12639520R0055P00001.pdf

SEE ADDENDUMIS CHECKED

CODE 18a. PAYMENT WILL BE MADE BY

CODE

FACILITYCODE

17b. CHECK IF REMITTANCE IS DIFFERENT AND PUT SUCH ADDRESS IN OFFER

OFFEROR

APHIS-MN-126395

MINNEAPOLIS MN 55401

SUITE410

250 MARQUETTE AVE

USDA APHIS

CODE 16. ADMINISTERED BYCODE

X

X

325414

SIZE STANDARD:

% FOR:SET ASIDE:UNRESTRICTED ORAPHIS-MN-126395

RFPIFB

10. THIS ACQUISITION ISCODE

RFQ

14. METHOD OF SOLICITATION

13b. RATING

NAICS:

SMALL BUSINESS

07/26/2021 1700 ET

07/27/2020

612-336-3205ROBERT ZEGLIN

(No collect calls)

INFORMATION CALL:

FOR SOLICITATION 8. OFFER DUE DATE/LOCAL TIMEb. TELEPHONE NUMBER a. NAME

4. ORDER NUMBER3. AWARD/ 6. SOLICITATION

12639520R0055

5. SOLICITATION NUMBER

SOLICITATION/CONTRACT/ORDER FOR COMMERCIAL ITEMS 1. REQUISITION NUMBER PAGE OF

1 120 OFFEROR TO COMPLETE BLOCKS 12, 17, 23, 24, & 30

TELEPHONE NO.

17a. CONTRACTOR/

15. DELIVER TO

MINNEAPOLIS MN 55401

SUITE410

250 MARQUETTE AVE

9. ISSUED BY

7.

2. CONTRACT NO.

EFFECTIVE DATE

1,250

18b. SUBMIT INVOICES TO ADDRESS SHOWN IN BLOCK 18a UNLESS BLOCK BELOW

ISSUE DATE

DELIVERY FOR FOB DESTINA-

TION UNLESS BLOCK IS

MARKED

11.

SEE SCHEDULE

12. DISCOUNT TERMS

THIS CONTRACT IS A

RATED ORDER UNDER

DPAS (15 CFR 700)

13a.

SERVICE-DISABLED

VETERAN-OWNED

SMALL BUSINESS

HUBZONE SMALL

BUSINESS

8(A)

USDA APHIS

WOMEN-OWNED SMALL BUSINESS

(WOSB) ELIGIBLE UNDER THE WOMEN-OWNED

SMALL BUSINESS PROGRAM

EDWOSB

24.

AMOUNT

23.

UNIT PRICE

22.

UNIT

21.

QUANTITY

20.

SCHEDULE OF SUPPLIES/SERVICES

19.

ITEM NO.

Tax ID Number: Not Available DUNS Number: Not Available FMD VAC for the NAFMDVB

(Use Reverse and/or Attach Additional Sheets as Necessary)

HEREIN, IS ACCEPTED AS TO ITEMS:

DATED

ROBERT J. ZEGLIN

. YOUR OFFER ON SOLICITATION (BLOCK 5),

INCLUDING ANY ADDITIONS OR CHANGES WHICH ARE SET FORTH

COPIES TO ISSUING OFFICE. CONTRACTOR AGREES TO FURNISH AND DELIVER

ARE

ARE

31c. DATE SIGNED

27b. CONTRACT/PURCHASE ORDER INCORPORATES BY REFERENCE FAR 52.212-4. FAR 52.212-5 IS ATTACHED. ADDENDA

31a. UNITED STATES OF AMERICA (SIGNATURE OF CONTRACTING OFFICER)

30c. DATE SIGNED 31b. NAME OF CONTRACTING OFFICER (Type or print)

ALL ITEMS SET FORTH OR OTHERWISE IDENTIFIED ABOVE AND ON ANY ADDITIONAL

SHEETS SUBJECT TO THE TERMS AND CONDITIONS SPECIFIED.

27a. SOLICITATION INCORPORATES BY REFERENCE FAR 52.212-1, 52.212-4. FAR 52.212-3 AND 52.212-5 ARE ATTACHED. ADDENDA

26. TOTAL AWARD AMOUNT (For Govt. Use Only)

OFFER

STANDARD FORM 1449 (REV. 2/2012)

Prescribed by GSA - FAR (48 CFR) 53.212

ARE NOT ATTACHED.

ARE NOT ATTACHED.

AUTHORIZED FOR LOCAL REPRODUCTION

PREVIOUS EDITION IS NOT USABLE

30b. NAME AND TITLE OF SIGNER (Type or print)

30a. SIGNATURE OF OFFEROR/CONTRACTOR

28. CONTRACTOR IS REQUIRED TO SIGN THIS DOCUMENT AND RETURN

25. ACCOUNTING AND APPROPRIATION DATA

29. AWARD OF CONTRACT:

REF.

32e. MAILING ADDRESS OF AUTHORIZED GOVERNMENT REPRESENTATIVE

32c. DATE 32b. SIGNATURE OF AUTHORIZED GOVERNMENT REPRESENTATIVE

ACCEPTED, AND CONFORMS TO THE CONTRACT, EXCEPT AS NOTED:

32a. QUANTITY IN COLUMN 21 HAS BEEN

RECEIVED INSPECTED

40. PAID BY39. S/R VOUCHER NUMBER38. S/R ACCOUNT NUMBER

37. CHECK NUMBER

FINALPARTIAL

36. PAYMENT

FINALPARTIAL

35. AMOUNT VERIFIED

CORRECT FOR

34. VOUCHER NUMBER33. SHIP NUMBER

COMPLETE

32g. E-MAIL OF AUTHORIZED GOVERNMENT REPRESENTATIVE

42d. TOTAL CONTAINERS42c. DATE REC'D (YY/MM/DD)

42b. RECEIVED AT (Location)

42a. RECEIVED BY (Print)

41c. DATE41b. SIGNATURE AND TITLE OF CERTIFYING OFFICER

41a. I CERTIFY THIS ACCOUNT IS CORRECT AND PROPER FOR PAYMENT

STANDARD FORM 1449 (REV. 2/2012) BACK

24.

AMOUNT

23.

UNIT PRICE

22.

UNIT

21.

QUANTITY

20.

SCHEDULE OF SUPPLIES/SERVICES

19.

ITEM NO.

32f. TELEPHONE NUMBER OF AUTHORIZED GOVERNMENT REPRESENTATIVE

32d. PRINTED NAME AND TITLE OF AUTHORIZED GOVERNMENT REPRESENTATIVE

120 2 of

Request for Proposals (RFP)

SECTION B – SCHEDULE

B.1 Solicitation Information

The Government intends to award multiple firm fixed price Indefinite Delivery Indefinite Quantity (IDIQ) contracts for Foot and Mouth Disease (FMD) Vaccine Antigen Concentrate (VAC) and Finishing of VAC into vaccine. As a multiple award opportunity, the government may begin evaluating proposals as soon as they are received. Awards can be made beginning 30 days from the publishing of the solicitation and may be made up to one year from date of issuance of the solicitation.

Vaccine production is a rapidly evolving field. As such, there may be changes to our technical requirements throughout the solicitation period. Should changing technical requirements be identified, this solicitation may be amended. Contracts already awarded under this solicitation will not be subject to the changes outlined in an amendment except by contract modification.

Indicate the price per dose of vaccine. Please include pricing for all pricing structures indicated below (regardless of whether the price changes). FMD VAC may be ordered in large quantities, as such the Government is interested in any bulk discounts that can be offered. If you have additional volume discounts you would like to offer, please identify them in a continuation page. Minimum order quantities will be contract specific based on desirability of the FMD strains offered, price, and other negotiated terms with the vendor.

B.2 Bid Schedule

Please enter the guaranteed shelf life for all FMD VAC you are offering. (In years) _______________

Item No. Supplies/Services

Unit of Issue Unit Price

Production and storage of vaccine antigen concentrate (VAC), also known as "For Further Manufacture" (FFM), sufficient to produce a quantity between 1.0 Million and 2.5 Million doses of formulated vaccines. Cost must include storage of VAC at manufacturer for length of shelf life. Purchase of VAC under this line will only be allowed during years 1-5 of the contract. *

Dose (Vaccine)

Production and storage of vaccine antigen concentrate (VAC), also known as "For Further Manufacture" (FFM), sufficient to produce a quantity of 2.5 Million Doses or greater of formulated vaccines. Cost must include storage of VAC at manufacturer for length of shelf life.

Purchase of VAC under this line will only be allowed during years 1-5 of the contract. *

Dose (Vaccine)

Conversion of stored VAC into formulated vaccine upon request and Free on Board (FOB) destination shipment to any U.S, Mexico or Canada International Airport to be identified on order. Pricing is valid for years 1-5 of contract **

Dose (Vaccine)

Conversion of stored VAC into formulated vaccine upon request and Free on Board (FOB) destination shipment to any U.S, Mexico or Canada International Airport to be identified on order. Pricing is valid for years 6-10 of contract **

Dose (Vaccine)

Conversion of stored VAC into formulated vaccine upon request and Free on Board (FOB) destination shipment to any U.S, Mexico or Canada International Airport to be identified on order. Pricing is valid for years 11-15 of contract if applicable **

Dose (Vaccine)

Conversion of stored VAC into formulated vaccine upon request and Free on Board (FOB) destination shipment to any U.S, Mexico or Canada International Airport to be identified on order. Pricing is valid for years 16-20 of contract if applicable **

Dose (Vaccine)

* Line items 1 and 2 are for purchase of VAC only during years 1-5 of the contract. Purchase of VAC beyond year 5 will require a new contract. The only difference between lines 1 and 2 are the quantity ordered. This allows vendors to offer a price discount when a quantity of 2.5 Million or more is ordered.

If the no discount is offered, please enter the same price in both fields.

** Line items 3, 4, 5 and 6 are time based. It allows the vendor to provide different pricing for finishing of the VAC based on the period of time the conversion is ordered.

B.2.1 Schedule Notes

1. The resulting contracts will be Indefinite Delivery Indefinite Quantity (IDIQ) contracts with fixed price line items.

2. In accordance with FAR 52.212-1: Please ensure your firm provides all necessary items to be considered responsive as outlined in Section E.1.2.

3. Questions – All questions must be submitted via email to: Robert.J.Zeglin@usda.gov mailto:Robert.J.Zeglin@usda.gov

B.3 Proposal due date, time and format This solicitation will remain open for a period of one year. (Estimated 7/27/2020 – 7/26/2021) Awards may be made beginning 30 days from the date of posting. As a multiple award solicitation, offers will be evaluated as they are received throughout the solicitation period. The government reserves the right to make multiple awards against this solicitation up to 30 days after close of the solicitation. Offers received after the solicitation is closed will not be considered for award.

Funds are presently available to place orders for FMD VAC. Interested offerors are highly encouraged to submit proposals within the first thirty days of the solicitation period to be considered for competition at the order level. Please note that only orders where multiple awardees offer a product will be competed. Orders for products not offered by multiple awardees will not be competed.

Please submit all proposals and supporting documentation via email to the contracting officer. File size limitations of 10MB per email should be used. If multiple emails are necessary to provide all documentation, please ensure the email indicates such and is marked sequentially (I.E. 1 of 3, 2 of 3 etc.).

All proposals must list the solicitation number in the subject field of the email. 12639520R0055

SECTION C – DESCRIPTION/SPECIFICATIONS/WORK STATEMENT

C.1 Definitions/Acronyms

VAC – Vaccine Antigen Concentrate sometimes referred to by industry as “For Further Manufacture.”

FFM – “For Further Manufacture” used interchangeably with VAC

F.O.B. destination – See clause 52.247-34

FUP – Final Use Product. VAC quantity is defined in terms of the minimum number of doses of finished vaccine it can yield. The finished vaccine is also referred to as FUP.

Guaranteed Shelf Life – The period of time during which the contractor guarantees their VAC will pass potency, purity and efficacy tests.

C.2 SPECIFICATIONS

The United States Department of Agriculture (USDA), Animal and Plant Health Inspection Service (APHIS) on behalf of the North American Foot and Mouth Disease Vaccine Bank (NAFMDVB), is seeking to secure the production of a foot and mouth disease (FMD) vaccine antigen concentrates (VAC), and as required, the opportunity to finish VAC into final vaccine. The effective period of the contract will be equivalent to the manufacturer’s guaranteed shelf-life from date of release of the VAC and is dependent upon successful performance in the efficacy test (PD50).

The contract will have the following components:

1. Production of FMD Vaccine Antigen Concentrates (VACs). Production of each FMD (VAC) serial shall be purified, concentrated, and shall provide a minimum of 1.0 Million doses (Quantity to be specified on orders) of vaccine (AKA final use product (FUP)). Please thoroughly review the Technical Annex (Section F) for VAC suitability.

2. Storage of VACs on manufacturer premises The Manufacturer will be required to store and guarantee VAC for the duration of shelf-life from date of release to bank. VAC storage requirements are outlined in the Technical Annex. (Section F)

3. Performance of quality control testing, and reporting of quality control testing results to the NAFMDVB during the storage period.

The Contractor shall submit documentation on the manufacture, formulation, quality control and storage of the VAC(s) as detailed in the Technical Annex.(Section F)

4. Submission of samples upon request under the conditions outlined in the Technical Annex (Section F) This task includes the periodic submission of test samples to USDA APHIS VS upon request for safety, potency and efficacy testing. Please see Technical Annex (Section F) for further details regarding vendor testing requirements and information about the testing performed by USDA.

5. Finish VAC into final vaccine (AKA final use product or FUP) if required.

Upon request from NAFMDVB, the vaccine(s) will be prepared using one or more of the VACs held by the NAFMDVB, singly or in combination, produced under this contract.

C.3 Specifications/Milestones for Component 1: Production of FMD Vaccine Antigen Concentrates (VACs)

The Contractor will be responsible for the production of a specified VAC, with the capacity to yield a minimum 1.0 Million doses of deliverable finished vaccine. Delivery timelines will be determined prior to order placement to ensure vendors have sufficient production lead time.

C.4 Shipment/Delivery

All shipping and delivery costs associated with delivery of finished vaccine to any international airport in the U.S, Mexico or Canada, as designated at time of order, shall be included in the unit price of the VAC conversion cost. Sample Shipping and Delivery costs to USDA at either Plum Island, NY or Manhattan, KS for testing shall be included in the unit cost of the VAC. Further details regarding the delivery and shipment terms for finished vaccine and sample submissions is included in the Technical Annex. (Section F)

Contractor may be invited to send representative(s) to participate in USDA Veterinary Services table-top exercises (TTX). In the event direct attendance is not feasible, teleconference capability is anticipated.

These exercises are not mandatory but highly encouraged. Expenses incurred as a result of attendance of these exercises are the sole responsibility of the contractor.

Regarding finished vaccine, when a Contract is awarded, the Contractor agrees to provide Material Safety

Data Sheets (SDS) during the TTX to the Contracting Officer’s Representative (COR) and the National Veterinary Stockpile (NVS).

The Government may require finished vaccine shipments to be imported through any international airport in the United States, Mexico or Canada. Contractor must use the most time efficient flight route from the country of manufacture or finishing. Notifications of shipment must be made to the individuals specified on the order.

SECTION D. CONTRACT ADMINISTRATION

D.1 Fair Opportunity / Ordering D.1.1 Fair Opportunity National security interests require that specific FMD VAC and Vaccine purchase information will not be made available publicly. The government will require vendors to provide updated listings of the specific FMD products they offer. When the government determines specific FMD VAC or vaccine needs, only those vendors with IDIQ contracts offering the desired FMD product will be notified of the requirement.

Delivery order will be placed with the lowest price vendor who can meet our required delivery timelines.

The Government may place orders with multiple vendors to meet necessary requirements.

D.1.2 Ordering Ordering processes and procedures will be included in resulting awards.

D.2 Acceptance D.2.1 Acceptance of VAC Once a VAC is released by the manufacturer and after completion of all the quality control tests for safety, innocuity, potency, and purity, 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/serial number, virus strain, release date, 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 in advance of the quality control tests that may be performed by the NAFMDVB as described in the Technical Annex.(Section F) Documentation of the manufacturer’s testing procedures (e.g., APHIS Forms 2008), results, and certificate(s) of analysis for the VAC (also known as FFM) will be provided to the USDA.

The Center for Veterinary Biologics (CVB) reviews inactivation kinetic study reports. Study reports describe inactivation procedure and testing methods. If CVB agrees a study report supports the inactivation procedure and testing methods then those must be included in the approved Outline of Production (OOP) Sections IV and V, on file at the CVB.

The Contractor must perform inactivation (i.e., innocuity) tests on each batch/lot/serial of VAC. Copies of safety or innocuity test results, as well as other manufacturer tests performed for VAC release, should be submitted to the CVB and NAFMDVB on APHIS Form 2008 the day of the transfer of the VAC into long-term storage at the manufacturer. The Contractor’s in process (e.g. OOP Section IV) inactivation kinetics and innocuity test results must be provided when requested by 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 twelve (12) months after notification by the NAFMDVB of the test results as detailed in the Technical Annex. (Section F) If VAC fails a PD50 test, the manufacturer will be required to issue a $70,000.00 credit on future purchases to cover the cost of the failed test. (See technical annex for additional details) The PD50 test will be repeated on the replacement VAC. Each batch of VAC will be subject to a PD50 test. This includes replacement VAC.

Please review the technical annex (Section F) for further details.

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 placed into storage for the NAFMDVB.

The government reserves the right to inspect the contractor in accordance with Section VI: Inspections of the technical annex (Section F). Typically inspections are conducted by a team led by a representative from APHIS. At the government’s request, inspections will occur during regular business hours with a minimum 48 hour notice communicated to the vendor prior to inspection dates.

Acceptance of Finished Vaccine

Finished vaccine acceptance will occur upon delivery to the destination International Airport designated at time of order.

D.3 Period of Performance The period of performance for this contract shall be equivalent to the manufacturer guaranteed shelf-life of the VAC from the date the Contractor’s quality assurance (QA) or qualified person (QP) releases the VAC and dependent upon successful performance in the required testing further detailed in the Technical Annex (Section F). In the event of testing failure it may become necessary for the period of performance to be amended by contract modification to ensure finishing and storage of VAC for the entirety of guaranteed shelf-life. The time passed between acceptance and notification of a PD50 failure will count towards the guaranteed shelf life of the VAC. Time to produce and replace said VAC will not count towards the guaranteed shelf life.

The ordering period for VAC and finished vaccine will be limited to 5 years. Depending on guaranteed shelf life and the length of time it takes to replace VAC that fails testing, these contracts could be issued for 18-20 years. Note that the purpose for all contract years beyond year five is to allow for the possible finishing of the vaccine during its guaranteed shelf life and ensure the contract terms cover the full storage life. New contracts are likely to be needed every five years to allow for the purchase of VAC and Vaccine.

D.4 Invoicing All invoicing will be submitted through the government electronic invoicing platform IPP.gov, or other method approved by USDA.

E. Submission and Evaluation Factors E.1 Minimum Qualification Factors E.1.1 Evaluation Factors

In this acquisition, the Government will obtain best value by using the Tradeoff Process source selection approach which permits tradeoffs among cost or price and non-cost factors and allows the Government to accept other than the lowest priced proposal. As a multiple award opportunity, the government may begin evaluating proposals as soon as they are received.

Awards will be made beginning 30 days from the publishing of the Solicitation and may be made up to one year from date of issuance of the solicitation.

EVALUATION FACTORS:

Price

Please complete the price schedule in Section B above. Each price element will be evaluated separately. The VAC price will be evaluated based on the price per dose per year of guarantee.

I.E. dose price/ # of years guaranteed

Examples:

Vendor A offers a 10 year guaranteed shelf life at $0.10 per dose for VAC.. The per dose price per year of guaranteed VAC shelf life would be $0.01. T

Vendor B offers a 5 year guaranteed shelf life at $0.08 per dose for VAC. The per dose price per year of guaranteed VAC shelf life would be $0.016.

Technical Capability

Vendor submittals must successfully demonstrate the vendor’s capability to comply with the extensive technical requirements outlined in the statement of work and technical annex (Section F)

Past Performance

Past performance is a measure of the degree to which an Offeror has satisfied customers in the past, and complied with federal, state, and local laws and regulations.

Offerors with no past performance information will be given a neutral rating. Offerors with past performance information will be assigned a rating of low confidence, moderate confidence or high confidence. Those assigned a rating of low confidence may be deemed ineligible for award.

Price, Technical Capability and Past Performance are equally important relative to each other.

E.1.2 Items required to be submitted for Award The following items are required to be submitted in order to be eligible for award:

1) A signed copy of the SF 1449 Form. Please complete Block 17a including vendor name, address, phone number, Federal Tax ID number, and DUNS number. Then, sign in block 30a.

2) Price schedule with pricing provided for all line items and a value for the guaranteed shelf life located in section B.

3) Documentation that the Offeror has demonstrated the ability to access field strains, or engineer Master Seed Viruses (MSV), that can be used to manufacture vaccines against FMD field strains. This should include a listing of all FMD products the vendor currently has the ability to offer.

4) Documentation that applicable and approved MSV and propagation cell line data are on file at the Center for Veterinary Biologics (CVB)

5) Copy of a United States Veterinary Biological Product License or Permit for Distribution and Sale issued by the USDA, or evidence an application has been submitted to the CVB

6) Documentation that safety data demonstrating an acceptable safety profile are on file at the CVB

7) Documentation, if applicable, that an inactivation kinetics study report demonstrating inactivation methods/procedures are effective has been found acceptable by the CVB

8) Documentation, if applicable, that National Environmental Protection Act data are on file at the CVB

9) Documentation that efficacy data, or reasonable expectation of efficacy data, are on file at the CVB

10) Documentation that Outlines of Production (OOP) prepared according to 9 CFR 114.9 are on file at CVB

11) Documentation that facility documents (e.g., blueprints, blueprint legends, plot plans, plot plan legends) are on file at the CVB and the facility documents show the Offeror has a suitable manufacturing facility

12) Past Performance: Three (3) past performance references detailing FMD VAC or Vaccine purchases. Include:

a. Company or agency name

b. Size/frequency of Order

c. Point of contact

i. Name

ii. Phone Number

iii. Email Address If past performance information is not provided and no relevant past performance information can be located by the Contracting Officer, the vendor will receive a neutral rating for past performance.

13) SYSTEM for AWARD MANAGEMENT (SAM) REGISTRATION: SAM Registration is required of all federal contractors. SAM registration enables electronic funds transfer of contract payments. If your company is not already registered, please register in the SAM database at https://www.sam.gov/portal/public/SAM/.

a) A DUNS number is required for SAM registration. If your company does not have

DUNS #, obtain one by calling 800-333-0505.

F. Technical Annex F.1 Section 1: Regulatory requirements, Documentation, and Information F.1.1 Outlines of production (OOP) The Contractor shall submit two outlines of production to APHIS Center for Veterinary Biologics (CVB):

one outline for further manufacture (FFM) production of the vaccine antigen concentrate (VAC), and one outline for the finishing of the VAC to a final use product (aka FUP or finished bottled labeled 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-VS-CVB webpage.

F.1.2 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 biologic products offered for sale or use in the United States meet requirements for purity, safety, potency, and efficacy.

Vaccines shall be eligible for a product license or a permit for distribution and sale in the United States.

If a license or permit for distribution and sale has not yet been issued, then eligibility will be considered if the Contractor is making a good faith effort to obtain a license or permit for distribution and sale as demonstrated by its submissions to the CVB including a license or permit application, Outline of Production (OOP), safety data, applicable master seed virus and propagation cell line data, applicable National Environmental Protection Act data, reasonable expectation of efficacy data and facility documents (blueprints, plot plans, plot plan legends) that demonstrate the Contractor has a suitable manufacturing facility. The Contractor must designate representatives (e.g., designated liaison) in the United States who can be contacted regarding licensing/permitting questions and issues. Submissions to CVB may be shared with the North American Foot and Mouth Disease Vaccine Bank (NAFMDVB) unless the Contractor provides sufficient justification regarding why some submissions should not be shared.

F.1.3 Ingredients of animal origin The contractor certifies that additives in the contractor’s FMD vaccines conform to the USDA’s Veterinary Services Memorandum No. 800.51. Each lot of ingredient additive of animal origin used to prepare an administered biological product must be sterilized or tested as prescribed in 9 CFR 113.53. 2.

Ingredients of animal origin are sourced from the United States or countries considered free, low risk, or not affected with foreign animal diseases of concern and with negligible or controlled risk of bovine spongiform encephalopathy (BSE), according to APHIS’ Animal Disease Status designations, which may be viewed at: https://www.aphis.usda.gov/aphis/ourfocus/animalhealth/animal-and-animal-productimport-information/animal-health-status-of-regions

The foreign animal diseases of concern to the Center for Veterinary Biologics (CVB) are: • Foot-and-mouth disease (FMD), • African swine fever (ASF), • Classical swine fever (CSF), • Highly pathogenic avian influenza (HPAI), and • Newcastle disease (ND).

No animal ingredients of avian origin may be sourced from a country if HPAI or ND is present in any region of the country. No ingredients of mammalian origin may be sourced from a country if FMD, ASF, or CSF is present in any region of the country. If an outbreak of any of these diseases occurs in countries providing ingredients of animal origin, consult the CVB for an assessment of risk. A risk assessment, including an analysis of the risk of contamination to licensed biologics, must be submitted to the CVB for review to justify using an ingredient of animal origin from a country that has a foreign animal disease of concern. This guidance does not abrogate any other import requirements; all National Import and Export Services restrictions apply. 3. Manufacturers must maintain a comprehensive list of all ingredients of animal origin used in production of biological products. This list should include the name of the material, the supplier, the country of origin, and the date of purchase of each lot. This list may be reviewed and certification of materials required at the time of inspection by the CVB Inspection and Compliance (IC), or as requested by the CVB.

F.1.4 Personnel requirements The Contractor shall have adequately trained personnel, sufficient production equipment and instrumentation for quality control, and possess the production expertise (including pilot serial production expertise) and capacity necessary to meet the needs of the NAFMDVB. The Contractor’s manufacturing facility must be inspected by the USDA and determined adequate for the purpose of consistently manufacturing high quality FMD vaccines. A list of Key personnel and their qualifications shall be filed with the CVB (APHIS Forms 2007) and NAFMDVB; changes in key personnel must be reported within 2 months.

F.2 Section II: Testing by the Manufacturer F.2.1 Identification and Purity of the Master Seed Virus Strain Strain identity and purity of the master seed virus (MSV) must be verified by procedures acceptable to APHIS. The Contractor must provide the NAFMDVB with a list of MSVs which have been tested and approved by APHIS for use in production, and a separate list of MSV which are used to prepare commercial vaccines but have not yet been approved by APHIS.

F.2.2 Extraneous agents in Master Seed Virus and Master Cell Stocks MSVs must be tested for extraneous agents by procedures acceptable to APHIS. Approved MSVs will be included in the OOP on file at the CVB.

Master Cell Stock (MCS) must be tested by procedures acceptable to APHIS. Approved MCSs will be included in the OOP on file at the CVB.

F.2.3 Sterility Testing MSVs and MCSs must be tested by the contractor for extraneous viruses, bacteria (including Mycoplasmas), and fungi according to procedures acceptable to APHIS and described in OOPs on file at

CVB.

F.2.4 Inactivation Studies Validation of the inactivation procedure must be conducted in accordance with Veterinary Services Memorandum (VSM) 800.117, Guidance for Inactivation, or otherwise acceptable to APHIS. Inactivation kinetics study data are presented to CVB and NAFMDVB for approval. VSM 800.117 may be viewed at:

https://www.aphis.usda.gov/animal_health/vet_biologics/publications/memo_800_117.pdf https://www.aphis.usda.gov/animal_health/vet_biologics/publications/memo_800_117.pdf

F.2.5 Innocuity Testing The results of inactivation (i.e. innocuity) testing to confirm complete inactivation must be reported on APHIS Form 2008 for each FFM (i.e. VAC) serial. In FFM OOP, sections IV or V, describe the inactivation confirmation test procedure, the test validity criteria, and the criteria for satisfactory result.

Contractors must submit APHIS Forms 2008 for each serial/lot/batch of VAC (i.e. FFM) accepted by the NAFMDVB. If the NAFMDVB orders FUP then the serial/lot/batch number for each NAFMDVB owned and tested VAC that is used to manufacture FUP must be included on the APHIS Form 2008 submitted for the FUP. All FFM OOP section V results must be reported to CVB and NAFMDVB on APHIS Form 2008;

virus inactivation kinetics and innocuity test results must be reported to NAFMDVB.

F.2.6 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 shall be sufficient for the manufacture of the number of deliverable 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, provided to the NAFMDVB, detailing the 146S content of the VACs in samples tubes stored with the VACs.

F.2.7 In Vivo/In Vitro Potency Testing The contractor will perform an in vivo/in vitro potency test by vaccinating at least five head of cattle with a pilot serial (AKA small batch or pilot/trial blend vaccine) 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, and the procedure must be described in their OOP. 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 pilot serial prepared from the accessory VAC samples in four (4) head of cattle performing VNTs using serum taken 21 days post-vaccination for each group. These 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 to compare with the VNT potency results.

F.2.8 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 virus inactivation and innocuity test results, as well as other manufacturer’s tests performed for the VAC release, shall 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, shall be reported to the NAFMDVB within two months of the completion of the tests.

F.3 Section III: Testing Completed by the North American Foot and Mouth Disease Vaccine Bank (NAFMDVB)

F.3.1 Extraneous Agents testing The NAFMDVB will perform testing for the detection of extraneous agents in Master Seed Virus (MSV) samples provided by the manufacturer according to 9 CFR § 113.55, § 9 CFR 113.46, 9 CFR § 113.47 and other procedures deemed appropriate by APHIS.

F.3.2 Nucleotide Sequencing The NAFMDVB may choose to characterize the vaccine virus master seed, the challenge virus, the VAC, and pilot serial 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 without the consent of the Contractor. The sequence information generated from the MSV 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 pilot serial Vaccine

F.3.3 Innocuity Testing Tests for inactivation (innocuity test) shall be conducted on the VAC by NAFMDVB 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, or other susceptible 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 sub-culture. Observing CPE for any reason designates a failure of innocuity testing.

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

An aliquot of VAC

F.3.4 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

F.3.5 Sterility Testing The NAFMDVB may perform identity and purity tests on master-seed viruses challenge viruses and VAC samples and sterility tests on pilot serials.

F.3.6 Quantification of 146S Antigen Content of the VAC 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 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 shall be stable for the minimum guarantee period and any variance in testing results shall be within expected tolerance limits. If however during a minimum guarantee 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

F.3.7 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 pilot serial 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 minimum guarantee storage period.

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

are at least 6 months of age and weigh a minimum of 350-450 pounds;

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 cattle that will be sham vaccinated to serve as control animals. The amount of antigen each group of 5 cattle 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 cattle will receive 2.0 ml of vaccine;

5 cattle will receive 0.5 ml of vaccine;

5 cattle will receive 0.125 ml of vaccine;

and the 2 sham-vaccinated control cattle 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 BID50 (50% bovine infectious doses, 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 pilot serial. 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 pilot serial is calculated.

To qualify as a successful test, the vaccine shall 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 within 12 months. If a VAC fails the PD50 test, upon request by the NAFMDVB, the manufacturer must replace the VAC or its antigenic equivalent at no cost to USDA within 12 months, and the manufacturer must reimburse the government the cost of the failed PD50 test in the amount of $70,000. If the NAFMDVB does not purchase subsequent VAC, these credit(s) must be reimbursed to USDA in the form of monetary compensation.

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. In the case of an unsatisfactory results of the test and each time there is a question of quality of the VAC, USDA will notify the manufacturer of the test results and provide test data to the manufacturer no more than 30 days after the failure of the test.

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

An aliquot of Challenge Virus

A Trial Blend Vaccine

F.3.8 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 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 pilot serial prior to challenge, the ELISA test will be repeated. If NSP antibody presence is confirmed, 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, USDA will notify the manufacturer of the results of the test and provide test data. Upon request by the NAFMDVB, the contractor shall replace the VAC at no cost to USDA within 12 months.

F.3.9 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 in each control animal, 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 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

F.4 Section IV: Samples provided by Manufacturer to NAFMDVB F.4.1 VAC and Sample identification Each cryopreservation vessel shall be clearly identified with a NAFMDVB label; and labels affixed to the individual VAC-containers shall bear the following identifying information:

the serotype/subtype of virus;

the serial number of the batch;

volume of antigen;

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.

F.4.2 Pilot Serial The following information regarding the formulation of a pilot serial 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 pilot serial label shall contain:

batch/serial number;

the dose volume; the valence of the vaccine;

the true name of the product, including serotype(s)/subtype(s) of the vaccine strain(s);

the date of manufacture;

the date of expiration;

The Storage temperature 2°C-8°C the total volume in the vial.

Sample Requirements Sample

Type Sample Volume

Number Samples

Sample Characteristic and Anticipated Delivery

Master Seed Virus

1.0. ml 10 Titer of at least 100,000 CCID50/ml Within 6 months of VAC delivery

Antiserum 1.0 ml 15 Capacity to neutralize a titer of at least 100,000 CCID50/ml Within 6 months of VAC delivery

Challenge Virus*

1.0 ml 10 Each vial must contain a minimum of 106 BID50/ml; challenge virus must have a different passage history from the Master

Seed Virus and VAC; and the challenge virus must retain wild-type virulence

Within 6 months of VAC delivery VAC 8.0 ml 20 VAC used for 146S determination, identity, safety, and innocuity Delivered annually, based on VAC delivery date

Pilot serial 300 doses or 600 ml

10 Each pilot serial must contain 300 doses Delivery will occur by request

*This virus will be propagated by the NAFMDVB in tissue culture for use in virus neutralization tests.

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

F.4.3 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.

F.4.4 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 shall 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.

F.4.5 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.

F.4.6 VAC Samples for 146S A total of 10 vials x 5.0 ml each shall 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 shall 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 shall be kept as retention samples or in case the tests need to be repeated.

F.4.7 VAC Samples for Pilot Serial Vaccine, Safety Test, and Innocuity Test Twenty antigen samples of each VAC, each sample containing a volume adequate to prepare a pilot serial 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.

F.4.8 Pilot Serials The manufacturer will be required to prepare up to 5 pilot serials over the guaranteed period for vaccine efficacy studies. Each pilot serial will be for 300 bovine doses (600 ml). Although small scale, the pilot serials shall use the same formula, same ingredients and sources, and similar production methods and equipment as commercial scale production.

The Contractor will…