Regulations for the Sale, Barter, or 
Exchange of Any Virus, Therapeutic 
Serum, Toxin, Antitoxin 
or 
Analogous Product 
or 
Arsphenamine or its Derivatives (or 
Any Other Trivalent Organic 
Arsenic Compound) 
In the District of Columbia or in Interstate Traffic 
or in Export or Import Traffic 
Approved: January 16, 1947 
To supersede Regulations issued October 12, 1940 
and amendments thereto 
MISCELLANEOUS PUBLICATION No. 10 FEDERAL SECURITY AGENCY 
United States Public Health Service 
Thomas P arran, Surgeon General 
DIVISION OF PUBLIC HEALTH METHODS 
G. St. J. Perrott, Chief of Division 
UNITED STATES GOVERNMENT PRINTING OFFICE, WASHINGTON ; 1947 
For sale by the Superintendent of Documents, U. S. Government Printing Office 
Washington 25, D. C. - Price 10 cents PREFACE 
Issuing authority.—Regulations contained in §§ 22.35-22.39, 22.50- 
22.55, 22.70-22.79, and 22.90-22.96, prescribing standards designed to 
insure the continued safety, purity, and potency of products, issued 
jointly by the Surgeon General of the Public Health Service, the 
Surgeon General of the Army, and the Surgeon General of the Navy, 
with the approval of the Federal Security Administrator; regulations 
contained in §§ 22.1-22.14, 22.20-22.24, 22.30-22.32, issued by the Sur- 
geon General of the Public Health Service, with the approval of the 
Federal Security Administrator. 
[seal] 
Surgeon General of the Army. 
N. T. Kirk, 
C. A. Swanson, 
Surgeon General of the Navy. 
James A. Crabtree. 
Acting Surgeon General of the Public Health Service. 
Approved: January 16,1947. 
Maurice Collins, 
Acting Federal Security Administrator. 
Authority: §§ 22.1 to 22.96, inclusive, issued under sec. 351, 58 Stat. 702 ; 42 
U. S. C., Sup. 262. Statutes giving special authority are cited in parentheses, at 
the end of affected sections. 
Cross Reference ; Federal Security Agency regulations relating to drugs as 
defined in the Federal Food, Drug, and Cosmetic Act (21 U. S. C. 301 et seq.). See 
Food and Drug Administration, Federal Security Agency, 21 CFR. Chap. I, Parts 
2, 135, 141, 144, 145, 146. Exemption from section 505 of the Federal Food, Drug, 
and Cosmetic Act (21 U. S. C. 355) of new drugs licensed under the Public Health 
Service Act; see 21 CFR, Chap. I, 2.109. Drugs intended solely for investigational 
use, see 21 CFR, Chap. I, 2.114. 
Cross Reference: Bureau of Customs regulations relating to viruses, serums 
and toxins: See Customs Duties, 19 CFR, Cum. Supp., 12.21-12.23. 
Cross Reference: Post Office regulations relating to importation and trans- 
portation of viruses, serums, and antitoxins by mail: See Postal Service, 39 CFR 
6.14, 21.54. 
Effective date; 'prior regulations superseded.—The regulations in 
this part shall be effective with respect to all products, as herein 
defined, thirty days after their publication in the Federal Register, 
and as of such date shall supersede all regulations, not heretofore 
revoked, issued under the authority of the act of July 1,1902 (32 Stat. 
728) ; the regulations contained in §§ 21.1 to 21.9, inclusive, and §§ 22.1 
to 22.114, inclusive, Title 42, Code of Federal Regulations, Cum. Supp., 
are hereby repealed as of such date. 
[F. R. Doc. 47-573; Filed, January 20,1047 ; 8:48 a. m.] TABLE OF CONTENTS 
DEFINITIONS 
Sec. 
22.1 Definitions. 
LICENSES ; PROCEDURE 
22.2 Application. 
22.8 Inspection of establishments and 
examination of products prior 
to licensing, 
22.4 Form of license: domestic estab- 
lishments. 
22.5 Product licenses. 
22.6 Changes to be reported. 
22.7 Products under development. 
22.8 Issuance, revocation or suspen- 
sion. 
22.9 Licenses heretofore issued. 
22.10 Summary suspension. 
22.11 Review Board. 
22.12 Opportunity for hearing. 
22.13 Suspension and revocation; pub- 
lication. 
22.14 Reissuance. 
FOEEIGN ESTABLISHMENTS AND PRODUCTS 
22.20 Licenses required. 
22.21 Procedure. 
22.22 Form of license. 
22.23 Smallpox vaccine; importation 
prohibited. 
22.24 Samples to accompany each im- 
portation. 
ESTABLISHMENT INSPECTION 
22.30 Inspectors. 
22.31 Time of inspection. 
22.32 Duties of inspector. 
establishment standards 
22.35 Responsible head. 
22.36 Records, samples, cultures. 
22.37 Physical establishment; con- 
struction, equipment and care. 
ESTABLISHMENT STANDARDS COD. 
Sec. 
22.38 Animals used in production. 
22.39 Human blood donors. 
STANDARDS FOE PRODUCTS : LABELS 
22.50 Container labels. 
22.51 Proper name on outside label. 
22.52 Outside label; additional items. 
22.53 Divided manufacturing respon- 
sibility to be shown. 
22.54 Name of selling agent or dis- 
tributor. 
22.55 Products for export. 
STANDARDS FOB PRODUCTS : GENERAL 
22.70 Tests prior to release. 
22.71 Tests: by whom made. 
22.72 Ingredients, preservatives, dil- 
uents. 
22.73 Total solids in serums. 
22.74 Permissible combinations. 
22.75 Container and closure. 
22.76 Standard units or samples. 
22.77 Standards of potency ; particular 
products. 
22.78 Dating period ; date of manufac- 
ture. 
22.79 Dating period; products in cold 
storage. 
ADDITIONAL STANDARDS .' TEIVALENT OR- 
GANIC ARSENICALS 
22.90 Tests prior to release. 
22.91 Pretesting by Institute; samples 
of each lot. 
22.92 Expiration date. 
22.93 Composition of product. 
22.94 Container. 
22.95 Final container label. 
22.96 Outside label. 
Appendix A.—Excerpts from the law. DEFINITIONS 
§ 22.1 Definitions.—As used in this part: 
(a) “Act” means the Public Health Service Act (58 Stat. 682), 
approved July 1, 1944. 
(b) “Administrator” means the Federal Security Administrator. 
(c) “Surgeon General” means the Surgeon General of the United 
States Public Health Service, 
(d) “Institute” means the National Institute of Health in the 
Public Health Service. 
(e) “State” means a State or the District of Columbia, Hawaii, 
Alaska, Puerto Rico, or the Virgin Islands. 
(f) “Possession” includes, among other possessions, Puerto Rico 
and the Virgin Islands. 
(g) “Biologic product” means any virus, therapeutic serum, toxin, 
antitoxin, or analogous product applicable to the prevention, treat- 
ment or cure of diseases or injuries of man: 
(1) A virus is a product containing the minute living cause of an 
infectious disease. 
(2) A therapeutic serum is the product obtained from the blood 
of an animal by removing the clot or clot components and the blood 
cells and intended for administration by a route other than ingestion. 
(3) A toxin is a product containing a soluble substance poisonous 
to laboratory animals or to man in doses of 1 milliliter or less (or 
equivalent in weight) of the product, and having the property, fol- 
lowing the injection of nonfatal doses into an animal, of causing to 
be produced therein another soluble substance which specifically 
neutralizes the poisonous substance and which is demonstrable in the 
serum of the animal thus immunized. 
(4) An antitoxin is a product containing the soluble substance in 
serum or other body fluid of an immunized animal which specifically 
neutralizes the toxin against which the animal is immune. 
(5) A product is analogous: 
(i) To a virus if prepared from or with a virus or agent actually 
or potentially infectious, without regard to the degree of virulence or 
toxicogenicity of the specific strain used. 
(ii) To a therapeutic serum, if composed of whole blood or plasma 
or containing some organic constituent or product other than a hor- 
mone or an amino acid, derived from whole blood, plasma, or serum 
and intended for administration by a route other than ingestion. 2 
(iii) To a toxin or antitoxin, if intended, irrespective of its source 
of origin, for the prevention, treatment, or cure of diseases or injuries 
of man through specific immunization. 
(h) “Trivalent organic arsenicals” means arsphenamine and its 
derivatives (or any other trivalent organic arsenic compound) appli- 
cable to the prevention, treatment, or cure of diseases or injuries of 
man. 
(i) “Products” includes biologic products and trivalent organic 
arsenicals. A product is deemed “applicable to the prevention, treat- 
ment or cure of diseases or injuries of man” irrespective of the mode 
of administration or application recommended, including use when 
intended, through administration or application to a person, as an 
iiid in diagnosis or in evaluating the degree of susceptibility or im- 
munity possessed by a person; and including also any other use for 
purposes of diagnosis if the diagnostic substance so used is prepared 
from or with the aid of a biologic product. 
(j) “Proper name”, as applied to a product, means the name desig- 
nated in the license for use upon each container of the product. 
(k) “Dating period” means the period beyond which the product 
cannot be expected beyond reasonable doubt to yield its specific results. 
(l) “Expiration date” means the date of termination of the dating 
period. 
(m) The word “standards” means specifications and procedures 
applicable to an establishment or to the production, content, testing, 
labeling, or release of products prepared therein, which are prescribed 
in this part and which are designed to insure the continued safety, 
purity and potency of such products. 
(n) The word “continued” as applied to the safety, purity and 
potency of products is interpreted to apply-to the dating period. 
(o) The word “safety” is interpreted to apply to the relative free- 
dom from harmful effect to the recipient when a product is prudently 
administered, taking into consideration the character of the product in 
relation to the condition of the patient at the time, 
(p) The word “purity” is interpreted to mean the degree of freedom 
from extraneous matter, whether harmful to the recipient, deleterious 
to the product or otherwise, in the finished product. 
(q) The word “potency” is interpreted to mean the specific ability or 
capacity of the product, as indicated by appropriate laboratory tests 
or by adequately controlled clinical data obtained through the admin- 
istration of the product in the manner intended, to effect a given result. 
(r) “Manufacturer” includes any individual, trust or estate, associa- 
tion, partnership or corporation engaged in the manufacture of a prod- 
uct subject to license under the act. 3 
(s) “Establishment” means that portion of the properties of any 
manufacturer which is given over to the manufacture of a product 
subject to license, including equipment and animals used, and the per- 
sonnel engaged in such manufacture. 
(t) “Selling agent” or “distributor” means any person engaged in 
the unrestricted distribution, other than by sale at retail, of products, 
subject to license. 
§ 22.2 Applications.—To obtain a license for any establishment, 
biologic product or trivalent organic arsenical, the manufacturer shall 
make application to the Surgeon General on forms prescribed for such 
purpose, and, in the case of an application for a product license, shall 
submit samples of the product and specimens of the labels, enclosures, 
and containers proposed to be used for such product. 
§ 22.3 Inspection of establishments and examination of products 
prior to licensing.—Licenses shall be issued only after inspection of 
the establishment and examination of the product for which a product 
license is desired and upon a determination that the establishment and 
the product meet the standards prescribed in the regulations in this 
part. Additional product licenses shall be issued only upon examina- 
tion of the product and a determination that the product meets the 
standards prescribed in the regulations in this part. 
§ 22.4 Foim of license: domestic establishments.—The following 
form of license is prescribed for establishments located in any State 
or possession of the United States: 
Establishment License No. 
This is to certify that of , through 
the establishment identified as located at 
is hereby licensed, pursuant to section 351 of the Public Health Service Act, 
approved July 1, 1944 (58 Stat. 682), and regulations thereunder, to propagate or 
manufacture, and to prepare for sale in the District of Columbia, or for sending, 
bringing or carrying from any State or possession into any other State or posses- 
sion or into any foreign country any virus, serum, toxin, antitoxin, or analogous 
product, or arsphenamine or its derivatives (or any other trivalent organic arsenic 
compound) for the propagation and manufacture of which the establishment 
holds an unsuspended and unrevoked license issued by the Federal Security 
Administrator pursuant to said act and regulations. 
LICENSES; PROCEDURE 
Federal Security Administrator 
Date _ 
§ 22.5 Product licenses.—Each product license shall designate: 
(a) The manufacturer. 
(b) The establishment. 
(c) The license number of the establishment. 
739333—47 2 4 
(d) The proper name of the product, with additional specifications, 
if any, which may be approved or required for additional labeling 
purposes. 
§ 22.6 Changes to he reported.—lmportant changes in location, 
equipment, management and responsible personnel, or in production 
methods and labeling of any licensed product or of any product for 
which an application for a license is pending shall be immediately re- 
ported to the Institute by any establishment holding a license, and, 
unless in case of an emergency, not less than 30 days in advance of the 
time such changes are made; failure to make such report shall con- 
stitute a ground for summary suspension of a license pending reinspec- 
tion of the establishment or re-examination of the product. 
§ 22.7 Products under development.—A biologic product or trival- 
ent organic arsenical undergoing development, but not yet ready for a 
product license, may be shipped or otherwise delivered from one State 
or possession into another State or possession, for purposes of con- 
trolled investigation, only in accordance with regulations under section 
505 (i) of the Federal Food Drug, and Cosmetic Act, as amended. 
§ 22.8 Issuance, revocation or suspension.—A license shall be issued 
by the Administrator upon the recommendation of the Surgeon Gen- 
eral and upon the finding by the Surgeon General that the establish- 
ment or the product, as the case may be, meets the standards established 
by the regulations in this part as herein prescribed or hereafter 
amended. Licenses shall be valid until suspended or revoked. An 
establishment or product license shall be revoked upon application of 
the manufacturer giving notice of intention to discontinue the manu- 
facture of all products or of intention to discontinue the manufacture 
of a particular product for which a license is held. The Surgeon Gen- 
eral shall recommend to the Administrator that a license be suspended 
or revoked whenever he finds, after notice and opportunity for hearing, 
that the establishment or the product for which-the license has been 
issued fails to conform to the standards in the regulations in this part 
as herein prescribed or hereafter amended to insure the continued 
safety, purity and potency of the manufactured product. In case of 
suspension, if the faulty condition is not corrected within 60 days or 
within such other period as may be specified in the notice of suspension, 
he shall recommend that the license be revoked. Except as provided 
in § 22.10, prior to the institution of proceedings looking to the suspen- 
sion or revocation of a license the licensee shall be advised in writing of 
the facts or conduct which may warrant such action and shall be 
accorded opportunity within a reasonable period prescribed by the 
Surgeon General to demonstrate or achieve compliance with the regu- 
lations in this part. 5 
§ 22.9 Licenses heretofore issued.—Any license heretofore issued 
and in effect upon the effective date of the regulations in this part 
shall remain in effect unless and until superseded by a new license, 
or suspended or revoked, pursuant to the regulations in this part. 
§ 22.10 Summary suspension.—Whenever the Surgeon General 
has reasonable ground to believe that an establishment or product for 
which a license has been issued fails to conform to the standards 
prescribed in the regulations in this part, and that by reason of such 
failure and of failure of the manufacturer to take prompt corrective 
measures on notice thereof, the distribution or sale of a licensed prod- 
uct wrould constitute a danger to health, or that the establishment and 
production methods have been so changed as to require in order to 
protect the public health a new showing that the establishment or 
product meets the standards prescribed in the regulations in this part, 
he may recommend to the Administrator that the license for the estab- 
lishment or the product be summarily suspended and the manufacturer 
be required (a) to notify the selling agents and distributors to whom 
such product or products have been delivered of such suspension, (b) 
to furnish complete records of such deliveries and notice of suspension, 
and (c) to show cause within 60 days or such other period as may be 
specified in the order why the license should not be revoked. 
§ 22.11 Review Board.—When deemed advisable by the Surgeon 
General, in matters involving the safety, purity and potency of 
licensed products or products for which an application for license is 
pending, the reports of inspection and laboratory examinations, to- 
gether with any pertinent data the establishment may submit, shall be 
passed upon by a special board of three officers appointed by the 
Surgeon General for that purpose. The board shall report its findings 
to the Surgeon General who will forward its report, together with his 
findings and recommendations, to the Administrator. 
§ 22.12 Opportunity for hearing.—Any manufacturer whose appli- 
cation for a license has been denied, or whose establishment or product 
license has been summarily suspended, without prior opportunity for 
hearing, may appeal from such denial or suspension and shall be 
entitled to a hearing thereon before a review body constituted as pro- 
vided in § 22,11. The Surgeon General, upon review of the record, 
may affirm, reverse, or modify the findings of the review board, or may 
direct the taking of further testimony and shall forward his deter- 
minations and recommendations to the Administrator. 
§ 22.13 Suspension and revocation: publication.—Notice of sus- 
pension or revocation of license, with statement of cause therefor, may 
be published by the Administrator. 
§ 22,14 Reissuance.—An establishment license, previously revoked 
or suspended may be reissued or reinstated upon inspection of the 6 
establishment, or upon examination of the product showing that the 
reasons for revocation or suspension have been corrected, except that 
in case of a product license revoked upon application or because of 
failure to meet changes in standards prescribed by amendment to the 
regulations in this part after the issuance of such license, only such 
inspection and examination as may be considered advisable by the 
Institute shall be required. 
FOREIGN ESTABLISHMENTS AND PRODUCTS 
§ 22.20 Licenses required; 'products for controlled investigation 
only.—Any biologic or trivalent organic arsenical propagated or manu- 
factured and prepared in any foreign country and intended for sale, 
barter or exchange shall be refused entry by collector of customs 
unless produced in an establishment holding an unsuspended and un- 
revoked establishment license and license for the product. Unlicensed 
products intended solely for purposes of controlled investigation are 
admissible only if in accord with applicable regulations under section 
505 (i) of the Federal Food, Drug, and Cosmetic Act, as amended. 
§ 22.21 Procedure.—Except as otherwise provided in this part, li- 
censes for foreign establishments and products shall be issued, sus- 
pended or revoked in the same manner as licenses for domestic estab- 
lishments and products. Each foreign establishment holding a license 
and consigning any licensed biologic product or trivalent organic ar- 
senical into any State or possession shall be required to file with the 
Surgeon General the name and address of any representative or repre- 
sentatives authorized by the establishment to distribute the product, 
and such representative or representatives shall keep such records of 
such distribution as are required of domestic licensed establishments, 
and failure to maintain such records shall constitute ground for revoca- 
tion of license. 
§ 22.22 Form of license.—Licenses for establishments located in 
foreign countries shall be in form similar to that for domestic estab- 
lishments except that they shall authorize preparation for sending, 
carrying, or bringing for sale, barter or exchange from the foreign 
country designated in the license into any State or possession of the 
United States and shall specify that it is issued upon the condition that 
the licensee will permit the inspection during all reasonable hours of 
the establishment by any officer, agent, or employee of the Federal 
Security Agency authorized by the Federal Security Administrator 
for such purpose. 
§ 22.23 Smallpox vaccine; importation prohibited.—The importa- 
tion of smallpox vaccine into any State or possession from any foreign 
country is prohibited except that smallpox vaccine may be sent from 7 
any foreign country, in containers indicating plainly the limited pur- 
pose intended, to the Institute for test or research purposes or for vac- 
cine production .(Sec. 361, 58 Stat. 702; 42 U. S. C., Sup. 262). 
§ 22.24 Samples to accompany each importation.—Each foreign 
importation of a biologic product or trivalent organic arsenical from a 
licensed establishment, whether or not intended for investigational 
use only, shall be accompanied by at least two final containers of each 
lot of any biologic product and by at least 15 final containers of each 
lot of any trivalent organic arsenical contained in the shipment. Such 
samples shall be forwTarded by the collector of customs at the port of 
entry to the Institute for examination. If separate samples are not 
found accompanying the shipment, samples shall be obtained from the 
shipment by the collector of customs and forwarded to the Institute 
(Sec. 801, 52 Stat. 1058; 21 U. S. C. 381). 
ESTABLISHMENT INSPECTION 
§ 22.30 inspectors.—lnspections shall be made by an officer of the 
Public Health Service having special knowledge of the methods used 
in the production and control of biologic products and designated for 
such purpose by the Surgeon General or by any officer, agent, or 
employee of the Federal Security Agency specifically designated for 
such purpose by the Administrator. 
§22.31 Time of inspection.—The inspection of an establishment 
for which a license is pending need not be made until the establishment 
is in operation and is manufacturing the complete product for which 
a product license is desired. In case the license is denied following in- 
spection for the original license, no reinspection need be made until 
assurance has been received that the faulty conditions which were the 
basis of the denial have been corrected. An inspection of each licensed 
establishment shall be made at least once each year. Inspections may 
be made with or without notice, and shall be made during regular 
business hours unless otherwise directed. 
§ 22.32 Duties of inspector.—The inspector shall: 
(a) Call upon the active head of the establishment, stating the ob- 
ject of his visit, 
(b) Interrogate the proprietor or other personnel of the establish- 
ment as he may deem necessary, 
(c) Examine the details of location, construction, equipment and 
maintenance, including stables, barns, warehouses, production labora- 
tories, bleeding clinics maintained for the collection of human blood, 
shipping rooms, record rooms, and any other structure or appliance 
used in any part of the propagation, manufacture, and preparation of 
a product, 8 
(d) Investigate as fully as he deems necessary the methods of prop- 
agation, processing, testing, storing, dispensing, recording, or other 
details of manufacture and distribution of each licensed product, or 
product for which a license has been requested, including observation 
of these processes in actual operation, 
(e) Obtain and cause to be sent to the Institute adequate samples for 
the examination of any product or ingredient used in its preparation, 
(f) Bring to the attention of the manufacturer any fault observed 
in the course of inspection in location, construction, production meth- 
ods, or administration of a licensed establishment which might lead 
to impairment of a product, 
(g) Inspect and copy, as circumstances may require, any records 
required to be kept pursuant to § 23.36, 
(h) Certify as to the condition of the establishment and of the pro- 
duction methods followed and make recommendations as to action 
deemed appropriate with respect to any application for license or any 
license previously issued. • 
ESTABLISHMENT STANDARDS 
§ 22.35 Responsible head.—A responsible person shall be in perma- 
nent and full control of the establishment in all matters relating to 
the manufacture of products. A responsible person is one who has 
been trained in the manufacturing techniques employed and the 
fundamental scientific facts upon which the manufacture of products 
rests, who is capable of enforcing discipline among the employees 
under his supervision, and to whom sufficient authority has been dele- 
gated for such purpose. 
§ 22.36 Records, samples, cultures—(a) Production and distribu- 
tion records.—Records shall be kept, with dates of the various steps 
in the manufacture, testing, disposition, and distribution of each lot, 
so that at any time these steps as regards any lot number may be traced 
by an inspector. The records shall be retained for such interval be- 
yond the expiration date as is considered necessary for the individual 
product to permit the return of any clinical report of unfavorable 
reactions. This interval will vary with the type of product and its 
geographic distribution. A minimum of 6 months after the expiration 
date with 5 years as the extreme interval under all circumstances is 
considered adequate. Records of distribution of each lot shall in any 
event be kept as long as the lot remains the property of the licensed 
manufacturer. 
(b) Records of recall.—Complete records shall be maintained per- 
taining to the recall from distribution of any product upon notification 
from the Institute of failure to conform with the standards prescribed 9 
in the regulations in this part, deterioration of the product or any other 
factor by reason of which the distribution of the product would consti- 
tute a danger to health. 
(c) Sterilization records.—Records including the date, duration, 
and temperature of each sterilization shall be made by means of auto- 
matic registering devices or under a system of recording which gives 
reasonable assurance of the accuracy and reliability of the record. 
(d) Animal necropsy records.—A necropsy record shall be kept on 
each animal from which a biologic product has been obtained and which 
dies or is killed because of disease while employed in production of a 
product. 
(e) Retention of reference samples.—Reference samples from each 
lot shall be retained by the manufacturer until the entire lot has become 
outdated and for 6 months thereafter. Exceptions may be authorized 
by the Institute when the lot yields relatively few final containers and 
when such lots are prepared by the same method in large numbers 
and in close succession. 
(f) Cultures.—Cultures and other materials while used in the pro- 
duction of licensed products shall be labeled and preserved in a safe 
and orderly manner. 
(g) Records in case of divided manufacturing responsibility.—lf 
two or more establishments participate in the manufacture of a prod- 
uct, the records of both establishments must show plainly the degree of 
responsibility of each in the manufacturing process. 
§ 22.37 Physical establishment • construction, equipment and care— 
(a) Work with spore-bearing organisms.—All work with spore-bear- 
ing micro-organisms shall be carried out in (1) an entirely separate 
building with its own entrance, or (2) a portion of a building used for 
the manufacture of other products constructed in such a manner as to 
be completely walled-off so that admission to the special unit may be 
gained only through an entrance independent of the remainder of the 
building. All containers used shall be permanently marked so as to 
avoid the possibility of contamination of products. 
(b) Work of a diagnostic nature.—Laboratory procedures of a 
clinical diagnostic nature involving possibly contaminated materials 
shall be in space set apart from that used for the production of licensed 
products, except that production space which is used only occasionally 
may be used for diagnostic work provided spore-bearing pathogenic 
micro-organisms are not involved and provided the space is thoroughly 
cleaned before production is resumed. 
(c) Laboratory and bleeding rooms.—Laboratory rooms for the 
production of licensed products, including the bleeding rooms and 
other places where cleanliness is essential, shall be efficiently screened 
and kept free of flies and other insects or vermin. Building construe- 10 
tion shall be such as to insure freedom from dust, smoke and deleterious 
or obnoxious odors in the laboratory and bleeding rooms and such as to 
permit thorough cleaning an*d, when necessary, chemical disinfection 
of bleeding rooms and rooms for smallpox vaccine animals. 
(d) Stables.—Stables shall be well lighted and well ventilated, and 
the floors shall be so constructed and cared for as to insure cleanliness. 
(e) Sterilization.—Sterilization equipment and methods used shall 
be such as to insure the complete destruction of contaminating, living 
organisms, including living spores. The containers, filling apparatus, 
and other pieces of apparatus or materials which may come in contact 
with biologic products during manufacture shall be scrupulously clean. 
Such equipment shall be absolutely sterile unless the product is pro- 
tected by subsequent sterilizing treatment, 
(f) Containers used in 'production.—All containers used in prepara- 
tion of biologic products shall be of such construction as will readily 
permit inspection for cleanliness. 
(g) Hot water available.—Hot water shall be provided in bleeding 
rooms and stables for smallpox vaccine animals. 
(h) Disposal of manure.-—No manure shall be so stored as to permit 
the breeding of flies on the premises nor shall the establishment be 
located in close proximity to off-property manure storage capable of 
engendering fly breeding. 
(i) Isolation of hog cholera production.—All personnel, animals, 
and equipment used in the production of hog cholera serum shall be 
kept entirely separate from personnel, animals, and materials used in 
the production of biologic products for human use. 
§ 22.38 Animals used- in production—(a) Quarantine and care.— 
Animals used in production of biologic products shall be kept under 
competent daily inspection and preliminary quarantine for a period 
of at least 7 days before use. Only healthy animals free from com- 
municable disease shall be used for production purposes and at all 
times shall be adequately housed, fed, and humanely treated. Par- 
ticular care shall be taken during the quarantine period to eliminate 
those animals of the equine genus which may be infected with glanders, 
and those of the bovine genus which may be infected with tuberculosis. 
(b) Inrmmnization against tetanus.—All horses used in the produc- 
tion of biologic products, except those which are under active immu- 
nization for the production of tetanus antitoxin, shall receive injec- 
tions of tetanus toxoids in such amounts and at such intervals as 
experience has shown adequate to insure immunity to tetanus. 
(c) Disposal of used animals.—No animal used for production or 
testing of products shall be removed from the premises while it is ca- 
pable of transmitting disease. An animal which is unsuitable because 
of its physical condition for the production or testing of a product 11 
shall not be removed from the premises alive except for the purpose 
of being utilized for animal by-products. No animal shall be allowed 
to continue to live unnecessarily when to do so would be an inhumane 
act. 
(d) Reporting of certain diseases required.—ln case of actual or 
suspected infection with foot-and-mouth disease, glanders, tetanus, 
anthrax, gas gangrene, equine infectious anemia, or equine encephalo- 
myelitis among animals intended for use or used for the production 
of biologic products, the manufacturer shall immediately notify the 
Institute. 
(e) Smallpox vaccine yt'oduction animals.—Animals used for prop- 
agation of smallpox vaccine shall be thoroughly cleaned with soap and 
water at the beginning of the quarantine and at its conclusion. No 
area of the animal shall be vaccinated which is liable to be contami- 
nated by feces. 
(f) Treatment of vaccinated animals.—Preliminary to taking 
smallpox vaccine material from vaccinated animals, such animals shall 
be killed or rendered insensible to pain. 
(g) Restriction on attendants.—Personnel while caring for small- 
pox vaccine animals shall be excluded from horse stables and paddocks 
and from contact with horses. 
§ 22.39 Human Hood donors.—Only those persons may serve as a 
source of the whole blood for use in preparing a licensed product whose 
physical condition is such that the withdrawal of the desired amount 
of blood will not endanger their health and who are certified by a 
qualified doctor of medicine as being free of disease transmissible by 
blood transfusion as far as can be determined from the donor’s per- 
sonal history, from physical examination and such clinical tests as 
appear necessary for each donor on the day upon which the blood is 
withdrawn from the donor, except that this requirement may be modi- 
fied by the Institute if the licensed product is processed by a method 
which insures the destruction or complete removal of the causative 
agent of such disease. 
STANDARDS FOR PRODUCTS: LABELS 
§ 22.50 Container labels.—The following items shall appear on the 
label affixed to each container of a product capable of bearing a full 
label: 
(a) The proper name of the product; 
(b) Name, address, and license number of manufacturer; 
(c) Lot number; 
(cl) The expiration date. 
If the final container is capable of bearing only a partial label, the 
final container shall show as a minimum the name (expressed either 12 
as the proper or common name), the lot number, and the name of the 
manufacturer and, if the final container is incapable of bearing any 
label, the items shall appear only on the outside label. 
If the final container is a multiple-dose container, the container 
label must indicate the recommended dose. When the label has been 
affixed to the container a sufficient area of the container must remain 
uncovered for its full length or circumference to permit inspection of 
the contents. 
§ 22.51 Proper name on outside label.—The proper name in the 
form designated in the product license for such purpose must appear 
upon the outside label in legible type and shall be given precedence 
in position and prominence over any trade-mark or trade name used: 
(a) The “outside label” is the label of the carton enclosing one or 
more final containers, except that if no such carton is used the label of 
the individual final container is regarded as the outside label. 
(b) “Legible type” includes only type of a size and character which 
can be read with ease when held in a good light and with normal vision. 
(c) “Precedence in position” of the proper name will have been 
observed if it is placed above any trade-mark or trade name and pro- 
vided it is symmetrically arranged with respect to other printing on 
the label. 
(d) “Precedence in prominence” of the proper name will have been 
observed if the style of type is of the same or greater point size and 
of equal face, or heavier, than that used in printing the trade-mark or 
trade name, and if the contrast in color value between the proper name 
and the background is not less than that between the trade-mark or 
trade name and the background. 
§ 22.52 Outside label; additional items.—The label affixed to the 
outside carton shall include, in addition to the proper name and the 
items required on the label of the final container, the following: 
(a) The preservative used and its concentration, 
(b) The volume of the contents, if a liquid, or the weight, if a solid, 
and the potency or dosage if more than one strength is dispensed. 
(c) The recommended storage temperature, 
(d) The words “Shake Well,” or equivalent, when indicated by the 
character of the product, 
(e) The dose and route of administration recommended or refer- 
ence to such directions in an enclosed circular, 
(f) The source of the product when a factor in safe administration, 
(g) Minimum potency of product expressed in terms of official 
standard of potency or, if potency is a factor and no standard of 
potency has been prescribed, the words “No. U. S. standard of potency.” 
§ 22.53 Divided manufacturing responsibility to be shown.—If two 
or more establishments participate in the manufacturing process, the 13 
name, address, and license number of each must appear on the label of 
the final container, if capable of bearing a full label, and on the outside 
label. 
§ 22.54 Name of selling agent or distributor.—The name and ad- 
dress of the selling agent or distributor of a product may appear on 
the label under the designation of “selling agent” or “distributor” pro- 
vided that the name and address of the manufacturer is given prece- 
dence in prominence. 
§ 22.55 Products for export.—Labels on packages or containers of 
products for export may be adapted to meet specific requirements of 
the regulations of the country to which the product is to be exported 
provided that in all such cases the minimum label requirements 
prescribed in § 22.50 are observed. 
STANDARDS FOR PRODUCTS; GENERAL 
§ 22.70 Tests prior to release—(a) Required for each lot.—No lot 
of any licensed product shall be released by the manufacturer prior 
to the completion of tests for conformity with the standards applicable 
to such product. 
(b) Potency.—Tests for potency shall be made on each lot only after 
completion of those processes of manufacture which may affect the 
potency of the final product. 
(c) Identity and safety.—The contents of a final container of each 
filling of each lot shall be tested for identity, if such a test is available, 
and for safety either after the labels have been affixed to the final 
container or affixed, both outside and inside, to the multiple container 
storage receptable just prior to its sealing for storage purposes, except 
that exceptions to this procedure may be authorized by the Institute 
to apply when the volume of the final container is very large and when 
more than one lot is processed each day. 
(d) Sterility.—Samples from final containers selected at random 
after each filling from each lot of products shall be tested for sterility. 
§22.71 Tests: by whom made.—Tests for safety, purity and 
potency applicable to the product shall be completed for each lot of 
any licensed product prior to its release by the manufacturer, and 
samples of any lot of any licensed product may at any time be required 
to be sent to the Institute for examination. 
§ 22.72 Ingredients, preservatives, diluents.—All ingredients used 
in a licensed product, and any diluent provided as an aid in the 
administration of the product shall meet generally accepted standards 
of purity and quality. Any preservative used shall be 
nontoxic so that the amount present in the recommended dose of the 
product will not be toxic to the recipient, and in the combination used 14 
shall not denature the specific substances in the product below the 
minimum acceptable potency within the dating period when stored 
at the recommended temperature. 
§ 22.73 Total solids in serums.—Except as otherwise provided by 
regulation, no liquid serum or antitoxin shall contain more than 20 
percent total solids. 
§ 22.74 Permissible combinations.—Licensed products may not be 
combined with other licensed products, either therapeutic, prophy- 
lactic or diagnostic, except as a license is obtained for the combined 
product. Licensed products may not be combined with nonlicensable 
therapeutic, prophylactic, or diagnostic substances except as a license is 
obtained for such combination. 
§ 22.75 Container and closure.—Glass used in the container of a 
licensed product intended for administration by injection shall be 
colorless and fully transparent. The quality of the glass and of the 
closure used shall be such as will not hasten the deterioration of the 
licensed product or render it less suitable for the use intended within 
the dating period. 
§ 22.76 Standard units or samples.—Standard units or samples for 
comparison made available by the Institute shall be applied in testing 
for potency all forms of diphtheria antitoxin, tetanus antitoxin, 
botulism antitoxin Type A, botulism antitoxin Type B, perfringens 
antitoxin, scarlet fever streptococcus antitoxin, vibrion septique anti- 
toxin, antipneumococcic serum (Types I, 11, V, VII, and VIII), 
dysentery antitoxin (Shiga), staphylococcus antitoxin, histolyticus 
antitoxin, oedematiens antitoxin, and sordelli antitoxin and other 
products for which such units are available. 
§ 22.77 Standards of potency/ particular products.—Diphtheria 
antitoxin shall have a potency of not less than 500 units per milliliter. 
Tetanus antitoxin shall have a potency of not less than 400 units per 
milliliter. Scarlet fever streptococcus antitoxin shall have a potency 
of not less than 400 units per milliliter. Antitoxins dispensed in the 
dried state shall represent liquid antitoxins of not less than these 
potencies. 
§ 22.78 Bating period; date of manufacture.—The dating period 
shall be determined with reference to the date of manufacture which 
shall be: 
(a) For products for which an official standard of potency exists 
or which are subject to official potency tests, the last date of satisfac- 
torily passing a potency test; 
(b) For products for which no official standard of potency exists 
or which are not subject to official potency tests, 
(1) The date of removal from the animal in case of animal 
products; 15 
(2) The date of extraction in the case of products used for specific 
desensitization; 
(3) The date of solution in case of venoms, and 
(4) The date of cessation of growth in case of other products; 
(c) For products which are submitted to the Institute for approval 
prior to release, the date of official release notice. 
§ 22.79 Dating period; products in cold storage.—The dating 
period may be determined with reference to the period of issue from 
cold storage, Provided, That, except as may be otherwise prescribed 
for individual products, the date of such issue is not more than 6 
months after the date of manufacture and the product is kept con- 
stantly at a temperature not exceeding 10° C., or not more than 1 year 
after the date of manufacture if the product is kept constantly at 
a temperature not exceeding 5° C., or not more than 2 years if the 
product is kept constantly at a temperature not exceeding 0° C. 
ADDITIONAL STANDARDS: TRIYALENT ORGANIC ARSENICALS 
§22.90 Tests 'prior to release.—Tests required to be made, prior 
to the release of each lot of a licensed product, shall be supplemented 
in the case of the trivalent organic arsenicals by tests for: 
(a) Stability. 
(b) Solubility. 
(c) Arsenic content, 
(d) Moisture. 
(e) Relative nontoxicity. 
§ 22.91 Pretesting by Institute; samples of each lot.—Prior to the 
release of any lot of the product, the manufacturer shall forward to 
the Institute no less than 15 ampoules of the largest single-dose size 
in such lot, together with protocols showing the results of each test 
required prior to release. 
§ 22.92 Expiration date.—Notification from the Institute that lot 
samples forwarded in accordance with § 22.91 have satisfactorily 
passed prescribed tests shall indicate a date which may be taken as 
the date of manufacture for the purpose of fixing the expiration date. 
The date of issue shall be the same as the date of manufacture. 
§ 22.93 Composition of product.—Solutions or solutions of mix- 
tures in the concentrations recommended for clinical administration 
shall be of such hydrogen ion value and tonicity as to be physiologi- 
cally compatible with human blood. 
§ 22.94 Container.—The product shall be hermetically sealed under 
vacuum or under a dry nonoxidizing gas in ampoules prepared from 
glass of the quality prescribed in § 22.75. 
§ 22.95 Final container label.—ln addition to the labeling require- 
ments stated in § 22.50 the final container label of the trivalent organic 16 
arsenicals shall bear the statements required in § 22.96 (b) and (c) 
and an additional statement giving the amount of the drug contained 
in the ampoule. 
§ 22,96 Outside label.—The outside label, in addition to the com- 
plete proper name and all other items required for products generally 
shall show conspicuously: (a) If the product is dispensed as a mixture 
or solution, the name of all admixed substances, 
(b) If the ampoule is a multiple dose container, the fact that it is 
a multiple dose container, 
(c) Specific method of preparation, if any, required prior to ad- 
ministration, as, for example, alkalinization. Appendix A 
EXCERPTS FROM THE LAW 
[Public Law 410—78 th Congress] 
[Chapter 373—2 d Session] 
[H. R. 4624] 
An act to consolidate and revise the laws relating to the Public 
Health Service, and for other purposes. 
Be it enacted by the Senate and House of Representatives of the 
United States of America in Congress assembled, 
TITLE I—SHORT TITLE AND DEFINITIONS 
SHORT TITLE 
Section 1. Titles I to V, inclusive, of this Act may be cited as the 
“Public Health Service Act.” 
TITLE lI—ADMINISTRATION 
PUBLIC HEALTH SERVICE 
Sec. 201, The Public Health Service in the Federal Security Agency 
shall be administered by the Surgeon General under the supervision 
and direction of the Administrator. 
TITLE lII—GENERAL POWERS AND DUTIES OF 
PUBLIC HEALTH SERVICE 
Part F—Biological Products 
REGULATION OF BIOLOGICAL PRODUCTS 
Sec. 351. (a) No person shall sell, barter, or exchange, or offer 
for sale, barter, or exchange in the District of Columbia, or send, 
carry, or bring for sale, barter, or exchange from any State or pos- 
session into any other State or possession or into any foreign country, 
or from any foreign country into any State or possession, any virus, 
therapeutic serum, toxin, antitoxin, or analogous product, or arsphe- 
namine or its derivatives (or any other trivalent organic arsenic com- 18 
pound), applicable to the prevention, treatment, or cure of diseases 
or injuries of man, unless (1) such virus, serum, toxin, antitoxin, or 
other product has been propagated or manufactured and prepared 
at an establishment holding an unsuspended and unrevoked license, 
issued by the Administrator as hereinafter authorized, to propagate 
or manufacture, and prepare such virus, serum, toxin, antitoxin, or 
other product for sale in the District of Columbia, or for sending, 
bringing, or carrying from place to place aforesaid; and (2) each 
package of such virus, serum, toxin, antitoxin, or other product is 
plainly marked with the proper name of the article contained therein, 
the name, address, and license number of the manufacturer, and the 
date beyond which the contents cannot be expected beyond reason- 
able doubt to yield their specific results. The suspension or revoca- 
tion of any license shall not prevent the sale, barter, or exchange of 
any virus, serum, toxin, antitoxin, or other product aforesaid which 
has been sold and delivered by the licensee prior to such suspension 
or revocation, unless the owner or custodian of such virus, serum, 
toxin, antitoxin, or other product aforesaid has been notified by the 
Administrator not to sell, barter, or exchange the same. 
(b) No person shall falsely label or mark any package or container 
of any virus, serum, toxin, antitoxin, or other product aforesaid; nor 
alter any label or mark on any package or container of any virus, 
serum, toxin, antitoxin, or other product aforesaid so as to falsify 
such label or mark. 
(c) Any officer, agent, or employee of the Federal Security Agency, 
authorized by the Administrator for the purpose, may during all 
reasonable hours enter and inspect any establishment for the propa- 
gation or manufacture and preparation of any virus, serum, toxin, 
antitoxin, or other product aforesaid for sale, barter, or exchange in 
the District of Columbia, or to be sent, carried, or brought from any 
State or possession into any other State or possession or into any 
foreign country, or from any foreign country into any State or 
possession. 
(d) Licenses for the maintenance of establishments for the propa- 
gation or manufacture and preparation of products described in sub- 
section (a) of this section may be issued only upon a showing that the 
establishment and the products for which a license is desired meet 
standards, designed to insure the continued safety, purity, and potency 
of such products, prescribed in regulations made jointly by the Sur- 
geon General, the Surgeon General of the Army, and the Sur- 
geon General of the Navy, and approved by the Administrator, and 
licenses for new products may be issued only upon a showing that 
they meet such standards. All such licenses shall be issued, suspended 
and revoked as prescribed by regulations and all licenses issued for 19 
the maintenance of establishments for the propagation or manufacture 
and preparation, in any foreign country, of any such products for 
sale, barter, or exchange in any State or possession shall be issued 
upon condition that the licensees will permit the inspection of their 
establishments in accordance with subsection (c) of this section. 
(e) No person shall interfere with any officer, agent, or employee 
of the Service in the performance of any duty imposed upon him 
by this section or by regulations made by authority thereof. 
(f) Any person who shall violate, or aid or abet in violating, any 
of the provisions of this section shall be punished upon conviction by 
\i fine not exceeding $5OO or by imprisonment not exceeding one year, 
or by both such fine and imprisonment, in the discretion of the court. 
(g) Nothing contained in this Act shall be construed as in any 
way affecting, modifying, repealing, or superseding the provisions 
of the Federal Food, Drug, and Cosmetic Act (U. S. C., 1940 edition, 
title 21, ch. 9). 
PREPARATION OF BIOLOGICAL PRODUCTS 
Sec. 352. (a) The Service may prepare for its own use any prod- 
uct described in section 351 and any product necessary to carrying 
out any of the purposes of section 301. 
(b) The Service may prepare any product described in section 351 
for the use of other Federal departments or agencies, and public or 
private agencies and individuals engaged in work in the field of medi- 
cine when such product is not available from establishments licensed 
under such section. 
Approved July 1, 1944.