International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

___________________________________________Research Article

Packaging Validation of Paracetamol Tablets BP 500 mg

K. Chitra1, J. Beena2, G. Jagadheesan2 and D. Narayana murthy1*
1Sri

Ramachandra College of Pharmacy, Sri Ramachandra University, Chennai 600116,

Tamil Nadu, India.

2Fourrts

(India) Laboratories. Pvt. Ltd., Plant-II, Venkatamangalam, Kandigai, Chennai 600 048,

Tamil Nadu, India.

_____________________________________________________________________________________
ABSTRACT Validation is documented evidence which provide high degree of assurance that specific process will consistently produce product with predetermined specification and quality attributes. And it is considered as key requirement of all GMP guidelines as it enables consistent manufacturing and packaging of products in accordance with the product quality and market requirements in a cost effective and secure manner. Packaging is defined according to WHO as a process that bulk material must undergo finished product. The basic need for packaging validation is that it enables packaging process to meet the product and market requirements i.e. quality attributes and consumer needs in a cost effective and consistency efficient process with minimum down time, rejects and errors. For this purpose, the validation study for packaging process was carried out for forming temperature & sealing temperature optimization, speed optimization, efficiency of tablet feeder, Blister inspection system, print registration control, function of base and lidding foil end sensor, splice detector efficiency, shrink wrapping and impact assessment of de-blistered tablets. And this article clearly emphasizes different types of test involved in packaging validation, importance of packaging validation and key activities to achieve it successfully. Keywords: Validation, packaging, Blister inspection system, Print registration control, PPM. INTRODUCTION Packaging is the art of science and technology of preparing products for sale in a cost effective manner.1,2 With respect to pharmaceuticals, packaging is a key component of the product and must preserve the product from environmental degradation or contamination, contain the product securely in order to avoid leakage, identify the product from its pack and thereby provide traceability, provide security against tampering and counterfeiting of the product, provide to the patient the information on use for compliance, provide convenience in use of the product for medical staff or patient. All these things must be ensured for the life of the product and achieved within a complex regulatory environment. To carry out a meaningful packaging validation following are key areas which have impact on the robustness of a packaging process. a. Packaging line layout: This will have a major impact on the efficiency of the packaging line. And this layout should include the ability to manage quick change over, perform line clearance between batches of product and clean the line in an easy and controlled manner. The layout should provide easy access for operators and the engineers for various machine adjustments and /or maintenance without affecting the product on or near the machine. In this first step of the validation includes identification of topology of the system, and next is to identify and list the system functionality i.e. the software and hardware of the system to be tested and verified as being in working order to enable validation to be performed. b. Well designed equipment will lend itself to efficient production of a consistent standard product. Where as incase of older equipment, it is often considered that they can be inflexible and have elements of poor design such as areas where packaging components or product may be trapped, resulting in product being incorrectly packed. This represents an ultimate risk to the patient and it is one of major reason for product recall in the industry. c. Assess the GMP risk: although all GMP risks are important one can specifically take into consideration product defect class 1 (critical) defect /intolerable

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International Journal of Research in Pharmaceutical and Biomedical Sciences

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defect (dangerous and pose serious health hazard) leading to product recall. e.g. the contents of the package do not match the labeling on the package, printing errors on labels and package inserts, incorrect packaging component in the final assembly. d. Standard Operating Procedure: It is one of important aspect of packaging validation exercise. SOP should be clear and it should contain instructions on how to operate, adjust, and maintain each piece of equipment. In addition to that there should be a procedure in detail how a batch has to be packaged. Besides that SOP should explain how each material is received in to the line and checked for correctness, quantity by the operators e. Packaging testing program: It basically involve all written specification for packaging materials and the product package and include the nature, extent and frequency of routine test such as: Visual inspection, test to identify the materials, dimensional tests, physical, chemical and microbiological test f. Training : It is one of most important element in any validation activity. Training of operators and engineers on a packaging line is integral to equipment installation and qualification. Records of

relevant training and experience maintained and be available.

should

be

g. Qualification protocols: It is one of basic approach to any validation is that to prepare test protocols for design qualification, installation qualification, operational qualification and performance qualification. Information gathered from the each stage is fed into the next to ensure that the system is adequately tested. h. Performance qualification (PQ): It is last but most important stage in equipment validation and it should reflect real production environment. It is an area where one needs to pay lot of attention as depending upon the line topography. It requires to: Test each piece of equipment in the line and to test the interaction between different pieces of equipment/ system, ensure that the validation activity is designed to test all the critical steps, provide a list of test which are to be performed and acceptance limits for each test.3 MATERIALS AND METHODS In this study Paracetamol tablets manufactured are packed in blister packages. Three batches of the tablets each of batch size 5, 50,000 tablets are taken into consideration. The list of equipments and materials used for primary and secondary packaging validation studies are mentioned in Table 01 and 02.

Table 1: List of equipment and materials used in packaging

Equipment Check weigher Blister packaging machine Inkjet printer De-blistering machine Weighing balance Shrink wrap machine Qualification status Qualified Qualified Qualified Qualified Qualified Qualified

Table 2: List of materials used in packaging

S. No. 01 02 03 04 Item Shipper leaflet PVC film clear Printed blister Aluminium foil Characteristic 7ply corrugated For patient guidance PVC film clear 142 mm Printed blister aluminium foil 142 mm

PROCEDURE Paracetamol tablets were manufactured are packed in blister packages. Three batches of the tablets, each of batch size 5, 50,000 tablets are taken into consideration. The entire process is divided into various stages.

Blister packing: After line clearance issued from QA personnel the materials which were required for packaging operation is brought to the primary packaging area and then to secondary packing area. After careful setting of printed blister aluminium foil and PVC film clear foil to the machine. The machine

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International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

was switched on and checked for following parameters 1. Forming temperature optimization: Forming temperature optimization was carried out for all validation batches during this operation forming temperature was setted at different temperature i.e. 110 oC, 120 oC, 130 oC, 140 oC and observed for blister quality. Based on the result minimum forming temperature & maximum forming temperature was determined. At the established optimum forming temperature range the speed of machine kept at 15, 20, 25, 30 PPM and observed for blister quality. 2. Sealing temperature optimization: Taking the optimum forming temperature established, sealing temperature verification was done. It is carried out for all validation batches during this operation sealing temperature was set at different temperature i.e. 180 o C, 190 oC, 195 oC, 200 oC, 210 oC and observed for blister quality. Based on the result optimum sealing range is established i.e. minimum sealing temperature & maximum sealing temperature. At the established optimum sealing temperature range the speed of the machine kept at 15, 20, 25, 30 PPM and observed for blister quality. 3. Speed optimization: At the established optimum speed i.e. minimum and maximum & optimum forming temperature i.e. minimum and maximum blister quality was observed. At the established optimum speed i.e. minimum and maximum & optimum sealing temperature i.e. minimum and maximum blister quality was observed. 4. Verification of optimum forming temperature and optimum speed range: At the established maximum forming temperature and minimum established machine speed blister were checked for its quality and leak test is performed for 09 blisters. And at the established minimum forming temperature and maximum established machine speed blister were checked for its quality and leak test is performed for 09 blisters. 5. Verification of optimum sealing temperature and optimum speed range: At the established maximum sealing temperature and minimum established machine speed blisters were checked for its quality and leak test is performed for 09 blisters. And at the established minimum sealing temperature and maximum established machine speed blister were checked for its quality and leak test is performed for 09 blisters.

6. Efficiency of tablet feeder : It is carried out for all validation batches during this operation flow of tablets from hopper chute brush box to forming plate was observed and checked for the presence of chipping, breaking and jamming of tablet. 7. Blister Inspection System efficiency (BIS): It is checked for following parameters a. Non filled blister detector accuracy : In this one or more tablets were removed from the blister and passed through BIS camera. Blister without any tablet was detected and rejected. b. Black spot detector efficiency : In this one of the tablet is marked with black spot with marker and passed through BIS camera. Blister with black spot was detected and rejected. c. Shaped tablet detector accuracy : In this different shape tablet was placed in blister cavity instead of circular shape. Blister with different shape tablet was detected and rejected. d. Foreign particle detector accuracy: In this operation along with the tablet in the blister cavity foil pieces are kept in the blister cavity and passed through the BIS camera. Blister with foreign particles (Foil pieces) was detected and rejected. 8. Print registration control: PRC value is set as per respective BPR. All the printed lidding foil in between two eye marks and join the foil with the help of cellophane tape and pass through the PRC sensor. If PRC value mismatched with the set value it should be detected by the PRC sensor and machine should stop. 9. Splice detector: In this case if no splice is present in any of the base/lidding foil, insert one splice in either of base/lidding foil by cutting the foil and joining the foil with the help of cellophane tape and pass through the splice detector. It is carried out for all validation batches and the presence of splice foil in the blister was detected by the detector and the same blister was rejected. 10. Function of base and lidding foil: With out base and lidding foil the machine should not start. 11. Carton with missed leaflet and carton with additional leaflet was detected by check weigher and same carton was detected and rejected. And set compressed air pressure at 3, 4, 5, 6 and 7 Kg /cm2 and verify for rejection incase of missing leaflet. 12. Shrink wrapping: The machine was set with the temperature as mentioned in the respective BPR and carton with shrink film was passed through the

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International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

conveyor. And sample was collected for finished product testing. 13. Impact assessment: After completion of first run packaging blister to be de-blistered are de-blistered by de-blistered machine and tablets were collected and inspected. And the de-blistering process is done for 2 nd run and 3 rd run. And only 3 rd run samples were sent QC for description, Identification by IR, hardness, thickness, friability, dissolution & assay. At

the end of operation switch off the main, wait for 3 minutes and again switch on the main and start the packaging, observe for physical parameters and perform the leak test for 09 blisters. After completion of shrink packaging pass 01 shrink bundle 03 times each through the shrink packaging machine and collect 01 shrink box and send to QC for description, identification by (IR), hardness, disintegration test, friability, dissolution, related substances and assay.

RESULTS Table 3: Results for forming & sealing temperature optimization

RESULTS OF FORMING TEMPERATURE OPTIMIZATION Batch-I Machine speed: 20 PPM ( Speed Constant) Observation Acceptance criteria 110 120 130 Physical appearance of the forming should be proper Cutting should be uniform on all sided without any angular cuts Over printing should be visible and readable Complies Complies Complies Proper knurling should be observed No pinholes should be when observed against fluorescent light All 09 blister to comply to leak test All 09 blister packs should Pass Pass Pass pass the leak test RESULTS OF SEALING TEMPERATURE OPTIMIZATION Batch-I Machine speed: 20PPM (Speed Constant) Acceptance criteria 180 Cutting should be uniform on all sided without any angular cuts Over printing should be visible and readable Proper knurling should be observed No pinholes should be when observed against fluorescent light All 09 blister to comply to leak test All 09 blister packs should pass the leak test 190 Observation 195 200 210

S.NO

Measured parameter

140

01

Blister quality

Complies

02

Leak test

Pass

S.NO

Measured parameter

Blister quality

Complies

Complies

Complies

Complies

Complies

02

Leak test

Pass

Pass

Pass

Pass

Pass

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International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

Table 4: Results of speed optimization

RESULTS OF SPEED OPTIMIZATION Batch-I Minimum forming temperature set: 120 C Acceptance criteria 15 20 Forming cavity should be proper Complies Complies Physical appearance of forming cavity should be proper Cutting should be uniform on all sided without any angular cuts Embossing should be visible and readable and knurling should be proper No pinholes should be when observed against fluorescent light All 09 blister packs should pass the leak test Pass Pass Maximum forming temperature: 140 C Acceptance criteria Forming cavity should be proper Physical appearance of forming cavity should be proper Cutting should be uniform on all sided without any angular cuts Embossing should be visible and readable and knurling should be proper No pinholes should be when observed against fluorescent light All 09 blister packs should pass the leak test 15 Complies 20 Complies

S.NO 01

Measured parameters Blister quality

Observation 25 Complies

30 Complies

02 S.NO 01

Leak test Measured parameters Blister quality

Pass observation 25 All other parameter was found to comply with the acceptance criteria. Improper cutting was observed

Pass

30 All other parameter was found to comply with the acceptance criteria. Improper cutting was observed Pass

02

Leak test

Pass

Pass

Pass

Table 5: Results of speed optimization

RESULTS OF SPEED OPTIMIZATION Batch-I Minimum sealing temperature set: 180 C Observation S.NO Measured parameters Acceptance criteria Cutting should be uniform on all sided without any angular cuts Embossing should be visible and readable and knurling should be proper No pinholes should be when observed against fluorescent light 15 20 25 All other parameter was found to comply with the acceptance criteria Improper cutting was observed Pass observation 15 Cutting should be uniform on all sided without any angular cuts Embossing should be visible and readable and knurling should be proper No pinholes should be when observed against fluorescent light All 09 blister packs should pass the leak test 20 25 All other parameter was found to comply with the acceptance criteria. Improper cutting was observed 30 All other parameter was found to comply with the acceptance criteria. Improper cutting was observed 30 All other parameter was found to comply with the acceptance criteria Improper cutting was observed Pass

01

Blister quality

Complies

Complies

02

Leak test

All 09 blister packs should pass the leak test Pass Maximum sealing temperature: 210 C Acceptance criteria

Pass

S.NO

Measured parameters

01

Blister quality

Complies

Complies

02

Leak test

Pass

Pass

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International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

Table 6: Results of Minimum speed & Maximum forming temperature, Maximum speed & Maximum forming temperature
Batch-I Minimum speed: 15 PPM Maximum forming temperature: 140 C S.NO Measured parameter Acceptance criteria Observation

01

Blister quality

02

Leak test

Physical appearance of forming cavity should be proper Physical appearance and forming cavity was proper. Cutting should be uniform on all Cutting was uniform on all sides with out any angular sided without any angular cuts cuts. Embossing should be visible and Embossing was visible and readable. readable and knurling should be Proper knurling was observed. proper No pinholes was observed against fluorescent light No pinholes should be when observed against fluorescent light All 09 blister packs should pass the Pass leak test Maximum speed: 20 PPM Minimum forming temperature: 120 C Acceptance criteria Physical appearance of forming cavity should be proper Cutting should be uniform on all sided without any angular cuts Embossing should be visible and readable and knurling should be proper No pinholes should be when observed against fluorescent light All 09 blister packs should pass the leak test Observation

S.NO

Measured parameter

01

Blister quality

Physical appearance and forming cavity was proper. Cutting was uniform on all sides with out any angular cuts. Embossing was visible and readable. Proper knurling was observed. No pinholes was observed against fluorescent light

02

Leak test

Pass

Table 7: Results of minimum speed & maximum sealing temperature, Maximum speed & Minimum sealing temperature
Batch-I Minimum speed: 15 PPM Maximum sealing temperature: 210 C S.NO Measured parameter Acceptance criteria Observation

01

Blister quality

02

Leak test

Cutting should be uniform on all sided without any angular cuts Cutting was uniform on all sides with out any angular Embossing should be visible and cuts. readable and knurling should be Embossing was visible and readable. proper Proper knurling was observed. No pinholes should be when No pinholes was observed against fluorescent light observed against fluorescent light All 09 blister packs should pass the Pass leak test Maximum speed: 20 PPM Minimum sealing temperature: 180 C Acceptance criteria Cutting should be uniform on all sided without any angular cuts Embossing should be visible and readable and knurling should be proper No pinholes should be when observed against fluorescent light All 09 blister packs should pass the leak test Observation Cutting was uniform on all sides with out any angular cuts. Embossing was visible and readable. Proper knurling was observed. No pinholes was observed against fluorescent light Pass

S.NO

Measured parameter

01

Blister quality

02

Leak test

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International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

Table 8: Results of optimum speed & optimum temperature

S. No. Measured parameter Acceptance criteria Cutting should be uniform on all sided without any angular cuts Embossing should be visible and readable and knurling should be proper No pinholes should be when observed against fluorescent light All the 09 blister packs should pass the leak test Observation Optimum temperature: 195 C Optimum speed set : 18 PPM Batch-I Batch-II Batch-III

01

Blister quality

Complies

Complies

Complies

02

Leak test

Pass

Pass

Pass

Table 9: Results of verification of tablet feeder efficiency at blister packaging stage

S. No. 01 Test Flow of tablets from hopper through chute brush box to forming plate Chipping, breaking and jamming of tablets Effective of feeder level sensor Acceptance criteria Proper flow of tablets should be observed and all formed pockets should be filled. Tablet feeding should be smooth without chipping braking & jamming of tablets When the tablets reaches below the minimum feeder level the vibrator should switched on automatically and the tablets should be filled in the feeder Batch-I Complies Observation Batch-II Complies Batch-III Complies

02

Complies

Complies

Complies

03

Complies

Complies

Complies

Table 10: Results of verification blister inspection system

S. No. 01 02 03 04 Test Non-filled detector Black spot detector Shaped tablet detector Foreign particle detector Acceptance criteria Blister with non-filled pack should be detected & rejected Blister with black spotted tablet should be detected and rejected Blister with different shape tablet should be detected and rejected Blister(Tablet with foreign particle should be detected and rejected) Batch-I Complies Complies Complies Complies Observation Batch-II Complies Complies Complies Complies Batch-III Complies Complies Complies Complies

Table 11: Results for print registration control/splice/foil end sensor

S. No. 01 Test PRC sensor verification Splice detector efficiency Base foil/lidding foil sensor verification Acceptance criteria when the PRC value mismatched with set value it should be detected by the PRC sensor& the machine should stop The splice detector should detect the spliced foil ( joint in between the foil) and the same blister should be rejected by the machine With out base foil & lidding foil sensor should be detected and machine should stop Batch-I Complies Complies Observation Batch-II Complies Complies Batch-III Complies Complies

02

03

Complies

Complies

Complies

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International Journal of Research in Pharmaceutical and Biomedical Sciences

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Table 12: Results of verification of sensor in check weigher

S. No. 01 Test Verification of missing leaflet in marked carton Verification of additional leaflet in marked carton Compressed air pressure verification Acceptance criteria Carton with missed leaflet should be rejected & rejected carton should be dropped in the rejection box Carton with additional leaflet should be rejected & carton should be dropped in the rejection box Carton should be rejected and rejected carton should be dropped in the rejection box Batch-I Complies Complies Complies for 4 to 7 Kg/cm2. Not complies for 3.0 Kg/cm 2 Observation Batch-II Complies Complies Complies for 4 to 7 Kg/cm2. Not complies for 3.0 Kg/cm2 Batch-III Complies Complies Complies for 4 to 7 Kg/cm2. Not complies for 3.0 Kg/cm2

02

03

Table 13: Results of de-blistered tablets 3 rd run

Observation S. No. Test Batch-I White, flat, circular uncoated tablet with PARA/500 debossed on one side and plain on other side Complies 564.4mg Avg: 564.4mg Min: 560.2mg Max: 574.6mg Avg: 177.5N Min: 149.6N Max: 223.4N Max: 3.88mm Min: 3.82mm 02 minutes 47 seconds 0.09% Avg: 99.7% Min: 99.1% Max: 100.3% 99.8% Batch-II White, flat, circular uncoated tablet with PARA/500 debossed on one side and plain on other side Complies 567.2mg Avg: 567.2mg Min: 560.1mg Max: 575.5mg Avg: 241.5N Min: 208.5N Max: 287.0N Avg: 3.92mm Min: 3.84mm Max: 4.00mm 03minutes 05 seconds 0.08% Avg: 97.9% Min: 96.7% Max: 98.9% 100.5% Batch-III White, flat, circular uncoated tablet with PARA/500 debossed on one side and plain on other side Complies 567.9 mg Avg: 567.9 mg Min: 560.7 mg Max: 576.1 mg Avg: 217.4N Min: 180.6N Max: 24.9N Avg: 3.85mm Min: 3.83mm Max: 3.88mm 02 minutes 28 seconds 0.11% Avg: 99.9% Min: 98.99% Max: 100.75% 99.7%

01

Description

02 03 04

Identification By IR Average weight Uniformity of weight Hardness

05

06 07 08 09 10

Thickness Disintegration test Friability Dissolution Assay

Table 14: Results of impact assessment for power failure

S. No. Measured parameter Acceptance criteria Batch-I Cutting should be uniform on all sided without any angular cuts Embossing should be visible and readable and knurling should be proper No pinholes should be when observed against fluorescent light All 09 blister should comply with the leak test Observation Batch-II Batch-III

01

Physical verification of blister after resumption of power

Complies

Complies

Complies

02

Leak test

Pass

Pass

Pass

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International Journal of Research in Pharmaceutical and Biomedical Sciences

ISSN: 2229-3701

Table 15: Results of shrink wrapping after 3 runs

Observation S. No. Test Batch-I White, flat, circular uncoated tablet with PARA/500 debossed on one side and plain on other side Complies 568.8mg Avg: 568.84mg Min: 565.1mg Max: 572.8mg Avg: 168.0N Min: 156.6N Max: 178.2N Avg: 3.86mm Max: 3.91mm Min: 3.81mm 03 minutes 19 seconds 0.1% Avg: 100.2% Min: 99.7% Max: 100.6% 100.6% Batch-II White, flat, circular uncoated tablet with PARA/500 debossed on one side and plain on other side Complies 566.0mg Avg: 566.0mg Min: 560.3mg Max: 573.4mg Avg: 218.7 N Min: 100.2 N Max: 271.2 N Avg: 3.89mm Min: 3.84mm Max: 3.93mm 03minutes 05 seconds 0.07% Avg: 98.9% Min: 99.6% Max: 98.9% 100.8% Batch-III White, flat, circular uncoated tablet with PARA/500 debossed on one side and plain on other side Complies 565.5mg Avg: 565.5 mg Min: 559.7mg Max: 573.1mg Avg: 198.4N Min: 185.2N Max: 213.3N Avg: 3.83mm Min: 3.80mm Max: 3.85mm 03 minutes 23 seconds 0.07% Avg: 99.5% Min: 98.79% Max: 100.32% 99.4%

01

Description

02 03 04

Identification By IR Average weight Uniformity of weight Hardness

05

06 07 08 09 10

Thickness Disintegration test Friability Dissolution Assay

CONCLUSION All the in-process parameters for packaging validation were checked and found well within the limit. All the results found well meeting the predetermined specifications. No significant deviation was found in the entire packaging process. No change in any process parameters was observed during operation of batch packing. After reviewing the above observations, it is concluded that the product is consistently meeting its predetermined specifications for the validation batches (Batch-I, Batch-II & Batch-III).

REFERENCES 1. Jain N K, Pharmaceutical Product development: Pharmaceutical Packaging, CBS publisher, 2005, 525-533. 2. Malukani J., Packaging Validation of Sotalol Hydrochloride Tablets, Inventi journal. 2012; 1(3): 1-7. 3. Manek S P., Validation of Pharmaceutical Packaging. Pharma times. 2012; 44 (2):1517.

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