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_________________________________________Research Article
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.
and package inserts, incorrect packaging Table 1: list of equipment used in packaging
component in the final assembly. Equipment
Qualification
status
Check weigher Qualified
d. Standard Operating Procedure Blister packaging
It is one of important aspect of packaging Qualified
machine
validation exercise. SOP should be clear and it Inkjet printer Qualified
should contain instructions on how to operate, De-blistering machine Qualified
adjust, and maintain each piece of equipment. In Weighing balance Qualified
Shrink wrap machine Qualified
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
Table 2: List of materials used in packaging
in to the line and checked for correctness, quantity
by the operators. S.NO. Item Characteristic
01 Shipper 7ply corrugated
02 leaflet For patient guidance
e. Packaging testing program 03 PVC film clear PVC film clear 142 mm
It basically involve all written specification for Printed blister Printed blister aluminium
04
packaging materials and the product package and Aluminium foil foil 142 mm
include the nature, extent and frequency of routine
test such as: PROCEDURE
a. Visual inspection, test to identify the materials, Paracetamol tablets were manufactured are packed
dimensional tests, physical, chemical and in blister packages. Three batches of the tablets,
microbiological test. each of batch size 5, 50,000 tablets are taken into
consideration. The entire process is divided into
f. Training various stages.
It is one of most important element in any
validation activity. Training of operators and Blister packing
engineers on a packaging line is integral to After line clearance issued from QA personnel the
equipment installation and qualification. Records materials which were required for packaging
of relevant training and experience should be operation is brought to the primary packaging area
maintained and be available. and then to secondary packing area. After careful
setting of printed blister aluminium foil and PVC
g. Qualification protocols film clear foil to the machine. The machine was
It is one of basic approach to any validation is that switched on and checked for following parameters
to prepare test protocols for design qualification,
installation qualification, operational qualification 1. Forming temperature optimization
and performance qualification. Information Forming temperature optimization was
gathered from the each stage is fed into the next to carried out for all validation batches
ensure that the system is adequately tested. during this operation forming temperature
was setted at different temperature i.e. 110
o
h. Performance qualification (PQ) C, 120 oC, 130 oC, 140 oC and observed
It is last but most important stage in equipment for blister quality. Based on the result
validation and it should reflect real production minimum forming temperature &
environment. It is an area where one needs to pay maximum forming temperature was
lot of attention as depending upon the line determined. At the established optimum
topography. forming temperature range the speed of
It requires to test each piece of equipment in the machine kept at 15, 20, 25, 30 PPM and
line and to test the interaction between different observed for blister quality.
pieces of equipment/ system, ensure that the
validation activity is designed to test all the critical 2. Sealing temperature optimization
steps, provide a list of test which are to be Taking the optimum forming temperature
performed and acceptance limits for each test.3 established, sealing temperature
verification was done. It is carried out for
MATERIALS AND METHODS all validation batches during this operation
In this study Paracetamol tablets manufactured are sealing temperature was set at different
packed in blister packages. Three batches of the temperature i.e. 180 oC, 190 oC, 195 oC,
tablets each of batch size 5, 50,000 tablets are taken 200 oC, 210 oC and observed for blister
into consideration. The list of equipments and quality. Based on the result optimum
materials used for primary and secondary sealing range is established i.e. minimum
packaging validation studies are mentioned in sealing temperature & maximum sealing
Table 01 and 02. temperature. At the established optimum
sealing temperature range the speed of the 7. Blister Inspection System efficiency
machine kept at 15, 20, 25, 30 PPM and (BIS)
observed for blister quality. It is checked for following parameter.
a) Non filled blister detector
3. Speed optimization accuracy
At the established optimum forming In this one or more tablets were
temperature range run the machine at removed from the blister cavity
different speed 15, 20, 25, 30 PPM and and passed through BIS camera.
verify the blister quality. And conduct Blister without any tablet was
leak test for 09 blisters (03 blisters per detected and rejected.
cut). Based on the result optimum speed b) Black spot detector efficiency
range is established i.e. minimum speed In this one of the tablet is
and maximum speed. marked with black spot with
At the established optimum sealing black marker manually. And
temperature range run the machine at mark the blister with marker and
different speed 15, 20, 25, 30 PPM and place the tablet in the blister
verify the blister quality. And conduct cavity and pass through BIS
leak test for 09 blisters (03 blisters per camera. Blister with black spot
cut). Based on the result optimum speed was detected and rejected.
range is established i.e. minimum speed c) Shaped tablet detector
and maximum speed. accuracy
In this different shape tablet was
4. Verification of optimum forming placed in blister cavity instead of
temperature and optimum speed range circular shape. Blister with
At the established maximum forming different shape tablet was
temperature and minimum established detected and rejected.
machine speed blister were checked for its d) Foreign particle detector
quality and leak test is performed for 09 accuracy
blisters (03 blisters per cut). And at the In this operation along with the
established minimum forming temperature tablet in the blister cavity foil
and maximum established machine speed pieces are kept in the blister
blister were checked for its quality and cavity and passed through the
leak test is performed for 09 blisters (03 BIS camera. Blister with foreign
blisters per cut). particles (Foil pieces) was
detected and rejected.
5. Verification of optimum sealing
temperature and optimum speed range 8. Print registration control: PRC value is
At the established maximum sealing set as per respective BPR. All the printed
temperature and minimum established lidding foil in between two eye marks and
machine speed blisters were checked for join the foil with the help of cellophane
its quality and leak test is performed for tape and pass through the PRC sensor. If
09 blisters (03 blisters per cut). And at the PRC value mismatched with the set value
established minimum sealing temperature it should be detected by the PRC sensor
and maximum established machine speed and machine should stop.
blister were checked for its quality and
leak test is performed for 09 blisters (03 9. Splice detector
blisters per cut). Based on the result In this case if no splice is present in any of
optimum speed with optimum sealing the base/lidding foil, insert one splice in
temperature is established. either of base/lidding foil by cutting the
foil and joining the foil with the help of
6. Efficiency of tablet feeder cellophane tape and pass through the
It is carried out for all validation batches splice detector. It is carried out for all
during this operation flow of tablets from validation batches and the presence of
hopper – chute – brush box to forming splice foil in the blister was detected by
plate was observed and checked for the the detector and the same blister was
presence of chipping, breaking and rejected.
jamming of tablet and effectiveness of
feeder level sensor. 10. Function of base and lidding foil
Without base and lidding foil the machine
should not start.
11. Carton with missed leaflet and carton with collected and inspected. And the de-
additional leaflet was detected by check blistering process is done for 2nd run and
weigher and same carton was detected and 3rd run. And only 3rd run samples were
rejected. And set compressed air pressure sent QC for description, Identification by
at 3, 4, 5, 6 and 7 Kg /cm2 and verify for IR, hardness, thickness, friability,
rejection in case of missing leaflet. dissolution & assay. At the end of
operation switch off the main, wait for 3
12. Shrink wrapping minutes and again switch on the main and
The machine was set with the temperature start the packaging, observe for physical
as mentioned in the respective BPR and parameters and perform the leak test for
carton with shrink film was passed 09 blisters. After completion of shrink
through the conveyor. And samples were packaging pass 01 shrink bundle 03 times
collected for finished product testing. each through the shrink packaging
machine and collect 01 shrink box and
13. Impact assessment send to QC for description, identification
After completion of first run packaging by (IR), hardness, disintegration test,
blister to be de-blistered are de-blistered friability, dissolution, related substances
by de-blistered machine and tablets were and assay.
RESULTS
Table 6: Results of Minimum speed & Maximum forming temperature, Maximum speed
& Maximum forming temperature
Batch-I
Minimum speed: 15 PPM
Maximum forming temperature: 140º C
Measured
S.NO Acceptance criteria Observation
parameter
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.
01 Blister quality 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
02 Leak test Pass
leak test
Maximum speed: 20 PPM
Minimum forming temperature: 120º C
Measured
S.NO Acceptance criteria Observation
parameter
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.
01 Blister quality 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
02 Leak test Pass
leak test
Table 7: Results of minimum speed & maximum sealing temperature, Maximum speed
& Minimum sealing temperature
Batch-I
Minimum speed: 15 PPM
Maximum sealing temperature: 210º C
Measured
S.NO Acceptance criteria Observation
parameter
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.
01 Blister quality 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
02 Leak test Pass
leak test
Maximum speed: 20 PPM
Minimum sealing temperature: 180º C
Measured
S.NO Acceptance criteria Observation
parameter
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.
01 Blister quality 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
02 Leak test Pass
leak test
CONCLUSION REFERENCES
All the in-process parameters for packaging 1. Jain NK. Pharmaceutical Product
validation were checked and found well within the development: Pharmaceutical Packaging,
limit. All the results found well meeting the CBS publisher, 2005, 525-533.
predetermined specifications. No significant 2. Malukani J. Packaging Validation of
deviation was found in the entire packaging Sotalol Hydrochloride Tablets, Inventi
process. No change in any process parameters was journal. 2012; 1(3): 1-7.
observed during operation of batch packing. After 3. Manek SP. Validation of Pharmaceutical
reviewing the above observations, it is concluded Packaging. Pharma times. 2012;44 (2):15-
that the product is consistently meeting its 17.
predetermined specifications for the validation
batches (Batch-I, Batch-II & Batch-III).