S.I. No. 46/1936 - Therapeutic Substances (Saorstát Eireann) (Amendment) (No. 2) Regulations, 1936.

DEPARTMENT OF LOCAL GOVERNMENT AND PUBLIC HEALTH.

THE THERAPEUTIC SUBSTANCES (SAORSTÁT EIREANN) (AMENDMENT) (No. 2) REGULATIONS, 1936.

The Minister for Local Government and Public Health in exercise of the powers conferred on him by the Therapeutic Substances Act, 1932 , does by this his Order, after consultation with the Therapeutic Substances Advisory Committee, make the following Regulations, that is to say:—

1.—(1) These Regulations may be cited as the Therapeutic Substances (Saorstát Eireann) (Amendment) (No. 2) Regulations, 1936, and shall be construed as one with the Therapeutic Substances (Saorstát Eireann) Regulations, 1934 and 1935.

(2) The Therapeutic Substances (Saorstát Eireann) Regulations, 1934 and 1935, and these Regulations may be cited together as the Therapeutic Substances (Saorstát Eireann) Regulations, 1934 to 1936.

(3) In these Regulations, the expression "the Principal Regulations" means the Therapeutic Substances (Saorstát Eireann) Regulations, 1934.

(4) These Regulations shall come into operation on the First day of April, 1936.

2.—The Principal Regulations shall be amended by the addition to the Second Schedule thereof of Parts I and II of the Schedule to these Regulations in manner following, that is to say:—

(a) Part I of the Schedule to these Regulations shall be appended to Part II (Toxins and Antigens) of the Second Schedule to the Principal Regulations; and

(b) Part II of the Schedule to these Regulations shall be appended to Part IV (Provisions applicable to particular Sera and Antitoxins) of the Second Schedule to the Principal Regulations.

3.—Part II (B) of the Second Schedule to the Principal Regulations is hereby rescinded and Part III of the Schedule to these Regulations shall be substituted therefor.

SCHEDULE.

PART I.

(F)

PROVISIONS APPLICABLE TO STAPHYLOCOCCUS TOXOID.

Definition and proper name.

1. Staphylococcus Toxoid is staphylococcus toxin (the sterile filtrate from a culture on a suitable medium of a toxigenic strain of staphylococcus), the specific toxicity of which has been reduced to a low value by the action of chemical substances in such a manner that it retains efficient properties as an immunising antigen. Its proper name is "Staphylococcus Toxoid."

Staphylococcus Toxoid may be issued either—

(a) undiluted; or

(b) already diluted with an appropriate saline solution to the strength suitable for injection.

Labelling.

2. The label on the container shall indicate the dose, or doses, appropriate for administration at one injection to a human subject.

Tests.

3. Staphylococcus Toxoid shall be submitted to the following tests; it shall not be issued unless it passes all of the tests.

(a) Tests to determine that the specific toxicity of the toxin used in its preparation has been sufficiently reduced.

(i) One volume of the undiluted staphylococcus toxoid shall be added to four volumes of physiological saline solution; equal volumes of this dilution of staphylococcus toxoid and of a 2 per cent. suspension of washed red blood corpuscles of the rabbit shall be mixed; when the mixture is heated to 37° C. for one hour there must be no significant haemolysis.

(ii) 0.2 c.c. of the undiluted staphylococcus toxoid shall be injected intracutaneously into a normal rabbit or guinea-pig; this injection may cause a slight local reaction but must not produce necrosis.

(iii) Two rabbits shall be injected intravenously with doses of staphylococcus toxoid calculated at the rate of 2.5 c.c. per kilogram body weight; this injection must not cause the death of either rabbit within three days following the injection.

(b) Test for non-specific toxicity.

Two normal mice shall be injected intraperitoneally with 0.5 c.c. of the undiluted toxoid; this injection must not cause the death of either animal within seven days following the injection.

(c) Tests for potency as an immunising antigen.

1 c.c. of the undiluted staphylococcus toxoid shall be injected into each of not less than nine normal guinea-pigs on each of two occasions separated by an interval of not more than four weeks; at a date not later than two weeks after the second injection the staphylococcus antitoxin present in the serum of each guinea-pig shall be determined.

If the serum of each of two-thirds or more of the guinea-pigs tested contains 0.5 unit or more of staphylococcus antitoxin per c.c. of serum, or, alternatively, if the serum of each of one-third or more of the guinea-pigs tested contains 1 unit or more of staphylococcus antitoxin per c.c. of serum, the toxoid shall be accepted as sufficiently potent.

PART II.

(F)

PROVISIONS APPLICABLE TO ANTIPNEUMOCOCCUS SERUM (TYPE I).

Proper Name.

1. Antipneumococcus Serum (Type I) is the serum, or the globulins containing the specific immune substances, separated from the blood of animals which have been immunised against cultures of a pneumococcus (Diplococcus pneumoniæ) of the variety known as Type 1. The proper name of the substance is "Antipneumococcus Serum (Type I)".

Standard Preparation.

2. The standard preparation is a quantity of dried antipneumococcus serum (Type I) kept in an institution approved by the Minister.

Quality.

3.—(1) Antipneumococcus Serum (Type I) shall be issued for therapeutic use in the form of either—

(a) the natural serum i.e., the fluid obtained from the coagulated blood or plasma of the immunised animals, without any addition other than antiseptic, or subtraction; or

(b) the solution of the globulins containing the specific immune substances; or

(c) the dried solid prepared from (i) the natural serum or (ii) the globulins containing the specific immune substances.

(2) If issued in fluid form the liquid shall, at the time of issue, be clear or show, at most, a slight opalescence or precipitate. Preparations of the natural serum (the liquid product of decantation of the coagulated blood or plasma without any addition, other than antiseptic, or substraction) shall not contain more than 10 per cent. of total solid matter. A solution of the separated globulins shall not contain more than 20 per cent. of total solid matter.

Strength.

4. The potency in units of antipneumococcus serum (Type I) shall be determined, in accordance with a method approved by the Minister, by comparison of the activity of the serum under test in protecting animals against the lethal action of a virulent culture of Diplococcus pneumoniæ (Type I) with the activity under identical conditions of the standard preparation of antipneumococcus serum (Type I).

Unit of Standardisation.

5. The unit of antipneumococcus serum (Type I) for the purposes of these Regulations is that quantity of the standard preparation which the Minister may from time to time indicate as the quantity exactly equivalent to the unit accepted for international use.

Labelling.

6.—(1) The label on the container shall indicate—

(a) the minimum total number of units in the container, and

(b) either (i) the potency of the preparation expressed as the minimum number of units per c.cs. in the case of liquid products or as the minimum number of units per gramme in the case of dry products; or

(ii) the total number of c.c. in the container.

(2) The label on the container or the label or wrapper on the package shall indicate the nature of the particular product, that is to say, whether natural serum, a solution of antitoxic globulins, dried natural serum or dried antitoxic globulins.

(3) The date to be indicated under Regulation 8 (3) (e) shall not be later than two years after the date of manufacture.

Mixed Antipneumococcus Sera.

7. A mixed antipneumococcus serum containing antibodies against strains of Diplococcus pneumoniæ other than those of the variety known as Type I, shall, with respect to its content in units of antipneumococcus serum (Type I) conform with paragraphs 4, 5 and 6 of this part of this Schedule.

(G)

PROVISIONS APPLICABLE TO ANTIPNEUMOCOCCUS SERUM (TYPE II).

Proper Name.

1. Antipneumococcus Serum (Type II) is the serum, or the globulins containing the specific immune substances, separated from the blood of animals which have been immunised against cultures of a pneumococcus (Diplococcus pneumoniæ) of the variety known as Type II. The proper name of the substance is "Antipneumococcus Serum (Type II)."

Standard Preparation.

2. The standard preparation is a quantity of dried antipneumococcus serum (Type II) kept in an institution approved by the Minister.

Quality.

3.—(1) Antipneumococcus Serum (Type II) shall be issued for therapeutic use in the form of either—

(a) the natural serum i.e., the fluid obtained from the coagulated blood or plasma of the immunised animals, without any addition other than antiseptic, or subtraction; or

(b) the solution of the globulins containing the specific immune substances; or

(c) the dried solid prepared from (i) the natural serum or (ii) the globulins containing the specific immune substances.

(2) If issued in fluid form the liquid shall, at the time of issue, be clear or show, at most, a slight opalescence or precipitate. Preparations of the natural serum (the liquid product of decantation of the coagulated blood or plasma without any addition, other than antiseptic, or substraction) shall not contain more than 10 per cent. of total solid matter. A solution of the separated globulins shall not contain more than 20 per cent. of total solid matter.

Strength.

4. The potency in units of antipneumococcus serum (Type II) shall be determined, in accordance with a method approved by the Minister, by comparison of the activity of the serum under test in protecting animals against the lethal action of a virulent culture of Diplococcus pneumoniæ (Type II) with the activity under identical conditions of the standard preparation of antipneumococcus serum (Type II).

Unit of Standardisation.

5. The unit of antipneumococcus serum (Type II) for the purposes of these Regulations is that quantity of the standard preparation which the Minister may from time to time indicate as the quantity exactly equivalent to the unit accepted for international use.

Labelling.

6.—(1) The label on the container shall indicate—

(a) the minimum total number of units in the container; and

(b) either (i) the potency of the preparation expressed as the minimum number of units per c.c. in the case of liquid products or as the minimum number of units per gramme in the case of dry products; or

(ii) the total number of c.c. in the container.

(2) The label on the container or the label or wrapper on the package shall indicate the nature of the particular product, that is to say, whether natural serum, a solution of antitoxic globulins, dried natural serum or dried antitoxic globulins.

(3) The date to be indicated under Regulation 8 (3) (e) shall not be later than two years after the date of manufacture.

Mixed antipneumococcus sera.

7. A mixed antipneumococcus serum containing antibodies against strains of Diplococcus pneumoniæ other than those of the variety known as Type II, shall, with respect to its content in units of antipneumococcus serum (Type II) conform with paragraphs 4, 5 and 6 of this part of this Schedule.

(H)

PROVISIONS APPLICABLE TO STAPHYLOCOCCUS ANTITOXIN.

Proper Name.

1. Staphylococcus antitoxin is the serum, or the antitoxic globulins, separated from the blood of animals which have been immunised against the toxin prepared by artificial culture on suitable media of Staphylococci obtained from cases of infection. The staphylococcus toxin is characterised by its lethal action when injected into susceptible animals, by the production of inflammation and necrosis when injected intracutaneously into susceptible animals, and by its lytic action in vitro on the red blood corpuscles of the rabbit. Staphylococcus antitoxin is characterised by its power of neutralizing these activities of the staphylococcus toxin when mixed with it in effective proportions. The proper name of the substance is "Staphylococcus Antitoxin".

Standard Preparation.

2. The standard preparation is a quantity of dried staphylococcus antitoxin kept in an institution approved by the Minister.

Quality.

3.—(1) Staphylococcus antitoxin shall be issued for therapeutic use in the form of either—

(a) the natural serum i.e., the fluid obtained from the coagulated blood or plasma of the immunised animals, without any addition other than antiseptic, or subtraction; or

(b) the solution of the globulins containing the specific immune substances; or

(c) the dried solid prepared from (i) the natural serum or (ii) the globulins containing the specific immune substances.

(2) If issued in fluid form the liquid shall, at the time of issue, be clear or show, at most, a very slight opalescence or precipitate. Preparations of the natural serum (the liquid product of decantation of the coagulated blood or plasma without any addition, other than antiseptic, or substraction) shall not contain more than 10 per cent. of solid matter. A solution of the separated antitoxic globulins shall not contain more than 20 per cent. of total solid matter.

Strength.

4.—(1) The potency in units of staphylococcus antitoxin shall be determined, in accordance with a method approved by the Minister and based on the specific neutralising action of the antitoxin under test on a staphylococcus toxin which has been standardised in relation to the standard preparation of staphylococcus antitoxin.

(2) Each container of staphylococcus antitoxin shall contain a sufficient number of units in excess of the total minimum of units indicated on the label to ensure that the said minimum total number of units will still be present in the container at the date appearing on the label pursuant to Article 8 (3) (e) of the Principal Regulations as the date up to which the preparation may be expected to retain its potency.

Unit of Standardisation.

5. The unit of staphylococcus antitoxin for the purposes of these Regulations is the specific neutralizing activity for staphylococcus toxin contained in such an amount of the standard preparation as the Minister may from time to time indicate as the quantity exactly equivalent to the unit accepted for international use.

Labelling.

6.—(1) The label on the container shall indicate—

(a) the minimum total number of units in the container; and

(b) either (i) the potency of the preparation expressed as the minimum number of units of antitoxin per c.c. in the case of liquid products, or as the minimum number of units of antitoxin per gramme in the case of dry products; or

(ii) the total number of c.cs. in the container.

(2) The label on the container or the label or wrapper on the package shall indicate the nature of the particular product, that is to say, whether natural serum, a solution of antitoxic globulins, dried natural serum or dried antitoxic globulins.

(I)

PROVISIONS APPLICABLE TO GAS-GANGRENE ANTITOXIN (OEDEMATIENS).

Proper Name.

1. Gas-Gangrene Antitoxin (œdematiens) is the serum, or the antitoxin globulins, separated from the blood of animals which have been immunised against the specific toxin prepared by the growth of Clostridium œdematiens in a fluid medium. The proper name of the substance is "Gas-Gangrene Antitoxin (œdematiens)".

Standard Preparation.

2. The standard preparation is a quantity of dried gas-gangrene antitoxin (œdematiens) kept in an institution approved by the Minister.

Quality.

3.—(1) Gas-Gangrene Antitoxin (œdematiens) shall be issued for therapeutic use in the form of either—

(a) the natural serum i.e., the fluid obtained from the coagulated blood or plasma or the immunised animals without any addition other than antiseptic, or subtraction; or

(b) the solution of the globulins containing the specific immune substances; or

(c) the dried solid prepared from (i) the natural serum or (ii) the globulins containing the specific immune substances.

(2) If issued in fluid form the liquid shall, at the time of issue, be clear or show, at most, a very slight opalescence or precipitate. Preparations of the natural serum (the liquid product of decantation of the coagulated blood or plasma without any addition, other than antiseptic, or substraction) shall not contain more than than 10 per cent. of solid matter. A solution of the separated antitoxic globulins shall not contain more than 20 per cent. of solid matter.

Strength.

4.—(1) The potency in units of gas-gangrene antitoxin (œdematiens) shall be determined, by a method approved by the Minister, by the injection into animals of a mixture of the antitoxin under test with a gas-gangrene (œdematiens) toxin which has been standardised in relation to the standard preparation of gas-gangrene antitoxin (œdematiens).

(2) Each container of gas-gangrene antitoxin (œdematiens) shall contain a sufficient number of units in excess of the mimimum total number of units indicated on the label to ensure that the said minimum total number of units will still be present in the container at the date appearing on the label pursuant to Article 8 (3) (e) of the Principal Regulations as the date up to which the preparation may be expected to retain its potency.

Unit of Standardisation.

5. The unit of gas-gangrene antitoxin (œdematiens) for the purposes of these Regulations is the specific neutralising activity for gas-gangrene (œdematiens) toxin contained in such an amount of the standard preparation as the Minister may from time to time indicate as the quantity exactly equivalent to the unit accepted for international use.

Labelling.

6.—(1) The label on the container shall indicate—

(a) the minimum total number of units in the container; and

(b) either (i) the potency of the preparation expressed as the minimum number of units of antitoxin per c.c. in the case of liquid products, or as the minimum number of units of antitoxin per gramme in the case of dry products; or

(ii) the total number of c.c. in the container.

(2) The label on the container or the label or wrapper on the package shall indicate the nature of the particular product, that is to say, whether natural serum, a solution of antitoxic globulins, dried natural serum or dried antitoxic globulins.

Mixed Antitoxins.

7. A mixed antitoxin, containing antitoxins against other toxins than that of Clostridium œdematiens shall, with respect to its content in units of gas-gangrene antitoxin (œdematiens) conform with paragraphs 4, 5 and 6 of this Part of this Schedule.

(J)

PROVISIONS APPLICABLE TO GAS-GANGRENE ANTITOXIN

(VIBRION SEPTIQUE).

Proper Name.

1. Gas-Gangrene Antitoxin (Vibrion septique) is the serum, or the antitoxic globulins, separated from the blood of animals which have been immunised against the specific toxin prepared by the growth of the clostridium commonly known as Vibrion septique in a fluid medium. The proper name of the substance is "Gas-Gangrene Antitoxin (Vibrion septique)".

Standard Preparation.

2. The standard preparation is a quantity of dried gas-gangrene antitoxin (Vibrion septique) kept in an institution approved by the Minister.

Quality.

3.—(1) Gas-Gangrene Antitoxin (Vibrion septique) shall be issued for therapeutic use in the form of either—

(a) the natural, i.e., the fluid obtained from the coagulated serum blood or plasma of the immunised animals without any addition other than antiseptic, or subtraction; or

(b) the solution of the globulins containing the specific immune substances; or

(c) the dried solid prepared from (i) the natural serum or (ii) the globulins containing the specific immune substances.

(2) If issued in fluid form the liquid shall, at the time of issue, be clear or show, at most, a very slight opalescence or precipitate. Preparations of the natural serum (the liquid product of decantation of the coagulated blood or plasma without any addition, other than antiseptic, or substraction) shall not contain more 10 per cent. of solid matter. A solution of the separated antitoxic globulins shall not contain more than 20 per cent. of solid matter.

Strength.

4.—(1) The potency in units of gas-gangrene antitoxin (Vibrion septique) shall be determined, by a method approved by the Minister, by the injection into animals of a mixture of the antitoxin under test with a gas-gangrene (Vibrion septique) toxin which has been standardised in relation to the standard preparation of gas-gangrene antitoxin (Vibrion septique).

(2) Each container of gas-gangrene antitoxin (Vibrion septique) shall contain a sufficient number of units in excess of the minimum total number of units indicated on the label to ensure that the said minimum total number of units will still be present in the container at the date appearing on the label pursuant to Article 8 (3) (e) of the Principal Regulations as the date up to which the preparation may be expected to retain its potency.

Unit of Standardisation.

5. The unit of gas-gangrene antitoxin (Vibrion septique) for the purposes of these Regulations is the specific neutralising activity for gas-gangrene (Vibrion septique) toxin contained in such an amount of the standard preparation as the Minister may from time to time indicate as the quantity exactly equivalent to the unit accepted for international use.

Labelling.

6.—(1) The label on the container shall indicate—

(a) the minimum total number of units in the container; and

(b) either (i) the potency of the preparation expressed as the minimum number of units of antitoxin per c.c. in the case of liquid products, or as the minimum number of units of antitoxin per gramme in the ease of dry products; or

(ii) the total number of c.c. in the container.

(2) The label on the container or the label or wrapper on the package shall indicate the nature of the particular product, that is to say, whether natural serum, a solution of antitoxic globulins, dried natural serum or dried antitoxic globulins.

Mixed Antitoxins.

7. A mixed antitoxin, containing antitoxins against other toxins than that of the clostridium commonly known as Vibrion septique shall, with respect to its content in units of gas-gangrene antitoxin (Vibrion septique) conform with paragraphs 4, 5 and 6 of this Part of this Schedule.

PART III.

(B)

PROVISIONS APPLICABLE TO DIPHTHERIA PROPHYLACTIC.

Definition and Proper Name.

1. Diphtheria Prophylactic is diphtheria toxin (the sterile filtrate from a culture on nutrient broth of Corynebacterium diphtheriœ), or material derived therefrom, the specific toxicity of which has been reduced to a low value by the action of chemical substances in such a manner that it retains efficient properties as an immunising antigen. To it may be added diphtheria antitoxin. Its proper name is "Diphtheria Prophylactic."

No preparations containing unmodified diphtheria toxin shall be issued for the prophylaxis of diphtheria.

Labelling.

2. The label on the container shall bear a statement of the dose (hereinafter referred to as the "human dose") appropriate for administration at one injection to a human subject.

Tests.

3. Diphtheria Prophylactic shall be submitted to the following tests:—

(a) Tests to determine that the, specific toxicity of the toxin used in its preparation has been so reduced that it does not exceed the prescribed maximum.—Five human doses of the Diphtheria Prophylactic under test shall be injected into each of five normal guinea-pigs each weighing 250 to 350 grammes. This injection must not cause the death of any of the guinea-pigs within six days following the injection. If all the guinea-pigs injected survive for six days but any of them die within thirty days following the injection from the specific toxæmia, one human dose of the Diphtheria Prophylactic under test shall be injected into each of five normal guinea-pigs, each weighing 250 to 350 grammes. This injection must not cause the death of any of the guinea-pigs within 30 days following the injection.

If a batch of Diphtheria Prophylactic is shown by either of these tests to have a greater toxicity than the maximum hereby indicated, it shall not be issued unless and until the toxicity has been so reduced by further treatment that it does not exceed that maximum.

(b) Tests for potency as an immunising antigen.—A quantity of Diphtheria Prophylactic not exceeding five human doses shall be injected on one occasion into each of at least ten normal guinea-pigs; or, alternatively, a quantity of Diphtheria Prophylactic not exceeding one-tenth of a human dose shall be injected into each of at least ten normal guinea-pigs on each of two occasions, separated by an interval of not more than four weeks. The guinea-pigs shall be tested for immunity to diphtheria toxin, if they have received the single injection hereinbefore prescribed, at a date not later than six weeks after injection, and if they have received the two injections hereinbefore prescribed, at a date not later than three weeks after the second injection, by intracutaneous injection into each guinea-pig of one test dose of Schick Toxin. If more than two out of ten guinea-pigs thus tested, or more than one quarter of the number tested if this is greater than ten, exhibit a positive Schick reaction, the batch of Diphtheria Prophylactic shall be treated as insufficiently potent, and shall not be issued:

Provided that in the case of the form of Diphtheria Prophylactic known as Toxoid-Antitoxin Floccules the Prophylactic may be similarly injected into nine or more normal guinea-pigs which may be tested for immunity to Diphtheria Toxin by two separate but simultaneous intracutaneous injections into each of at least nine of these guinea-pigs of one test dose and two test doses, respectively, of Schick Toxin. If two-thirds or more of the guinea-pigs tested do not exhibit a positive reaction to one test dose of Schick Toxin; or alternatively, if one-third or more of the guinea-pigs tested do not exhibit a positive reaction to two test doses of Schick Toxin, the batch shall be accepted as sufficiently potent.

Given under the Official Seal of the Minister for Local Government and Public Health this 14th day of February, One Thousand Nine Hundred and Thirty-six.

(Signed) SEÁN T. Ó CEALLAIGH,

Minister for Local Government and Public Health.