validation of pharmaceutical packaging
TRANSCRIPT
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Introduction
In the pharmaceutical industry, GMPsare essential to ensure that consistentquality products are manufactured and
delivered to the patients. Validation is nowa key requirement of all GMP Guidelines,as a validated process enables consistentmanufacturing and packaging of products
in accordance with the product quality andmarket requirements in a cost effective andsecure manner.
Validation activities for a pharmaceuticalproduct include requirements for:1) Process Validation
2) Cleaning Validation
3) Analytical Methods Validation
4) Computer Systems Validation
5) EquipmentsValidation(Qualication-IQ/OQ/PQ )
The requirements for all the validation
activities in a facility are captured in a MasterValidation Plan for the facility. It is observedthat Packaging Validation per se is generallynotspeciedasaseparatevalidationactivity
but considered as a part of Product ProcessValidation activity and some aspects of
it are covered during Process Validation.This article highlights the need and theimportance of packaging validation and keyactivities to achieve it successfully.
Packaging validation
It should form a part of the overall
validationprogramintheplanttoconrmthattheresultingproductfromaspeciedpackaging process consistently conforms
to product attr ibutes and customerrequirements. It is a risk-based approach,primarily focusing on the packagingprocesses that have the greatest potential
risk to product quality and thereby providesa rational framework for developing anappropriate scope for packaging validation
activities.
To achieve the ult imate goal ofpackaging a product perfectly every time,equipment engineers, packaging specialists,
packaging operators and quality teamsmust plan and work together through apackaging validation program in orderto create a robust packaging operation.
Though every validation activity is aimed
Article
Validation of Pharmaceutical Packaging*Dr. S. P. Manek
Hon. Secretary, Regulatory Affairs Division, Indian Pharmaceutical Association
*Email id: [email protected], [email protected]
towards ensuring regulatory compliance,
it should be remembered that the primaryobjectiveistheestablishmentofanefcientprocess with minimum down time, product
rejects and errors.
The key elements of packaging validation
activity are:
1) Qualif icat ion of New Packaging
equipmentincludingDesignQualication
(DQ), Installation Qualification (IQ),
Operational Qualification (OQ) and
PerformanceQualication(PQ)ofthe
equipment and the respective facility
and critical utilities. The focus during
equipmentqualicationistheevaluationof variance of various equipment settings
or parameters due to the operation of
the equipment and the assessment
of its impact on critical product quality
attributes.
2) Validationofaspecicproductpackaging
operation of a new product: In this case,
packaging operations for a new product
are validated in an existing packaging
line through evaluation of the impact
of equipment variance on the critical
product quality attributes.
The twowords,namely, Qualicationand Validation are used interchangeably as
QualicationandValidation are essentially
components of the same concept. The term
qualication is normally used for equipment,
utilities and systems: A system must be
qualied to operate in a validated process.
The term validation is normally used for
processes.In thissense,qualicationis
part of validation, e.g. you qualify a mixer,
whereas you validate a mixing process for
a blend. Qualicationshouldbecompleted
before process validation is performed.
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 consistently efcient
process with minimum down time, rejects
and errors. Since consistency and cost
effectiveness are, without doubt, key
business considerations, a validation
activity should be seen not as a regulatory
requirement but as a business necessity.
Packaging isdenedas“the art, science
and technology of preparing products for sale in a cost effective manner.” It involves
the operations of Filling, Sealing, Inspection,
Labeling,andnalpackagingofaproduct
and each of this stage need to be part of
packaging validation program.
In the context of pharmaceuticals,
packaging is a key component of the product
and must:
• preservetheproductfromenvironmental
degradation or contamination,
• containtheproductsecurelyinorderto
avoid leakage,
• identifytheproductfromits packand
thereby provide traceability,
• providesecurityagainsttamperingand
counterfeiting of the product,
• providetothepatienttheinformationon
use for compliance,
• provideconvenience inuseof the
product for medical staff or patient.
All these must be ensured for the
life of the product and achieved within a
complex regulatory environment. These
requirements need to be evaluated indetailforeachproducttonalizethekey
packaging attributes to be validated.
To carry out a meaningful packaging
validation, it is essential to ensure that
the following key areas impacting the
robustness of a packaging process should
be considered as a pre-requisite:
a) Packaging Line Layout: The design and
layout of equipment has major impact
ontheefciencyofthepackagingline.
Design for a line layout should include
the ability to manage quick change-over,
perform line clearance between batchesof product and clean the line in an easy
and controlled manner.
The majority of problems on packaging
lines are related in some way to poor line
clearance and therefore it is important to
design these problems out. 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.
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Asarststepofthevalidationstrategy,
oneneedstodenethetopologyofthesystemtohelpdenethescopeofthevalidation activity of the packaging line
system. Next is to identify and list thesystem functionality, i.e., the softwareand hardware of the system to be testedandveriedasbeinginworkingorder
to enable validation to be performed.
Similarly, it is equally important toidentify all the critical measuring devices
that need calibration e.g. pressuregauges, thermocouples, hygrometersetc. present on the system.
b) Well designed equipment will lend itselftoefcient productionofa consistentstandard product. In case of olderequipment, it is often observed that they
canbeinexibleandmayhaveelementsof poor design such as areas wherepackaging components or product may
be trapped, resulting in products beingincorrectly packed. This represents a
signicantrisktothepatientandisoneof the major reasons for product recall
in the industry. The greater the numberof stages there are in a packagingline, the lower its efficiency will be.Appropriate validation of the packaging
lines will challenge the robustness ofthe packaging operation establishingtheconditionsunderwhichefciencyis
maximized.
c) Assess the GMP risk: Though all GMPRisksareimportant,onecanspecically
look out for those that may causeproduct defect Class I (critical) defect
/ Intolerable defect (dangerous andposeserioushealthhazard)leadingto
product recall. Some of these examplesinclude:
– The contents of the package do not
match the labeling on the package.
– C o n t a m i n a t e d p r o d u c t :
microbiological / physical / chemical
contamination.
– Printing errors on labels and package
inserts.
– Incorrect packaging component in
thenalassembly-A‘rogue’printed
component mixed within a batchofotherproductsmisidentiesand
misinforms the user of its contents.
– It is observed that majority of the
product recalls in regulated markets
involve one or the other package
defect mentioned above. In most
cases, such defects arise due to
lack of proper packaging process
validation, lack of controls / training /
improper sampling and/ or testing.
d) In pharmaceutical product packaging, a
variety of packaging materials are now
used as per product requirements and
the same set of tests may not meet allthe requirements. Help of a PackagingTechnologist or specialist and the supplieris taken to determine the relevant tests to
be performed during validation, e.g. anefcientproductionlineneedsconsistentmaterials and for many packaging
materials, the storage and handling
of components is critical to maintainconsistency during packaging operation.Apart from different types of materials,
one may have multiple suppliers for thesame packaging item. To avoid issuesduring normal packaging operations,a good relationship with suppliers
is essential, together with rigorouspackaging material specifications,the supplier quality audit and material
qualicationareapre-requisitetoensuresuccessful packaging validation.
e) Standard Operating Procedures or
SOPS are important element of a
Packaging Validation exercise. Tooperate a packaging line, a number ofSOPs will be required.
It is vital that there are clear andunambiguous instructions on how tooperate, adjust, and maintain each
piece of equipment. In addition, therewill be procedures to detail how a batchis packaged. SOP usually explains how
each material is received on the line andchecked for correctness, quantity, etc.by the operators. Details of In ProcessControl (IPC) tests as well as Procedure
for Line clearance / change-over,including details of cleaning operationsto avoid cross-contamination will be
given in these SOPs.
Involving the line operators in developingthe SOPs will result in documents that
moreaccuratelyreectwhatisactuallyhappening on a day-to-day basis.Operators will also take ownership ofthe SOPs ensuring better compliance
and hence less problems on the line.
f) Package Testing Program : It includesallwrittenspecicationsforpackaging
materials and the product package and include the nature, extent and frequency
of routine tests such as :– visual inspection (cleanliness,
defects, visible contamination).
– tests to identify the material.
– dimensional tests.
– P h y s i c a l , c h e m i c a l a n d
microbiological tests, wherever
applicable.
– Functionality tests: Tests involving
compatibility with production use,
product use, distr ibution, etc.
For packaging validation activity,
the functional tests form a key
component of attributes to be tested.
Examples of such functional tests
include assembly tests like-
• CappingtorquesonPPcapsof
the bottles,
• PRINTSCUFFTEST-scuf f-
resistance of inks on labels,
blisters etc.,• Capacitytestsoncontainers,
• Leakagetestsforthecontainers,
ampoules, blisters, strips.
• Moisture vapor permeability oflaminates/containers etc.
g) Training: Training of operators andengineers on a packaging line isintegral to equipment installation and
qualif ication. The supplier shouldidentify training needs and provideappropriate training. Records of relevant
training and experience should bemaintained and be available as part
of the project documentation. Fortraining on an ongoing basis, one
needs to develop a Training Module forretraining / training new operators. It isimportant to periodically review training
requirements.
h) Qualification Protocols: A normalapproach to any validation is to prepare
testprotocols forDesignQualication(DQ), Installation Qualification (IQ),Operational Qualification (OQ) andPerformance Qualif icat ion (PQ).
Information gathered from each ofthese stages must be fed into the next
to ensure that the system is adequatelytested. Protocols should test each pieceof equipment or step in the process,however, it is important to have oneoverall protocol to test the interaction
between different pieces of equipmentand/or systems. The supplier normallyprovides a lot of support, includingdocumentation to develop and complete
the DQ, IQ and OQ for a packagingline.
i) Performance Qualification (PQ) is
the last but most important stage inequipmentvalidationandshouldreect
the‘real’productionenvironment,usingproduction materials in a normal dailyoperation. It is an area where one needsto pay a lot of attention as dependingupon the line topography. It requires
to:
– Test each piece of equipment in
the line and to test the interaction
between d i f ferent p ieces of
equipment /systems.
– Ensure that the validation activity
is designed to test all the critical
steps.
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– Provide a list of tests which are to
be performed, the details of test
procedures and the acceptance
limits for each test.
– Test beyond the normal operating
range to provide information on the
system behaviour, which can be
usedtonalizeoperationallimits.
– The exercise should extend over atimeperiodsufcienttoensurethat
shift working patterns and normal
lunch breaks etc. are included
and to certify that the systems are
challenged for stop/start, batch
changes etc.
The completion of the above activitiesensures that a new packaging lineinstalled in the facility is qualified
to operate as desired and capableof consistently delivering qualitypackaging.
Packaging Process ValidationIt is an activity performed when a new
product is being packagedforthersttimeonan existing packaging line, using current ornewpackagingmaterialsandconguration.First step involves preparing a PackagingProcess Validation Protocol with:
1) Short description of the packagingprocess for the product, with a summaryof the critical processing steps or criticalparameters to be monitored duringvalidation.
2) Additional testing intended to becarried out, with proposed acceptance
criteria and analytical validation asappropriate.
3) Sampling plan — where, when, how andhow many samples are taken for varioustests to be performed during validation(more sampling than normal IPC).
4) Details for recording and evaluation ofresults.
Examples of critical tests to be done toevaluate impact on the product include:• BlisterorBulkPackingofsoliddosage
forms :
– Need to study impact of MachineSpeed, Forming/Sealing Tempera-
ture, Pressure settings and rangewhen using different materials,sourced from different suppliers onquality attributes of different prod-ucts (tablets /caps ).
– Need to package at extreme rangeof temperatures and evaluate itsimpact on quality. The sealingquality leading to improper sealingcould be a function of impropertemperature and/or pressure setting.Non-destructive leak test can beperformed to determine propersealing, but need to have right
testing procedure and follow the right
testing frequency.
– Impact on integrity of the pack,
its appearance, including pack
aesthet ics, leg ib i l i ty o f text ,
overprinting matter clarity etc.
– For packaging validation of a product,
it requires various product quality
attributes such as stability, purity,assay etc. to be performed.
– Need to carry out validation under
user conditions – impact of breaks
( tea / lunch / machine breakdown )
etc.
– Evaluate contamination possibilities
– e.g. lubricants, product leakages
d u e t o im p a c t o f m a ch in e
components etc. This also highlights
the importance of cleaning validation
of packaging machines.
– Bulkpackingoftablet/capsulesneedcount accuracy to be established,
integrity of pack with respect to
sealing and container damage
evaluated. If operation leads to a
Pilfer-proof pack, efficacy of the
same needs to be evaluated. Cross
contamination in bulk packing is a
critical issue and hence, cleaning
validationofkeyidentiedareasof
the equipment is a must.
• PackagingvalidationofLiquids/Topical
Products /Ampoule / Vials involve
evaluation of impact of line speed onvarious critical product characteristicssuch as:
– Filling: Fill weight / volume variation
andllaccuracy.
– Splashing, spillage, container
damage.
– Seal quality: aesthetics, seal test
(leak test), ease of opening.
– Pack Labeling: Overprinting batch
data, label position.
– Barcodereading.
The Validation Report
Thenalvalidationreportshouldincludeall the test results together with details ofany changes made to the system. If thereare test failures, these must all be reported
and the resulting actions detailed. Anylearning points from the activity should belogged and recommendations for futureimprovements documented. It is important
to include a recommendation on the timescale for review of the system validation.The validation report must be reviewed and
approved by QA.
Once a packaging validat ion is
successfully completed, it is equallyimportant to maintain the system in avalidated state. Frequently, changes dotake place on the packaging system andthe process of Change Control becomesimportant to maintain the system in avalidated state. Change Control is a formalevaluation of the potential impact of planned
modicationsonthevalidatedstatusofaproduct / process.
Various changes that require revalidationof the system include software changes,operational changes, change of source ofmaterial, change in the packaging process,signicant equipmentchange,productionarea/site changes and support system / utilities changes.
Pharmaceutical industry is constantlychallenged to reduce cost; new markets andnew packs add complexity to the operationand the need to operate in an ever-changing regulatory environment demands
compliance. In other words, to ensure packintegrity,manage complexity,maximizeefciencyandminimizecosts;appropriatelydesigned packs running in validatedpackaging lines are a business necessityrather than a regulatory requirement.
If packaging validation is well plannedand documented, then GMP compliance willnaturally follow. For successful validation,the key points to take care of include:
1) Understandingthoroughlythepackagingsystem and its critical steps.
2) Never underestimating the amount oftime needed to develop plans. More timeyou spend in design of the protocols, theless you will waste in resolving issuesand investigating failures.
3) Developing a good, sound sampling plan- IPC tests are meaningful and provideuseful data on the line performance(samples should reflect the normaloperating conditions). The frequencyof IPC tests can be reduced afterreview of data, so, having a procedurein place to ensure that all the IPC datais routinely reviewed and assessed byknowledgeable people is a must.
4) Detecting and understanding sourcesand degree of variation, its impact
on product attr ibutes and controlvariations.
5) Finally, any validated system is asgood as the associated change controlprocess. Make sure all changes are fullyassessed and documented. The impactof the change on the validation statusof the system must be fully assessedbefore any changes are made.
The Quality of a product is designedand built into the process and the productduring design stage. The functionality,consistencyandrepeatabilityareconrmedby Validation.