Quality control tests for containers

Introduction to Quality Control Tests for Containers
Quality control test for glass container, Quality control test for plastic container
Presented by
P . Sudheer Kumar
Department of Pharmaceutical Analysis

1. 1 Presented by P . Sudheer Kumar (Reg. No: 20L81S0712) Under the guidance of Dr. k . vinod Kumar, M. Pharm., PhD Professor of Pharmaceutical Analysis, Head of department – PA&QA. Quality control tests for containers A seminar as a part of curricular requirement for 1 st year M. Pharm 1 st semester

2. 2 Quality control test for glass container Hydrolytic resistance (chemical resistance tests) Arsenic test Light transmission for colored light- protecting glass containers Containers for blood and blood components Quality control test for plastic container Test for injectable preparation Test for non- injectable preparation Contents

3. 3 A container for pharmaceutical use is an article that contains or is intended to contain a drug substance or a dosage form and is, or may be in direct contact with it. Types of containers: Primary packaging components which are or may be in direct contact with the dosage form. These include ampoules, vials, bottles and container liners. Secondary packaging components which are not or will not be in direct contact with the dosage form. These include container labels, administration accessories, shipping containers, etc. Container

4. 4 1.Hydrolytic resistance (chemical resistance tests) Surface test (water attack test) Powdered glass test Etched surface (distinction between types I & II glass ) 2.Arsenic Test 3.Light transmission for colored light- protecting glass containers 4.Containers for blood and blood components Resistance to thermal shock Resistance to centrifugation Quality control test for glass container

5. 5 SURFACE TEST (WATER ATTACK TEST) The degree of attack being determined by the amount of alkali released from the glass under the conditions specified. The number of containers to be examined and the volumes of test solution to be used are Hydrolytic resistance (chemical resistance tests)

6. 6 The test is carried out on the unused containers and the ampoules are filled with freshly prepared distilled water to the maximum volume and are sealed. Bottles or vials are filled to 90% of their calculated overflow volume and covered. Containers are placed in an autoclave at a temperature of 121°c for 60 mins and the cooled under running tap water The water content is collected and titration is carried out within one hour by adding methyl red to it and titrated against 0.01M hydrochloric acid . The volume of 0.01M hydrochloric acid required for each 100 ml of test solution is calculated. PROCEDURE

7. 7 POWDERED GLASS TEST  Powdered glass test is done to estimate the amount of alkali leached from the powdered glass, which usually happens at elevated temperatures. Glass containers are classified according to their resistance to chemical attack, a test executed by heating the glass in contact with water for 30 min at 121 degrees. The USP powdered glass test for glass containers was applied to different kinds of glasses used as containers for parenteral formulations. The decanted liquid is titrated with 0.01 M HCL using methyl red as indicator. Hydrolytic resistance

8. 8 Rinse the containers to be tested with water & dry in the hot-air oven. Powder the glass container to grains and pass through the 425- µm sieve but that is retained on the 250-µm sieve are taken. Remove any metal particles from the glass grains by passing a magnet over them Transfer about 22 g to a conical flask and wash with 60 ml of acetone for five time & then evaporate the acetone. Dry in an oven at 110°c for 20 minutes and allow to cool. Procedure

9. 9 20 g of the treated grains were taken in a 250- ml conical flask and 100 ml of carbon dioxide-free water added and weighed. In a second identical flask 100 ml of carbon dioxide-free water was taken to serve as the blank and weighed. Flasks were kept in the autoclave and maintained at 121°c for 30 minutes. After cooling weight was adjusted to the original weight by the addition of carbon dioxide-free water. Then the water is decanted and the alkali content is determined by titrating with 0.01 M Hcl using methyl red as indicator. Blank was prepared in the same manner and added methyl red and titrated against 0.01M hcl. Procedure

10. 10 TEST FOR HYDROLYTIC RESISTANCE OF THE ETCHED SURFACE The hydrolytic resistance is determined by the quantity of alkali released from the glass under the conditions specified. The surface etching test may be used to determine whether high hydrolytic resistance is due to chemical composition or due to surface treatment. Test results distinguishes between types I and ii glass Hydrolytic resistance (chemical resistance tests)

11. 11 Examined the number of containers indicated before and rinsed them twice with water and then filled completely with a 4% v/v solution hydrofluoric acid and allowed to stand at room temperature for 10 minutes and rinsed again. Then autoclaved the treated containers and titration is carried out as described in test for surface hydrolytic resistance. Titration is carried out within one hour by adding methyl red to it and titrated against 0.01M hydrochloric acid . Procedure

12. 12 Glass  containers  contain  arsenic and it is released during heating. The amount of arsenic release is determined. PROCEDURE Prepare a test solution as described in the test for hydrolytic resistance for an adequate number of ampoules to produce 50 ml. Pipette 10 ml of the test solution into a flask, add 10 ml of nitric acid and evaporate to dryness on a water-bath. Dry the residue in an oven at 130° for 30 minutes. Cool, add to the residue 10 ml of hydrazine-molybdate reagent, mix and heat under reflux on a water bath for 20 minutes. Cool to room temperature. Determine the absorption of the resulting solution at 840 nm, using hydrazine-molybdate reagent as the blank. The absorbance of the test solution should not exceed the absorbance obtained by using arsenic standard solution (0.1 ppm). Test for arsenic

13. 13  Light transmission test is done to determine the effect of light passing through the bottle wall on the product stability and appearance. The bottle wall thickness can have a significant effect on the results obtained. Procedure A piece of glass container is mounted on specimen holder (care is taken to avoid fingerprints or other marks) Place the specimen in the spectrophotometer. Measure the transmission of the specimen in the spectral region of 290 to 450 nm. Light transmission for colored light- protecting glass containers

14. 14 The observed light transmission in colored glass containers for parenteral preparations should not exceed the limits given in the following table

15. 15 Resistance to thermal shock Thermal shock resistance  test is carried out to measure the ability to withstand a rapid and significant  temperature  change. Procedure The containers are placed empty in an autoclave and the temperature is raised to 140°c and kept at this temperature for 30 mins. The empty container is treated to temperature of which is raised in to 250° and kept at this temperature for 1 hour. Filled to 70% of the maximum marked volume with a 0.9% w/v solution of sodium chloride and gradually cooled to –20° and kept at this temperature for 24 hours Submitted to a rapid drop of temperature the test is done to check whether the container can resists this temperature change. Containers for blood and blood components

16. 16 Resistance to centrifugation This test is carried out to check the ability of containers to withstand extreme conditions. Procedure Fill the container with water to the maximum marked volume and place in a suitable centrifuge. Balance the centrifuge and accelerate to 2000rpm over a period of at least 1 minute. The container pass the test if it resists these conditions for at least 30 minutes. Containers for blood and blood components

17. 17 Plastic containers for pharmaceutical products are made from plastics based on the following polymers: polyethylene (low or high density), polypropylene, polyvinyl chloride and polystyrene. The containers may consist of one or more polymers together with certain additives if necessary. Additives may consist of antioxidants, lubricants, plasticizers and impact modifiers but not antistatic agents and mould-release agents. They should be made of materials that do not leach out any ingredient into contents in such quantities so as to alter the efficacy or stability of the product or to present a toxic hazard. The plastic container chosen for any particular product should be such that the ingredients of the product in contact are not significantly adsorbed on its surface and do not significantly migrate into or through the plastic. Plastic containers

18. 18 1.Leakage test 2.Collapsibility test 3.Clarity of aqueous extract 4.Non-volatile residue Tests for Plastic Containers For Non- injectable Preparations

19. 19 LEAKAGE TEST Fill ten containers with water, fit with closures and keep them inverted at room temperature for 24 hours. If there are no signs of leakage from any container, then the containers are passed. COLLAPSIBILITY TEST This test is applicable to containers which are to be squeezed in order to remove the contents. A container, by collapsing inward during use, should yields at least 90% of its nominal contents at the required rate of flow at ambient temperature. The following tests are applicable to containers intended for filling oral liquids.

20. 20 Clarity is a relative term, it mean a clear container having a high polish that conveys to the observer that the product is of exceptional purity. Procedure Select unlabelled, unmarked and non- laminated portions from suitable containers, taken at random. Cut these portions into strips & wash the strips free from extraneous matter using distilled water. Select cut and washed portions of the sample (1250 cm 2) , transfer to a clean flask and add 250 ml of distilled water. Cover the flask with a beaker and autoclave at 121° for 30 minutes. Carry out a blank determination using 250 ml of distilled water. Cool and examine the extract if it is color less and free from turbidity or not. Clarity of aqueous extract

21. 21 This test is performed to check whether any non volatile material from the container interacts with the content. Procedure Evaporate 100 ml of the extract obtained in the test for clarity of aqueous extract to dryness and dry to constant weight at 105°c. The residue should not weighs more than 12.5 mg. Non-volatile residue

22. 22 1.Tests on Containers I. Leakage test ii. Collapsibility test iii. Transparency iv. Water vapour permeability V. Extractable di(2-ethylhexyl)phthalate 2.Tests on Container Material Barium, heavy metals, tin, zinc, residue on ignition Plastic Containers for Injectable Preparations

23. 23 Test on extracts Physico-chemical tests I. Appearance ii. Light absorption iii. Ph iv. non-volatile matter v. Buffer capacity vi. Oxidisable substance Biological tests i. Systemic injection test ii. Intracutaneous tests

24. 24 Leakage test, Collapsibility test Comply with the tests described under plastic containers for non-injectable preparations. iii. Transparency Prepare a 16-fold dilution of the suspension prepared for the standard suspension so as to give an absorbance Fill five empty containers to their nominal capacity with the diluted suspension (gives an absorbance of 0.37 to 0.43 at 640 nm). The cloudiness of the diluted suspension in each container should be detectable when viewed through the containers, as compared with a container of the same type filled with water. 1. Tests on Containers

25. 25 Water vapor permeability is a measure of the passage of water vapor through a membrane. It is the rate of water vapor transmission per unit area per unit of vapor pressure differential under test conditions. Procedure Fill five containers with the water and heat-seal the bottles. Weigh accurately each container and allow to stand for 14 days at a relative humidity of 60 ± 5% and a temperature between 20° and 25°. Reweigh the containers. The loss in weight in each container should not more than 0.2%. iv. Water vapour permeability

26. 26 Containers of plasticized polyvinyl chloride (PVC) for injectable preparations (i.V. Infusions) must comply with extractable di(2- ethylhexyl)phthalate test. Procedure Fill the empty container with dilute ethanol (of relative density 0.9373 to 0.9378), remove the air completely from the container. Place container in a horizontal position in a water-bath maintained at 36° to 38° for 60 minutes without shaking. Remove the container from the water- bath, invert it gently 10 times and transfer the contents to a glass flask. Immediately measure the absorbance at the maximum at about 272 nm. Calculate the percentage of di(2- ethylhexyl)phthalate from a calibration curve obtained from the absorbance of standard solutions of di (2-ethylhexyl) phthalate in alcohol. It should not more than 0.010% w/v. v. Extractable di(2-ethylhexyl)phthalate

27. 27 The test is conducted to check whether container material has any impact on the content I . BARIUM Moisten 2g of sample with hydrochloric acid and ignite in a platinum dish. Dissolve the residue in 10 ml of 1M hydrochloric acid, filter and add 1 ml of 1M sulphuric acid to the filtrate. Any turbidity produced should not be greater than that produced on adding 1 ml of 1m sulphuric acid to a mixture of 10 ml barium standard solution (10 ppm ba) and 10 ml of 1m hydrochloric acid. 2.Tests on Container Material

28. 28 ii. Heavy metals Take 2.5 g of sample & add 20 ml of sulphuric acid and heat for 10 minutes. Add hydrogen peroxide solution drop wise to the hot solution until it becomes colorless. Cool, transfer to a platinum dish and evaporate to dryness. Dissolve the residue in 10 ml of 1M hydrochloric acid and add sufficient water to produce 25 ml (solution a). To 10 ml of solution a, add 2 ml of acetate buffer ph 3.5 add 1.2 ml of thioacetamide reagent, mix and allow to stand for 2 minutes. Any yellow color in the solution should not be more intense than the yellow color obtained by repeating the operation using 10 ml of cadmium standard solution (10 ppm cd) in place of solution a. Any brown color in the solution should not be more intense than that obtained by repeating the operation using a mixture of 5 ml of lead standard solution (10 ppm pb) and 5 ml of water in place of solution a.

29. 29 iii. Tin To 10 ml of solution A obtained in the test for heavy metals add 5 ml of sulphuric acid (20%), 1 ml of a 1% w/v solution of sodium dodecyl sulphate and 1 ml of zinc dithiol reagent. Heat in a water-bath for 1 minute, cool and allow to stand for 30 minutes. Any red color in the solution should not be more intense than the red color obtained by repeating the operation using 10 ml of tin standard solution (5 ppm sn) in place of solution a. iv. Residue on ignition: The residue on ignition/ sulphated ash test is a method to measure the amount of residual substance not volatilized from a sample when the sample is ignited in the presence of sulfuric acid Take 5 g of the sample in a suitable tared crucible. Ignite to constant weight in a muffle furnace at 800 + 25 . Allow the crucible to cool in a desiccators. It should not be more than 0.1%.

30. 30 The following tests are based on the extraction of the plastic material. Take a portion plastic material and sub- divide into strips approximately 5 cm long and 0.3 cm wide. Take the strips in a 250 - ml, graduated cylinder of type I glass, and wash with purified water Transfer to a suitable extraction flask and add 200 ml of purified water and extract by heating in a water-bath at 70 for 24 hours or heat in an autoclave at 121 for 30 minutes and cool. Transfer 20.0 ml of the extract into a suitable container. Use this portion in the test for buffering capacity. Immediately decant the remaining extract into a suitable clean container and seal. Use purified water where a blank is specified in the following tests 3.Test on extracts

31. 31 I . APPEARANCE : the extract is colorless and is clear. II. LIGHT ABSORPTION : the light absorption of the extract, using water as the blank should not more than 0.08 in the range 220-240 nm and not more than 0.05 in the range 240-360 nm. III. PH: to 20 ml each of the extract and the blank add 1 ml of a 0.1% w/v solution of potassium chloride and determine the ph of the solutions. The difference in ph of the two solutions should not > 1.5. Iv. NON-VOLATILE MATTER : transfer 50.0 ml of the extract to a suitable silica crucible, evaporate on a water-bath and dry the residue at 105 for 1 hour. Repeat the operation with the blank; the difference between the residues obtained form the extract and the blank should not exceed 15 mg. 4. Physico - chemical tests

32. 32 v. BUFFER CAPACITY : The buffer capacity is defined as the amount of acid or base you can add without changing the ph by more than 1 P H uni t Titrate the previously collected 20 ml portion of the extract to a ph of 7.0 with 0.01M hydrochloric acid or 0.01M sodium hydroxide, determining the end- point potentiometrically. Repeat the operation with 20 ml of the blank. The difference between the two volumes of titrant should not be greater than 10.0 ml. vi. OXIDISABLE SUBSTANCE : Transfer 20.0 ml of the extract into a glass-stoppered flask, add 20.0 ml of 0.002M potassium permanganate and 1 ml of dilute sulphuric acid and boil for 3 minutes. Cool, add 0.1 g of potassium iodide, mix by shaking and allow to stand for 10 minutes in the dark. Titrate with 0.01M sodium thiosulphate using 0.25 ml of starch solution, added towards the end of the titration, as indicator. Repeat the operation with the blank; the difference between the two titration should not be more than 1.0 ml.

33. 33 The following tests are designed to determine the biological response of animals to plastics and other polymeric material by the injection or instillation of specific extracts from the material under test. The two biological tests are i. Systemic injection test ii. Intracutaneous test 5. Biological tests

34. 34 This test is designed to evaluate systemic responses to the extracts of materials under test following injection into mice. TEST ANIMALS : albino mice weighing between 17 and 23 g. EXTRACTING MEDIA : Sodium chloride injection (0.9% w/v) 5 % v/v solution of ethanol in sodium chloride injection. Polyethylene glycol 400 Vegetable oil – freshly refined & that meets the following requirement. PROCEDURE To three test animals, inject 0.2 ml intracutaneoulsly at each of 10 sites on each animal and examine the injected sites 24, 48 and 72 hours after injection. No site should shows a greater reaction, edema or erythema than 0.5cm in diameter i. Systemic Injection test

35. 35 This test is designed to evaluate local response to the extracts of materials being examined following intracutaneous injection into rabbits. TEST ANIMALS: select healthy, thin-skinned albino rabbits whose fur can be clipped closely and whose skin is free from mechanical irritation or trauma. In handling the animals, avoid touching the injection sites during observation periods, except to discriminate between edema and an oil residue. ii . Intracutaneous test

36. 36 Procedure : On the day of the test, closely clip the fur on the animal’s back on both side of the spinal column over a sufficiently large test area.  Avoid mechanical irritation and trauma. Remove loose hair by means of vacuum.  If necessary, swab the skin lightly with diluted ethanol, and dry the skin prior to injection. For each sample use two animals and inject each intracutaneously, using one side of the animal for the sample and the other side for the blank, as outlined in table:

37. 37 Extract or blank Number of sites (per animal ) Dose per site ( µl) Sample 5 200 Blank 5 20

38. 38 Examine injection sites for evidence of any tissue reaction such as erythema, edema and necrosis. Swab the skin lightly, if necessary, with diluted ethanol to facilitate reading of injection sites. Observe all animals at 24, 48 and 72 hours after injection. Rate the observations on a numerical scale for the extract of the sample and for the blank, using the following table.

39. 39 Reclip the fur as necessary during the observation period. The average erythema and edema scores for sample and blank sites are determined at every scoring interval (24, 48 and 72 hours) for each rabbit. After the 72 hours scoring, all erythema scores plus edema score are totalled separately for each sample and blank. Divide each of the totals by 12 (2 animals x 3 scoring periods x 2 scoring categories) to determine the overall mean score for each sample versus each corresponding blank. The requirements of the test are met if the difference between the sample and the blank mean score is 1.0 or less. If at any observation period the average reaction to the sample is questionably greater than the average reaction to the blank, repeat the test using three additional rabbits. The requirements of the test are met if the difference between the sample and the blank mean score is 1.0 or less.

40. 40 C.rambabu, V.ananth, R. T.srikanth, S.K.dona, K. G.arun, T.tinu, manavalan, B. M, venkanna, S. H, viswa, J. K, ghaharin. A concise textbook of QC & QA . KMCH college of pharmacy, coimbatore. 2011. 179-189. Government of india, ministry of health. Indian pharmacopoeia volume I . The indian pharmacopoeia commission, ghaziabad. 2010. 683-692. References

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