Food and Drug Regulations (C.R.C., c. 870)

C.04.574 The expiration date printed on the inner and outer labels of every package of Insulin Zinc Suspension — Prolonged shall be a date not later than two years after the date of filling of the immediate container.

Globin Insulin with Zinc

C.04.575 The insulin preparation “Globin Insulin with Zinc” shall be a sterile solution of insulin modified by the addition of globin prepared from beef blood, in the form of globin hydrochloride, and zinc, shall be a clear, yellowish, or almost colourless liquid free from insoluble matter and acceptably free from turbidity, shall have a pH of not less than 3.4 and not more than 3.8 and shall contain,

• (a) weight by volume, not less than 1.3 per cent and not more than 1.7 per cent glycerin, and either

  • (i) not less than 0.15 per cent and not more than 0.20 per cent cresol, or

  • (ii) not less than 0.20 per cent and not more than 0.26 per cent phenol, and

• (b) as determined by an acceptable method, for each 1,000 International Units of insulin,

  • (i) not more than 15.0 milligrams of total nitrogen,

  • (ii) not less than 36.0 milligrams and not more than 40.0 milligrams of globin calculated as 6.0 times the nitrogen content of the globin, and

  • (iii) not less than 2.5 milligrams and not more than 3.5 milligrams of zinc.

C.04.576 The globin hydrochloride used in the preparation of Globin Insulin with Zinc shall contain not less than 16.0 per cent and not more than 17.5 per cent nitrogen calculated on a dry, ash-free and hydrochloric acid-free basis, and its ash content shall be not more than 0.3 per cent as determined by an acceptable method.

C.04.577 The insulin used in the preparation of Globin Insulin with Zinc shall be obtained from one or more master lots and shall be present in an amount sufficient to provide either 40 or 80 International Units of insulin in each cubic centimetre of the Globin Insulin with Zinc.

• C.04.578 (1) The Canadian Reference Standard for Globin Insulin with Zinc shall be the standard adopted therefor by the Minister from time to time.

• (2) Upon application of a person who holds an establishment licence, the Minister shall furnish him with a portion of the Canadian Reference Standard with directions for comparative testing.

• (3) The testing of the biological reaction of Globin Insulin with Zinc shall be made by an acceptable method and that biological reaction shall be comparable to the biological reaction of the portion of the Canadian Reference Standard furnished by the Minister.

C.04.579 No person shall sell Globin Insulin with Zinc unless

• (a) it is dispensed in a vial of approximately 10 cubic centimetre capacity that contains an excess volume sufficient to permit withdrawal of 10 cubic centimetres; and

• (b) each cubic centimetre thereof provides,

  • (i) 40 International Units of insulin, or

  • (ii) 80 International Units of insulin.

• C.04.580 (1) A fabricator shall not sell Globin Insulin with Zinc unless he

  • (a) has filed with the Minister, in accordance with subsection (2), a submission relating to that preparation, in a form and having a content satisfactory to the Minister;

  • (b) has furnished the Minister with such additional information as the Minister may require; and

  • (c) has received from the Minister a notice that the information contained in the submission is in accordance with the requirements of this section.

• (2) A submission filed pursuant to subsection (1) shall include at least,

  • (a) for each master lot of insulin or zinc-insulin crystals employed in the manufacture of Globin Insulin with Zinc,

    • (i) protocols of assay of its potency expressed in International Units per cubic centimetre in the case of insulin, and in International Units per milligram in the case of zinc-insulin crystals,

    • (ii) a report of its moisture content in percentage determined by drying to constant weight at 100°C in the case of zinc-insulin crystals, and

    • (iii) reports of assay of its nitrogen content in milligrams and its zinc content in milligrams per 1,000 International Units of insulin;

  • (b) for the master lot of globin hydrochloride used in the preparation of Globin Insulin with Zinc, reports of assay of

    • (i) its nitrogen content in per cent calculated on a dry, ash-free and hydrochloric acid free basis,

    • (ii) its chloride content in per cent calculated as hydrochloride, and

    • (iii) its ash content in percentage;

  • (c) for the components used in the preparation of the trial mixture of Globin Insulin with Zinc, a report on the quantity of

    • (i) insulin in grams, or in International Units,

    • (ii) zinc in grams, or in milligrams, per 1,000 International Units of insulin,

    • (iii) globin hydrochloride in grams or in milligrams, per 1,000 International Units of insulin, and

    • (iv) the volume of the preparation in cubic centimetres or litres;

  • (d) for the trial mixture of Globin Insulin with Zinc,

    • (i) a report of assay of its nitrogen content in milligrams per cubic centimetre or per 1,000 International Units of insulin,

    • (ii) a report of assay of its zinc content in milligrams per cubic centimetre or per 1,000 International Units of insulin,

    • (iii) protocols of the biological reaction showing the retardation of the insulin effect, and

    • (iv) a report on the determination of its pH;

  • (e) for the first finished lot of Globin Insulin with Zinc from each trial mixture of Globin Insulin with Zinc, a report on the amount of each component in the preparation; and

  • (f) for the first filling of the first finished lot of Globin Insulin with Zinc from each trial mixture of Globin Insulin with Zinc,

    • (i) a report of assay of its nitrogen content in milligrams per cubic centimetre or per 1,000 International Units of insulin,

    • (ii) a report of assay of its zinc content in milligrams per cubic centimetre or per 1,000 International Units of insulin, and

    • (iii) a report on the determination of its pH.

    • (iv) [Repealed, SOR/95-203, s. 6]

C.04.581 The expiration date printed on the inner and outer labels of every package of Globin Insulin with Zinc shall be a date not later than two years after the date of filling of the immediate container.

NPH Insulin or Isophane Insulin

C.04.582 The insulin preparation “NPH Insulin” or “Isophane Insulin” shall be a sterile preparation of rod-shaped crystals containing insulin, protamine and zinc, suspended in a buffered aqueous medium, shall have a pH of not less than 7.0 and not more than 7.8 and shall contain

• (a) weight by volume, not less than 0.15 per cent and not more than 0.25 per cent anhydrous disodium phosphate, and either

  • (i) not less than 1.4 per cent and not more than 1.8 per cent glycerin and not less than 0.15 per cent and not more than 0.17 per cent metacresol and not less than 0.06 and not more than 0.07 per cent phenol, or

  • (ii) not less than 0.40 per cent and not more than 0.45 per cent sodium chloride and not less than 0.7 per cent and not more than 0.9 per cent glycerin and not less than 0.18 per cent and not more than 0.22 per cent metacresol; and

• (b) as determined by an acceptable method, for each 1,000 International Units of insulin,

  • (i) not more than 8.5 milligrams of nitrogen,

  • (ii) not less than 3.0 milligrams and not more than 6.0 milligrams of protamine except that the ratio of the protamine to the insulin shall be not less than the isophane ratio and shall not exceed the isophane ratio by more than 10 per cent,

  • (iii) not less than 0.16 milligram and not more than 0.40 milligram of zinc, and

  • (iv) no protease activity significant for the stability of NPH insulin.

C.04.583 The protamine used in preparing NPH Insulin shall be obtained from the sperm or from the mature testes of fish belonging to the family Salmonidae, genera Oncorhynchus Suckley, or Salmo Linne.

C.04.584 The isophane ratio means the minimum number of milligrams of protamine required to precipitate 100 International Units of insulin and shall be determined by an acceptable method.

C.04.585 The insulin used in the preparation of NPH Insulin shall be obtained from one or more master lots and shall be present in an amount sufficient to provide either 40, 80 or 100 International Units of insulin in each cubic centimetre of the preparation when the precipitate is suspended uniformly.

C.04.586 The clear supernatant liquid obtained from NPH insulin shall contain not more than 0.4 International Units of insulin per cubic centimetre when the potency of the insulin preparation is 40 units per cubic centimetre, not more than 0.6 International Units of insulin per cubic centimetre when the potency of the insulin preparation is 80 units per cubic centimetre and not more than 0.7 International Units of insulin per cubic centimetre when the potency of the insulin preparation is 100 units per cubic centimetre, as determined by an acceptable method.

C.04.587 No person shall sell NPH Insulin unless

• (a) it is dispensed in a vial of approximately 10 cubic centimetre capacity that contains an excess volume sufficient to permit withdrawal of 10 cubic centimetres; and

• (b) each cubic centimetre thereof provides,

  • (i) 40 International Units of insulin,

  • (ii) 80 International Units of insulin, or

  • (iii) 100 International Units of insulin.

• C.04.588 (1) A fabricator shall not sell NPH Insulin unless he

  • (a) has filed with the Minister, in accordance with subsection (2), a submission relating to that preparation, in a form and having a content satisfactory to the Minister;

  • (b) has furnished the Minister with such additional information as the Minister may require; and

  • (c) has received from the Minister a notice that the information contained in the submission is in accordance with the requirements of this section.

• (2) A submission filed pursuant to subsection (1) shall include at least,

  • (a) for each master lot of zinc-insulin crystals employed in the manufacture of NPH Insulin,

    • (i) protocols of assay of its potency in International Units per milligram,

    • (ii) a report of its moisture content in per cent determined by drying to constant weight at 100°C, and

    • (iii) reports of assay of its nitrogen content in milligrams and its zinc content in milligrams per 1,000 International Units of insulin;

  • (b) for the master lot of protamine, a report of the isophane ratio for the insulin used in the preparation of the NPH Insulin;

  • (c) for the trial mixture of NPH Insulin,

    • (i) a report of assay of its nitrogen content in milligrams per cubic centimetre or per 1,000 International Units of insulin,

    • (ii) a report of assay of its zinc content in milligrams per cubic centimetre or per 1,000 International Units of insulin,

    • (iii) a report of the insulin content in International Units per cubic centimetre of the supernatant liquid after removal of the suspended precipitate,

    • (iv) a report on the determination of its pH, and

    • (v) a report on the microscopic examination of the precipitate;

  • (d) for the first finished lot of NPH Insulin from each trial mixture of NPH Insulin, a report on the amount of each component in the preparation; and

  • (e) for the first filling of the first finished lot of NPH Insulin from each trial mixture of NPH Insulin,

    • (i) a report of assay of its nitrogen content in milligrams per cubic centimetre or per 1,000 International Units of insulin,

    • (ii) a report of assay of its zinc content in milligrams per cubic centimetre or per 1,000 International Units of insulin,

    • (iii) a report on the determination of its pH,

    • (iv) a report on the microscopic examination of the precipitate, and

    • (v) a report of its identification as determined by an acceptable method.

    • (vi) [Repealed, SOR/95-203, s. 7]

C.04.589 The expiration date printed on the inner and outer labels of NPH Insulin shall be a date not later than two years after the date of filling of the immediate container.

Protamine Zinc Insulin

C.04.590 The insulin preparation “Protamine Zinc Insulin” shall be a sterile white suspension in a buffered aqueous medium, containing insulin modified by the addition of protamine and zinc, shall have a pH of not less than 7.1 and not more than 7.4, and shall contain,

• (a) weight by volume,

  • (i) not less than 0.15 per cent and not more than 0.25 per cent anhydrous disodium phosphate,

  • (ii) not less than 1.4 per cent and not more than 1.8 per cent glycerin, and

  • (iii) either not less than 0.18 per cent and not more than 0.22 per cent cresol, or not less than 0.22 per cent and not more than 0.28 per cent phenol; and

• (b) as determined by an acceptable method, for each 1,000 International Units of insulin,

  • (i) not more than 12.5 milligrams of total nitrogen,

  • (ii) not less than 10.0 milligrams and not more than 15.0 milligrams of protamine,

  • (iii) not less than 1.7 milligrams and not more than 2.5 milligrams of zinc.