standard; the term "penicillin potency" means the number of such units in a specified quantity of a substance. The term "unit" applied to bacitracin means a bacitracin activity contained in 23.8 migrograms of the bacitracin master standard after it is dried for 3 hours at 60° C. and a pressure of 5 millimeters or less; the term "bacitracin potency" means the number of such units in a specified quantity of a substance.

(m) The term "microgram" applied to streptomycin means the streptomycin activity (potency) contained in 1.38 micrograms of the streptomycin master standard after it is dried for 4 hours at 56° C. and a pressure of 50 microns or less. The term "microgram" applied to dihydrostreptomycin means the dihydrostreptomycin activity (potency) contained in 1.25 micrograms of the dihydrostreptomycin master standard after it is dried for 4 hours at 100° C. and a pressure of 50 microns or less. The term "microgram" applied to chlortetracycline means the chlortetracycline activity (potency) contained in 1.0 microgram of the chlortetracycline master standard. The term "microgram" applied to tetracycline means the tetracycline activity (potency) contained in 1.0 microgram of the tetracycline master standard. The term "microgram" applied to chloramphenicol means the chloramphenicol activity (potency) contained in 1.0 microgram of the chloramphenicol master standard.

(n) The term "penicillin G working standard" means a specific lot of a homogeneous preparation of one or more salts of penicillin G; the term "penicillin O working standard" means a specific lot of a homogeneous preparation of potassium penicillin O; the term "penicillin V working standard" means a specific lot of a homogeneous preparation of penicillin V; the term "streptomycin working standard" means a specific lot of a homogeneous preparation of one or more streptomycin salts; the term "dihydrostreptomycin working standard" means a specific lot of a homogeneous preparation of one or more dihydrostreptomycin salts; the term “chlortetracycline working standard" means a specific lot of a homogeneous preparation of one or more chlortetracycline salts; the term "tetracycline working standard" means a specific lot of a homogeneous preparation of one or more tetracycline salts; the

term "chloramphenicol working standard" means a specific lot of a homogeneous preparation of one or more chloramphenicols; the term "bactracin working standard” means a specific lot of a homogeneous preparation of one or more bacitracins. The potency or purity of each preparation has been deterbined by comparison with its master standard, and each has been designated by the Commissioner as working standards for use in determining the potency or purity of drugs subject to the regulations in this part.

(0) The term "batch" means a specific homogeneous quantity of a drug.

(p) The term "batch mark" means an identifying mark or other identifying device assigned to a batch by the manufacturer or packer thereof.

(q) The term "Commissioner" means the Commissioner of Food and Drugs and any other officer of the Food and Drug Administration whom he may designate to act in his behalf for the purposes of the regulations in this part.

(r) The term "U. S. P." means the official Pharmacopeia of the United States, including supplements thereto. The term "N. F." means the official National Formulary, including supplements thereto.

(s) The term "manufacture" does not include the use of a drug as an ingredient in compounding any prescription issued by a practitioner licensed by law to administer such drug.

(t) All statements, samples, and other information and materials submitted in connection with a request for certification shall be considered to be a part of such request.

(u) The definitions and interpretations of terms contained in section 201 of the Federal Food, Drug, and Cosmetic Act shall be applicable to such terms when used in the regulations in this part.

(v) Except as specifically provided by §§ 146.8 to 146.23, inclusive, no provision of any section in this part shall be construed as exempting any drug from any applicable provision of the act or other regulation thereunder.

(w) The regulations in Parts 141a, 141b, 141c, 141d, and 141e of this chapter prescribing tests and methods of assays shall not be construed as preventing the Commissioner from using any

other test or method of assay in his investigations to determine whether or not:

(1) A request for certification contains any untrue statement of a material fact; or

(2) A certification has been obtained through fraud, or through misrepresentation or concealment of a material fact.

(x) Wherever the potency of an antibiotic drug included in the regulations in this chapter is expressed in terms of weight, such potency shall be equivalent to that contained in the same weight of the master standard of the drug.

§ 146.2 Requests for working standards and certification; information and samples required. (a) A request for certification of a batch shall be addressed to the Commissioner and shall be in a form specified by him. A request from a foreign manufacturer shall be signed by such manufacturer and by an agent of such manufacturer who resides in the United States.

(b) The initial request for certification of a batch of any drug submitted by any person shall be preceded or accompanied by a full statement of the facilities and controls used to maintain the identity, strength, quality, and purity of each batch, including a description of (1) the methods and processes used in the manufacture of the drug; (2) the tests and assays of the drug made during the manufacture of the batch and after it is packaged; and (3) the laboratory facilities used in such controls. Such initial request shall also be preceded or accompanied by the key of the batch marks used by such person and by specimens of all labeling (including specimens of all brochures and other printed matter except readily available medical publications, referred to in such labeling) to be used for such drug. When any change is made in any such facility or control, or in any such key or labeling, such person shall promptly submit to the Commissioner a full statement of such change or, in the case of changed labeling, specimens showing all such changes.

(c) Each sample submitted pursuant to the regulations in this part shall be addressed to the Commissioner. Its package shall be clearly identified as to its contents and shall bear the name and post-office address of the person submitting it.

(d) In addition to the information and samples specifically required to be submitted to the Commissioner by the regulations in this part, the person who requests certification of a batch shall submit such further information and samples as the Commissioner may require for the purpose of investigations to determine whether or not such batch complies with the requirements of § 146.3 for the issuance of a certificate.

(e) Upon the request of any person, stating reasonable grounds therefor, the Commissioner shall furnish such person with a portion of the working standards.

§ 146.3 Certification. (a) If it appears to the Commissioner, after such investigation as he considers necessary, that:

(1) The information (including results of tests and assays) and samples required by or pursuant to the regulations in this part have been submitted, and the request for certification contains no untrue statement of a material fact; and

(2) The batch complies with the regulations in this part and conforms to the applicable standards of identity, strength, quality, and purity prescribed by the regulations in this part;

the Commissioner shall certify that such batch is safe and efficacious for use, subject to such conditions on the effectiveness of certificates as are prescribed by § 146.4, and shall issue to the person who requested it a certificate to that effect.

(b) If the Commissioner determines, after such investigation as he considers to be necessary, that the information submitted pursuant to the regulations in this part, or the batch covered by such request, does not comply with the requirements set forth in paragraph (a) of this section for the issuance of a certificate, the Commissioner shall refuse to certify such batch and shall give notice thereof to the person who requested certification, stating his reasons for refusal.

(c) Compliance of a drug with the standards of identity, strength, quality, and purity prescribed by regulations in this part shall be determined by the tests and methods of assay prescribed for such drug by regulations in Parts 141a to 141e of this chapter.

§ 146.4 Conditions on the effectiveness of certificates. (a) A certificate shall not become effective:

(1) If it is obtained through fraud or through misrepresentation or concealment of a material fact;

(2) With respect to any package unless it complies with the packaging requirements, if any, prescribed by the regulations in this part which were in effect on the date of the certificate;

(3) With respect to any package unless its label and labeling bear all words, statements, and other information required by the regulations in this part; or

(4) With respect to any package of penicillin, streptomycin, dihydrostreptomycin, chlortetracycline, chloramphenicol, or bacitracin, when it is included in a packaged combination with another drug, unless such other drug complies with the requirements of the regulations in this part.

(b) A certificate shall cease to be effective:

(1) With respect to any immediate container after the expiration date, if any, prescribed by the regulations in this part;

(2) With respect to any immediate container when it or its seal (if the regulations in this part require it to be sealed) is broken, or when its label or labeling is altered, mutilated, destroyed, obliterated, or removed in whole or in part, or ceases to conform to any labeling requirement prescribed by the regulations in this part, except that:

(i) If the drug in such container is repacked or used as an ingredient in the manufacture of another drug, and certification of the batch thus made is requested, such certificate shall continue to be effective for a reasonable time to permit certification or destruction of such batch;

(ii) If the drug is in a container packaged for dispensing and is used in compounding a prescription issued by a practitioner licensed by law to administer such drug, such certificate shall continue to be effective for a reasonable time to permit the delivery of the drug compounded on such prescription; or

(iii) If its label or labeling is removed in whole or in part for the purpose of relabeling and supplemental certification of the relabeled drug is requested, as provided by § 146.18.

(3) With respect to any immediate container of penicillin when it is included in the packaged combination penicillin with aluminum hydroxide gel

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or penicillin with a vasoconstrictor, or to any immediate container of bacitracin when it is included in the packaged combination bacitracin with a vasoconstrictor, except that when certification of the batch so included is requested, such certificate shall continue to be effective for a reasonable time to permit certification of such batch which is part of such combination;

(4) With respect to any package when the drug therein fails to meet the standards of identity, strength, quality, and purity which were in effect on the date of the certificate; except that those minor changes which occur before the expiration date and which are normal and unavoidable in good storage and distribution practice shall be disregarded;

(5) With respect to any package of penicillin, streptomycin, dihydrostreptomycin, chlortetracycline, chloramphenicol, or bacitracin, included in a packaged combination with another drug, when such other drug fails to meet the requirements of the regulations in this part; or

(6) With respect to any immediate container, if such regulations require its labeling to bear a caution against dispensing otherwise than on prescription, at the beginning of the act of dispensing or offering to dispense it otherwise than:

(i) By a practitioner licensed by law to administer such drug; or

(ii) On his prescription issued in his professional practice.

(a)

§ 146.5 Records of distribution. The person who requested certification shall keep complete records showing each shipment and other delivery (including exports) of each certified batch or part thereof by such person or by any person subject to his control. Such records shall show the date and quantity of each such shipment or delivery and the name and post-office address of the person to whom such shipment or delivery was made, and shall be kept for not less than three years after such date.

(b) Upon the request of any officer or employee of the Food and Drug Administration, or of any other officer or employee of the United States acting on behalf of the Secretary, the person to whom a certificate is issued shall at all reasonable hours make such records available to any such officer or employee and shall accord to him full opportunity to make inventory of stocks of such

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batch on hand and otherwise to check the correctness of such records.

§ 146.6 Authority to refuse certification service. When the Secretary finds, after giving notice and opportunity for hearing, that a person has:

(a) Obtained or attempted to obtain a certificate through fraud, or through misrepresentation or concealment of a material fact;

(b) Falsified the records required to be kept by § 146.5; or

(c) Failed to keep such records or to make them available, or to accord full opportunity to make an inventory of stocks on hand or otherwise to check the correctness of such records, as required by § 146.5, and such failure may materially impair the certification service;

the Secretary will immediately suspend service to such person under the regulations in this part and will continue such suspension unless and until such person shows adequate cause why such service should be resumed.

§ 146.7 New antibiotic and antibioticcontaining products. Any request that the Secretary provide for the certification of batches of a drug for which no provision for certification is made in the existing regulations in this part shall be in a form specified by the Commissioner and shall be accompanied by:

(a) A statement of the conditions for which the person who makes such request intends such drug to be used, and adequate directions for use in each such condition;

(b) Full reports of investigations which have been made to show whether or not such drug is safe and efficacious for use in such conditions;

(c) A full list of the articles used as components of such drug;

(d) A full statement of the composition of such drug;

(e) A full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and packing of such drug;

(f) A full description of, or references to publications containing practical and accurate tests and methods of assay to determine the identity, strength, quality, and purity of such drug;

(g) Such samples of such drug and of the articles used as components thereof as the Commissioner may require; and

(h) Specimens of all labeling (including all brochures and other printed matter, except readily available medical publications, referred to in such labeling) proposed to be used for such drug.

§ 146.8 Fees. (a) Fees for the services rendered under the regulations in this part shall be such as are necessary to provide, equip, and maintain an adequate certification service.

(b) The fee for such services with respect to each batch of a drug, certification of which is provided by the regulations in this part, is the fee prescribed in the section relating specifically to such drug, except that, in case of a supplemental request submitted pursuant to the provisions of § 146.18, the fee shall be $2.00.

(c) When the Commissioner considers it necessary to make investigations of a new penicillin, streptomycin, dihydrostreptomycin, chlortetracycline, chloramphenicol, or bacitracin product, on which a request has been submited in accordance with 146.7, the fee for such service shall be the cost thereof. In such case the request shall be followed by an advance deposit in such amount as the Commissioner specifies, and thereafter such additional advance deposits shall be made as the Commissioner estimates may be necessary to prevent arrears in the payment of such fee.

(d) A person requiring continuing certification services may maintain an advance deposit of the estimated cost of such services for a two-month period. Such deposit shall be debited with fees for services rendered, but shall not be debited for any fee the amount of which is not definitely specified in the regulations in this part unless the depositor has previously requested the performance of the services to be covered by such fee. A monthly statement for each such advance deposit shall be rendered.

(e) The unearned portion of any advance deposit shall be refunded to the depositor upon his application.

(f) Whenever in the judgment of the Commissioner the ratio between fees collected (which are based upon experience and the best estimate of costs and the best estimate of earnings) and the costs of providing the service during an elapsed period of time, in the light of all circumstances and contingencies, warrants a refund from the fund collected during such period, he shall make ratable refunds to those persons to whom

the services were rendered and charged, except for those services described under § 146.18.

(g) All deposits and fees required by the regulations in this part shall be paid by money order, bank draft, or certified check drawn to the order of the Treasurer of the United States, collectible at par at Washington, D. C. All such deposits and fees shall be forwarded to the Food and Drug Administration, Department of Health, Education, and Welfare, Washington 25, D. C., whereupon after making appropriate records thereof they will be transmitted to the Chief Disbursing Officer, Division of Disbursement, Treasury Department, for deposit to the special account "Certification and Inspection Services, Food and Drug Administration."

§ 146.9 Antibiotics for agricultural use. An article that contains one or more of the antibiotic substances described in this part and intended solely for application to plants for the control of plant diseases caused by microorganisms and conspicuously so labeled is not subject to the requirements of sections 502 (1) and 507 of the Federa! Food, Drug, and Cosmetic Act, if it contains one or more suitable denaturants that make it unfit for drug use; but in no case shall it be exempt from the requirements of sections 502 (1) and 507 of the act if it is represented or intended to be administered to man or other animals for the cure, mitigation, treatment, or prevention of disease or as an animal feed supplement.

§ 146.10 Antibiotics for export. Drugs containing penicillin, streptomycin, dihydrostreptomycin, chlortetracycline, tetracycline, chloramphenicol, or bacitracin intended for export will be certified notwithstanding failure to meet the labeling requirements of the applicable monographs if the labeling used for such drugs complies with the following conditions:

(a) It has been approved before use by the government authorities of the country to which the drugs are intended for export; and

(b) Such labeling represents that such drugs are for use only in those conditions for which they are certified for domestic distribution.

§ 146.18 Exemptions for labeling. (a) Except as provided by paragraphs (c) and (d) of this section, a shipment or

other delivery of a drug which is to be labeled at an establishment located elsewhere than at the place of manufacture shall be exempt, during the time of introduction into and movement in interstate commerce and the time of holding in such establishment, from the requirements of section 502 (1) of the act if the labeling of each shipping container bears the batch mark of the drug, the number of units per package, the expiration date, and if the person who introduced such shipment or delivery into interstate commerce holds a permit from the Commissioner authorizing shipment for labeling in such establishment.

(b) (1) An application for such a permit shall be in a form specified by the Commissioner, and shall give the name and location of the establishment in which such labeling is to be done.

(2) In case the applicant is the operator of such establishment, the application shall include a written agreement signed by him that he will request certification of each batch from which any shipment or delivery is made to such establishment unless it is exempt under section 801 (d) of the act or § 146.23; that he will not remove any of such drug from such establishment unless it complies with section 502 (1) of the act or is so exempt, or if certification is refused, unless it is returned within a reasonable time to permit reprocessing and certification, destruction, or such exemption at the establishment where it was manufactured; that he will keep complete records showing the date, quantity, and batch mark of each such shipment and delivery and the disposition thereof; that he will make such records available to any officer or employee of the Food and Drug Administration at any reasonable hour within three years after the date of such disposition; and that he will accord full opportunity to such officer or employee to make inventories of stocks on hand and otherwise check the correctness of such records.

(3) In case the applicant is not the operator of such establishment such application shall include or be accompanied by:

(1) A written agreement signed by the applicant that he will request certification of each batch from which any shipment or delivery is made to such establishment unless it is exempt under section 801 (d) of the act or § 146.23; that he will keep complete records showing the date, quantity, and batch mark