validation of pharmaceutical packaging

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7/30/2019 Validation of Pharmaceutical Packaging http://slidepdf.com/reader/full/validation-of-pharmaceutical-packaging 1/3 Pharma Times - Vol. 44 - No. 02 - February 2012 15 Introduction In the pharmaceutical industry, GMPs are essential to ensure that consistent quality products are manufactured and delivered to the patients. Validation is now a key requirement of all GMP Guidelines, as a validated process enables consistent manufacturing and packaging of products in accordance with the product quality and market requirements in a cost effective and secure manner. Validation activities for a pharmaceutical product 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 Master Validation Plan for the facility. It is observed that Packaging Validation per se is generally notspeciedasaseparatevalidationactivity but considered as a part of Product Process Validation activity and some aspects of it are covered during Process Validation. This article highlights the need and the importance of packaging validation and key activities to achieve it successfully. Packaging validation It should form a part of the overall validationprogramintheplanttoconrm thattheresultingproductfromaspecied packaging process consistently conforms to product attributes and customer requirements. It is a risk-based approach, primarily focusing on the packaging processes that have the greatest potential risk to product quality and thereby provides a rational framework for developing an appropriate scope for packaging validation activities. To achieve the ultimate goal of packaging a product perfectly every time, equipment engineers, packaging specialists, packaging operators and quality teams must plan and work together through a packaging validation program in order to 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 primary objectiveistheestablishmentofanefcient process with minimum down time, product rejects and errors. The key elements of packaging validation activity are: 1) Qualification 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 equipmentqualicationistheevaluation of 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) Validati onofaspecicproductpackaging 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. Thetwowords,namely, Qualication and 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.Inthissense,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, identifytheproductfromitspackand thereby provide traceability, providesecurityagainsttamperingand counterfeiting of the product, providetothepatienttheinformationon use for compliance, provideconvenienceinuseofthe 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 in detailforeachproducttonalizethekey 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 batches of 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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Page 1: Validation of Pharmaceutical Packaging

7/30/2019 Validation of Pharmaceutical Packaging

http://slidepdf.com/reader/full/validation-of-pharmaceutical-packaging 1/3

Pharma Times - Vol. 44 - No. 02 - February 2012 15

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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Pharma Times - Vol. 44 - No. 02 - February 2012 16

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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Pharma Times - Vol. 44 - No. 02 - February 2012 17

– 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.