Quality control test: Containers, Closures and Secondary packing materials

quality control tests for packaging materials in pharmaceutical industry

1. Quality control test: Containers, Closures and Secondary packing materials Name of student: Miss. Pranali Polshettiwar M. Pharm 1 st yr. Name of guide: Mrs. S. S. Gaikwad Assistant Professor M. Pharm (QAT) Sinhgad Institute of Pharmacy, Narhe Pune-41

2. Content Packing materials Quality control test for containers and closures Quality control test for secondary packing materials

3. Packing materials Any material that is used for packaging of products for their distribution and sale is said to be packing material. Primary packing:- comes in direct contact with the product e.g. bottles, vials, ampoules, tin, etc. Secondary packing:- used to cover primary packs e.g. cartons, boxes, etc. 1

4. Different types of materials used for container Glass container Plastic container Metal container Different types of materials used for closures Rubber closures Plastic closures Metal closures Different types of materials used for secondary packaging Paper Cartons/cardboards 2

5. Quality control test for containers and closures Quality control test for glass containers Chemical resistance test a)Powdered attack test b)Water attack test Hydrolytic resistance test Arsenic test Thermal shock test Internal bursting pressure test 3

6. Powdered glass test It is done to estimate the amount of alkali leached from the powdered glass, which happens at elevated temperatures. Sample containers are rinsed with purified water and dried The containers are grinded in a mortar to a fine powder and passed through sieve no. 20 & 50 10 gm of the sample is washed with acetone and dried 50 ml of purified water is added to the dried sample and autoclaved at 121°C 30 min and cooled and decanted The decanted liquid is titrated with 0.02N H 2 SO 4 using methyl red as indicator 4

7. 5 Test Container Vol. of 0.02N H 2 SO 4 (ml) Powdered glass test Type I (borosilicate glass) Type II (soda-lime glass) Type N.P (general purpose soda-lime glass) 1.0 8.5 15.0 Limits:- Sample with methyl red indicator

8. Water attack test This test is for type II glass. The principle involved in this is whether the alkali leaches from surface of container. The container is rinsed thoroughly with high purity water. It is then filled with water upto 90% of its capacity It is then autoclaved at 121 °C for 30 min. Then it is cooled and liquid is decanted Decanted liquid is titrated with 0.02N H 2 SO 4 using methyl red as an indicator The volume of H 2 SO 4 consumed is recorded and compared with limits 6

9. 7 Test Container Vol. of 0.02N H 2 SO 4 (ml) Water attack test Type II Size -100 ml Less than 100 ml 1.0 0.7 0.2 Limits:-

10. Hydrolytic resistance test The test is directly related to the stability of pharmaceuticals packed in it. Test 1 : Type I and Type II glass containers to distinguish from Type III glass containers Test 2 : Type I and Type II glass containers where it is necessary to determine whether the high hydrolytic resistance is due to the chemical composition or the surface treatment Nominal capacity of container (ml) No. of containers to be used Volume of test solution to be used for titration(ml) Up to 3 At least 20 25.0 5 or less At least 10 50.0 6 to 30 At least 5 50.0 More than 30 At least 3 100.0 8 Limits:-

11. Test 1 Each container is rinsed at least three times with CO 2 free water and filled with the same to their filling volume Vials and bottles are covered and autoclaved at 100 °C for 10 mins . and the steam is allowed to displace from the vent cork The temp. is risen from 100°C to 121°C over 20 mins . The temp. is maintained at at 121°C to 122°C for 60 mins . The temp. is lowered from 121°C to 100°C over 40 min. venting to prevent vaccum 9

12. 10 The containers are removed from autoclave, cooled and the liquids are combined in a conical flask and the volume is measured. This test solution is titrated with 0.01M HCl using methyl red as an indicator (methyl red is red in alkaline pH and pink in acidic) A blank titration is performed with water and the difference between the titration represents the volume of HCl consumed by the test solution Test 2 Rinse the container twice with water and fill completely with 4% v/v solution of Hydrofluoric acid and allow to stand at room temperature for 10 mins . Empty containers and rinse 5 times with water. Rest procedure are same as in test 1.

13. Limits:- Capacity of container (corresponding to 90% average flow volume)(ml) Volume of 0.01M HCl Type I or Type II glass(ml) Volume of 0.01M HCl per 100 ml of test solution Type III glass(ml) Not more than 1 2.0 20.0 More than 1 but NMT 4 1.8 17.6 More than 2 but NMT 5 1.3 13.2 More than 5 but NMT 10 1.0 10.2 More than 10 but NMT 20 0.80 8.1 More than 20 but NMT 50 0.60 6.1 More than 50 but NMT 100 0.50 4.8 More than 100 but NMT 200 0.40 3.8 More than 200 but NMT 500 0.30 2.9 11

14. Arsenic test This test is for glass containers intended for aqueous parenterals . The inner and outer surface of container is washed with fresh distilled water for 5 min. containers are covered and autoclaved at 100 °C for 10 mins . The temp. is risen from 100°C to 121°C over 20 mins . The temp. is maintained at at 121°C to 122°C for 60 mins . The containers are cooled and the liquids are combined and volume measured. 12

15. 10 ml from the final combined volume is pipetted out and to it 10 ml of HNO 3 is added and dried in an oven at 130 °C 10 ml of hydrogen molybdate is added and refluxed for 25 mins It is cooled and absorbance is measured at 840nm A Blank test is performed with 10 ml hydrogen molybdate . Limits:- The absorbance of the test solution should be less than the absorbance obtained using 0.1 ml of arsenic standard solution (10 ppm ) 13

16. Thermal shock test Sample container is placed in upright position in tray and the tray is immersed in hot water for a given time The container is then transferred in cold water bath and temp. should be controlled. Cracks are examined before and after test (45 °C temp. difference should be there) 14

17. 15 The amount of thermal shock a bottle can withstand is based on construction Small bottles- 60°C to 80°C Pint bottles- 30°C to 40°C

18. Internal bursting pressure test Instrument used American glass research increment pressure tester. The test bottle is filled with water and placed inside test chamber The internal pressure automatically raised by series of increment at set time Bottle are checked at preselected pressure level until container finally burst https://youtu.be/VH6I1wy9UPU Test chamber Glass bottle burst tester 16

19. Quality control test for plastic containers Leakage test Collapsibility test Clarity of aqueous extract Water vapour permeability test Transparency test 17

20. Leakage test 10 containers are filled with water and fitted with intended closures They are kept inverted at room temperature for 24 hours The test is said to be passed if there is no sign of Leakage from any container Plastic containers kept inverted 18

21. This test is applicable to containers which are to be squeezed in order to remove the contents. A container by collapsing inward during use, yield at least 90% of its normal contents at the required rate of flow at ambient temperature. Collapsibility tester 19 Collapsibility test

22. Clarity of aqueous extract A suitable container is taken at random, and unlabeled, unmarked and non-laminated portions is selected These portions are cut into strips, none of which has a total surface area of 20 cm 2 Strips are washed free from extraneous matter by shaking them with at least two separate portions of distilled water for about 30 secs . The processed sample is taken in to the flask, previously cleaned with chromic acid and rinsed with distilled water 250 ml of distilled water is added to the flask, covered and autoclaved at 121 °C for 30 mins . The extract is cooled and examined. It should be colourless and free from turbidity. 20

23. Water vapour permeability test 5 containers are filled with nominal volume of water and heat sealed with an aluminium foil, poly ethylene laminate or other suitable seal Then each container is weighed and allowed to stand (without any overwrap) for 14 days at a relative humidity of 60 +5% and a temperature between 20 and 25°C Containers are reweighed (the loss in weight in each container is not more than 0.2%) Water vapour permeability tester 21

24. Transparency test 5 containers are filled to their normal capacity with dil. suspension as per IP 1996 The cloudiness of suspension is observed when viewed through the container and compared with a similar container filled with water 22

25. 23 Quality control test for metal containers The metals commonly used for construction of containers are aluminium , tin plated steel, stainless steel, tin and lead. Test: Take 50 empty tubes filled with ointment base, sealed and kept overnight. A metal bacteriological filter assembly is fitted with with 4.25cm filter paper of suitable porosity and heated to melting range of ointment base. Base from all tubes squeezed at certain rate and extruded base is collected. Walls of the filter and filter paper is washed with 3 successive quantities of each of 30 ml, of chloroform, and filter paper is allowed to dry. Filter paper is then examined under oblique lighting using a magnifying glass.

26. Each metal particle detected on the filter paper is given a score as follows: Particles 1mm and above 50 Particles 0.5mm but less than 1mm 10 Particles 0.2mm but less than 0.5mm 2 Particles less than 0.2mm nil Limit If total score is <100 = comply If total score is >150 = fail If score is 100-150 = repeat 24

27. Quality control test for closures Residue on evaporation pH of aqueous extract Reducing substance test Sterility test Fragmentation test Residue on evaporation Penetrability test 25

28. Preparation of sample solution : The closures are washed in 0.2% w/v of anionic surface active agents for 5 mins . Rinsed 5 mins with distilled water and subjected to a flask with 200 ml water. Subjected to autoclave at 119°C to 123°C for 20-30 mins covering with aluminium foil. Cooled and solution is separated from closures. 26 Residue on Evaporation 50 ml of sample solution is evaporated at 105 °C. Residue obtained should be not more than 4 mg.

29. pH of Aqueous extract 20 ml of sample solution is taken and 0.1 ml of bromothymol blue is added to it The sample solution is titrated with 0.01M NaOH till colour changes from blue to yellow Volume is measured after the colour change Limits:- Vol. of NaOH – not more than 0.3 ml If HCl is used – not more than 0.8 ml 27

30. Reducing substance test 20ml of sample solution + 1M H 2 SO 4 + 0.002M KMnO 4 Boiled for 3 min and cooled down Add 1 gm of Potassium iodide Treat the solution with Sodium Thiosulphate using starch solution as indicator Blank titration is done and difference of sample and blank should be not more than 7.0 ml 28

31. 29 Container closure integrity testing (CCIT) is an assay that evaluates the adequacy container closure systems to maintain a sterile barrier against potential contaminants. Closures are subjected for sterilization Autoclaved at 64-66°C and pressure 0.7kPa Further testing is carried out by using culture media Sterility test

32. Fragmentation test This test is applicable to closures intended to be pierced by a hypodermic needle. 12 clean vials are taken with 4 ml water and closures are placed Allowed to stand for 16 hrs A hypodermic needle is used to inject 1 ml of water into the vial and1 ml of air is removed This operation is carried out for 4 times with new needle each time Water present in vial is passed through a filter with pore size of 0.5 micrometer No. of fragments of closure retained should be as per the limits Limits:- No. of fragments- not more than 10 (in case of butyl rubber) No. of fragments- not more than 15 30

33. Self – Sealability test 10 vials are filled with nominal volume of water and closures are placed Caps are pierced 10 times at different sites with hypodermic needle Vials are immersed in 0.1%w/v solution of methylene blue under pressure Containers are kept immersed for 30 mins Vials are washed and none of vials should contain traces of colour solution 31 Applicable to multidose containers

34. Penetrability This is to measure the force required to make a hypodermic needle penetrate easily through closure. It is measured by using piercing machine. The piercing force must not exceed a stated value, the hypodermic needle can get damage as a result of undesirable hardness of closure. https://youtu.be/ErrHvYiMIHI Penetratibility test machine 32

35. Quality control test for secondary packaging materials Quality control test for cartons Compression Carton opening force Quality control test for paper and board 33

36. Used to assess the strength of erected package there by estimating the degree of protection that it confers on the contents. This is useful for products with no inherent strength in one plane or another. https://youtu.be/dYGZYvspfpg Compression test machines 34 Quality control tests for Cartons Compression

37. The carton should spring open in to its original shape without a need for unreasonable force. If the carton does not spring open buckles in on itself, it may cause problems on cartooning machine. Carton opening force tester 35 Carton opening force

38. Quality control tests for paper and board Test conditions: Temperature- 23 °C ± 1°C ; Relative humidity- 50% ± 2% Moisture content Folding endurance Air permeability Tensile Strength Tear Strength Stiffness Bursting strength 36

39. Conditioned specimen is weighed and heated to a constant weight to expel the moisture. The difference of the two weights gives the moisture content of the paper. Paper moisture meter Moisture meter for Carton and paper 37 Moisture content test

40. 38 Folding Endurance Fold endurance measures the durability of paper when repeatedly folded under constant load; determining how many times the paper can be folded until it breaks. Fold the test piece back and forth until rupture occurs. https://youtu.be/LjyyElAVK-4 Folding endurance test machine

41. 39 Air permeability Important for using light weight uncoated paper on machine having vacuum pickup system

42. Maximum load that a material can support without fracture when being stretched, divided by the original cross section area of the material. Tensile strengths have dimensions of force per unit area. These test provides measurement of attributes we can see and feel: strength, stiffness and resistance to stretching . 40 Tensile strength Tensile strength formula: S= F/A Where, S= Breaking strength F= Force that caused the failure A=Least Cross sectional area of material

43. The mean force required to continue the tearing of an initial cut in a single sheet of paper. Tearing test is a simple method developed in 1940s, usually known as Elmendorf test, for evaluating a particular type of paper strength, the tear strength. In this test method an impact load is applied to pull paper apart perpendicular to its faces. According to Van den Akkers tear strength theory, it is dependent of two phenomena. The work associated with breaking of fibers and then pulling fibers out of the fiber network. These two phenomena of course depend on the degree of fiber bonding, fiber strength and fiber length in the paper sheet. https://youtu.be/VfR8CL7zYa0 41 Tear Strength

44. Stiffness Degree of resistance offered by paper/board when it is bent. This involves testing a board piece and folding it through 90 °. It will then try to recover its position when bending force is removed. https://youtu.be/xI-VSJF-WdM stiffness test machines 42

45. Digital hydraulic burst tester 43 Bursting strength The burst test is used as a general guide to the strength of paper, solid board and corrugated board. Bursting strength is usually quoted in kPa . We determine bursting strength using digital hydraulic board burst tester. Burst index = burst strength/basis weight https://youtu.be/Wp7jRO20xE8

46. Key References Roop Khar , S. P. Vyas , Farhan Ahmad, Gaurav Jain, Lachman / Liberman’s The Theory and Practice of Industrial Pharmacy 4 th edition CBS publishers . Sahil Jasuja and Mahesh Kataria ., 2013. Quality Control Testing of Packaging Materials. Pharmatutor , Pharmacy Infopedia . The Indian Pharmacopoeia Commission Ghaziabad, Indian Pharmacopoeia 2007 volume I, pg. no. 363-371. United States Pharmacopoeia 2007, volume I pg. no. 661. Lachman Leon, Liberman H. A. and Kaing J. L., 2013. The Theory and Practice of Industrial Pharmacy. 3 rd edition. New Delhi: CBS Publishers & Distributors Pvt. Ltd. Pg. no. 711-732.