Division 4

(a) in the case of a product for which a standard of potency exists, the date it satisfactorily passes a potency test,

(b) in the case of an animal product for which no standard of potency exists, the date of its removal from the animal, and

(c) in the case of a product other than an animal product for which no standard of potency exists, the date of cessation of growth; (date de fabrication)

“drug” means a drug listed in Schedule D to the Act that is in dosage form, or a drug that is a bulk process intermediate that can be used in the preparation of a drug listed in Schedule D to the Act; (drogue)

C.04.001.1 No distributor referred to in paragraph C.01A.003(b) or importer shall sell a drug unless it has been fabricated, packaged/labelled, tested and stored in accordance with this Division.

C.04.002. This Division does not apply to a drug in oral dosage form that contains micro-organisms if the drug is recommended solely for restoring, normalizing or stabilizing the intestinal flora.

C.04.003. The date of issue of a drug shall be the date on which the finished product is removed from cold storage but in any case shall be, not later than

(a) six months after the date of manufacture for a drug that has been kept constantly at a temperature not exceeding 10°C;

(b) 12 months after the date of manufacture for a drug that has been kept constantly at a temperature not exceeding 5°C; or

C.04.004. to C.04.006. [Repealed, SOR/97-12, s. 34]

C.04.007. [Repealed, SOR/97-12, s. 67]

C.04.008. to C.04.012 [Repealed, SOR/97-12, s. 36]

C.04.013. Every fabricator and packager/labeller shall safely segregate all work with spore-bearing, pathogenic micro-organisms and other infectious agents known to require special precautions in manipulation and shall take such care of equipment and arrangements for supervision that the possibility of contamination of other drugs is avoided.

C.04.014. No person shall conduct laboratory procedures of a diagnostic nature in their premises unless those procedures are entirely segregated from the fabrication, packaging/labelling and testing of drugs.

C.04.015. On written request from the Director, every fabricator, packager/labeller, tester, distributor referred to in paragraph C.01A.003(b) and importer of a drug shall submit protocols of tests together with samples of any lot of the drug before it is sold, and no person shall sell any lot of that drug if the protocol or sample fails to meet the requirements of these Regulations.

C.04.016. All animals from which drugs are prepared and preserved shall be

(b) kept in quarantine by the fabricator for at least seven days before use; and

C.04.017. A fabricator shall keep necropsy records of all animals that die or are killed after having been used in the production of a drug.

C.04.018. A fabricator shall immediately segregate, and report the fact to the Minister, any animal with actual or suspected vesicular stomatitis, foot and mouth disease, encephalomyelitis, infectious anaemia, glanders, anthrax, tetanus or any other serious infectious disease.

C.04.019. The provisions of section C.01.004 do not apply to a drug as defined in this Division but every package of such drug shall carry

(i) the proper name of the drug, which proper name, where there is a brand name, shall immediately precede or follow the brand name in type not less than one-half the size of that of the brand name,

(vi) the expiration date except upon the inner label of a single-dose container, and

(ii) for whole blood and its components, the establishment licence number of the distributor referred to in paragraph C.01A.003(b), preceded by the words “Establishment Licence Number”, “Numéro de licence d’établissement” or an abbreviation thereof,

(iii) the proper name, or the common name if there is no proper name, and the amount, of any preservative in the drug,

(iv) a statement that the drug shall be stored at a temperature of not less than 2°C and not more than 10°C, unless the Minister has received evidence demonstrating that such a statement is not required, and

C.04.020. Except in the case of the following drugs, every package of a drug listed in Schedule F of these Regulations shall carry the symbol Pr on the upper left quarter of the principal display panel of both its inner and outer labels or, in the case of a single dose container, on the upper left quarter of its outer label:

C.04.050. Except as provided in this Division, a bacterial vaccine shall be a sterile suspension of killed cultures of bacteria, with or without the addition of other medication, and shall not include an autogenous vaccine.

C.04.051. No person shall sell a bacterial vaccine unless the culture that has been used in its preparation has been tested by an acceptable method for identity and purity and when so tested it shall be true to name and a pure strain, and a record of the culture shall be maintained which shall include a statement of its origin, properties and characteristics.

C.04.052. No fabricator shall use a substrate (culture medium), in the production of a bacterial vaccine, that contains any horse meat or horse serum.

C.04.053. A fabricator of a bacterial vaccine prepared from a bacterium that does not grow readily in ordinary culture media shall test its sterility in media which are specially favourable to the growth of such bacterium, and it shall be sterile.

C.04.054. Except as provided in sections C.04.083, C.04.084 and C.04.090, both the inner and outer labels of every multiple-dose container and the outer label of every single-dose container of a bacterial vaccine shall carry a statement of

(a) the number of bacteria per millilitre, or the weight of dried substance of bacteria per millilitre,

(b) the number of bacteria per millilitre, or the weight of dried substance of bacteria per millilitre, of each species or immunogenic type for a vaccine that contains a number of different species or immunogenic types of bacteria,

and the inner label of a single-dose container shall carry a statement that it contains only one dose.

C.04.055. The expiration date of a bacterial vaccine shall be not later than 18 months after the date of manufacture or the date of issue.

C.04.060. Cultures of Salmonella typhosa used in the preparation of typhoid vaccine shall be smooth, motile, and in the Vi form, with the following antigenic structure IX,XII,Vi; d.-.

C.04.061. No person shall sell any lot of typhoid vaccine unless such lot has been shown to meet a test for potency made by an acceptable method.

C.04.065. A fabricator shall, in the preparation of pertussis (whooping cough) vaccine, use only strains of Bordetella pertussis that meet the requirements of an antigenic test made by an acceptable method.

C.04.066. No person shall sell any lot of pertussis (whooping cough) vaccine unless such lot has been shown to meet a test for potency made by an acceptable method.

C.04.070. B.C.G. vaccine shall be prepared from living B.C.G. organisms that

C.04.071. No fabricator shall employ any person in the manufacture of B.C.G. vaccine unless such person

(b) undergoes every six months a medical examination, that shall include an X-ray examination of the chest, for the presence of tuberculosis, such examination being made by a qualified, practising physician who shall sign a certificate of such person’s freedom from tuberculosis, and such certificate shall be kept on file and be available at all times, and

C.04.072. The preparation, preservation and packaging/labelling of B.C.G. vaccine shall be conducted under the direct supervision of an experienced bacteriologist who has

(a) not less than three years postgraduate training in bacteriology and immunology;

C.04.073. No fabricator shall permit any culture that is not a B.C.G. culture to be at any time on any premises that are used for the manufacture of B.C.G. vaccine.

C.04.074. A packager/labeller shall test by an acceptable method, after filling of the final container, each lot of B.C.G. vaccine for the presence of contaminating micro-organisms and when so tested it shall be free therefrom.

C.04.075. Notwithstanding section C.04.074, a fluid B.C.G. vaccine may be released for sale if no growth has appeared upon the test culture medium after an incubation of 24 hours, but if there is evidence of the presence of contaminating micro-organisms in any lot during the test period of 10 days the packager/labeller shall at once recall such lot.

C.04.076. Every fabricator and packager/labeller shall determine the number of viable B.C.G. organisms in each lot of vaccine by an acceptable method and shall keep a record of the number.

C.04.077. A fabricator of B.C.G. vaccine shall keep, at a temperature not exceeding 5.0°C, and for not less than six months,

(a) the culture on glycerine-water potato medium from which the Sauton I and Sauton II subcultures were made, and

C.04.078. Every fabricator and packager/labeller of B.C.G. vaccine shall keep, in form satisfactory to the Minister, continuous clinical records of the use of B.C.G. vaccine in humans.

C.04.079. A fabricator of B.C.G. vaccine shall examine pathologically all test animals used and shall immediately report to the Minister any evidence of active, progressive tuberculosis in any such animals.

C.04.080. The expiration date for B.C.G. vaccine shall be not more than

(b) 12 months after harvesting in the case of freeze dried vaccine stored at a temperature of 4°C or above; or

C.04.081. No person shall sell fluid B.C.G. vaccine that is not packaged in containers sealed by fusion.

C.04.082. No inner label shall be required for fluid B.C.G. vaccine in single-dose containers.

C.04.083. The label of fluid B.C.G. vaccine shall carry, in lieu of the statements provided in paragraphs C.04.054(a) and (b), a statement of

C.04.084. The label of freeze-dried B.C.G. vaccine shall carry, in lieu of the statements provided in paragraphs C.04.054(a) and (b), a statement of

C.04.085. The provisions of subparagraph C.04.019(b)(iv) do not apply to freeze-dried B.C.G. vaccine.

C.04.090. A product analogous to a bacterial vaccine shall be

and shall conform to the requirements of these Regulations for bacterial vaccines except those of paragraphs (a) and (b) of C.04.054.

C.04.091. The expiration date of a product analogous to a bacterial vaccine shall be not later than 18 months after the date of manufacture or the date of issue, but for dried tuberculin and tuberculin containing at least 50 per cent glycerin the expiration date shall be not later than five years after the date of manufacture or the date of issue, and for all other tuberculins not more than 12 months after the date of manufacture or the date of issue.

C.04.100. A virus vaccine, rickettsial vaccine, shall be a suspension of, or prepared from, living or killed viruses or rickettsiae.

C.04.101. No person shall sell a virus or a rickettsial vaccine unless the fabricator has submitted to the Minister details of the source of the strains of viruses or rickettsiae used, the method of their propagation, the method of fabrication of the vaccine, the methods employed for determining sterility, safety, identity and potency and any other tests required by these Regulations.

C.04.102. Upon written request from the Director every fabricator and packager/labeller shall submit with respect to each lot of virus or rickettsial vaccine, when ready for sale, detailed protocols of sterility, safety, identity, potency, and of any other tests required by these Regulations.

C.04.110. Smallpox vaccine

(i) the vesicles produced in the skin of healthy calves by inoculation of vaccinia virus,

(iii) suitable tissue culture infected with vaccinia virus or its derivatives; and

C.04.111. Every fabricator and packager/labeller shall fabricate and package/label smallpox vaccine only in an independent unit that is isolated from all other laboratory activities, and in or about which no extraneous materials are permitted or stored.

C.04.112. A fabricator shall exclude the personnel who care for the vaccine animals from horse stables and paddocks and from contact with horses while smallpox vaccine is being propagated.

C.04.113. Every fabricator and packager/labeller shall dispense smallpox vaccine only in sterile glass containers that are sealed under aseptic conditions.

C.04.114. Every fabricator and packager/labeller shall test smallpox vaccine to establish that it is free from

C.04.115. Smallpox vaccine, when tested by acceptable methods,

(a) shall be free from extraneous micro-organisms, in the case of vaccine prepared for use by jet gun; and

(b) shall contain not more than 500 viable non-pathogenic bacteria per millilitre, in the case of vaccine prepared for use by the multiple pressure technique or by scarification.

C.04.116. Smallpox vaccine must demonstrate evidence of disease prevention that is at least equivalent to that of a vaccine that

(b) meets the potency of equal to or greater than 108 pockforming units per millilitre, as determined using chick embryo chorioallantoic membranes.

C.04.117. No person shall sell smallpox vaccine unless

(a) in the case of fluid vaccine, it has been stored at a temperature below —10°C;

(b) in the case of dried vaccine, it has been stored at a temperature below 10°C; and

C.04.118. Notwithstanding the provisions of section C.04.003, the date of issue of smallpox vaccine shall be not later than

(a) in the case of fluid vaccine, nine months after the date of manufacture; and

C.04.119. The expiration date of smallpox vaccine shall not exceed the following, unless supported by evidence of stability satisfactory to the Minister:

C.04.120. No inner label shall be required for smallpox vaccine in single-dose containers or when dispensed in capillary tubes.

C.04.121. No person shall sell smallpox vaccine to which an antibiotic has been added.

C.04.122. Poliomyelitis vaccine shall be an aqueous suspension of killed poliomyelitis viruses, Types I, II, and III.

C.04.123. Poliomyelitis vaccine shall be prepared in acceptable tissue culture medium from strains of poliomyelitis virus proven capable of producing vaccine of acceptable potency.

C.04.124. Poliomyelitis vaccine in its final form shall contain not more than 0.35 milligram per millilitre of total nitrogen, nor more than one part per million of animal serum.

C.04.125. No person shall sell poliomyelitis vaccine unless it has been tested by an acceptable method for potency and safety and when so tested it shall be safe and of acceptable potency.

C.04.126. The outer label shall carry a statement of any antibiotic present in the vaccine.

C.04.127. The expiration date of the poliomyelitis vaccine shall be not later than 12 months after the date of the last satisfactory potency test unless evidence, satisfactory to the Director, is presented that a longer period is appropriate.

C.04.128. Poliovirus Vaccine, Live, Oral or Poliovirus Vaccine, Live, Oral (Naming the strains) shall be prepared from living poliomyelitis virus types I, II and III that

(d) are proved to be capable of multiplying in the human alimentary tract and of producing type specific neutralizing antibodies when administered orally; and

(e) have a history of successful use in the production of polio-virus vaccine, live, oral.

C.04.129. Poliovirus vaccine, live, oral, shall be fabricated, packaged/labelled and tested in premises separated from buildings where other products are fabricated, packaged/labelled or tested, and from buildings where control tests involving the use of cell lines or virus strains not employed in the fabrication, packaging/labelling and testing of poliovirus vaccine, live, oral, are carried out.

C.04.130. No fabricator shall permit the introduction of any bacterial or viral cultures other than those used in the manufacture of poliovirus vaccine, live, oral on any premises that are used for the manufacture of poliovirus vaccine, live, oral.

C.04.131. Notwithstanding sections C.04.129 and C.04.130, a fabricator may manufacture other drugs in an area in which polio-virus vaccine, live, oral is manufactured at times when that vaccine is not being manufactured, if

(a) both prior to and following each manufacture the area is cleaned and disinfected by methods acceptable to the Director; and

(b) the fabricator has received written permission from the Director to carry out such manufacture.

C.04.132. Poliovirus vaccine, live, oral shall be prepared only

C.04.133. No fabricator shall sell poliovirus vaccine, live, oral, unless he has tested each lot for extraneous micro-organisms and the vaccine is free therefrom.

C.04.134. A fabricator of poliovirus vaccine, live, oral shall test, by a method acceptable to the Director, each lot of vaccine for neurovirulence and for genetic markers and it shall meet the requirements established by the Director.

C.04.135. No fabricator shall employ any person in the manufacture of poliovirus vaccine, live, oral unless such person

(b) has been vaccinated successfully against poliomyelitis by poliovirus vaccine, live, oral; and

C.04.136. A fabricator of poliovirus vaccine, live, oral shall not permit the entry to a building in which the vaccine is manufactured of any person who

(b) has been working on the same day with experimental animals or with infectious agents.

C.04.137. Bacteriophage shall be a virus preparation with specific lytic action against micro-organisms actually or potentially pathogenic.

C.04.138. The expiration date of bacteriophage shall be not later than 12 months after the date of manufacture or the date of issue.

C.04.140. Schick test reagents for the diagnosis of susceptibility to diphtheria shall be

C.04.141. Diphtheria toxin for Schick test shall be sterile diluted diphtheria toxin stabilized by an acceptable method.

C.04.142. Schick control shall be suitably diluted

C.04.143. The human test dose of diphtheria toxin for Schick test, when aged toxin containing a preservative is used, shall be determined by

(a) intracutaneous injection into normal guinea pigs in mixtures with different proportions of diphtheria antitoxin, and one test dose mixed with 1/750 or more of a unit of antitoxin must cause no local reaction but mixed with 1/1,250 or less of a unit of antitoxin must cause a definite local reaction of the type known as the “positive Schick reaction”; and

(b) intracutaneous injection into normal guinea pigs without admixture with antitoxin, and 1/50 of one test dose must not cause, and 1/25 of one test dose must cause, a definite local reaction of the type known as the “positive Schick reaction”.

C.04.144. The human test dose of diphtheria toxin for Schick test, when fresh toxin containing no preservative is used, shall be determined by

(a) intracutaneous injection into normal guinea pigs in mixtures with different proportions of diphtheria antitoxin, and one test dose mixed with 1/750 or more of a unit of antitoxin must cause no local reaction, but mixed with 1/1,500 or less of a unit of antitoxin must cause a definite local reaction of the type known as the “positive Schick reaction”; and

(b) intracutaneous injection into normal guinea pigs without admixture with antitoxin, and 1/100 of one test dose must not cause, and 1/50 of one test dose must cause, a definite local reaction of the type known as the “positive Schick reaction”.

C.04.145. The human test dose for the Schick control shall give a negative Schick reaction when injected intracutaneously into normal guinea pigs.

C.04.146. No person shall sell diphtheria toxin for Schick test unless both the inner and the outer labels carry a statement of the number of human test doses it contains together with the name of any stabilizer.

C.04.147. The expiration date of Schick test reagents for the diagnosis of susceptibility to diphtheria shall be not later than 12 months after the date of manufacture or the date of issue.

C.04.160. Liquid diphtheria toxoid shall be sterile, formalized, detoxified diphtheria toxin and shall not contain more than 0.02 per cent free formaldehyde.

C.04.161. Diphtheria toxoid alum precipitated shall be prepared from diphtheria toxoid, and shall not contain more than 15 milligrams of alum per human dose.

C.04.162. The alum used in the preparation of diphtheria toxoid alum precipitated shall contain not less than 99.5 per cent pure potassium alum, Al K(SO4)2,12H2O.

C.04.163. No fabricator shall use a culture medium for the production of diphtheria toxin that contains horse protein or Witte peptone or that has not been freed as far as possible from any other allergenic ingredient.

C.04.164. Diphtheria toxin from which diphtheria toxoid is prepared shall have a toxicity, as indicated by an L+dose, of not more than 0.20 millilitre or by an M.L.D. of not more than 0.0025 millilitre.

C.04.165. A fabricator shall test each bulk container of diphtheria toxoid, before being dispensed into the final containers, for toxicity by an acceptable method, and it shall be non-toxic.

C.04.166. No person shall sell any lot of diphtheria toxoid unless such lot has been shown to meet a test for antigenicity made by an acceptable method.

C.04.167. A fabricator shall fill diphtheria toxoid aseptically into clear glass containers and where preservative is not added shall seal the containers by fusion.

C.04.168. No person shall sell diphtheria toxoid that contains phenol.

C.04.169. No person shall sell diphtheria toxoid unless both the inner and the outer labels carry a statement of the appropriate dose for purposes of immunization.

C.04.170. The expiration date of diphtheria toxoid shall be not later than two years after the date of manufacture or the date of issue.

C.04.180. Liquid tetanus toxoid shall be sterile, formalized, detoxified tetanus toxin, and shall not contain more than 0.02 per cent free formaldehyde.

C.04.181. Tetanus toxoid alum precipitated shall be prepared from tetanus toxoid, and shall not contain more than 15 milligrams of alum per human dose.

C.04.182. The alum used in the preparation of tetanus toxoid alum precipitated shall contain not less than 99.5 per cent pure potassium alum, Al K(SO4)2, 12H2O.

C.04.183. No fabricator shall use a culture medium for the production of tetanus toxin that contains horse protein or Witte peptone or that has not been freed as far as possible from any other allergenic ingredient.

C.04.184. Tetanus toxin from which tetanus toxoid is prepared shall have a toxicity as indicated by an M.L.D. for the guinea pig of not more than 0.0001 millilitre.

C.04.185. A packager/labeller shall test each bulk container of tetanus toxoid, before being dispensed into the final containers, for toxicity by an acceptable method, and it shall be non-toxic.

C.04.186. No person shall sell any lot of tetanus toxoid unless such lot has been shown to meet a test for antigenicity made by an acceptable method.

C.04.187. No person shall sell tetanus toxoid unless both the inner and the outer labels carry a statement of the appropriate dose for purposes of immunization.

C.04.188. A fabricator shall fill tetanus toxoid aseptically into clear glass containers and where a preservative is not added shall seal the container by fusion.

C.04.189. No person shall sell tetanus toxoid that contains phenol.

C.04.190. The expiration date of tetanus toxoid shall be not later than two years after the date of manufacture or the date of issue.

C.04.210. An antitoxin or antiserum shall be the serum or fraction thereof separated from the blood of animals that have been artificially immunized against the by-products or antigenic fractions of specific cultures of micro-organisms, or against specific venoms.

C.04.211. The potency of an antitoxin or antiserum shall be determined by an acceptable method and where applicable the unit of potency shall be the International Unit.

C.04.212. Liquid diphtheria antitoxin shall have a potency of not less than 500 International Units per millilitre.

C.04.213. Liquid tetanus antitoxin shall have a potency of not less than 400 International Units per millilitre.

C.04.214. A liquid antitoxin or antiserum shall contain not more than 20 per cent solids.

C.04.215. A dried antitoxin shall be prepared from a liquid antitoxin and, when reconstituted to the original volume of the liquid antitoxin, shall have a potency not less than that prescribed for such liquid antitoxin.

C.04.216. A dried antitoxin or antiserum shall not contain more than one per cent moisture when determined by an acceptable method.

C.04.217. Each lot of antitoxin or antiserum shall be tested by an acceptable method for pyrogenicity and it shall be pyrogen-free, and, after filling into the final containers, for identity and it shall be true to name.

C.04.218. No person shall sell an antitoxin or antiserum unless both the inner and the outer labels carry a statement of the species of animal used, when other than the horse, and the net contents in millilitres or the number of units in the container.

C.04.219. In respect of antitoxins, the expiration date shall be

(a) for liquid antitoxins with standards of potency, not later than five years after the date of manufacture;

(b) for dried antitoxins with standards of potency, not later than five years after the date of manufacture;

(d) for dried antitoxins with no standards of potency, not later than five years after the date of manufacture.

C.04.220. In respect of antisera, the expiration date shall be

(a) for liquid antisera with standards of potency, not later than three years after the date of manufacture;

(b) for dried antisera with standards of potency, not later than five years after the date of manufacture;

(d) for dried antisera with no standards of potency, not later than five years after the date of manufacture.

C.04.230. Preparations from human sources shall be pooled blood plasma, or pooled blood serum, or fractions of either separated by a method satisfactory to the Minister.

C.04.231. A fabricator shall obtain human serum, or human plasma, only from a person certified by a qualified medical practitioner to be healthy.

C.04.232. A fabricator shall not use a person to serve as a donor of blood, placenta, or cord who has a history of a disease transmissible by blood transfusion including syphilis, infectious hepatitis, or malaria.

C.04.233. The operation of drawing blood from a donor shall be under the supervision of a qualified medical practitioner, and shall be carried out in a suitable bleeding room under the control of the fabricator.

C.04.234. A fabricator shall obtain human placenta and cord used in the manufacture of preparations from human sources only from women confined in public hospitals, and the donor of such placenta and cord shall have been free from the toxaemias of pregnancy, and the placenta and cord shall not show gross evidence of any pathological condition.

C.04.235. (1) Subject to subsections (2) and (3), dried human serum, dried human plasma or dried fractions of either shall not contain more than one per cent moisture when determined by an acceptable method.

(2) Dried Rho(D) Immune Human globulin shall not contain more than three per cent moisture when determined by an acceptable method.

(3) Dried Antihemophilic Factor Human shall not contain more than two per cent moisture when determined by an acceptable method.

C.04.236. A fabricator shall provide directions or means for the removal of particles of such size as to be dangerous to the recipient from preparations from human sources that are issued in fluid form or that are reconstituted from the dried form.

C.04.237. A fabricator of preparations from human sources shall maintain complete records of all donors, which records shall include the medical certificate required by section C.04.231.

C.04.238. A fabricator, packager/labeller or distributor referred to in paragraph C.01A.003(b) may issue human serum or human plasma, or fractions of either of them, for prophylactic or therapeutic use in any of the following forms:

(a) immune human serum, which shall be serum separated from the blood of persons recovered from the disease or from persons specifically immunized against the disease for which the serum is intended as a prophylactic or therapeutic agent;

(b) immune human globulins, or other immune human serum fractions, which shall be prepared from immune human serum or plasma;

(c) normal human serum, or normal human plasma, or fractions of either of these prepared from the blood of normal individuals; and

C.04.239. No person shall sell a preparation from human sources unless both the inner and the outer labels clearly indicate that the preparation is derived from human sources.

C.04.240. The expiration date for preparations from human sources issued in fluid or dried form shall be not later than five years after the date of filling the immediate container.

C.04.241. The date of manufacture of preparations from human sources shall be the date of bleeding the donor.

C.04.300. and C.04.301. [Repealed, SOR/81-335, s. 3]