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

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.

C.04.591 The protamine used in the preparation of Protamine Zinc Insulin shall be obtained from the sperm or from the mature testes of fish belonging to the family Salmonidae, genera Oncorhunchus Suckley or Salmo Linne.

C.04.592 The insulin used in the preparation of Protamine Zinc 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.04.593 (1) The Canadian Reference Standard for Protamine Zinc Insulin 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 Protamine Zinc Insulin 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.04.594 No person shall sell Protamine Zinc 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.04.595 (1) A fabricator shall not sell Protamine Zinc 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 insulin or zinc-insulin crystals employed in the manufacture of Protamine Zinc Insulin,

    • (i) protocols of assay of its potency 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 on 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 components used in the preparation of the trial mixture of Protamine Zinc Insulin, 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) protamine in grams or in milligrams, per 1,000 International Units of insulin, and

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

  • (c) for the trial mixture of Protamine Zinc 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 per 1,000 International Units of insulin,

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

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

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

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

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

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

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

    • (iv) [Repealed, SOR/95-203, s. 8]

C.04.596 The expiration date printed on the inner and outer labels of every package of Protamine Zinc Insulin shall be a date not later than two years after the date of filling of the immediate container.

Sulphated Insulin

C.04.597 The insulin preparation “Sulphated Insulin” shall be a clear or slightly turbid, colourless or almost colourless, sterile, isotonic preparation of zinc-insulin crystals chemically modified by treatment with sulphuric acid, shall have a pH of not less than 6.0 and not more than 7.0, and shall contain,

• (a) weight by volume,

  • (i) not less than 0.6 per cent and not more than 1.0 per cent sodium chloride, and

  • (ii) not less than 0.2 per cent and not more than 0.3 per cent phenol; and

• (b) as determined by an acceptable method,

  • (i) not more than 200 milligrams protein for each 1,000 International Units of insulin, and

  • (ii) not less than 5.5 and not more than 6.5 sulphate groups per insulin molecule.

C.04.598 The neutralization ratio means the amount of anti-beef-insulin serum required to neutralize one unit of Sulphated Insulin divided by the amount required to neutralize one unit of beef insulin, and shall be determined by an acceptable method.

C.04.599 The neutralization ratio of Sulphated Insulin shall be not less than 4 to 1.

C.04.600 No person shall sell Sulphated 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 100 International Units of insulin as determined by an acceptable method.

• C.04.601 (1) A fabricator shall not sell Sulphated 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 Sulphated Insulin,

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

    • (ii) a report of its moisture content in percentage 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; and

  • (b) for each lot of Sulphated Insulin prepared from each master lot of zinc-insulin crystals,

    • (i) a report of the amount of each component,

    • (ii) a report of the protein content in milligrams per 1,000 International Units of insulin,

    • (iii) a report on the determination of the neutralization ratio,

    • (iv) a report on the determination of the number of sulphate groups per insulin molecule,

    • (v) protocols of assay of its potency expressed as International Units per cubic centimetre, and

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

    • (vii) [Repealed, SOR/95-203, s. 9]