend label should contain:

· the commercial name of the vaccine (e.g. Aftopor);

· the dose volume; the valence of the vaccine;

· the serotype(s)/subtype(s) of the vaccine strain(s) included;

· the date of manufacture; the date of expiration;

· and the total volume in the vial.

Sample Requirements

Samples Sample Characteristic and Anticipated Delivery

Within 6 months of VAC delivery

Within 6 months of VAC delivery

Within 6 months of VAC delivery

Delivered annually, based on VAC delivery date

Delivery will occur by request

This section describes the samples the manufacturer should provide for confirmation of purity, safety, potency, and efficacy.

Master Seed Virus Samples The manufacturer will provide ten vials of Master Seed Virus (MSV). The titer of the MSV shall be in the range of 100,000 CCID 50%/ml. These samples will be used to confirm the results of extraneous agents testing performed by the manufacturer and nucleotide sequencing for confirmatory identification.

Antiserum Samples The manufacturer will provide fifteen 1.0 ml vials of antiserum produced against an MSV homologous virus capable of neutralizing at least 100,000 CCID50/ml of virus. The antiserum should be produced with a strain of virus of the same subtype as the MSV, but with a history of origin different than that of the master seed virus.

Challenge Virus Samples The manufacturer will provide ten vials of virulent FMD challenge virus each adequate to challenge inoculate 20 cattle. Naive animals inoculated in the tongue with 104 BID50 should develop FMD lesions in at least 3 feet within 8 days post inoculation. The virus must be derived from an acceptable known reference stock of the same serotype retaining its wild-type virulence. Origin and passage history of the challenge virus will be submitted together with the challenge virus material.

VAC Samples for 146S A total of 10 vials x 5.0 ml each should be taken and stored along with the VAC. The Contractor shall supply one vial x 5.0 ml of VAC to the NAFMDVB for 146S antigenic mass determination at the time of QA release and delivery to the storage at the liquid nitrogen freezer. Information with the micrograms of 146S antigen content per ml will be provided together with samples. The remaining nine (9) 5.0 ml samples should be kept with the VAC and one vial shipped once every year for the next 4 years to the NAFMDVB for 146S determination. The rest of the samples should be kept as retention samples or in case the tests need to be repeated.

VAC Samples for Trial Blend Vaccine, Safety Test, and Innocuity Test Ten (10) antigen samples of each VAC, each sample containing a volume adequate to prepare a trial blend of 300 doses of finished vaccine and to perform the 146S particle determination. One of these samples will be used for the safety test in cattle and innocuity test in vitro.

Trial Blends The manufacturer will be required to prepare up to 5 trail blend batches over a period of 5 years for vaccine efficacy studies. Each trial blend will be for 300 bovine doses (600 ml) The Contractor will produce and deliver a vaccine trial blend, and will send information on the formulation indicating volume of antigen concentrate, volume of buffers, and volume of mineral oil and emulsifying agents.

The Contractor shall prepare a representative trial blend (containing at least 300 doses) at the Contractor's vaccine finishing facility in accordance with the Contractor's approved Outline of Production for finishing vaccines. The Contractor shall perform 146S particle determinations on the VAC sample used for the pilot vaccine production and report this concentration in μg per dose to the NAFMDVB. The finished pilot serial shall be delivered to the NAFMDVB within four months of request.

Extra Samples Besides the samples described in this section, the manufacturer has to be cognizant and comply with the 9CRR 113.3 sampling of biological products. The NAFMDVB, in rare occasions, may collect extra test samples of each VAC when needed to retest in case of inconclusive results, to confirm the Contractor's results and perform acceptance tests.

Sample Labelling The label of each sample should be printed in a legible, permanent, and cryo-stable manner and should include:

· Type of sample; i.e. MSV, challenge virus VAC, etc.,

· Batch number,

· Volume,

· Concentration or titer if possible (or supplied at a later date),

· and VAC samples must display the strain identification code

For older samples with no label, supporting documentation must accompany the shipment that includes the specific information that would have been on a label otherwise.

Finished vaccine should be shipped to the airport indicated in the delivery order.

Finished vaccine shipments could be imported through any international airport in Canada, Mexico, or the United States using a direct flight from the country of manufacture or finishing. Notifications of shipment should be made to the following individuals:

a. The Director of the National Veterinary Stockpile (NVS): Rodney White, office phone: (301) 851-3477; Mobile: (301) 789-3157; e-mail: Rodney.A.White@usda.gov

b. The Director of Foreign Animal Disease Diagnostic Laboratory: Kimberly A. Dodd, office phone: (631) 323-3113, e-mail: Kimberly.A.Dodd@usda.gov

c. The Manager of the NAFMDVB: Hernando Duque, office phone (631) 323-3151, e-mail: Hernando.Duque@usda.gov

Section V: Shipping of Samples and Finished Vaccine

DELIVERY REQUIREMENTS

Export approvals, including licensing and permits, must be in place prior to shipment.

The following instructions must be followed for any shipment of master seed virus, master cell stocks, VAC samples, trial blends, or challenge viruses sent to the Foreign Animal Disease Diagnostic Laboratory (FADDL) at the Plum Island Animal Disease Center. For shipment of finished vaccine refer to numeral 9 below.

2. Shipment of foot-and-mouth disease virus (FMDV) and other foreign animal disease (FAD) agents must be under a select agent transfer authorization (SATA) issued by the US CDC/APHIS. All other non-select agent biological materials of livestock or poultry origin, must enter the United States under a US Department of Agriculture import permit. A copy of the provided SATA or import permit should be placed in an outside envelope attached to the shipping box for easy access upon arrival inspection.

3. For packaging instructions see the diagrammed instructions attached to the permit. Do not use aqueous ice; use either dry ice or frozen (gel) packs. Indicate on the outside of the package the temperature at which the materials are to be stored (e.g. 4C, -20C, -70C, or liquid nitrogen). Also, indicate if the materials are for diagnostic testing, or for safety testing, or reference materials.

4. All packages should be addressed as follows:

US Department of Agriculture Attn: FADDL Lab Chief

APHIS, VS, NVSL, FADDL

40550 Route 25 Orient, New York, 11957, USA Phone: 631-323-3256 Fax: 631-323-3366

It is very important the package is addressed to the US Department of Agriculture (not just USDA) to expedite clearance through US Customs.

5. Make arrangements with FADDL prior to shipping materials to ensure that there is someone available to receive the materials and immediately upon shipping, notify the NAFMDVB Manager, by telephone at (631)323-3151, fax (631) 323-3366 or email at Hernando.Duque@usda.gov with the following information:

a) Airline and flight number

b) Date and time of arrival

c) Air waybill number (without this number the package cannot be located at the airport)

Notification can be made 7 days a week, 24 hours a day. If calling other than normal business hours (8:30 am to 4:15 pm Eastern standard time, Monday through Friday) call 631-375-5314 to leave a message.

6. If at all possible, arrange for packages to arrive at John F. Kennedy International Airport in New York, NY during the following days: Monday through Thursday.

7. Live FMDV is classified by the Federal Select Agent Program as a Tier 1 Select Agent and requires a select agent authorization (SATA) issued by CDC/APHIS. Do not ship master seed virus, master cell stocks, VAC samples, trail blends, and challenge viruses to or through any airport in the United States except John F. Kennedy International Airport (JFK), New York, NY unless there is no other alternative. If it is not possible to obtain a direct flight into JFK and the shipment enter through another point of entry such as Miami International Airport or any other port of entry, then clearly mark on the outside of the package that the shipment is to clear customs only at John F. Kennedy International Airport, New York, NY.

8. Avoid changing airline carriers at any international airport. This is important because air waybill numbers change with airline carrier; thus increasing the chances of the shipment being lost.

9. DO NOT USE ANY COMMERCIAL EXPRESS CARRIERS (e.g. FED EX, DHL, AIRBORNE) for shipment of biological materials to FADDL. Most of these carriers enter the US through their own hub airports which are not approved international ports of entry. Packages containing restricted biological materials sent this way may be confiscated and destroyed upon arrival.

Section VI: Inspections

A team of inspectors from the NAFMDVB, led by the Inspection and Compliance department of the USDA Center of Veterinary Biologics is entitled to inspect the manufacturing facilities at two year intervals. Through these periodic inspections, the NAFMDVB will ensure that the manufacturer has adequately trained personnel, appropriate equipment, and sufficient production capacity etc. in its vaccine manufacturing facility in order to formulate each VAC and that manufacturing is performed according to the Outlines of Production (OOP).

Representatives of NAFMDVB are entitled to:

· inspect the storage facilities where the NAFMDVB VAC is maintained;

· Inspect the dewars holding the VAC in the vapor phase of liquid nitrogen;

· And inspect and review the storage records, batch numbers, and labels on the product to ensure that these agree with the documentation supplied by the manufacturer.

The NAFMDVB must give the contractor two (2) business days’ notice of an inspection and, where reasonably practicable, an indication of which documents and/or class of documents the inspector may wish to evaluate.

The NAFMDVB may have one or more observers at the contractor’s facilities during the production of the trial blend vaccine. The NAFMDVB may observe the finishing of the VAC(s) into finished vaccine and help to facilitate its shipment. Until delivered, finished vaccine will be stored in a refrigerated quarantine area in the contractor's facilities.

Section VII: Transfer of VAC to Long-Term Storage Facilities

Once a VAC is released by the manufacturer and after completion of all the quality control tests for safety, innocuity, potency, and sterility, the contractor shall deliver the VAC(s) to the storage vessels on the contractor’s premises dedicated for use by the NAFMDVB.

At the time that the contractor delivers the VAC(s) into storage, the contractor shall also include the VAC samples for safety testing, innocuity testing, periodic 146S testing, and the preparation of trial blend vaccines. These ancillary VAC samples are to be stored together with the VAC. The VAC identification (i.e. batch number, virus strain, date of manufacture, volume) shall be noted on each vial. Samples should be clearly identified in a permanent manner appropriate for liquid nitrogen storage conditions.

The NAFMDVB agrees to accept each VAC(s) in advance of the quality control tests that may be performed by the NAFMDVB as described in the Section on NAFMDVB. Testing conducted by the NAFMDVB will be considered as the final official results. In the event that the tests performed by the NAFMDVB indicate a particular VAC covered under this contract does not meet the requirements for purity, safety, efficacy, or potency, the contractor must replace the VAC free of charge in a reasonable time period, not to exceed six (6) months after notification by the NAFMDVB of the test results as detailed in Section III.

At the time of transfer, the manufacturer will send a report of the transfer indicating the serotype, virus strain, the serial or batch number, the volume or weight of VAC in the vessel, and the date the VAC was transferred to the NAFMDVB (specifically, time zero [T0] will begin the moment that VAC is placed in storage.