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APPENDIX 11 CONTAINERS

11.1 GLASS CONTAINERS 

          Glass containers for pharmaceutical products principally consist of silicon dioxide together with varying amounts of other oxides such as those of sodium, potassium, calcium, magnesium, aluminium, boron, and iron. Glass containers should not impart any potential hazards to the pharmaceutical products contained therein and should meet the requirements set up for each type of glass containers.

Glass Types

          Glass containers suitable for packaging pharmaceutical products may be classified as in Table 1.

          Containers of Type I borosilicate glass or neutral glass are generally used for preparations that are intended for parenteral administration, either acidic, neutral, or alkaline preparations. Those of Type II glass, that is soda-lime glass suitably de-alkalized, are usually used for packaging acidic and neutral parenteral preparations and where stability data demonstrate their suitability, for alkaline parenteral preparations also. Type III soda-lime glass containers usually are not used for parenteral preparations, except where suitable stability test data indicate that Type III glass is satisfactory for the parenteral preparations that are packaged therein. Type NP glass containers are intended for packaging non-parenteral articles; i.e., those intended for oral or topical use.

          Containers for parenteral preparations are made from uncoloured glass except that, for substances known to be extremely light-sensitive, coloured glass may be used; such preparations should not show any change of colour during storage. Containers fabricated of Type II or Type III glass and intended for parenteral preparations should be used once only.

Light Transmission

          A container intended to provide protection from light or offered as a “light-resistant” container meets the requirements for Light Transmission, where such protection or resistance is by virtue of the specific properties of the material of which the container is composed, including any coating applied thereto. A clear and colourless or a translucent container that is made light-resistant by means of an opaque enclosure is exempt from the requirements for Light Transmission.

          Apparatus Use a spectrophotometer of suitable sensitivity and accuracy, adapted for measuring the amount of light transmitted by either transparent or translucent glass materials used for pharmaceutical containers. For transparent glass pharmaceutical containers, use a spectrophotometer of suitable sensitivity and accuracy for measuring and recording the amount of light transmitted. For translucent glass pharmaceutical containers, use a spectrophotometer as described above that, in addition, is capable of measuring and recording light transmitted in diffused as well as parallel rays.

          Preparation of sample Break the container or cut it with a circular saw fitted with a wet abrasive wheel, such as a carborundum or a bonded diamond wheel. Select sections to represent the average wall thickness in the case of blown glass containers, and trim them as necessary to give segments of a size convenient for mounting in the spectrophotometer. After cutting, wash and dry each sample, taking care to avoid scratching the surfaces. If the sample is too small to cover the opening in the sample holder, mask the uncovered portion of the opening with opaque paper or masking tape, provided that the length of the sample is greater than that of the slit in the spectrophotometer. Immediately before mounting in the sample holder, wipe the sample with lens tissue. Mount the sample with the aid of a tackywax, or by other convenient means, taking care to avoid leaving fingerprints or other marks on the surfaces through which light must pass.

          Procedure Place the section in the spectrophotometer with its cylindrical axis parallel to the plane of the slit and approximately centred with respect to the slit. When properly placed, the light beam is normal to the surface of the section and reflection losses are at a minimum.

Table 1 Glass Types and Test Limits

          Measure the transmittance of the section with reference to air in the spectral region of interest, continuously with a recording instrument or at intervals of about 20 nm with a manual instrument, in the region of interest, continuously with a recording instrument or at intervals of about 20 nm with a manual instrument, in the region of 290 to 450 nm.

          Limits The observed light transmission does not exceed the limits given in Table 2 for containers intended for parenteral use.

          The observed light transmission for containers of Type NP glass for products intended for oral or topical administration does not exceed 10 per cent at any wavelength in the range from 290 to 450 nm.

Table 2 Limits for Glass Types I, II, and III

Note Any container of a size intermediate to those listed above exhibits a transmission not greater than that of the next larger size container listed in the table. For containers larger than 50 ml, the limits for 50 ml apply.

Tests

          The following tests are designed to determine the degree of alkali released from the new (not previously used) glass containers under the influence of the attacking medium and the conditions specified. The tests should be conducted in an area relatively free from fumes and excesssive dust.

Apparatus

          AUTOCLAVE An autoclave capable of maintaining a temperature of 121º±2º, equipped with a thermometer, a pressure gauge, a vent cock, and a rack adequate to accommodate at least 12 test containers above the water level.

          MORTAR AND PESTLE A hardened-steel mortar and pestle, made according to the specifications in the accompanying illustration (Fig. 1).

          GLASSWARE Laboratory glassware of highly resistant borosilicate glass.

          OTHER EQUIPMENT Stainless steel sieves, 20.3 cm (8 inches) in diameter, including the No. 850, No. 425 and No. 280 sieves along with the pan and cover, a 900-g (2-Ib) hammer and a permanent magnet.

Fig. 1 Special Mortar and Pestle for Pulverizing Glass Dimensions in mm

Reagents

          HIGH-PURITY WATER1 The water used in these tests is copper-free water which has a conductivity at 25º of not greater than 0.15 μmho/cm and meets the requirements of the tests under Purified Water.

          METHYL RED SOLUTION Dissolve 24 mg of methyl red sodium in water to make 100 ml. If necessary, neutralize the solution with 0.02 M sodium hydroxide or acidify it with 0.01 M sulfuric acid so that the titration of 100 ml of high-purity water, containing 5 drops of the indicator, does not require more than 0.02 ml of 0.020 M sodium hydroxide to effect the colour change of the indicator, which should occur at a pH of 5.6.

I. Powdered Glass Test

          Procedure Digest (age) two 250-ml conical flasks and two glass beakers that are of such size that, when inverted, the inner sides of their bottoms fit snugly down on the top rims of the flasks, with high-purity water in a bath at 90º for at least 24 hours or at 121º for 1 hour.

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 ¹ There must be an assurance that this water is not contaminated by copper or its products (e.g., copper pipes, stills, or receivers). The water may be prepared by passing distilled water through a deionizer cartridge packed with a mixed bed of nuclear-grade resin, then through a cellulose ester membrane having openings not exceeding 0.45 μm. Do not use copper tubing. Flush the discharge lines before water is dispensed into test vessels. When the low conductivity specification can no longer be met, replace the deionizer cartridge.

          Rinse thoroughly with water six or more containers selected at random, and dry them with a stream of clean, dry air. Coarsely break the containers into fragments about 25 mm in size. Divide about 100 g of the crushed glass into three approximately equal portions and transfer one portion of the sample to the mortar. Insert the pestle and strike 3 or 4 blows with the hammer. Nest the sieves and transfer the contents of the mortar to the No. 850 sieve. Repeat the operation on each of the two remaining portions until the whole sample has been treated. Rapidly sift the glass, and remove the portion retained on the No. 850 and No. 425 sieves, and again crush and sieve as before. Repeat again this crushing and sieving operation. Empty the receiving pan, reassemble the nest of sieves, and shake mechanically or manually for 5 minutes. Reserve the portion of the sample passing through the No. 425 sieve but retained by the No. 280 sieve, which should weigh in the excess of 10 g. Spread the reserved sample on a piece of glazed paper and pass a magnet over it to remove any metal particles that may be introduced during the crushing. Transfer the sample to a 250-ml conical flask of resistant glass, and wash it with six 30-ml portions of acetone, swirling each time for about 30 seconds to suspend all fine particles and rapidly decanting the supernatant liquid. Spread the glass powder in an evaporating dish, evaporate the acetone at room temperature and dry in an oven at 140º for 20 minutes. Transfer the glass powder to a weighing bottle and cool in a desiccator. Use the test sample within 48 hours after drying.

          Transfer 10.00 g of the prepared sample, accurately weighed, to one of the two 250-ml conical flasks previously digested (aged) with high-purity water as described above and add 50.0 ml of high-purity water. Ensure that the glass powder is uniformly spread over the bottom of the flask. In the second aged flask place 50.0 ml of high-purity water to serve as a blank. Close the flasks with the inverted glass beakers that previously have been similarly treated. Place the closed flasks in the autoclave, and close it securely, leaving the vent cock open. Heat until steam issues vigorously from the vent cock, and continue heating for 10 minutes. Close the vent cock, and raise the temperature from 100º to 121º over 20 minutes. Maintain the temperature at 121º±2º for 30 minutes, counting from the time when this temperature is reached. Lower the temperature from 121º to 100º over 40 minutes, being vented as needed to prevent the formation of a vacuum. Remove the flasks from the autoclave and cool them at once in running water. Decant the supernatant water from the sample flask into a suitably cleansed conical flask, and wash the residual powdered glass with four 15-ml portions of high-purity water, adding the decanted washings to the main portion. Discard the flask containing the washed glass powder. To each flask add 5 drops of methyl red solution, and titrate immediately with 0.01 M sulfuric acid VS. Record the volume of 0.01 M sulfuric acid VS used to neutralize the extract from the prepared sample of glass, corrected for a blank. The volume does not exceed that in the table for the type of glass concerned.

II. Water Attack

          Test The following test is designed to determine the hydrolytic resistance of glass containers. The hydrolytic resistance is the resistance offered by the inner surface of the glass to the release of soluble mineral substances into water under conditions specified. It is evaluated by titrating the alkalinity of the solution.

          Procedure Rinse thoroughly with high-purity water at room temperature three or more randomly selected containers twice. Digest (age) a similar number of glass beakers that are of such size that, when inverted, the inner sides of their bottoms fit snugly down on the top rims of the selected containers, with high-purity water in a bath of 90º for at least 24 hours or at 121º for 1 hour. Fill each container to 90 per cent of its overflow capacity with high-purity water, and close the containers with the inverted glass beakers previously treated as described above. Place the closed containers in the autoclave, and close it securely, leaving the vent cock open. Heat until steam issues vigorously from the vent cock, and continue heating for 10 minutes. Close the vent cock, and raise the temperature from 100º to 121º over 20 minutes. Hold the temperature at 121º±2º for 1 hour, counting from the time when this temperature is reached. Lower the temperature from 121º to 100º over 40 minutes, being vented as needed to prevent the formation of a vacuum. Remove the containers from the autoclave.

          Empty the contents from one or more containers to obtain a volume of 100 ml. Place the pooled sample in a 250-ml conical flask of resistant glass, add 5 drops of methyl red solution and titrate, while warm, with 0.01 M sulfuric acid VS. Complete the titration within 1 hour after removing the containers from the autoclave. Record the volume of 0.01 M sulfuric acid VS used, corrected for a blank obtained by titrating 100 ml of high-purity water in the same manner. The volume does not exceed that indicated in the table for the type of glass concerned.

III. Arsenic

          Test solution Prepare the test solution as directed for Procedure under Water Attack Test, using 35 ml of the water from one Type I glass container or in the case of smaller containers, 35 ml of the combined contents of several Type I glass containers.

          Procedure Perform the test according to the “Limit Test for Arsenic” (Appendix 5.2), the limit is 0.1 ppm.