This document provides an overview of Good Manufacturing Practices (GMP) regulations for laboratories and cleanrooms. It discusses that GMP regulations aim to ensure safe and effective delivery of products to patients by establishing quality control throughout the entire manufacturing process, from raw materials to storage and transportation. Compliance with GMP is important given past issues like contaminated vaccines that harmed patients. The document outlines some of the key international and national laws and guidelines that make up GMP regulations, and emphasizes that adhering to GMP is the duty of all pharmaceutical companies and testing labs.

1. GMP Regulations:
APracticalGuide
for Laboratory
and Cleanroom
Compliance
PRACTICAL GUIDE

2. A Roadmap to GMP Compliance for Regulated
Laboratories andCleanrooms
Good Manufacturing Practices (GMP)
Establishing and maintaining compliance in a highly
regulat- ed laboratories and cleanrooms can be
complex and over- whelming. It is important to gain a
full understanding of the numerous aspects and
processes that touch the product throughouttheentire
manufacturingprocesstoultimately ensuresafeand
effectivedeliverytopatients.Fromquality systems and
documentation, to outsourcing, storage and self-
inspection,thisguidewillexploretheneedtofocuson GMP
andprovidepracticaladvicetokeystakeholders.
Quality — The Most Important Consideration
Throughoutlife,peoplesufferfromavarietyofailments that
take different courses and have various manifestations. In
mostcases,peopledecideontheirownorontheadvice of
theirdoctor,totakemedicationtoeasethesymptoms and
treattheirillness.Thisraisesthequestionofwhether the
medicationusedtotreattheillnessiseffectiveand
whether the person using it will be able to tolerate it.
Furthermore,asaresultofheadlinesinthenews,weare
now highly aware of the issue of drug safety.
Effectiveness,tolerance,andsafetyareverymuchdeter-
minedbythequalityofthedrugproduct.Quality,inturn,
dependsontheproductionoftheactiveingredientsand
accompanyingsubstancesthatareused,thecombination
andassemblyofthesesubstances,packaging,storageand
transportation, the experience and training of all partic-
ipants, the validation of procedures, the qualification of
systems,andtheserviceprovidersandconsultantsinvolved
intheprocess.Asaresult,therearenumerousactorsand
potentialsourcesoferrorsthathaveadirectimpacton
quality.
These considerations are especially important with respect
to vaccines. Because vaccines are produced using
biological andgeneticengineeringprocesses,stepsmust
betakento preventcontamination.Theprocessesusedto
ensurequal- ityofmedicinesandvaccinesmustbeflawless,
nothingleft tochance.Patientsassumeallpartiesinvolved
—manufac- turers,labs,packagers,warehouseworkers,
transporters, andpharmacists—meetallquality
requirementsatall times and trust the medicine is safe.
Is trust enough when it comes to your health?
Probably not.Thisiswhereregulationscomein.Theyare
precise requirementsthatmustbeobservedwithrespect
tothe production, storage, transportation, testing, and
sale of drug products. These are the rules of GMP. As
global stan- dards,theyaredefinedinnationallawsaround
theworld. InGermany,theyareoutlinedintheMedicinal
ProductsAct (AMG).

3. 3
“This paper is intended for everyone who is involved in the
production,packaging,storage,transportation,orotherhandlingof
rawmaterialsandactivesubstances,drugproducts,andvaccines;
itshouldbemadeavailabletoallsuchpersons.Itisintendedto
draw attention, makepeopleawareof theissue, andprovide a good
justificationforGMP—inshort,itisintendedtobeasimpleand
easy-to-understand training tool.”
If Everyone Acted Responsibly
Thewomenandmenwhoworkinthepharmaceutical
industry have a wide variety of training levels and
special- izations,fromsalesstafftoengineers,fromlab
assistantsto cleaning specialists. The regulatory framework,
laws, guide- lines,andregulationsaroundtheworldareso
complex, theirimpactcanbefeltbeyondtheproduction
sitesand labs.Theycanalsoaffectallcorporatelevels.
Therefore,allemployeesmustunderstandtheaimand
purposeoftheirrole,theirwork,andhowGMPregulations
affecttheirwork.Awillingnesstoassumeresponsibilityin
thisregardisessentialtoensurethehealthrisktopatients
andtheassociatedeconomicriskstothecompanyhave
beenminimizedasmuchaspossible.Ultimately,acompany
willrealizethatthereisabreak-evenpointfortheaddition- al
workthatisrequiredbyGMP.Netgainwillcomefrom your
company’s compliance.
Historyshowsthatpatientshavesufferedseriousnegative
healthconsequences–andinsomecasesevendeath–
as aresultoferrorsintheproductionprocessorasaresult
of errorsduringtheanalysisstage.Inmanyinstances,
these errors could have beenavoided ifGMP
requirements had been applied at the time.
GMP — What Is It?
Drug products are developed and produced in order
to preventorcureillnessesortoprovideillpatientswith
relief. Drug products are purchased with the trust and
the confidencethatthemanufacturersdoeverythingthey
can duringtheproductionanddevelopmentprocessto
ensure highqualityandpreventrisksduringthe
process.
Theawarenessthatdrugproductscanleadtosubstantial
risksarose,inpart,intheearly1960sasaresultoftheCon-
tergan scandal, when deformations and deaths occurred
amonginfantsaftertheirmothershadtakensleepingaids
whiletheywerepregnant.Atnearlythesametime,millions of
peopleaccidentallybecameinfectedwiththeSV40sim- ian
virus when they were immunized against polio
because theoralvaccinewascontaminated.SV40can
causecancer. Forexample,SV40virusescause
lymphomas,lungcancer, bonecancer,andbraintumorsin
hamsters.Thisshows
thattherearesignificantrisksassociatedwithmedication
thathavenotbeentestedsufficiently,thathavebecome
contaminatedorotherwisetainted,orthathavebeenthe
subjectofanactofsabotage.Topreventsuchrisks,stan-
dardstoensure auniformqualityassurance(QA)system
mustbedevelopedandupdatedonacontinuousbasis.
However,GMPitselfisnotaQAsystem,butinsteadonly
providesspecificinstructionsforproductionprocessesand
for controlling the products that are manufactured.
GMP mustbeintegratedinanexisting,functionalquality
man- agement system(QMS).
InGermany,compliancewithGMPismandatedbylawin
Section54oftheAMG.Theunderlyingframeworkarethe
EUGMP guidelines,whichsince 2006haveconsisted of
two largesectionsandtherelatedannexes.Theactual
autho- rizationtomanufacture,distribute,ortestdrug
products
isprovidedbythemanufacturingauthorizationpursuant
totheAMG.InGermany,suchauthorizationisgrantedby
various authorities, including district governments, regional
councils, and other state authorities.

4. 4
Inthe US,theFood andDrugAdministration (FDA)isthe
sole agency responsible for food and drug products.
Title 21oftheCodeofFederalRegulations(CFR)Part
211out- linestheGMPrequirementsforfinished
pharmaceutical products.
TheGMPguidelines,whichwereoriginallypublishedby
theWorldHealthOrganization(WHO)in1968,havebeen
updatedcontinuouslysincethe1980s.Basedonthese
guidelines,thereisanobligationforbothmanufacturers
andproductanalyststodefine,priortotheintroduction ofa
drugproductonthemarket,amandatory,multi- stage
approvalprocess.Thisobligationwasfirstdefined inthe
US.ThefirstUSlawrelatedtodrugproductswas the
PureFood andDrug Actof1906, which required that
drugproductsbeclearlylabeled;however,thislawdidnot
introduce an approval process. This occurred three
decades laterwiththeFederalFood,Drug,andCosmetic
Actof 1938,whichwaspassedasaresultofthe
sulfanilamide disaster,inwhichmorethan100peopledied
aftertaking anantibioticthathadnotbeentestedsufficiently.
Thekey provisions of this law were strengthened by the
Kefauver HarrisDrugAmendmentof1962,whichwas
passedatthe sametimeastherevelationoftheContergan
scandal.This amendmentrequired,forthefirsttime,proofof
adrug’s therapeuticeffectivenessandsafetyasshownin
adequate and well-controlled clinical studies. A number
of drug laws inothercountriessubsequentlyalso
requiredproofofa drug’seffectiveness.Inmanyrespects,
USdruglawssince 1962haveservedasamodelusedby
alargenumberof other countries.
Internationally,guidelinesregardinghowandunderwhat
conditionsdrugproductsmaybedeveloped andmanufac-
tured have been formulated and enshrined in law in
order toensureandcontinuouslyimproveproductquality.
Taken together,alloftheseguidelines andlawsarecalled
GMP. Strictimplementationof,compliancewith,and
adherence toGMPisthemostimportantdutyof
pharmaceutical com- paniesandtestinglabsduringtheir
day-to-dayactivities.
InGermany,companieshaveonlybeenallowedtoproduce
approved drug products if they have demonstrated
that theyaresuitablemanufacturersbyreceivingofficial
au- thorizationsince theintroduction oftheAMG in1976.
On thebasisofofficialinspections,suchsuitabilityis
carefully reviewedbyrepresentativesofthestate
(inspectors)and, ifthemanufacturerisdeemedtobe
suitable,document- edinamanufacturingauthorizationin
accordancewith Section13oftheAMG.Aftertheinitial
inspection,the
official representatives conduct additional checks at regular
intervals(inGermany,everytwotothreeyears,usinga
risk-basedapproach).ThedetailsaresetoutintheGeneral
AdministrativeRegulationsfortheImplementationofthe
AMG(AllgemeineVerwaltungsvorschriftzurDurchführung
des Arzneimittelgesetzes – AMGVwV).
How is GMP to be implemented? Although there are
nu- merouslaws,guidelines,andregulationsthataddress
the topicofGMP,thelevelofdetailthathasbeendefinedwith
respecttotheiractualimplementationisusuallyinsuffi-
cient.Asaresult,eachindividualcompanymustgenerally
decideforitselfhowtoensureacertifiedGMPenviron-
ment.Wewill look moreclosely atthis questionofhowto
implement GMP in the next section.
GMP Is Everyone’s Business — Not Just Production
As a result of advances in research, the requirements
imposedonthemanufacturersofpharmaceuticalproducts
arebecomingincreasinglycomplexandmoretime-con-
suming.Atthesametime,however,therequirements for
managementstructuresfromaregulatoryperspectiveare
alsoincreasing,asitisnownecessaryforcompaniesto
haveatleastonequality assurancemanager(thoughthey
generallymusthaveanentirequalityassurancedepart-
ment). This department is responsible for implementing
andmonitoringtaskswithintheirareaofactivitiesrelated to
compliancewithqualitystandards,anditsmembersare
appointed directly by management.
The era when the rules of GMP were applied solely to
pro- ductionisover.“Everyoneinvolvedinthelongvalue
chain ofamedication arenowaffected byGMP andmust
adhere tothecorrespondingrequirements.Inadditionto
the manufacturer, this also includes retailers, service
providers, servicetechnicians,softwaresuppliers,andeven
garbage disposal companies.”
Theoverarchinggoalofqualityassuranceistoestablisha
systemwithineachcompanythatensuresimplementation of
the applicable national and international rules, ordinanc- es,
andlaws,includingGMP.Thedepartmentmust,there- fore,
ensureseamlessandcompleteproofoftheexistence of the
necessary QA system.
Milestones in the Development of GMP
Asindicatedabove,GMPhaschangedoverthecourseof
the last century. These changes were mainly due to
events thatcanstillbefoundinthemediatodayandthat
aredis- cussedregularlyatGMPconferences,training
sessions,and meetingsinordertoraiseawarenessofthe
needforGMP.

5. 5
Is It Really All History?
SomestudiesstillshowGMPfailuresareontherise.In
the2018reportingperiod,theFederalUnionofGerman
AssociationsofPharmacists(ABDA)aloneproduceda
total of9,486spontaneousreports/noticesaboutdrug
product risks/sideeffectsfrom4,846pharmacists.Nearly
2,959re-
portsinvolvedobservationsofundesiredeffectsorthemis-
use or improper use of drug products that were
forwarded tothecompetent higher federal authorities.
The vast majority of reports received involved
complaints about pharmaceutical quality (with 6,527 such
cases), with packagingerrorsleadingtheway,followedby
preparation defects,mechanicalproblems,and
declarationerrors.In addition,therewereatotalof53
reportsofsuspectedma- nipulationsorcounterfeits(2017:
57reports).Theauthor- itiesresponsibleformonitoringthe
relevantauthorization holderwereimmediatelynotifiedin
around40percent
ofreports(2,570of6,527reports)relatingtosuspected
quality defects.
Thereportingpharmacistsalsomadeasignificantcontribu-
tionin2018toincreasingthesafetyofdrugproductsand
therapies,andthuspatientsafety.Therewereatotalof
43DrugCommissionoftheGermanMedicalAssociation
(DCGMA) notices based on 181 reports from 147 pharma-
cists.Another660spontaneousreportsfrom593phar-
macistsledtotheinitiationofcorrective,risk-minimizing
measures by the relevant manufacturer.
The trend is clear. There has (once again) been an
increase indefectssince2015.Thistrendrunscounter
toGMP
andmeansthattherulesmustbeintroduced,applied,
andmonitoredevenmoreforcefully,includinginother
countriesaroundtheworld,inordertoavoidunnecessarily
endangeringthehealthandwell-beingofpatients.Thus,
GMPmakesabsolutesenseandmustserveasan
example and be implemented at all levels.
GMP Will Haunt You Until You Get It Right
The events of the last years and century are just
examples ofwhatcanhappenduringtheproduction,
testing,andsale ofdrugproductsandtheresulting
consequences.Thelistof mishaps could be longer.
Butwhydotheyoccurinthefirstplace?Amongother
things,enormouscostpressureisincreasinglydrivingphar-
maceuticalcompaniestoimportcheapstartingmaterials
andfinisheddrugproductsfromnon-Europeancountries,
mainlyfromAsia.Itisdifficulttoensurethatthesemanu-
facturersarecomplyingwithdomesticqualityrequire-
ments.Inanycase,thereisnotfulltraceability.
Costsversusquality.Thisisadifficultbalancingactbut
onethatcanbemasteredeffectivelywiththehelpofGMP
rules.Forexample,theDCGMApublished40so-called
redhandwarnings for2018onitswebsite informingmanu-
facturers and associations of manufacturers of finished
drugproductsaboutpotentialrisksandrecallsofdrug
products. Additional warning letters about potential health
andotherriskscanbefoundonthewebsite oftheFederal
InstituteforDrugs andMedicalDevices (BfArM).
Thenextpatientcouldbeyou,amemberofyourfamily,or
your beloved pet! We want to achieve the highest level
of safety.Thisstartswitheachoneofusinourdailywork.
However,wenowhaveanincreasingnumberofindepen-
dentGMP requirements,suchasGMPforadvanced
therapy medicinal products (ATMP) and GMP for sterile
drug prod- ucts.Inaddition,thereareevermoredetailed
documents, suchasAnnex1andAnnex17oftheEUGMP
guidelines.So let’srisetothechallengeandmake
medicationsafe.
GMP: Chapter by Chapter
InallregulationsincludingGMPandgooddistributionprac-
tice(GDP),thereisonlyonethingthatmatters:thequality of
thedrugsmustbeflawlessthroughoutmanufacturing and
distributiontoguaranteesafetyforthepatient.
Thus, GMP regulations cover a wide range of aspects
and processes that touch the product, including the
chapters below.
1. Quality System
2. Personnel
3. Premises andEquipment
4. Documentation
5. Production
6. Quality Control
7. Outsourced Activities
8. Complaints and Product Recall
9. Self Inspection
10. Storage andTransport
GMPthusaffectseverysingleemployeeinvolvedinthe
pharmaceuticalmanufacturingprocesschain:fromactive
ingredient suppliers, purchasing, warehousing,technology,
processing, packaging, inspection, through to dispatch and
transport.
Quality is the result of teamwork. Every single job must be
carriedoutcorrectly onadailybasis,evenifatfirstglance it
seems insignificant. In the following, the most important
GMPrequirementsarelisted(butnotexhaustively).

6. 6
1. Quality System
Quality of Medicinal Products
The quality of medicinal products and active substances
mustnotbearandomproduct,buttheresultofcareful
planning, correct implementation, good documentation
andsystematicmonitoring.Qualityisnotamatterfor
discussion.Theexactqualitythatmustbemaintainedis
describedintheapprovaldocumentssubmittedtothe
authorities.Beforeabatchofpharmaceuticalsisreleased for
sale,thequalifiedperson(QP)checkswhetherallthese
quality criteria have been met. The responsibility for quality
doesnotendattheloadingramp.Storage,transport,and
distributionmustalsobeplannedandcontrolledinsucha
way that the drugs cannot spoil or be mixed up.
Quality Management
Manufacturers of medicinal products or active substances
arerequiredtodocumentinwritinghowtheproductshave
maintained integrity. Even companies that only carry
out individualmanufacturingorpackagingstepsonbehalf
of others (outsourcing) must describe exactly how they
reliably ensurethequalityrequiredbyGMPandGDP,
accordingto legislation.Theclientcontinuestobearthe
responsibilityfor ensuringthatthecontractordeliversthe
requiredquality.
Qualitycontrolis,therefore,animportantpartofthequality
management system but not the onlyone.
Otherimportantelementsarecarefuldocumentation;the
qualification of buildings, equipment, machines, personnel
andsuppliers;auditing;thecorrecthandlingofchangesand
errors;aswellasthevalidationofprocedures.Inorderto
beabletoplanqualityinatargetedmanner,itisimportant to
constantly record the current data during production,
packaging,maintenance,warehousing,ortesting(onpaper
ordigitally).Thisdatamustbecontinuouslyevaluatedto
identify trends (productqualityreview —PQR)inorderto
identifyweakpoints,preventerrors,andimproveprocesses
(continuousimprovementprocess—CIP).Themanage-
ment of the company (as the responsible body) is
informed oftheresultsoftheseperiodicPQRs.Theaimisto
immedi- atelyidentifyandeliminatepotentialhazardsto
quality.
Quality Risk Management
Somedosageformsaredifficulttomanufactureorinvolve
specialrisksforthepatient,likesteriledosageforms(eye
drops, injections, infusions). For this reason, every company
musttailoritsprocessespreciselytotherespectivedrugs
andjustifyinwritinghowitcontrolsallqualityrisks(quality
riskmanagement).Itisnotenoughtoconcentrateonthe
productionofthefinalproduct.Qualitycanbecompro-
misedduringthedevelopmentofactivesubstancesand
duringdrugdevelopmentprocesses.Thus,GMPrequire-
mentsapplythroughoutadrug’slifecycle— frominception
to consumption.
Change Control (Management of Changes)
“Compliance” means that everyone must adhereexactly
tothevalidworkinstructions,simplifiedworkflows,im-
provements,orotherchangesthatarepermittedwithprior
writtenapproval.However,beforeachangecanbemade to
methods, processes, regulations, input materials, rooms, or
facilities,ateamofexpertsmustcarefullyevaluatewhat
consequencesthischangecouldhavefordrugquality.
Inevitably,changeshaveaninfluenceontheproduct,which
must be identified, evaluated, and documented accordingly.
Unplannedchanges,forexample,withinthescopeofa
repairoramajormaintenancetask,mustalsobesubse-
quentlycheckedandevaluatedinthesameway.
This investigation is carried out across departments. The
investigationconsiders notonlyproductionbutalsoengi-
neering,validation,qualitycontrol,qualityassurance,and
approval. The review will determine whether requalification
(installations) (see “Qualification section below), revalida-
tion(procedure),ornotificationofchangetotheapproval
authorities is required. Before each implementation, chang-
esmustbeapprovedinwritinganddefinedmeasures(e.g.,
requalification) must be taken. The application, review,
approval,follow-up,andimplementationofthechange
shouldbeassessedandrecorded.Allinformationshouldbe
easily retrievable.
Deviations, Errors, and Out-Of-Specification
(OOS) Despitecarefulplanningandconscientiouswork,
therecan bedeviationsanderrorsineverycompanyat
anytime– thisisultimatelyunavoidable.Thedecisive
factorinsuch
situationsishowcompaniesdealwiththem.Adocumented
and investigated deviation or error is not an “infringement”.
Undetectedorignoreddeviationsandunreportederrors, on
theotherhand,areviolations,whichcanleadtosignifi- cant
qualitydefects–andthese,inturn,couldputpatients atrisk
orcauseunnecessaryexpensesfromdeliveryfailure and
productdestruction.

7. 7
Anyone who discovers a deviation must report it to their
superior and document it promptly and
comprehensive- ly, regardless of whether they have
causeditornot.This
appliestoeventhesmallestdeviation.Nooneisallowedto
decideontheirownwhetheraproductisokay.Thisapplies
toalldeviations,defects,orfaultsdetectedduringproduc-
tion or quality control.
Astandardoperatingprocedure(SOP)shouldclearlyregu-
lateanddescribewhosubsequentlyassessesthedeviation
andwhomayormustmakefurtherdecisions.Specialrules
applyifananalyticaltestresultisoutsidethespecified
range(specification)(OOS).ThereisaspecialOOS-SOP
for this. Under no circumstances should the analyses
be repeatedasoftenasnecessaryuntilrandomresultsare
obtained that comply with the specifications (testing into
compliance).Thiscanseriouslyendangerthepatient.
Cause Analysis & Corrective and Preventive Actions
(CAPA)
Alldeviationsorerrorsmustbethoroughlyinvestigated.
Theaimistoidentifythecause(rootcauseanalysis)and
takeprecautionstokeeptheerrorfromreoccuring.This is
notaboutblame.Sensiblemeasurescanonlybetaken if
thecauseisknown.Ifnecessary,theinvestigationsare
carried out across departments (e.g., production, quality
control, quality assurance, technology, development). If
thecausecannotbeclearlyidentified,thismustalsobe
documentedaccordingly.Theexaminations,aswellasany
correctivemeasuresdeterminedarecheckedbythere-
sponsiblepersons(e.g.,headofproduction,headofquality
control).
All investigations must be completed and reported/
documentedinafailureinvestigationreport(FIR)within a
specifiedtime.Iftheinvestigationcannotbecompleted
withinthisperiod,atleastaninterimreportmustbedrawn
up.Deviations/defectivebatchesmustbeexaminedwith
regardtotrendsandevaluatedwithintheframeworkofthe
periodic PQRs.
Protection Against Counterfeit Drugs
Internationaltradeinactiveingredientsandmedicines
makesiteasierforcriminalstoreplaceormixmedicines
withineffectiveorharmfulcounterfeits.Qualitynaturally
goesunnoticedincounterfeitsandcanputpatients’livesat
risk.Everypharmaceuticalcompanyislegallyobligedtodo
everythinginitspowertomakeitasdifficultaspossibleto
imitate its products.
SinceFebruary2019,allmanufacturerswithintheEUand
UShavetocomplywiththeserializationasalegalrequire-
ment. Serialization (i.e.,traceability along theentire supply
chain) is intended to counteract counterfeit medicines
and thusguaranteepatientsafety.Thisisachievedby
affixing security features to each individual package
(machine-read- able,serializedcodetoidentifyauthenticity
atanypoint andatanytime,afterdatabasecomparison)and
byaffixing adevice,makingitpossibletodetecttampering
withthe outerpackagingwrapper.Theregulationsforthe
serial- izationofdrugsareperhapsthemostimportant
criteriain theglobalmarketingofdrugsandother
pharmaceutical solutions.Itisnecessarytounderstand
andplanforthe corresponding obligations in order for
serialization to be accurate and successful.
Activesubstancesandexcipientscanonlybeobtained
fromreliablesourcesthathavebeenthoroughlychecked
beforehand. Otherwise, the risk of counterfeitsubstances are
too high.
Thestorageandtransportofactivesubstancesandmedi-
cinal products must be well supervised and secure in
order toprotectthemfromunauthorizedaccess.Seal
marks, adhesives, or wrappings indicate whether a
pharmaceutical package has been openedsinceitwas
manufactured and whether its contents have been
altered.
2. Personnel
Training (Education)
Itisimperativethatallpersons,includingemployeesof
outsidecompanies,areawareofallinstructionsandregu-
lationsthattheyneedfortheirwork.Eachindividualmust
understand what they are responsible for and how
the qualityofthemedicinescanbecompromised.To
ensure that everyone receives the training they need
on an ongo- ingbasis,thereshouldbeatrainingplanora
qualification matrix.
Thetrainingplanspecifieshoweachemployeeistobe
trainedinGMP/GDPandtheinternaloperatingprocedures
he/sheistocarryout.Trainingfornewpersonnelisalso
regulated in the training schedule. All employees must
reg- ularly receive GMP training in accordance with
the training plan (e.g., on SOPs, hygiene requirements,
documentation, and CAPA).
Phases of the CAPA model

8. 8
Itisimportanttocontinuouslyrefreshanddeepenthis
knowledgeaswellaspointoutchangesinSOPs.Employ-
eesshouldtakepartinregulartrainingcoursesandput
whattheyhavelearnedintopractice.Participantsofeach
training course as well as the course content must be
documented.Theresponsiblepersonsareobligedtocheck
whether the training content have been understood.
This cantakeplaceimmediatelyafteratrainingcourseor
later. Ifthetrainingwasdeemedunsuccessful,thetraining
has to be repeated promptly and the assessment has
to be completed again.
Responsibility
Each employee is personally responsible for ensuring
that he orshe is familiarwith the GMP andGDP rules,
complies withthem,andbehaveshygienicallyinthe
manufacturing area. This includes showering, washing
and disinfecting handsbeforestartingwork;wearingGMP
clothingcorrect- ly;nojewelry,eating,chewing,nor
smokingintheGMP area;nocontactwithopenproducts;
andreportinginfec- tiousdiseases.Eachindividualis
responsibleforensuring thattheassignedtaskiscarried
outexactlyinaccordance with the approved SOP and
that it is recorded legibly and truthfully.Thisappliesto
allworkintheGMPareasuchas cleaning, maintenance,
calibration, control steps, monitor- ing,activities in
warehouses, and logistics.
Inaddition,everyonemustdocumentdeviations,defects,
machine malfunctions, faults, or inexplicable observations,
irrespectiveofwhocausedthem,andreportthemimmedi-
ately to their supervisor.
Noonemaymakechangestoanyregulations,protocols,
equipment, software, or processes until they are approved.
The change control procedure must be adhered to.
Man- agers also bear special responsibility. They
must ensure thattheirinstructionsareunderstoodand
carriedout.In theeventofdeviations,theymustbe
preparedtomake follow-up decisions.
Compliance
Everycompanydealingwithpharmaceuticalsmustcomply
withthecurrentrequirements.Everyemployeemust,
therefore,complypreciselywiththecorrespondingSOPs
andorganizationregulationsapplicabletohisorherwork-
placeonadailybasis—evenifnosupervisorispresent
or there are constricting time constraints. Inspections and
audits are regularly carried out by authorities and custom-
ers to check whether pharmaceutical companies and their
employees comply with all regulations.
3. Premises andEquipment
Buildings and Rooms
Onlysufficientlyqualifiedroomswithsuitableandqualified
supplysystems,(e.g.airconditioning,ventilationsystems,
waterpipes),maybeusedfortheproductionofpharma-
ceuticalsandactivesubstances.Aregularmaintenance
program must be available for buildings and rooms.
Mainte- nanceworkcarriedoutmustbedocumented.
Responsi- bilitiesshouldbedefinedinamaintenanceplan.
Theenvi- ronmental conditions (e.g., temperature, humidity,
particle count) must be monitored and controlled. The
records must be easy to find and retrieve.
Changestobuildingsorroomsthatcouldinfluenceprocess
flowsorprocessconditionsmustbesubjecttoachange
controlprocedure.Inordertoavoidcontaminationofa
productwithanotheractivesubstance(crosscontami-
nation),onlyoneproductperroommaybeprocessed.
Before another medicinal product or active substance is
manufacturedinthatroom,thepreviousproduct,samples,
and waste must be removed and the room
thouroughly cleaned.Allrelevantroomsmustbemarked
accordingto theiroperatingcondition(e.g.,cleaned,in
maintenance,
inoperation)ideallywithdetailsofthecurrentlyrunning
product/process.Inordertoavoiderrors,onlynecessary
materialsshouldbeavailableinproductionorpackagingar-
eas,whicharerequiredfortherespectiveprocessingstep.
Cleaning and Hygiene
Impurities(e.g.,microorganisms,dust,residuesofwater or
cleaningagents)inpharmaceuticalscaneitherdirectly
harmpatients orspoiltheproductsothatitisnolongeref-
fective. Therefore,itisessentialthatcleaningandhygiene
regulationsarestrictlyfollowedbyallpersonsentering
GMP areas.

9. 9
Allareasinproduction,qualitycontrol,andstoragemust be
ingood,tidy,andcleanconditionandfreefrompests. All
personsintheproductionareamuststrictlyobservethe
currentclothingregulations(e.g.,cleanroomclothing).It
isparticularlyimportantthattheclothingisalwaysworn
correctly.Evenifahygienezoneisonlyenteredorleftfora
shorttime,theprescribedclothingmustbeputonortaken
off.Thisalsoappliestoemployeesofexternalcompanies
andvisitors.Precisetrainingandmonitoringisessential.
Cleaninganddisinfectinghandsisanefficientmeasureto
reducethespreadofmicroorganismsandviruses.Forthis
reason,carefulhandhygienemustbeensuredafterleaving
the sanitary areas and at every entry into GMP zones.
A hygieneplanmustbedrawnup,andthe staffarerequired
to be trained and monitored accordingly. Suitable hand
hy- giene products should be available, periodically tested,
and changedifnecessarytoavoidantimicrobialresistance.
Specifichygienicbehaviorismandatoryincleanrooms.
Prohibitions include eating, drinking, chewing, scratching,
coughing,andsneezing.Youarenotallowedtobendover
open containers and plant components. A fresh mouth
guard and fresh gloves should always be worn around
open plant components.
The cleaning regulations for rooms, installations, and equip-
mentspecifyexactlyhowoftenandwithwhichmaterials
/cleaningagentscleaningmustbecarriedout.Itisimper-
ativethattheseregulationsarefollowedprecisely.Forex-
ample, SOPs may direct detergent dilution and setting time.
Cleaning utensils must not be stored damp.
Disposable items must be disposed of immediately.
Multiple articles must be disinfected or sterilized and
stored in a dry place. Diluteddetergentanddisinfectant
solutionsmayonlybe stored for the time indicated on the
label.
Devices, Machines, Systems
GMPrequiressystemstobequalified.Aqualifiedsystemis
onethatisinstalledproperly,secure,protectedbyredun-
danceis,repairedasneeded,andmaintainedaccordingly
(see“Production”sectionbelow).Allworkcarriedout
during maintenance or repair must be documented
care- fully and in detail. The logs must be archived in
such a way that they are easyto find and available.
Systems should be cleaned in accordance with the
detailed cleaningSOPs.Aftercleaningcontainers,
equipment,and plantcomponents,theymustbecarefully
driedandstored insuchawaythattheyareprotectedfrom
contamination untilreused.Beforechangesaremadeto
installationsand equipment,theimpactofthechangemust
beassessedin accordance with change control
procedures. This includes theinstallationofnewsoftware
(patches,updates)andmay require revalidation.
Maintenance and Servicing
Software-basedsystemsarealsosubjecttoTitle21CFR
Part11andmustbevalidatedaccordingly.Althoughthe
CFRisaUSregulation,itisnowconsideredtobestate
oftheartworldwide.Updatesandupgradesofsoftware
mustbestrictlyregulatedandcontrolled(documentation
andvalidation,ifapplicable).Maintenancedatashouldbe
analyzed regularly in order to initiate appropriate corrective
actions before problems compound.
Unusual observations of any kind must beevaluated and
reported to production and quality assurance. The main-
tenance and inspection of special tools and format parts
(e. g., tabletting tools) must be carried out in accordance
with the organization’s SOP. After maintenance or repair
work,partsincontactwiththeproductmayhavetobe
cleaned.Recalibrationmaybenecessaryorsparepartsmay
havetobequalified(see“Qualification“section).
Qualification
Qualificationmeansprovingthatsomeoneorsomethingis
suitableforacertaintask.Quality-criticalfacilities,utilities,
equipment,andmachinesintheGMPareamustbequali-
fiedsothattheyaresuitablefortheintendedpurpose.The
effortinvolvedcanvaryandshouldbecommensuratewith
the level of risk to the patient.
Theobjectivesandscopeofthequalificationareclearly
definedinthequalificationmasterplanandintheindi-
vidualqualificationplansfortheindividualstages(design
qualification–DQ;installationqualification–IQ;functional
qualification,operationalqualification–OQ;performance
qualification–PQ).Eachqualificationplanmustbeap-
provedbeforeitsimplementation.Ifchangesorextensions
tothequalificationplanarenecessaryduringqualification,
theymustalsobeevaluated,approved,and,ofcourse,
documented. Every qualification, however, is fundamentally
precededbyariskassessmentinwhich,ifnecessary,mea-
suresaredefinedbeforethestartofthequalificationwork.
Afterthetestsspecifiedintheplanhavebeencarriedout,

10. 10
aqualificationreportisdrawnup.Inthissummaryreport, a
conclusion must be reached and approved by the
respon- siblepersons.Allchangestoqualifiedproduction
facilities or plants should only be carried out in
accordance with the changecontrolprocedure.Before
thechangeisapproved, theresponsiblepersonsassess
whetherarequalificationis necessary.Risksmayalsoneed
tobereassessed.Nottaken intoaccountarethevalidation
statusofthesoftwareand, asmentionedabove,
compliancewithCFR21Part11for computer-based
systems.
Calibration
All measuring instruments and indicators must be
regularly calibrated to ensure that the displayed or
printed reading is withintheacceptablerangeatalltimes.
Calibrationsmust beperformedanddocumentedbythe
specifieddate.Sys- temswithoverduecalibrationmayno
longerbeused.
The calibration instructions contain the necessary informa-
tion about calibration standards, permitted tolerances, and
calibrationintervals.Referencesusedmustbetraceable
toanationalorinternationalmeasurementstandard(ac-
creditationaccordingtoISO17025).Detailedrecordsofthe
calibration should be kept.
Ifthecalibrationresultsdiffer,productionandquality
assurancemustbenotifiedimmediatelyandmeasurement
results from the previous calibration interval re-evaluated. If
thedeviationistoolarge,thiscanalsoleadtoarecall.
Calibrationdatamustbecheckedfortrendsandanycorrec-
tive action required (trending).
Employeeswhocarryoutcalibrationsmusthavesufficient
competenceinthisareaandprovethisregularly,(e.g.,by
keeping competency records). References must be checked
periodically by an accredited company according to
ISO 17025.Comprehensiverecordsshouldbekeptforall
refer- ences.
Computer-Aided Systems (IT Systems)
Hardly any of the work we carry out nowadays can do
without computer-aided systems for control, measurement,
regulation, data processing, data transmission, data record-
ing,oralarming.Inorderforustobeabletorelyonthis
computerdata,itmustbeproventhatthecomputersystem
doesexactlywhatweexpectittodo(computervalidation). IT
(informationtechnology)systemsarerequiredtobevali-
datedinaccordancewithanapprovedcomputervalidation
plan. Access to IT systems must be controlled. This
means that only trained users have access rights to
thesystem.
Passwords,tokens,chipkeys,orothermeans ofauthenti-
cating usersmustneverbepassed ontootherpersonsor
shared by several users.
Changes to the IT systems are also subject to the
change controlprocedure.TocomplywithGMP,computer
data mustbetreatedinthesamewayaspaperrecords,
and its integrity must be maintained. Deletion, overwriting,
or
modificationmustnotbepossibleunlesstheoriginalinfor-
mationremainsverifiableinanaudittrail.Usefulbackup and
disaster recovery procedures must be set up if the
systemisunavailableforacertainperiodoftime.
The electronic processing and storage of measurements,
validationplandata,orreportsrelatingtotheauthorization of
amedicinalproductoractivesubstanceshouldbebased on
thefollowingrequirements:CFR21Part11andGood
Automated Manufacturing Practice(GAMP) 5.
CFR21Part11isaUSregulationthatdefinescriteriafor
FDA-regulatedpharmaceuticalindustriestoensurethat
electronic records and electronic signatures on
comput- er-based systems are credible and reliable.
This standard appliesonlytoinstallationsand
equipment,whichare connectedtoacomputer and
usesoftware.
GAMP5,ontheotherhand,isaguidelineandhasdevel-
opedintothestandardsetofrulesforthevalidationof
computer-aided systems in the pharmaceutical industry
(manufacturersandsuppliers).However,theGAMPregula-
tions are not legally binding.
4. Documentation
Records
Careful documentation is essential in the manufacturing
anddistributionofpharmaceuticals.Documentationneeds
to cover who did what, when, and how. This in turn is
importantfordrugandpatientsafetytoensureallprotocals
have been followed.

11. 11
“The correct and up-to-date SOPs
mustbeavailableattheappropriate
workstation,eitherelectronicallyon
screenorasacontrolledpaperversion,
at all times.”
Accordingtogooddocumentationpractice,alldocuments
shouldbelegible,complete,properlysigned,dated,
tamperproof, and colorfast. All relevant activities must be
promptlyrecordedbythepersoncarryingouttheactivity.
Under no circumstances may data be captured in an
un- official or uncontrolled manner. Additional
documentation isprohibited,toincludeunauthorized
copiesornotesnot capturedinthesystem.Documents,
signatures,andtimed entries(e.g.,inminutes)must
neverbedatedforward
orbackward.Alldocumentationrequirementsshouldbe
accurateandcomplete,toincludethedateandsignature
of the assigned party. The records are made
according to approvedprotocols,whetheritbein
logbooks,forms,or in a corresponding validated
computer system.
Unforeseeneventsanderrorsoccur.Forexample,unex-
pectedmeasuredvalues(outofspecificationresults–
OOS)aregeneratedorunusualobservationsaremadeon
machines,systems,materials,andworkprocesses.When
processes are interrupted, records must indicate the details
ofwhattookplace.Itisimportantthatthesupervisoror
headofqualitycontrol(QC)isinformedsothattheycanre-
spondappropriatelyanddecidewhetheradeviationreport
must bewritten.
Errors in the actual logging process must be corrected
so that the original entry remains legible. If the reason
for the correctionisnotobvious,itmustbebrieflyexplained
with predetermined abbreviations. The correction must be
dated and initialed.
The4-eyes-principleverifies(checks)alldataandcalcula-
tionsindocumentsandmustalsobecarriedoutextremely
carefully.
Documentsanddatarelatingtoproductionandquality
control/assurancemaynotbedestroyed.Theymustalways
becarefullyarchiveduntilthelegalretentionperiodshave
expired.Iflongerarchivingperiodshavebeenspecifiedin
qualityframeworkagreements,thesemustbeobserved.
The legal periods are also not the same everywhere
and must be considered and observed separately
depending on the country.
Batch Documentation
Batch documentation (manufacturing or processing instruc-
tionandinspectioninstruction)islinkedtotheprocessdoc-
umentation.Thisincludesthemonitoringanddocumenta-
tionaswellasthevisualizationoftheentiremanufacturing
and processing procedures, including cleaning/disinfection
and sterilization. This means that the complete manufactur-
ingprocessshouldbefullytraceable.Thisdocumentation
must correspond to an approved master document.
Master documentsandtestinstructionsmustcorrespond
tothe submittedapprovaldocumentsandallsubsequent
change notifications.
Thebatchdocumentationmustbeeasytounderstandand
clearly formulated to prevent misunderstandings.
Under nocircumstancesmaychangestothese
regulationsbe
made without prior approval in accordance with the
change control procedure. Permission to do so must be
formally granted in advance by quality assurance.
Standard Operating Procedures (SOP)
Inordertoproducemedicinalproductsandactiveingredi-
entsofuniformquality,theremustbenoroomforinter-
pretationintheperformanceofanyactivity.Toensurethat
everyonedoestheirjobcorrectlyatthefirstattempt,all
recurringactivitiesmustbedescribedindetailintheSOPs.
Thesemustbesimple,clearlyformulated,andunambigu-
ous.Day-to-dayworkmayonlybecarriedoutinaccordance
with the currently approved SOPs.
Accordingly, the control of these documents is essential,
clearlydescribedandstrictlyadheredto.Often,theofficial
SOPisapaperrecord.Thequalitydepartmentdistributes
copiestotheappropriateparties.However,moreandmore
paperless(computer)systemsarefindingtheirwayinto
practice,whereprinting,distribution,etc.,isdeliberately
avoided.GMPrequiresthecomputersystemstobeofficial-
ly qualified and validated. Ultimately, the correct and up-to-
dateSOPsmustbeavailableattheappropriateworkstation
–eitherelectronicallyonscreenorasacontrolledpaper
version.
The SOPs must be strictly adhered to and followed.
Desired changesmustbebroughttotheattentionofthe
responsi- ble person. The quality framework agreement may
stipulate thatthirdpartiesmustbeinformedofsuch
changesand that their consent to the change must
also be obtained
in advance. Changes may only be implemented after they
have been approved by the appointed manager of the
asso- ciated department.
Nevertheless, SOPs must be updated/revised regularly.
Chronologicalrecordsmustbekeptofallchanges/revisions
toensuretraceability.Forexample,itshouldbeeasytofind
whathasbeenchangedfromversion2to3,eventhough
version 5 is already valid.

12. 12
Data Integrity
Huge amounts of data and documents are generated
in connectionwiththedevelopment,approval,production,
testing,andshipmentofdrugs.Thesedocumentsanddata
are important in order to be able to demonstrateve the
qualityofthedrugsatanytime(traceability).Thedataand
documentsmustalwaysbeup-to-date,accessible,andmay
not be conflicting, deleted, or (accidentally or even deliber-
ately) changed.
Inthiscontext,dataintegritymeansdataiscorrectand
trustworthy because it has been protected from
unautho- rizedaccessandanykindofmodificationfromits
creation to its archiving.
Everycompanyalongthevaluechainofdrugsandactivein-
gredients must therefore regulate precisely who has
access towhichdataanddocumentsandwhocanread,
modify, copy, approve, or otherwise edit them.
Both electronic records and paper records must be
protect- ed against loss and alteration.
Forelectronicdataanddocuments,anelectronicaudit trail
mustalsorecordwhichuserhasaccessedwhichdata,
when,andwhatexactlywasdone.Theaudittrailmustonly
bemadeaccessibletoafewpeople,includingaregulatory
inspector.Theaudittrailultimatelyservesasamonitor-
ing instrument for electronic processes. In the case of
paper-basedrawdata,theaudittrailmustbeobservedand
updated in writing/text.
5. Production
Starting Materials: Active Substances, Raw Materials,
Auxiliary Materials or Packaging Materials
Thequalityofpharmaceuticalsisverymuchdependenton
thequalityoftherawmaterials,includingpackagingmate-
rials. Therefore, all pharmaceutical starting materials/raw
materials must be handled with particular care. Starting
materials for medicinal products may only be
purchased fromqualifiedsupplierswhohavemadea
contractualcom- mitment to quality and have been
audited by QA. Inspectioninthiscontextmeanstocheck
thesupplier’s processesduringanon-siteauditbefore
startingbusiness activities(initialqualificationand
release)andthento repeattheauditperiodicallyandrisk-
based(monitoring). Approvedsuppliersshouldbekeptina
listforthispurpose. Thecertificationstatusofthesupplier
mustbekeptinmind andisideallypartofaqualityframework
agreementtobe concluded.Makeanoteofthis:The
manufacturerisequally responsible for defects that a
supplier introduces into his own product.
Onceasupplierhasbeenapproved,apurchaseordercan
beplaced.Atthearrival,assignedpersonnelshouldensure
the delivery corresponds to the order and whether all
con- tainersareclean,undamagedontheoutside,and
correctly labelled.Inaddition,itisimportanttocheck
whetherthe physicalenvironmentalconditions(e.g.,
temperature,hu- midity) were correctly maintained
during transport orthere were deviations.
Allincomingmaterialsthathaveanimpactonthequality of
the end product must be sampled in accordance with
theorganization’sSOP,andthesamplesmustbeforwarded
toqualitycontrolforevaluation.Materialsthathavenot yet
beenreleasedand/orrejectedmustbeimmediately
quarantinedandprotectedfromunauthorizedaccess.Only
released raw materials and end products may be
used.
AnSOPshouldpreciselydescribetheflowofgoods(e.g.,
first-in,first-out–FiFo)andstorage.Environmentalcondi-
tionsmustbemonitored.Allincomingandoutgoinggoods
must be controlled and documented. The use of all
outgo- ing/rawmaterialsmustbetraceableatalltimes.
Thereisaparticularlyhighriskofmislabelingprinted
packagingmaterials.Forexample,agivenconcentrationof
anactiveingredientcanbeconfused–20mgofpenicillinis
inadvertentlypackedinapackagecontaining40mgofpen-
icillin.Oranouterpackagethatwassupposedtocontain
“Starting materials formedicinalproducts mayonly bepurchased
fromqualified suppliers whohavemade acontractualcommitment
to quality and have been audited by QA.”

13. 13
“Storageofsuchreferenceandretained
samplesshouldbeinroomswhere
the storage conditions (temperature,
humidity) are continuously monitored
inaccordancewiththemanufacturer’s
specifications.”
penicillinsuddenlycontainsibuprofen.Therefore,printed
packagingmaterialsmayonlybestoredinareaswithaccess
control systems. Incoming and outgoing goods with
printed packaging materials must be monitored,
traceable, and countable.Inaddition,amaterialbalance
mustbedrawn upforeachuseofprintedpackaging
materialsaswellas yield limits.
Manufacturing and In-Process Controls (IPC)
IPCsaretheinspectionscarriedoutduringthecourseof
production.Themanufacturingspecificationsidentifyhow
manysamplesshouldbeinspectedbasedonstatistical
informationintheriskassessment.Forexample,according
toISO2859,anacceptancesamplinginspectionisbasedon
thenumber ofnonconforming units ordefects –where the
consumer’s risk is usually below 10 percent. Ultimately, IPCs
ensure thattheproductionprocesscomplies with the de-
finedspecifications.IPCsarefixedmandatorycomponents
inthemanufacturingprocess.IfIPCsamplesaretakenat
atimeotherthantheprescribedtime,itmustbeclearly
documented and justified in the manufacturing record.
Weighing in raw material is a good example of an
import- ant IPC. Errors that occur during weighing
can hardly be correctedafterwardsandarealsodifficultto
detect.For thisreason,weighingmustonlybecarriedout
byspecially trained personnel.
Toprevent mislabeling, all ingredients, intermediate stages,
containers,rooms,andmachinesmustalsobelabeled
clearlyandlegiblyatalltimes.Beforeanyfurtherprocess-
ing,alllabelsandmarkingsshouldbereviewedagain.
Validation
All manufacturing and packaging processes, analytical
methods,andcleaningproceduresmustbevalidated.
Validationshowsthatthesemethodsorprocedurescanbe
reproduced to create the intended result.
Beforevalidationbegins,ariskassessmentdetermines
problemsthatcouldimpactpatientsafetyandhowto
reduce the risks at the outset.
Followingtheriskanalysis,thevalidationplanisthencre-
ated.Theresultofthisriskanalysisisdirectlyincorporated
intothevalidationplan.Thevalidationplandefinesthe
objectives, procedure, and responsibilities for each valida-
tion.Italsodefinesacceptancecriteria,testmethods,and
regulatory basis. The actual execution of the validation can
onlybeginafterthevalidationplanhasbeenapprovedin
writingbytheresponsiblepersons.Ifchanges/additionsto
thevalidationplanarenecessaryduringtheexecutionof
thevalidation,theymustbedocumented,evaluated,and
also approved in accordance with change
management.
Afterthevalidationplanisexecuted,areportiscreated. The
validationreportmustcontainapassorfailconclusion,
which is approved and released by the responsible
persons. Ifthevalidationfails,appropriatedocumentation
and evaluationshouldbecarriedout.Repeatingtestsuntil
the expectedresultisachievedisstrictlyprohibited(“testing
intocompliance”).Therefore,the4-eyeprinciplesmustbe
strictly observed during validation.
Reference Samples and Retained Samples
GMPspecifiesthatappropriatereferencesamplesofstart-
ing materials, packaging materials, critical intermediates,
andfinishedmedicinalproductsmustbetakenduringand
afterproduction.Thesesamplesshouldprovideevidenceof
good qualityatalater date if storedproperly.
After each packaging process, retained samples of packaged
medicinal products should provide evidence that the
correct packaging materials, labels, and variable data (batch
numberandexpirydate)wereused.Thequantityofrefer-
ence samples and retained samples as well as the
respon- sibilitiesmustbepreciselyregulatedand
describedinan SOP.Therisk-basedapproachin
conjunctionwithstatistical processcontrolisagoodguide
totheoptimalquantity.
Basically,thisisanarchivefacilitywithlimitedaccessonly for
authorized persons and with corresponding
documenta- tionofthedataonreceipt,monitoring,
alarming,removal and use.

14. 14
6. Quality Control
Specifications
Starting materials, intermediate products, and the end
product all have quality standards called specifications. Speci-
ficationsaredescriptionsoftheirpropertiesandthecriteria in
which to conform in order to be deemed acceptable for
theintendeduse. Thespecificationsofthestartingmaterials
must be clearly formulated and unambiguous for ease
of understanding. Any change must be made in
accordance withthechangecontrolprocessand,
accordingly,mayonly beimplementedafterapprovaland
documentation.
Productspecificationsandallsubsequentlyapprovedchan-
gesmustcorrespondtotheapprovaldocumentssubmitted
totheauthorities/regulatorybodies.Inaddition,wherever
applicable,theymustmeetorexceedtherequirementsof
local and overarching pharmacopoeias (e.g., Pharmacopoea
Europea–Ph.Eur.,PharmacopoeaHelvetivaPh.Helv.).
Stability
Theusabilityperiodprintedonapharmaceuticalpackage
mustbesufficientlydocumentedbystabilitydata(stability in
thecorrespondingpackaging).Thisdatamustalreadybe
determined in the development phase and is then
docu- mented in the stability plan. The test intervals
and storage conditionsmustbeclearlyandunambiguously
specifiedin the stability plan. They must be in
accordance with the ap- provaldocumentsandall
subsequentlyapprovedchanged applications. The
stability plan must be authorized or released as a
controlled document by designated persons (e.g., head
ofquality control, qualified person). The stability tests are
carried out in accordance with the stability plan and
mustbecompletedwithinthespecifiedtime.The stability
datamustbeevaluatedforpossibledeviations and/or
tendencies andassessedwithin theframework of the
periodicPQR.
Anydeviationfromthespecifiedstorageconditionsmust
bereported immediatelytotheQC managementorthe
responsible party to be investigated.
Release
Thelastqualityassurancestepistherelease.Thisessential
stepisultimatelythestepthatisintendedtopreventany
defectivestartingmaterialsfrombeingprocessedoreven
defective drugs from being circulated and consequently
usedbypatients.Thereleaseofstartingmaterialsorend
productsmayonlytakeplacewhentheanalysisresults
complywithallcurrentspecificationsandthebatchdocu-
mentation has been checked accordingly.
The batch record review ensures the proper
documents formaterials,manufacturing,andpackaging
supportthe qualityoftheproductbeforeitisreleased.Batch
bybatch, thereviewincludesanalysisreports,
manufacturingand
packaging protocols (including IPCs), deviation reports,
raw material certificates, room monitoring reports, etc.
andarecheckedforcompletenessandplausibility.
Market Release
Thefinalmarketreleaseofmedicinalproductsisapproved
bythequalifiedperson(inGermanyaccordingto§14of
theGerman Medicines Act).InSwitzerland,therelease
offinishedmedicinalproductsistheresponsibilityofthe QP
(FvP)—providedthatthecompany’soperatinglicense
permits its own market releases.
Theexactprocessofthereleaseandultimatelythemarket
release must be regulated internally according to the
SOP.
7. Outsourced Activities
Pharmaceutical manufacturers outsource many activities to
external service providers, which could directly or indirectly
influencethequalityofdrugs.Theseexternalservicecom-
panies include:
Suppliers of active ingredients, excipients, packaging
materials, andequipment
Serviceprovidersforqualificationormaintenanceof
roomsandequipment,cleaning,pestcontrol,micro-
biologicalmonitoring,archiving,IT,anddatahosting
Contract manufacturers and contract laboratories
that carryoutmanufacturingorpackagingstepsor
analysis Logisticscompaniesthathandlethestorageand
transport of materials and products
TheresponsibilityforoutsourcedGDP/GMPtasks,pro-
cesses,andotherrelatedactivitiesalwaysremainswiththe
pharmaceuticalentrepreneurormarketingauthorization
holderthatis printedonthepharmaceuticalpackage.The
pharmaceutical entrepreneur must, therefore, ensure that all
quality-relevantcontractualpartnersaresuitablefor

15. 15
performingtheintendedtasks(supplierqualification).This
canbedone,forexample,bymeansofaudits,comparative
analyses, error statistics, and contractual agreements. In ad-
dition,theresponsibilitiesbetweenclientsandcontractors
mustbepreciseandclearlydefined.Thecontractincludesa
delimitation of responsibility agreement, quality assurance
agreement, framework agreement, and a non-disclosure
agreement.
After an initial supplier qualification, periodic supplier
monitoring (evaluation, assessment, re-qualification) must
becarriedoutinordertoensurethecontinuityofquality. Itis
importanttocheckforup-to-datecertifications(e.g., ISO
9001, 17025, ...), deviations, complaints, and other key
performanceindicators(KPI)necessaryforre-evaluation.
Inthecaseofcontractmanufacturers,itmustalsobe
specifiedinwritingwhetherthecompetentpersonofthe
contractedcompanywillcarryoutthemarketreleaseofthe
finishedmedicinalproductorwhetherthistaskwillremain
with the client.
Inordertoavoidmisunderstandingsorproblems,the
workingmethodsandallnecessaryinformationshouldbe
describedindetailandformallyapprovedby bothparties,
oftencalledtechnologytransfer.Thecontractormust
adhere exactly to the contractual agreements as well
as specifications and similar requirements. If there are
devia- tionsorchanges,hemustinformtheclient,
documentthe deviationsorchanges,andwaitfor
instructions.
8. Complaints and Product Recall
Inthe company,theremustbe aresponsible body known to
everyone,towhichallcomplaintsandclaims(processand
product,internalandexternal)areforwarded.Allincoming
complaints must be investigated immediately and answered
within a specified period of time (e.g., thirty calendar days). In
quality framework agreements with suppliers/subcon-
tractorsetc.,differentperiodsoftimemaybedefined.If the
investigationcannotbecompletedwithinthedefined
period,an interim reportmustbe prepared.
Anintegralpartoftheinvestigation istodetermineifthe drug
is subjecttoacounterfeit.Eachcomplaint,itsinvestiga- tion,
anysupportingdatamaterial,andcorrectivemeasures must
bedocumentedinanerrorreportsuchasaCAPAor8D. 8D
isareportthatexamineseightobligatoryprocesssteps
toinvestigateacomplaintinordertoeliminatetheoriginal
causeoftheerrorandidentifymeasuresforcorrectingthe
error.Allcomplaintsandobjectionsmustbeanalyzedwith
regard to trends (trending) and must be assessed and
evalu- atedwithintheframeworkoftheperiodicPQR.
9. Self Inspection
Internalauditsservetoidentifyweakpointsbeforedamage
occurs (preventive quality assurance measure). Audits must
beplanned inthe beginningoftheyearandcontinuetobe
carried out in regular intervals. The audits should
cover all areasandfunctionsoftheprocess.Therecanalso
beunan- nounced and thus unplanned audits; these
can be added to theplanafterwardsandmarkedas
“unannounced”.
An SOP should specify and describe the audit
process, schedule,andcategorizationofdeviations.
Auditsalso servetoidentifyimprovements(continuous
improvement process–CIP)tooptimizeprocesses.Each
auditmustbe documentedinwriting.Inadditiontothe
documentationof observations,correctiveactionsand
deadlinesfortheseac-
tionsmustbedefinedanddocumented.Theimplementation
ofthecorrectivemeasuresmustbemonitoredaccordingly.
Corrective measures required from previous audits should
alsobepartoftheauditagenda.Failuretomeetdeadlines for
theimplementationofcorrectiveactionsshouldleadtoa
reassessmentand,ifnecessary,toapost-audit.
Inspections by Authorities
Pharmaceutical companies, their suppliers, and also lo-
gisticspartnersareregularlyinspectedbytheresponsible
monitoringauthorities.Theinspectorscheckveryclosely
whether the GMP rules have been and are being
observed.
Indoingso,veryconscientiousattentionispaidtothecor-
rect implementation of SOPs, manufacturing instructions,
testinstructions,etc.Compliancewiththeregulationsis
referred to as GDP/GMP compliance.
Audits of Service Providers
Anyonewhomanufacturesoroutsourcesactivitiestoexter-
nal service providers must carry out an audit of the
service provider to ensure that the contractor strictly
complies with GDPandGMPregulationsandall
contractualagreements,

16. 16
sothattheservicecompanycancontinuetobeconsidered
asuitablepartner.Anyonewhomanufactures,tests,or
performs other services on behalf of a customer must
be auditedandcomplywithallagreements,asthe
customer bears the ultimate responsibility.
10. Storage andTransport
Inventory Management
Carefulstorageisthebasicprerequisiteforensuringthat
starting materials, semi-finished, and finished products
maintainqualityandareeasilyidentifiable.Storageareas
mustbetidy,clean,andfreeofvermin.Allmaterialmustbe
storedaccordingtothespecifiedconditionsandawayfrom
thefloorandwallswithsufficientclearancetofacilitate
cleaning,allowingcirculation,preventingheataccumula-
tion and penetration of moisture.
In areas with controlled storage conditions,environmental
controls (temperature, humidity, light) must be carried
outandrecorded. Alarmsystemareavailabletonotify
responsiblepartiesofunfavorableconditions.Thereare
monitoring systems that store the data electronically
to
improvedataintegrity.Incaseofdeviations,measuresmust
betakeninaccordancewithanappropriateSOP.Stored
containers must be correctly labeled and clearly marked
accordingtoanSOP.Printedpackagingmaterialsandquar-
antinematerialsmustbeprotectedagainstunauthorized
access.
Medicinal products and other materials intended for
de- structionmustbestoredseparatelyfromallother
materials so that they are not used or dispatched in
error or inten- tionally.Theymustbedisposedofproperly
andwithout delay. Unauthorized access must be
avoided at all costs.
Thetypeofdestructionandthequantitydisposedmustbe
documented to ensure all materials are accounted for.
Transportation
Activeingredientsandmedicinesmustbepackedfortrans-
portinsuchawaythattheyarenotdamagedbyheat,frost,
andimpact.Forrefrigeratedandcoldchainmedicines,the
packagingschememustbefollowedexactly.Hypothermia
due to too many cooling elements can damage the
drug
inthesamewayasoverheating.Temperaturemonitoring
duringtransportisessentialandmustbecarriedoutin
accordancewithGDPregulations.Atransportvalidationis
thereforenecessary.Ariskanalysisshouldbecarriedoutin
advance.
Inordertoavoidtheftorreplacementbycounterfeits,only
specialized,trustworthylogisticscompaniesshouldbecon-
tractedforthetransport.Sealmarks,seals,dataloggers,
andGPS (global positioning system)trackingorMobileIoT
real-time monitoring are used to detect irregularities during
transport and tampering with containers and vehicles.
SincetheoriginalGMPguidelineswerecreated,GDPs
were createdbyregulatoryauthoritiesasamuchclearer
guid- ance document.
Summary
Therearemanyfacetsofgoodmanufacturingpracticesthat
needtobeconsideredforyourqualitycontrolledprocesses
andproducts.Ultimately,youareresponsibletoensurethe
patientreceivesasafeandefficaciousmedicine.BeingGMP
compliantisaconstantworkinprogress.Leveragingtech-
nology and data systems can ease the burden and
ensure robustdocumentationofyourqualitycontrol
operations.

17. PRACTICAL GUIDE | GMP REGULATIONS FOR LAB AND CLEANROOM COMPLIANCE 18
ThispracticalguideispartoftheGxPServiceswebsitecontentforsupplychainand
QApractitioners.TopicsincludetheneedforGMPs,thehistoryofGMPs,andalso
the individual chapters of it.