Pt. 114 9 CFR Ch. I (1–1–21 Edition)

perform a neutralization study, or an- SOURCE: 39 FR 16869, May 10, 1974, unless other type of study acceptable to otherwise noted. APHIS, to demonstrate functionality of product antibody. § 114.1 Applicability. (c) Potency. Bulk or final container Unless exempted by regulation or samples of completed product from otherwise authorized by the Adminis- each serial shall be tested for IgG con- trator, all biological products prepared, tent as provided in this paragraph. sold, bartered or exchanged, shipped or Samples of the test serial and of an IgG delivered for shipment in or from the Reference Product established in ac- United States, the District of Colum- cordance with paragraph (a) of this sec- bia, any Territory of the United States, tion shall be concurrently tested for or any place under the jurisdiction of IgG content by the RID method re- the United States shall be prepared in ferred to in paragraph (a)(5) of this sec- accordance with the regulations in this tion. Five IgG measurements shall be part. The licensee or permittee shall made on each. If the IgG level per dose adopt and enforce all necessary meas- of the test serial does not meet or ex- ures and shall comply with all direc- ceed that of the reference, one com- tions the Administrator prescribes for plete retest, involving five IgG meas- carrying out such regulations. urements on both the reference and two samples of the test serial, may be [52 FR 11026, Apr. 7, 1987, as amended at 56 conducted. If, upon retest, the average FR 66784, Dec. 26, 1991] IgG level per dose of the two samples of the test serial does not meet or exceed § 114.2 Products not prepared under li- that of the reference, or if a retest is cense. not conducted, the serial is unsatisfac- (a) When an establishment license is tory. issued, if biological products which [61 FR 51777, Oct. 4, 1996] were not prepared in compliance with the regulations are in the establish- PART 114— REQUIRE- ment, such products shall not be MENTS FOR BIOLOGICAL PROD- shipped or delivered for shipment or otherwise dealt with as having been UCTS prepared under such regulations. Sec. (b) Except as provided in 9 CFR part 114.1 Applicability. 103, a biological product shall not be 114.2 Products not prepared under license. prepared in a licensed establishment 114.3 Separation of establishments. unless the person to whom the estab- 114.4 Identification of biological products. lishment license is issued holds an un- 114.5 Micro-organisms used as seed. expired, unsuspended, and unrevoked 114.6 Mixing biological products. product license issued by the Adminis- 114.7 Personnel at licensed establishments. trator to prepare such biological prod- 114.8 Outline of Production required. 114.9 Outline of Production guidelines. uct, or unless the products prepared 114.10 Antibiotics as preservatives. are subject to the provisions of § 107.2 114.11 Storage and handling. of this subchapter. 114.12 Expiration date required for a serial. (c) A biological product produced in a 114.13 Determination of the dating period of USDA-licensed establishment shall be a product. produced under a U.S. Veterinary Bio- 114.14 Extension of expiration date for a se- logical Product License or a license rial or subserial. 114.15 Disposal of unsatisfactory products granted by a State under § 107.2 (re- and byproducts. ferred to as a State biological product 114.16 Producing subsidiaries. license and the products prepared pur- 114.17 Rebottling of biological products. suant thereto as State-licensed biologi- 114.18 Reprocessing of biological products. cal products, including autogenous bio- AUTHORITY: 21 U.S.C. 151–159; 7 CFR 2.22, logics), but not under both a U.S. Vet- 2.80, and 371.4. erinary Biological Product License and

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a State biological product license. Be- that holds both a State and a U.S. Vet- fore a U.S. Veterinary Biological Prod- erinary Biological Products License for uct License (including a conditional li- autogenous biologics, the isolate shall cense) is issued, the licensee shall re- be designated by the licensee for use in linquish its State license for that prod- the production of an autogenous bio- uct: Provided, That autogenous bio- logical product under either the State logics shall not be subject to this pro- product license, or the U.S. Veterinary vision when they are prepared in ac- Biological Product License: Provided, cordance with the provisions of para- That the isolate meets the require- graph (c)(5) of this section. ments of the respective regulatory au- (1) State-licensed biological products thority for an autogenous biologic. If, (including autogenous biologics) shall after producing the product pursuant only be distributed or shipped intra- to one license, the licensee elects to state, must not bear a U.S. Veterinary produce an autogenous biologic from Biologics Establishment License Num- the same isolate under provisions of ber, and must not otherwise be rep- the other license, the licensee may do resented in any manner as having met so only with the approval of the other the requirements for a U.S. Veterinary licensing authority. Biological Product license. Labeling of (ii) The true name of a State-licensed State- and USDA-licensed biological autogenous biologic shall specify the products produced in the same estab- State of licensure: e.g. lishment must be distinctly different ‘‘ lllll Autogenous Bacterin’’ in color and design. (2) All biological products in USDA- (State) licensed establishments, whether li- or lllll Autogenous Vaccine’’. censed by USDA or by the State, shall (State) be prepared only in locations indicated in legends filed in accordance with 9 [39 FR 16869, May 10, 1974, as amended at 60 CFR part 108. A description of each FR 48021, Sept. 21, 1995] State-licensed product must be filed § 114.3 Separation of establishments. with the Animal and Plant Health In- spection Service as part of the blue- (a) Each licensed establishment shall print legends and must be sufficient for be separate and distinct from any other Animal and Plant Health Inspection establishment in which a biological Service to determine any risk to the product is prepared. production of other products in the li- (b) No biological products authorized censed establishment and to determine to be prepared in a licensed establish- that adequate procedures are followed ment shall be prepared in whole or in to prevent contamination during pro- part by another licensed establishment duction. except as provided in paragraphs (c) (3) Records in such establishments and (d) of this section. must be maintained in accordance with (c) When a partially prepared biologi- §§ 116.1 and 116.2 of this subchapter and cal product cannot be completed at a shall include all products licensed by licensed establishment due to failure of the State or USDA. essential equipment, the Administrator (4) Reports prescribed in § 116.5 of this may authorize the use of similar equip- subchapter for USDA-licensed estab- ment at another licensed establish- lishments shall be submitted for all ment: Provided, That, such authoriza- veterinary biological products in the tion shall be limited to the duration of establishment. the emergency and to the phase of pro- (5) Under the following conditions, an duction affected by the equipment fail- autogenous biologic may be produced ure. in a USDA-licensed establishment (d) Partially prepared products or se- under either a State or U.S. Veterinary rials of completed products for further Biological Product License: manufacture may be moved from one (i) When a culture of microorga- licensed establishment to another li- nisms, isolated from a herd in a State, censed establishment, imported under is received at a USDA-licensed estab- the provisions of § 104.5, or moved from lishment that is in the same State but a licensed establishment for purpose of

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being exported under conditions pre- identification of the serial, shall be ap- scribed in an Outline of Production plied to identify it with the records of filed with Animal and Plant Health In- preparation and labeling. spection Service. Licensed products or products imported for distribution and § 114.7 Personnel at licensed establish- sale may be prepared and recommended ments. for final use, for further (a) Each licensee shall designate a purposes, or both. All serials shall be person(s) to make all official contacts subject to the requirements for testing with Animal and Plant Health Inspec- and release specified in § 113.5 or § 113.10 tion Service on matters pertaining to and to the requirements for identifica- the preparation of biological products tion specified in § 114.4. under the Virus-Serum-Toxin Act. The licensee shall file three copies of bio- [39 FR 16869, May 10, 1974, as amended at 40 graphical summary with Animal and FR 46093, Oct. 6, 1975; 49 FR 45846, Nov. 21, Plant Health Inspection Service for 1984; 56 FR 66784, Dec. 26, 1991] such designated person and for each § 114.4 Identification of biological person responsible for any phase of products. preparation of a biological product. (b) All personnel employed in the Suitable tags or labels of a distinct preparation of biological products at a design shall be used for identifying all licensed establishment shall be com- ingredients used in the preparation of petent in good laboratory techniques biological products, all component through or training, or both, parts to be combined to form a biologi- so as to consistently prepare high qual- cal product, all biological products ity products. while in the course of preparation and (c) All biological products prepared all completed biological products held at licensed establishments shall be pre- in storage at licensed establishments: pared and handled with due sanitary Provided, That, if such ingredients, precautions. Good sanitary measures components, or biological products are shall be practiced at all times by all not so identified, they shall be disposed personnel involved in such preparation of as provided in § 114.15. and handling of biological products. (1) The clothing worn by persons § 114.5 Micro-organisms used as seed. while preparing biological products Micro-organisms used in the prepara- shall be clean. All persons, imme- tion of biological products at licensed diately before entering laboratory establishments shall be free from the rooms of a licensed establishment, causative agents of other diseases or shall change their outer clothing or ef- conditions. A complete record of such fectively cover the same with gowns or micro-organisms shall be kept cur- other satisfactory clean garments. rently correct and a list submitted to (2) Unsanitary practices such as, but Animal and Plant Health Inspection not limited to, eating, smoking, or ex- Service upon request of the Adminis- pectorating on the floors or otherwise trator. creating a nuisance in any room, com- (Approved by the Office of Management and partment, or place in which biological Budget under control number 0579–0059) products are prepared, handled, or stored at licensed establishments are [39 FR 16869, May 10, 1974, as amended at 48 prohibited. FR 57473, Dec. 30, 1983; 56 FR 66784, Dec. 26, 1991] (Approved by the Office of Management and Budget under control number 0579–0013) § 114.6 Mixing biological products. [39 FR 16869, May 10, 1974, as amended at 48 Each biological product, when in liq- FR 57473, Dec. 30, 1983; 56 FR 66784, Dec. 26, uid form, shall be mixed thoroughly in 1991] a single container. During bottling op- erations, the product shall be con- § 114.8 Outline of Production required. stantly mixed sufficient to maintain An Outline of Production shall be on physical uniformity of the entire fill. A file with Animal and Plant Health In- serial number, with any other mark- spection Service for each licensed bio- ings that may be necessary for ready logical product or for each biological

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product authorized to be imported into (2) The Outline of Production to be the United States for Distribution and kept in the active file shall be des- Sale. Preparation of a biological prod- ignated. If more than one has been filed uct in a licensed establishment shall be for a product, only the Outline of Pro- in accordance with the Outline of Pro- duction currently being used shall be duction for such product filed with included. Animal and Plant Health Inspection (f) The Administrator may, upon the Service as provided in this section, but basis of information not available to subject to changes as may be required him at the time the current Outline of under § 114.8(f). Production for a biological product was (a) The Outline of Production shall filed, object to the methods or proce- be prepared as prescribed in § 114.9 and dures being used in the preparation of submitted to Animal and Plant Health such biological product and notify the Inspection Service for filing. When ob- licensee to modify the filed Outline of jectionable features, if any, are cor- Production to eliminate such objec- rected and no further exceptions are tions. If the licensee does not comply taken by Animal and Plant Health In- with the notice, the Administrator spection Service to an Outline of Pro- may, after affording opportunity for a duction for a biological product, such hearing to the licensee, suspend the Outline of Production shall be ap- product license for the biological prod- proved for filing. uct involved; in which case, the li- (b) Each page shall be stamped as censee shall not prepare such product filed on the date such action was taken until subsequent notice of withdrawal in the bottom right hand corner. Al- of the suspension is given to the li- though the filed outline may be re- censee. ferred to as an approved outline, ap- (Approved by the Office of Management and proval for filing constitutes no en- Budget under control number 0579–0013) dorsement by Animal and Plant Health [39 FR 16869, May 10, 1974, as amended at 48 Inspection Service of such biological FR 57473, Dec. 30, 1983; 56 FR 66784, Dec. 26, product or the methods and procedures 1991; 75 FR 20773, Apr. 21, 2010] used to prepare such biological prod- uct. § 114.9 Outline of Production guide- (c) One copy of the Outline of Produc- lines. tion shall be retained by the Animal Each Outline of Production shall be and Plant Health Inspection Service prepared in accordance with the appli- and one copy returned to the licensee cable directions provided in this sec- or permittee. tion. (d) Each licensee shall review each (a) General requirements. (1) All copies Outline of Production for accuracy and of each Outline of Production or spe- sufficiency not less frequently than cial outline or revised pages of either once a year. Revisions necessary to shall be prepared on heavy paper (8.5″ × bring an Outline of Production into 11″) of a type receptive to permanent compliance with the regulations shall stamp ink. be submitted to Animal and Plant (2) The name of the biological prod- Health Inspection Service. uct (or component), the establishment (e) When a list of licensed products to license number, and the date prepared be continued in production at a li- shall appear on a front cover page and censed establishment is requested by each page of the Outline of Production the Administrator in accordance with or special outline. The name of the li- § 102.5(d) of this subchapter, the li- censee (or foreign manufacturer) shall censee shall supplement the list with appear on the front cover page. information for each product as fol- (3) The pages shall be numbered in lows: the upper center. At least 11⁄2 inch mar- (1) The Outline of Production cur- gin shall be left at the top of the first rently being used shall be identified as page and a 2 inch margin at the bottom to the date when last revised and filed of each page for the Animal and Plant with Animal and Plant Health Inspec- Health Inspection Service stamp. tion Service and the date of the last re- (4) Amended pages shall be numbered view made by the licensee. the same as those being superseded.

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They shall bear the date prepared and 4. Proportions of each micro-organism and refer to the date on the pages being su- strain. perseded. If one replacement page su- B. Identification methods used for each micro-organism and frequency with which persedes more than one page, the new these methods are applied. page shall indicate same, but if several C. Virulence and purity of cultures or anti- replacement pages are added to super- gen and the determination and maintenance sede one page, the page number fol- thereof. Range of subcultures or passages to lowed by letters shall be used. be used in production. (5) The last page of both copies of ei- D. Attenuation, if any, before use for pro- ther a new or a completely rewritten duction purposes. E. Character, size, and shape of containers Outline of Production and each page used for growing micro-organisms. revised separately shall be signed in F. Media used for stock, seed, and antigen the lower left corner by the authorized cultures (composition and reaction of). May representative of the licensee (or for- refer to a special outline by number. eign producer). Stamped or facsimile G. Preparation of the antigen or toxin and signatures are not acceptable. toxoid. Complete and full description of each (6) A summary of changes shall ap- step and its manner of accomplishment and number these steps in sequence. Include all pear on an attached page and refer to tests for each antigen, and the specifications each page, paragraph, or subparagraph for character, identity, virulence, concentra- being changed. tion, and standardization. (7) Transmittal forms shall be used III. Immunization of animals. A. Outline for the original and subsequent revi- fully with special attention given to the fol- sions. Transmittal forms are available lowing: on the Internet at (http:// 1. Character and dose of the antigen. 2. Method and frequency of injections. www.aphis.usda.gov/ animallhealth/ 3. Time required for immunization or vetlbiologics/ vblforms.shtml). hyperimmunization. (b) Special outline. An outline describ- 4. Preliminary bleedings and tests, if any, ing the preparation of a component of to ascertain of serum. a biological product or an operation 5. All other similar matters, including performed in the preparation of a bio- treatments between bleedings. logical product may be required if such B. Period of time elapsing between last in- jection and first bleeding; and between bleed- special outline could be referred to in ings. Outlines of Production to eliminate C. Technique of bleeding operations; vol- repetition. Each special outline shall ume of blood collected at each bleeding; and be identified by number and shall not period of rest. be used until accepted and filed by Ani- IV. Preparation of the biological product. A. mal and Plant Health Inspection Serv- Describe fully and show each step of prepara- ice. tion from the first bleeding to the comple- tion of the preserved product in bulk con- (c) Outline of Production for anti- tainers prior to filling of final containers. serum, antitoxin, and normal serum B. Composition of the preservative and shall be written according to the fol- proportions used. Indicate at which step of lowing: production, and the method used in adding the preservative. OUTLINE GUIDE FOR PRODUCTION OF ANTI- C. Agglutination and complement-fixation SERUM AND ANTITOXIN AND NORMAL SERUM titers and the methods of their determina- License No. Name of Product Date tions. D. Disposition of unsatisfactory biological I. Serum animals. A. Species, conditions, products and infective materials not used in age, and general health. production. B. Examination, preparation, care, quar- E. Assembly of units to make a serial; vol- antine, tests, and treatment of animals be- ume of the average serial; and the volume of fore injections are started. the maximum serial. C. Holding, handling, exercising, and moni- V. Testing. Indicate the stages in the prepa- toring the condition of animals after injec- ration of the biological product at which tions are started. samples are collected. Refer to all applicable II. Antigens. A. Composition and character Standard Requirements. Outline all addi- of the antigen. tional tests in detail and state minimum re- 1. Micro-organisms. quirements for each satisfactory test. 2. Source and date of accession of each A. Purity. micro-organism. B. Safety. 3. Strains. C. Potency.

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D. Other tests. removal of micro-organisms or tissues for VI. Post preparatory steps. production purposes. A. Form and size of final containers in B. Minimum and maximum period of time which the product is to be distributed. elapsing from time of inoculation until har- B. Methods and techniques of filling final vest. containers. Volume of fill for each size final C. Technique of harvesting micro-orga- container. nisms or tissues (specify) for production pur- C. Collection, storage, and submission of poses. representative samples. Indicate at which D. Specifications for acceptable harvest steps in the production these samples are material. taken. E. Handling of discarded material not used D. Expiration date based on the earliest in production. date of harvest and the date of the last satis- F. Include any additional pertinent infor- potency test. mation. E. Use, dosage, and route of administration IV. Preparation of the product. Describe for each animal species for which it is rec- fully and show each step of preparation from ommended. harvest of antigen containing tissues or pro- F. Include any additional pertinent infor- duction cultures to the completion of the mation. finished product in final containers. In de- (d) Outline of Production for vaccines, scribing the preparation of the product, em- phasize the following: bacterins, antigens, and toxoids shall be A. Method of inactivation, attenuation, or written according to the following: detoxification. B. Composition of preservative, adjuvant OUTLINE GUIDE FOR VACCINES, BACTERINS, or stabilizer, and proportions used stated in ANTIGENS, AND TOXOIDS such a manner that the concentration can be License No. Name of Product Date calculated; stage and method of addition. I. Composition, etc., of the product. A. Micro- C. Method and degree of concentration. organisms used. Give the isolation and pas- D. If product is standardized to give con- sage history. centration of antigen, show procedures and B. Source and date of accession of each calculations. micro-organism. E. 1. Assembly of units to make a serial (il- C. Strains. lustrate by example). D. Proportions of each strain. 2. Volume of average serial. II. Cultures. A. Brief description of methods 3. Volume of maximum serial. of identifying each micro-organism and the 4. Any other pertinent information. frequency with which these methods are ap- F. Volume of fill for each size vial. Type of plied. vial if unusual. B. Virulence and purity of cultures and the G. Method and technique of filling and determination and maintenance thereof. sealing of final containers. Range of subcultures or passages to be used H. Desiccation, including moisture control. in production. Give maximum percent moisture. C. Composition and reaction of media used I. Amount of antigenic material per dose for seed and production cultures. Include the or doses in final container. source of eggs, tissue, or cell cultures, and V. Testing. Indicate the stages in the prepa- the tests to determine that eggs, tissues, and ration of the biological product at which the cells are free of contamination. samples are collected. Refer to all applicable D. Character, size, and shape of containers Standard Requirements. Outline all addi- used for growing cultures. tional tests in detail and state the minimum E. Storage conditions of seed cultures. requirement for each satisfactory test. F. Methods of preparing suspensions for A. Purity. seeding or inoculation. B. Safety. G. Technique of inoculating (1) seed media; C. Potency. (2) production media. Titer or concentration D. Moisture, if desiccated. of inoculum, and the volume of medium for E. Any other tests. each size and type of culture container. VI. Post preparatory steps. A. Form and size H. Period of time and conditions for incu- of final containers in which the product is to bation and degree of temperature used for be distributed. each micro-organism or group of micro-orga- B. Collection, storage, and submission of nisms. representative samples. Indicate at which I. Character and amount of growth; obser- steps in the production these samples are vation as to contamination of growth. taken. J. Method of attenuation, if any, before C. Expiration date based on the earliest used for production purposes. date of harvest and the date of the last satis- III. Harvest. A. Handling and preparation of factory potency test. If applicable, give the cultures and media (including eggs) before date of lyophilization.

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D. Use, dosage, and route of administration OUTLINE GUIDE FOR DIAGNOSTIC TEST KITS for each animal species for which the bio- License No. Name of product Date logical product is recommended. (e) Outlines of Production for aller- Introduction genic extracts shall be written accord- Provide a brief description of the kit as fol- ing to the following: lows: 1. Principle of the test (ELISA, latex ag- OUTLINE GUIDE FOR ALLERGENIC EXTRACTS glutination, etc.). License No. Name of Product Date 2. Antigen or antibody detection test. 3. Sample(s) used for testing (serum, whole I. Composition of the product. A. Source and blood, tears, etc.). type of raw material. 4. List reagents, references, and equipment B. Weight/volume concentration. included. II. Preparation of the product. A. Describe 5. Identify materials obtained under split fully and show each step of preparation to manufacturing agreements. the completion of the finished product in 6. General description of test interpreta- true containers. In describing the prepara- tions and their limitations, including fol- tion of the product, emphasize the following: lowup tests. 1. Method of extraction. 2. Composition of preservative, adjuvant or I. Antibody Components stabilizer, and proportions used; stage and method of addition. A. Production of polyclonal antibody com- 3. Method and degree of concentration. ponents. 4. Standardization of the product. 1. If purchased, list suppliers, criteria for 5. (a) Assembly of units to make a serial. acceptability, and describe all tests per- (b) Volume of average serial. formed after receipt to determine that speci- (c) Maximum serial. fications have been met. 6. Volume of fill for each size vial. 2. If produced in-house, describe the spe- 7. Method and technique of filling and seal- cies, age, weight, conditions, and general ing of final containers. health of all animals used in antiserum pro- 8. Amount material per dose or doses in duction. final container. a. Preinjection considerations: III. Testing. Indicate the stages in the prep- Describe the examination, preparation, aration of the biological product at which care, quarantine procedures, and treatments the samples are collected. Refer to all appli- administered before immunization(s). De- cable Standard Requirements. Outline all ad- scribe all tests used to determine suitability ditional tests in detail and state the min- for use. Describe the preparation of any imum requirement for each satisfactory test. standard negative serum(s) collected prior to A. Purity. immunization. B. Safety. b. Immunization of animals. C. Potency. i. Describe the character and dose of the D. Any other tests. antigen; if adjuvant is used provide details E. Include any additional pertinent infor- on its preparation. If commercial product is mation. used include its true name as shown on the IV. Post preparatory steps. A. Form and size label, the manufacturer, serial number, and of final containers in which the product is to expiration date. be distributed. ii. Describe the method and schedule for B. Collection, storage, and submission of immunizations. representative samples. Indicate at which iii. Describe the method for harvesting and steps in the production these samples are evaluating the immunization product, in- taken. cluding tests for acceptability. C. Expiration date based on the earliest iv. Provide number and intervals between date of harvest and the date of the last satis- harvests, volume obtained, and any other factory potency test. pertinent information. D. Use, dosage, and route of administration B. Production of Monoclonal Antibody for each animal species for which the bio- Components. logical product is recommended. 1. Hybridoma components: (f) Outlines of Production for diag- a. If hybridoma components are purchased, nostic test kits based on antigen-anti- list suppliers and criteria for acceptability; body reactions, and other diagnostics if tests are performed after receipt, describe fully. whose production methods are ame- b. If hybridomas are prepared inhouse, nable to description as described herein identify the antigen(s) used, describe the im- shall be written according to the fol- munization scheme, and the species of ani- lowing requirements: mal used.

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c. Identify the tissue of origin, and the pro- B. Describe the preparation and standard- cedures for harvesting, isolating, and identi- ization of the conjugate(s). If purchased, list fying the immune cells. suppliers and criteria for acceptance. d. Describe the source, identity, and the C. Describe the preparation and standard- product secreted (light or heavy chain) by ization of the substrate(s). If purchased, list the parent Myeloma Cell Line. suppliers and criteria for acceptance. e. Summarize cloning and recloning proce- D. Identify buffers, diluents, and other re- dures, including clone characterization and agents included in the kit. The preparation propagation, if appropriate. of these components may be described in this f. If appropriate, describe procedures for section or in filed Special Outlines. establishing and maintaining seed lots. g. Describe any other pertinent tests or IV. Preparation of the Product procedures performed on the hybridoma cell Fully describe methods used to standardize line. antigens, reference standards, positive con- 2. Antibody production: trol serum, negative control serum, and a. Describe the production method. If pro- standard reagents from production/purchase duced in cell culture, animal serum additives to completion of finished product in final must conform to 9 CFR 113.53. If produced in containers, including the following: animals, describe fully including husbandry 1. Composition and quantity of preserva- practices and passage procedures. tive in each. b. Provide the criteria for acceptable monoclonal antibody, including tests for pu- 2. Method of filling, plating, or attaching rity. the antigen or antibody component to a solid phase. c. Describe all tests or other methods used to ensure uniformity between production 3. Minimum and maximum acceptable fill lots of monoclonal antibody. Include all re- volumes for each final container of reagent action conditions, equipment used, and reac- included in the kit. tivity of the component. 4. The disposition of unsatisfactory mate- d. Describe all characterization procedures rial. and include the expected reactivity of all ref- erence monoclonal antibodies. V. Testing Refer to all applicable standard require- II. Antigen Preparation ments. A. Identify the microorganism(s) or anti- A. Purity. gen being used. If previously approved Mas- Describe all tests of the kit for purity or ter Seed virus, bacteria, or antigen derived specify the exemption as provided in 9 CFR therefrom is used, provide pertinent infor- 113.4. mation on the testing performed, and details B. Safety. of dates of United States Department of Ag- In vitro products are exempt from safety riculture confirmatory tests and approval, as tests. appropriate. C. Potency. B. Describe all propagation steps, includ- Provide details of tests used to determine ing identification of cell cultures, media in- gredients, cell culture conditions, and har- the relative reactivity of the kit including vest methods. For antigen produced in eggs, minimum requirements for a satisfactory give the egg source, age, and route of inocu- test. Reference standards and control serum lation. If cell lines are being used, give dates used for this purpose should be identified by of testing and approval as specified in 9 CFR unique codes or lot numbers. 113.52. VI. Postpreparatory Steps C. Describe procedures used for extracting and characterizing the antigen. A. Describe the form and size of final con- D. Describe the method used to standardize tainers of each reagent/component included the antigen. in the kit. E. If the antigen is purchased, identify the B. Describe the collection, storage, and supplier and describe the criteria for accept- submission of representative samples. Refer able material, including all tests performed to 9 CFR 113.3(b)(7). by the producer and/or the recipient to deter- C. Specify the expiration date. Refer to 9 mine acceptability. CFR 114.13. III. Preparation of Standard Reagents D. Provide details of recommendations for use, including all limitations, qualifications, A. Describe the positive and negative con- and interpretation of results. trols included in the kit. If purchased, list suppliers and criteria for acceptance.

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E. Submit confidentiality statement iden- combination of penicillin and strepto- tifying specific parts of the outline con- mycin, or with a combination of poly- taining information, the release of which myxin B and neomycin. would cause harm to the submitter. (3) The maximum amount of each an- (Approved by the Office of Management and tibiotic in a combination shall be the Budget under control number 0579–0013) amount prescribed for such antibiotic [39 FR 16869, May 10, 1974, as amended at 48 in paragraph (b) of this section. FR 57473, Dec. 30, 1983; 56 FR 20124, May 2, (d) Antibiotics used in virus seed 1991; 56 FR 66784, Dec. 26, 1991; 75 FR 20773, Apr. 21, 2010] stock purification are not restricted as to kind or amounts provided carryover § 114.10 Antibiotics as preservatives. into the final product is controlled and Antibiotics are authorized for use as specified in outlines of production. preservatives for biological products if [39 FR 16869, May 10, 1974, as amended at 56 used within the limitations as to kinds FR 66784, Dec. 26, 1991] and amounts prescribed in this section. (a) When an antibiotic or combina- § 114.11 Storage and handling. tion of antibiotics, with or without a Biological products at licensed estab- fungistat is to be used in the prepara- lishments must be protected at all tion of a biological product, the kind(s) times against improper storage and and amount(s) of each shall be speci- fied in the outline for such product in handling. Completed product must be ° such a way that the concentration in kept under refrigeration at 35 to 46 F ° the final product may be calculated. (2 to 8 C), unless the inherent nature Except as may be approved by the Ad- of the product makes storage at dif- ministrator, only those individual anti- ferent temperatures advisable, in biotics or combinations of antibiotics which case, the proper storage tem- listed in paragraphs (b) and (c) of this perature must be specified in the filed section shall be used. Outline of Production. All biological (b) Permitted individual antibiotics: products to be shipped or delivered (1) The antibiotic level of a specified must be securely packed. individual antibiotic in one ml. of a bi- [81 FR 59436, Aug. 30, 2016] ological product, when prepared as rec- ommended for use, shall not exceed the § 114.12 Expiration date required for a amounts listed in this paragraph: Pro- serial. vided, That in the case a desiccated bio- logical product is to be used with an in- Unless otherwise provided for in a definite quantity of water or other Standard Requirement or filed Outline menstruum, the determination shall be of Production, each serial or subserial based on 30 ml. per 1,000 dose vial or of a biological product prepared in a li- equivalent. censed establishment shall be given an (2) Except as prescribed in paragraph expiration date according to the dating (c) of this section, only one antibiotic period of the product when computed shall be used as a preservative in a bio- from a date no later than the date of logical product. The kind and max- the initiation of the first potency test imum amount per ml. of such anti- of the serial or subserial. A licensed bi- biotic shall be restricted to: ological product shall be considered Amphotericin B ...... 2.5 mcg. worthless under the Virus-Serum- Nystatin (Mycostatin) ...... 30.0 units Toxin Act after the expiration date ap- Tetracyclines ...... 30.0 mcg. pearing on the label. Penicillin ...... 30.0 units Streptomycin ...... 30.0 mcg. [83 FR 11143, Mar. 14, 2018] Polymyxin B ...... 30.0 mcg. Neomycin ...... 30.0 mcg. Gentamicin ...... 30.0 mcg. § 114.13 Determination of the dating period of a product. (c) Permitted combinations: (1) Penicillin and streptomycin. The following requirements do not (2) Either amphotericin B or nys- apply to those biological products used tatin, but not both, may be used with for diagnostic purposes. one of the other antibiotics listed in (a) Stability criteria. Stability criteria paragraph (b) of this section, or with a include the specifications for potency

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at release, potency throughout the dat- (1) Newly licensed products whose ing period, and the length of the dating dating has not been confirmed; period. (2) Licensed products with confirmed (b) Stability study requirement. The dating but a major change to the prod- dating period of each fraction of each uct or to the potency test has occurred; product shall be confirmed by con- and ducting a stability study. (3) Licensed products with confirmed (c) Licensure prior to completion of a dating in which a change in one or stability study. Prior to licensure, the more of the stability criteria is re- licensee shall propose a dating period quested. for the product based on preliminary (h) Submitting data. At the comple- information available about the sta- tion of the real-time stability study to bility of each of its fractions. If the confirm or change the dating period, preliminary stability information is the data shall be submitted to Animal acceptable, the product may be li- and Plant Health Inspection Service censed with the provision that the pro- for approval for filing and the approved posed dating period must be confirmed for filing date shall be specified in sec- by conducting a real-time stability tion VI of the filed Outline of Produc- study with a stability-indicating po- tion at the next revision. tency assay that can detect changes (i) Monitoring stability of the product. over time in the potency of the prod- For products licensed subsequent to uct. April 13, 2018, the licensee or permittee (d) Use of stability-indicating assay. shall submit a plan to monitor the sta- Stability studies must be conducted bility of the product and the suit- with a stability-indicating assay, with ability of its dating period that in- the following exceptions: cludes regularly testing selected seri- (1) If the potency test specified in the als for potency during and at the end of filed Outline of Production of a li- dating. censed product is the one stated in the [83 FR 11143, Mar. 14, 2018] regulations, that potency test may be used in place of a stability-indicating § 114.14 Extension of expiration date assay for that fraction. for a serial or subserial. (2) If the initial confirmation of dat- (a) Unless otherwise provided for in a ing study of a product in development filed Outline of Production for the on April 13, 2018 has an approved po- product, the expiration date shall not tency assay, that assay may be used. be extended: (e) Number of serials. At least three (1) If all fractions of the product are production serials of the product shall not evaluated for potency by tests des- be selected for testing in the stability ignated in the filed Outline of Produc- study. tion for such product in accordance (f) Testing sequences—(1) Initial test. with § 113.4(b) of this subchapter. The first test in the sequence shall be (2) For any serial or portion of any as close as practical to the day of fill- serial which has left licensed premises: ing into final containers or the date of Provided, That product which has been final formulation if the potency of the shipped from one licensed premises to product is tested in bulk form. another licensed premises shall be ex- (2) Subsequent testing for in vitro as- empt from this requirement. says. (i) One test every 3 months during (3) For a serial or portion of a serial the first year of storage; if the expiration date has been ex- (ii) One test every 6 months during tended previously, unless otherwise au- the second year of storage; and thorized in accordance with § 114.1. (iii) One test annually thereafter (b) An extension of the expiration throughout the proposed dating period. date may be granted by Animal and (3) Subsequent testing for in vivo as- Plant Health Inspection Service if a re- says. One test at the end of the pro- quest from the licensee is substan- posed dating period. tiated by valid test data which dem- (g) When to conduct a stability study. onstrate the potency of the product Stability studies must be conducted for meets or exceeds the requirements for the following: release. The new expiration date shall

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be calculated from the date the latest (b) The rebottled product shall be satisfactory potency test was initiated. adequately identified by serial number The extension of the expiration date or subserial number, as the case may shall not exceed the maximum dating be. allowed in the filed Outline of Produc- (c) Required purity tests for final tion. container samples of the product shall (1) Serials are approved for redating be conducted on new samples selected under the condition that Animal and from the rebottled product (serial or Plant Health Inspection Service may subserials). Rebottled product found to require the firm to retest the redated be unsatisfactory by such tests shall serial for potency during the extended not be released. dating period and if found unsatisfac- (d) New test samples from each serial tory require it be removed from the or subserial and copies of test reports market by the licensee. (2) [Reserved] of all tests conducted on the rebottled product shall be submitted to Animal [50 FR 24903, June 14, 1985, as amended at 56 and Plant Health Inspection Service. FR 66784, Dec. 26, 1991] (e) The licensee shall not release the § 114.15 Disposal of unsatisfactory rebottled product unless notified by products and byproducts. Animal and Plant Health Inspection All biological products found to be Service that such product is eligible unsatisfactory for marketing, all bio- for release. Production records shall logical products which have become show the results of all tests conducted worthless subsequent to the expiration and shall accurately reflect the actions date, all refuse, other materials taken. deemed unsatisfactory for production [39 FR 16869, May 10, 1974, as amended at 56 purposes, all carcasses (part or whole) FR 66784, Dec. 26, 1991] of production or test animals, and any undesirable byproducts of manufacture § 114.18 Reprocessing of biological shall be disposed of as may be required products. by the Administrator. The Administrator may authorize a [41 FR 44687, Oct. 12, 1976, as amended at 56 licensee to reprocess a serial of com- FR 66784, Dec. 26, 1991] pleted product subject to the condi- tions prescribed in this section. § 114.16 Producing subsidiaries. (a) Reprocessing shall not include A serial or subserial of a biological any method or procedure which would product may be produced jointly by a be deleterious to the product. licensee and one or more subsidiaries, (b) All appropriate tests for purity, or by two or more subsidiaries. The safety, potency, and efficacy for the exact amount of each serial or sub- product shall be conducted on the re- serial credited to each participating processed product. A serial found un- producer shall be determined at the satisfactory by a required test shall time of labeling and packaging and not be released. shall be noted in the records for such serial or subserial. (c) The reprocessed serial shall be identified by a new serial number and [40 FR 46093, Oct. 6, 1975] the records for the serial shall accu- rately reflect the action taken. § 114.17 Rebottling of biological prod- ucts. (d) Test samples of the reprocessed serial and test reports for all tests con- The Administrator may authorize ducted shall be submitted to Animal the rebottling of a completed product and Plant Health Inspection Service. in liquid form subject to the conditions The licensee shall not release the serial prescribed in this section. until notified by Animal and Plant (a) All or part of a serial which has Health Inspection Service that the se- not left the licensed establishment may be aseptically returned to the rial is eligible for release. mixing tank, thoroughly mixed, and re- [50 FR 24904, June 15, 1985, as amended at 56 bottled in new final containers. FR 66784, Dec. 26, 1991]

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