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

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]

C.04.602 The expiration date printed on the inner and outer labels of every package of Sulphated Insulin shall be a date not later than two years after the date of filling of the immediate container.

Labelling of Insulin Preparations

C.04.650 The packager/labeller of Insulin Injection may label that insulin preparation “Insulin made from Zinc-Insulin crystals” only when it has been prepared from zinc-insulin crystals.

C.04.651 The packager/labeller of an insulin preparation shall print the information required by these Regulations to appear on both the inner and outer labels of every package of that insulin preparation as set out in the Table to this section.

C.04.652 The packager/labeller of an insulin preparation shall print on the outer label of every package thereof instructions to store the preparation in a refrigerator at 35° to 50°F (2° to 10°C) and to avoid exposing it to freezing.

C.04.653 The packager/labeller of an insulin preparation that consists of a precipitate suspended in a buffered aqueous medium shall print on the inner label of every package thereof the statement “Shake Carefully”.

C.04.654 The packager/labeller of an insulin preparation may, in lieu of printing adequate directions for its use on both the inner and outer labels thereof as required by subparagraph C.04.019(a)(vii), print the descriptions for use in a descriptive circular prepared in accordance with section C.04.655, but in such case he shall

• (a) enclose a copy of the circular in the package containing the preparation; and

• (b) state on the outer label of the package that such a circular is enclosed therein.

C.04.655 The descriptive circular referred to in section C.04.654 shall include, at least, the following information:

• (a) a statement that

  • (i) the treatment of diabetes mellitus requires medical supervision and review,

  • (ii) insulin preparations should be used only as determined by a physician for each patient in the light of blood-sugar and urinary-sugar findings, and

  • (iii) the physician’s instructions concerning diet, dosage, rest and exercise should be followed carefully;

• (b) an outline of the procedure to be followed in withdrawing the insulin preparation from the vial, including techniques for sterilization of the syringe and needle, vial-stopper and site of injection;

• (c) a statement explaining that injections should be subcutaneous, and not intravenous or intramuscular, and a caution against successive injections in any one site;

• (d) a statement that doses are specified in terms of Units of potency per cubic centimetre and that the volume of each dose will depend upon the potency in terms of units per cubic centimetre stated on the label of the insulin preparation and that, for these reasons, it is important that the patient understand the markings on syringes;

• (e) a brief explanation of hypoglycemia together with emergency measures suitable for use by patients and those caring for patients in the event of hypoglycemic reactions;

• (f) a statement indicating the possibility of undesirable reactions associated with illness or infection, with the omission or loss of a meal, and with a shortage of the insulin preparation;

• (g) a statement warning against using any other type of insulin preparation than that prescribed by the physician;

• (h) a statement that the use of a package should not be commenced after the expiration date printed on the package;

• (i) a statement that the contents should be used as continuously as practicable and that any vial from which a part of the contents has been withdrawn should be discarded in the event of its being in disuse for several weeks’ time;

• (j) a statement stressing the importance of visiting a physician regularly and of carefully following his instructions;

• (k) in the case of insulin preparations consisting of a clear, colourless or almost colourless solution, free from turbidity and from insoluble matter, a statement that if the contents of the vial become cloudy or turbid, use of that vial should be discontinued;

• (l) in the case of insulin preparations consisting of a precipitate suspended in a buffered aqueous medium, a statement explaining that it is necessary to shake the vial carefully before withdrawing a dose, noting that if the contents have become lumpy or granular in appearance or have formed a deposit of particles on the wall of the container, the use of that vial should be discontinued;

• (m) instructions that the insulin preparation should be stored in a refrigerator at 35° to 50°F (2° to 10°C) and should not be exposed to freezing; and

• (n) in the case of Sulphated Insulin, a statement explaining that this insulin preparation is not for ordinary use, but is a chemically modified insulin which may be more effective than the usual insulin preparations in certain insulin-resistant or insulin-allergic diabetic patients.