european INDUSTRIAL PHARMACY · availability and accessibility of these novel medicinal products....

ISSUE 35 • DECEMBER 2017www.industrialpharmacy.eu

www.eipg.eu

Regulatory consequencesof cata integrity failures

Revisions made toEuropean Pharmacopoeia

sterilisation chapters

Predicting productiontablet properties from

small scale manufacture

Qualification of visualinspection of parenteral

products

Regulatory consequencesof data integrity failures

Revisions made toEuropean Pharmacopoeia

sterilisation chapters

Predicting productiontablet properties from

small scale manufacture

Qualification of visualinspection of parenteral

products

europeanINDUSTRIALPHARMACY

2 european INDUSTRIAL PHARMACY December 2017 • Issue 35

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December 2017ISSN 1759-202X

MANAGING EDITORPhoebe SpeisPRODUCTIONSue Feather

SUBSCRIPTIONSJill Monk

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EDITORIAL BOARDMichael AnisfeldClaude FarrugiaMichael GamlenChing-Yi HsuJohn Jolley

Giorgos Panoutsopoulos

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features4 REGULATORY CONSEQUENCES OF DATA INTEGRITY

FAILURESData integrity inadequacies can easily lead to a statement ofnon-compliance, with serious regulatory consequences, andnot only for the manufacturer concerned.by David Cockburn

6 REVISIONS MADE TO EUROPEAN PHARMACOPOEIASTERILISATION CHAPTERSMethods of sterilisation and the assessment of sterilisationusing biological indicators represent important areas ofregulatory concern. by Tim Sandle

9 PREDICTING PRODUCTION TABLET PROPERTIES FROMSMALL SCALE MANUFACTUREWith growing use of the laboratory press system, the ability topredict production tablet properties from lab scale databecomes important. In this article, Michael Gamlen describeshow this can be done.by Michael Gamlen

13 QUALIFICATION OF VISUAL INSPECTION OF PARENTERALPRODUCTSVisual inspection of parenteral products is required by bothpharmacopoeias and good manufacturing practice. TheSFSTPF Commission have described the various methods andapparatuses commonly used in the pharmaceutical industryfor visual inspection. by Commission SFSTPF. Caire-Maurisier, F. Dumontier, P. Grel, C. Jolly, É. Levacher, S. Marcq, F. Sliwinski

regulars3 EDITORIAL COMMENT

35 REGULATORY REVIEW

39 PHARMA IN PLENARY

45 BOTTLED BROWN

46 EIPG NEWS

50 EUROPEAN MEDICINES VERIFICATION ORGANISATION(EMVO) PROGRESS MONITORING REPORT

52 EVENTS

The European Industrial Pharmacists Group extends a special thanks to Walgreens Boots Alliance and AesicaPharmaceuticals for their kind support of the publication of this journal.

The End of theBeginningDear friends and colleagues,

2017 has come to a close, andas I look back in reflection, Icannot but once again beimpressed by the far-reachingeffects of events that haveoccurred in the pharmaceuticalworld - effects that have not onlyhad an immediate impact but thatare likely to command ourattention for quite some time tocome. We have seen the firstmedicine approved with a digitalingestion tracking system, the firstgene therapy medicines approvedagainst cancer and againstinherited disease. The excitement that these scientificadvances represent is tempered by sombrecontemplation of the long-overdue changes in howhealthcare systems and health technology assessmentare dealing with the challenging questions surroundingavailability and accessibility of these novel medicinalproducts.

In this same year, one must mention two topicsparticular to the pharmaceutical industry in Europe. Thefirst is the set of impending milestones in theimplementation of the Delegated Regulation for thesafety features appearing on the packaging ofmedicinal products for human use. It might seem thatthere is time to spare, with the deadline more than ayear away, but some targets are much closer, not theleast of which the six-month full-scale testing periodrecommended in every country - which effectivelymeans that regulatory notifications and variations needto be submitted, serialised products ready within thesupply chain, repositories functional, and allstakeholders on board by August of this year. Thesecond topic is, of course, Brexit. Already we have seenthe impact in the decision for the relocation of the

European Medicines Agency, andthe effect that this will have onthe operations of the Agency andits role in healthcare throughoutEurope. Yet this is but a drop inthe ocean compared to thechanges that the pharmaceuticalindustry and the professionalswithin it will need to implement tobe prepared for Brexit, even withthe transitional period that theindustry is calling for. So much isat stake, and above all, thecontinued supply of medicines topatients who need them, with thepeace of mind that professionalswithin the industry have workedto the best of their abilities to

ensure their quality, safety and efficacy.Yes, we are about to see considerable changes in the

pharmaceutical world, and we must be prepared forthem. Change is inevitable, and it comes even to EIPG,or more specifically, to EIPG's involvement in europeanIndustrial Pharmacy. After more than nine years ofcollaboration with Euromed, and to whom I extend mythanks for their commitment and hard work over allthese years, the General Assembly has decided toexplore alternative paths for the future of EIPG'spublication portfolio, and we look to the future withcourage, for, in the words of the Bard, “Would I wear sofair on my journey! The first stretch is the worst,methinks.”

I wish you all a serene and fruitful 2018.

Professor Claude FarrugiaPresident, EIPG

3

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european INDUSTRIAL PHARMACY December2017 • Issue 35

We would like to thank Professor Farrugia for his kind words and his valuable service onthe EIP editorial board over the years. The European Industrial Pharmacy Journal was firstpublished by Euromed Communications nine years ago. We will continue to publish theIndustrial Pharmacy Journal and continue to offer it complimentary to our readers.Please click here to register which will ensure your continued receipt of the Journal.

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REGULATORYCONSEQUENCES OF DATAINTEGRITY FAILURESby David Cockburn

Without data integrity you cannot have adherenceto GMP. Regulators are now focussing more ondata integrity in the context of manufacturing.Ultimately, a GMP inspection by an EU authority canonly have one of two outcomes. Either the inspectedsite complies with GMP and receives a GMPcertificate or it does not. Data integrity inadequaciescan easily lead to a statement of non-compliance, withserious regulatory consequences, and not only for themanufacturer concerned.

from an EU regulatory perspective.That is not to say that there arefundamental differences on thistopic with other internationalregulators but authorities have tooperate under different regulatoryframeworks.

First of all, what do I mean by“Data integrity”? There is nodefinition of the term in EUlegislation or GMP guidance. TheUK’s Medicines and HealthcareProducts Regulatory Agency (MHRA)did however publish its owndefinition in 2015: “The extent towhich all data are complete,consistent and accurate throughoutthe data lifecycle.” This definitionshares the core fundamentals ofmore extensive definitions from theUS Food and Drug Administration(FDA) and the World HealthOrganisation (WHO) in 2016. Thosedefinitions go on to cite the so-

called ALCOA elements(attributable, legible, contempor -aneously recorded, original or a truecopy, and accurate).

The next question is what are theEU’s GMP requirements concerningdata integrity? Data integrity is notexplicitly mentioned in the GMPdirectives (2003/94/EC and91/412/EEC) or the counterpart foractive substances, Regulation1252/2014. This is rectified inDirective (EU) 2017/1752, which willreplace directive 2003/94/EC as aconsequence of the Clinical TrialsRegulation where a specificreference is found in article 9(1): “…The documentation system shallensure data quality and integrity…”

Although this new directive willnot come into operation until 2019at the earliest, it does not mean thatthe principles of data integrity donot already apply. It should be self-evident that you cannot comply withGMP based on incomplete orinaccurate data. Furthermore, theaforementioned ALCOA elementscan be found readily throughout theinterpretive GMP guidelines, asillustrated in the EuropeanMedicines Agency’s (EMA’s)published Questions and Answerson data integrity in August 2016 (seeQ&A number 13). Despite this, thereappears to be a desire among someinspectorates, as well as anexpectation by the regulatedindustry, to have more guidance ondata integrity. If this is to happen itis critical that internationalregulators work together on thetopic.

What are the regulatoryconsequences of data integrityfailures? In this context lack of dataintegrity is a failure to comply withGMP. This normally comes to lightduring a GMP inspection. Even if amanufacturer voluntarily reports thatit has a data integrity problem, orsomeone blows the whistle, aninspection would be triggered. EUlegislation requires an unambiguousconclusion following a GMPinspection, i.e. either themanufacturer complies with GMP, orit does not. In the former case,within 90 days, a GMP certificate is


David Cockburn is an experienced manufacturing quality compliance professional,with a grounding in both the pharmaceutical industry and the regulatory authoritiesat national and EU level and considerable wider international exposure. David spentthe last 15 years of his career at the European Medicines Agency (EMA) where hebecame head of the Manufacturing and Quality Compliance Service and held thechair of the GMP/GDP Inspectors Working Group. Prior to leaving EMA David wasthe EU technical lead working with US-FDA on mutual reliance in GMP inspectionsculminating in the signing of the EU-USA Mutual Recognition Agreement in 2017.This article is based on the author’s own opinions and does not represent the views

of EMA.

Data integrity has pre-occupied thepharmaceutical industry for manydecades. The US generics scandal inthe late 1980s uncovered, inaddition to bribery of FDA officials,fabrication of bioequivalence andother data. Despite greaterawareness and vigilance amongregulators, cases like that involvingGVK Biosciences, still emerge.Recently, the data integrity spotlighthas increasingly focussed on GMP-regulated activities. In 2005 awhistleblower exposed widespreadmalpractice at Ranbaxy whichechoed much of the 1980’s scandalincluding issues with manufacturingrelated data. Furthermore, theincreasing use of computerisedsystems provides new challenges tomaintaining data integrity. Thisarticle will focus on theconsequences of data integrityfailures in the GMP environment

issued and uploaded to the Union’sEudraGMDP database and in thelatter case, a statement of non-compliance is uploaded. PerfectGMP compliance is, arguably, anunrealistic expectation. Almost allGMP inspections (or companies’internal audits) reveal some non-compliance. In practice, a GMPcertificate will be issued if theinspector is satisfied that themanufacturer is generally compliantwith the principles and guidelines ofGMP as laid down in the relevantGMP directive (or Regulation),usually after acceptingcorrective/preventive actions takenor committed to for any identifiedfailures to comply. The GMP statusof a manufacturer relies heavily ondocumentation, and its supportingdata, whether paper or electronic.Any inspection finding that castsdoubt on the completeness,consistency or accuracy of data ishighly likely, unless the inspector canbe convinced that the occurrencesnoted are isolated and/or all verylow risk, to tip the balance towards anon-compliance statement.

The uploading of a statement ofnon-compliance is never undertakenlightly and normally indicates anextreme situation at the site inquestion, as would be the casewhere there is serious doubt aboutthe integrity of data. If it is clear thatdata are wilfully manipulated, thenthis is fraud and there can be littledoubt about the inspectionoutcome. Moreover, referral to therelevant enforcement authoritiesand criminal investigation couldfollow.

A non-compliance statement is

the first regulatory step taken tosafeguard public health and hasserious, far-reaching consequences.In effect it means that themanufacturing authorisation holderhas failed to fulfil its legal obligationto comply with GMP and soprovides grounds for suspension,variation or revocation of theauthorisation. When the non-compliance is connected with a siteoutside of the EU it is themanufacturing authorisation of theEU importer that is at risk. TheQualified Person, already personallyexposed to regulatory action, canno longer certify affected batchesprior to their release since thecertification would, de facto, beuntrue. In addition, any marketingauthorisation, listing the non-compliant site as a manufacturer,would not meet the conditions ofauthorisation so further EU supplywould be unlawful unless from analternative authorised source. Awhole range of more specificmeasures, including batch recalls,are available to regulators and willbe recommended to the EUregulatory network by the issuinginspectorate, tailored to the specificcircumstances of the inspectionfindings and as a result of aregulatory risk assessment.

Examination of the statements ofnon-compliance uploaded toEudraGMDP over the last 5 yearsreveal that well over 60% of themcite data integrity as a main factor.Several refer to deliberatefalsification of data. As I havealready mentioned a statement ofnon-compliance represents anextreme situation and so it is likely

that some, (lesser) data integrityproblems are being found ininspections that nevertheless endedup with a GMP certificate beingissued. In those cases manufacturersneed to address those problemswith the utmost vigour because ifthey persist there is a high risk thenext inspection will result in a non-compliance statement. Of all thepossible compliance topics,persistent data integrity issues willcompletely undermine trust andincrease suspicion of deliberatefalsification.

Something else stands out fromthe EudraGMDP data. I mentionedRanbaxy and GVK Biosciences at thestart of this article. The sites involvedin both cases were located in India.Non-compliance statements inEudraGMDP, particularly inconnection with data integrity, putsites in India at the top of the tablewith China not far behind, both wellahead of sites in other countries.Exploring that observation isbeyond the scope of this article butthere may be factors that at leastpartially explain this skew. Dataintegrity issues are neverthelessbeing found everywhere.

In conclusion, manufacturing/quality data is fundamental toeverything a manufacturer does soany data integrity issues present ahigh risk of being the subject of astatement of non-compliance. Thiswill lead to very serious andpotentially widespread regulatoryproblems as well as undermining amanufacturer’s credibility andreputation which could makerecovery even more difficult.

REGULATORY CONSEQUENCES OF DATA INTEGRITY FAILURES continued

5european INDUSTRIAL PHARMACY December 2017 • Issue 35

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IntroductionTwo guidance chapters in theEuropean Pharmacopoeia have beenupdated. The chapters are effectivefrom July 2017, and are containedwithin the recently published secondsupplement to the 9th edition of thepharmacopoeia.1 The revisedchapters are: 5.1.1 “Methods ofPreparation of Sterile Products” and5.1.2 “Biological indicators andrelated microbial preparations used inthe manufacture of sterile products”.The changes to the biologicalindicator chapter are more extensive,although the sterile products chapterintroduces aseptic processing to thechapter for the first time. This articlesummarises and discusses the mainchanges, highlighting someomissions which will ideally beaddressed in future revisions.

Methods of Preparation ofSterile ProductsChapter 5.1.12 has undergone ageneral revision and, for the most

european INDUSTRIAL PHARMACY December 2017 • Issue 35

part, it has been completely rewritten.The chapter covers the manufactureof sterile pharmaceutical products,either by terminal sterilisation or byaseptic processing. Both types ofsterile products are prepared incleanrooms: terminally sterilisedproducts are dispensed into vialswithin an EU GMP Grade C / ISO14644 Class 8 (in operation)environment; aseptic dispensing isperformed under an EU GMP GradeA / ISO 14644 class 5 environment.3

The most notable change to thechapter is with the sections on thedifferent sterilisation processes. Thedescriptions of each process nowhave the same format, which followsthe order of: principle, equipment,sterilisation cycle, cycle effectivenessand routine control. This makes thesections more readable. In addition,some specific information has beenadded pertaining to each sterilisationprocess. The sterilisation methodsaddressed in the chapter are:

• Steam sterilisation.• Dry heat sterilisation.• Ionising radiation sterilisation.• Gas sterilisation.• Membrane filtration.

In addition to these methods of‘sterilisation’ (which inactivate, destroyor remove microbial contamination),‘aseptic assembly’ has been added.

The most interesting issue with thelist is the reference to “gassterilisation” which has the phrase“vapour phase sterilisation” followingit in parentheses. In this section twomethods of sterilisation by gas aredescribed: alkylating agents, which isprincipally ethylene oxide (commonlyused to sterilise plastics, especiallythose that might become embrittledby gamma radiation); and oxidisingagents, which is principally hydrogenperoxide in the vapour form. Withhydrogen peroxide vapour, which isthe most common means of treatingthe inside environment of an isolator,it is more common to use the term‘decontamination’ (orbiodecontamination) rather than‘sterilisation’. Indeed, in this author’sexperience, regulatory agencies suchas the MHRA stress that hydrogenperoxide vapour is not a sterilant(primarily because it cannot penetratethe item being sterilised). Thismeans, with aseptic processingisolators, for instance, productcontact parts (such as filling needlesand stopper bowls) are sterilisedseparately and fitted in place prior torunning the hydrogen peroxide cycle.With the European Pharmacopoeiadescription this will no doubt causesome confusion within thepharmaceuticals and healthcaresectors over what is and what is not a‘sterilisation’ process.

With steam sterilisation theapproach to validation has beenupdated and the section on dry heatsterilisation (which is distinct fromdepyrogenation) has a widerdescription of the method and detailsregarding some of the types ofprocess equipment suitable for thismethod of sterilisation have beenadded. A note is made about dryheat sterilisation being less effective

6

REVISIONS MADE TOEUROPEANPHARMACOPOEIASTERILISATION CHAPTERSby Tim Sandle

Methods of sterilisation and the assessment ofsterilisation using biological indicators representimportant areas of regulatory concern. The twoapplicable guidance chapters in the EuropeanPharmacopeia have undergone revisions. This articleassesses the main changes. Notably these includereference to the production of sterile productsthrough aseptic processing for the first time; andchanges to the assessment of the suitability ofbiological indicators, including a new recommendationfor supplier auditing.

Tim Sandle, PhD, CBiol, MSBiol is Head of Microbiology at the UK Bio ProductsLaboratory overseeing microbiological contamination control policy and investigationand developing programmes for environmental monitoring, cleanroom classificationand batch review. In addition, Tim sits on LBI/30, the BSI Cleanrooms Committee, andthe Pharmig committee. He also runs a blog: Pharmaceutical Microbiology –http://www.pharmamicroresources.com/

than moist heat sterilisation. Withradiation sterilisation the reference tosuperseded European guidance hasbeen removed.

The main addition to the chapter,and of interest to users of cleanroomsin the pharmaceutical and healthcaresectors, is a new section titled ‘AsepticAssembly’. This is the first directmention of aseptic processing and, byimplication, cleanrooms to appear inthe European Pharmacopoeia. Unlikethe United States Pharmacopoeia,which has contained a chapter onaseptic processing for a couple ofdecades (USP ), this importantclass of sterile products has notfeatured outside of the pharmaco -poeia chapter on sterility testing(chapter 2.6.1). While the new sectionis welcome it does not offer verymuch in the way of detail. The sectiondiscusses the importance of bringingtogether a sterile product (which hasbeen sterile membrane filtered)together with sterile bottles andcontaining closures, and for these tobe processed under asepticconditions.

The aseptic section highlights areasof concern in relation to wheremicrobial contamination can arise from(environment, personnel and criticalsurfaces) and draws the reader’sattention to the risks associated withproduct transfer and hold times (wherelonger hold times, if improperlycontrolled, present opportunities formicrobial growth). Reference is alsomade to the importance ofconducting media simulation trials(where a cultured medium is used inplace of product) to qualify the asepticprocess. There is no reference,however, to the cleanroom standardISO 14644 and no direct reference tocleanroom design, certification oroperation. Given that a poorlydesigned cleanroom can significantlyimpact upon aseptic processing, thisstands out as a glaring omission.

In terms of definitions there isclarification with the term “SterilityAssurance Level”. The core concept ofthe term remains unchanged: theprobability of a single viablemicroorganism surviving on or in an

item after sterilisation. The changerelates to removal of a previousreference to exponential inactivation.This is because this is not appropriateto sterilisation by filtration given thatmembrane filtration is not a first-orderprocess (that is, it does not destroymicroorganisms at a predictable rateas occurs with steam sterilisation). Withmembrane filtration, detail about themicrobial challenge test has beendeleted (this now appears in chapter5.1.2, which is the second chapterreviewed in this article).

Biological indicators

Chapter 5.1.24 concerns biologicalindicators. Biological indicators arepreparations of specificmicroorganisms that have a highresistance towards particularsterilisation methods. In the past, abiological indicator was simply a‘spore strip’ (a spore populationinoculated onto a carrier, such as filterpaper). Today biological indicatorsinclude spores inoculated onto paperstrips, stainless steel discs, held inampoules in liquid media, and aspreparations used to challengemembrane filters. The required andshared characteristics of biologicalindicators are that: they must have aproven resistance to the sterilisationmethod; and they must be defined interms of identity, purity andpopulation.5

Different biological indicators areused for different sterilisationprocesses. Biological indicators aredesigned for use with:6

• Ethylene oxide gas (Bacillusatrophaeus).

• Hydrogen peroxide vapour(Geobacillus stearothermophilus).

• Dry heat (Bacillus atrophaeus).• Moist heat (steam) (Geobacillus

stearothermophilus).

• Radiation (Bacillus pumilus).• Membrane filtration

(Brevundimonas diminuta)

The opening section of the chapterhas been rewritten. With the revisedintroduction this describes when

biological indicators are intended tobe used (qualification andrequalification of sterilisationprocesses); where they are not used(routine sterilisation runs); as well aswhat falls outside the scope of thechapter (most of what falls under theheading of alternative methods ofsterilisation).

The introduction also clarifies thatbiological indicators can be used toassess the time point betweensurvival and kill. When biologicalindicators are subject to a fullsterilisation process there must be nosurvivors in order for the sterilisationprocess to be considered valid. Manyoperators of sterilisers think it is goodpractice to understand where in thesterilisation process the dividing linebetween microbial survival anddestruction occurs so that the degreeof additional overkill can beunderstood as well as ensuring thatthe level of overkill is sufficient.

The introductory section furtherdiscusses the different formats ofbiological indicators anddistinguishes between thosepurchased commercially (such as theclassic ‘spore strip’) with those thatare bespoke designs prepared in-house. Here the text adds a note ofcaution that such developed in-housebiological indicators will most likelyhave a higher resistance than thesource preparation. For this reason,the resistance of the carrier needs tobe independently assessed.

A note of caution is added aboutself-contained biological indicators,such as ampoules of mediacontaining bacterial spores. Suchindicators may not be suitable for allsterilisation processes because someself-contained systems cannot directlyassess penetration of the sterilisationagent.

The substantive part of the revisedchapter includes a section on qualityassessments of biological indicators.This includes the importance ofauditing manufacturers or,alternatively, conducting verificationtests upon receipt (and, as part ofqualification, at the end of the shelf-life).


REVISIONS MADE TO EUROPEAN PHARMACOPOEIA STERILISATION CHAPTERS continued

validation, in line with otherguidances, as a microbial challenge of107 per square centimetre of filterface. The recommendedmicroorganism is Brevundimonasdiminuta, for assessing nominal poresizes of 0.22 μm (with a mycoplasmachallenge recommended for poresizes of 0.1 μm, as would be requiredfor cell culture media).

There are some omissions from thechapter. Unfortunately the informationrelating to gas sterilisation is relativelylimited. The use of gas sterilisation fordisinfection is stated as falling outsidethe scope of pharmacopoeia; thisprocess is already complicatedthrough the numbers of differenttypes of gas sterilisation processesand lack of reference cycles. Anopportunity to add clarity to users ofisolators selecting biologicalindicators to use with hydrogenperoxide vapour cycles has been lost.

Summary

Both European Pharmacopoeiachapters – on sterilisation andbiological indicators – have beensubstantially rewritten and they bothcontain additional content,particularly relating to asepticprocessing, sterilisation by membrane

The chapter has several changesrelating to the specification and use ofbiological indicators. With steamsterilisation, the D-value range forGeobacillus stearothermophiluswidens from 1.5 to 3.0 minutes(previous version) to 1.5 to 4.5 minutesfor the reference temperature of121°C (new version). Similarly the dryheat biological indicator D-valuerange is extended to between 1 and 5minutes (with a reference temperatureof 160°C). D-value refers to decimalreduction time (or decimal reductiondose) and is the time (or dose)required at a given condition (e.g.temperature), or set of conditions, tokill 90% (or 1 log) of the exposedmicroorganisms. For sterile productsthat cannot be sterilised in their finalcontainers (that is, aseptic processingis required instead of terminalsterilisation) the sterilisation of liquidbulks through sterilising grade filters isa necessary step. A new section hasbeen added to cover the validation ofmembrane filters, and this helps toconnect this chapter to chapter 5.1.1and the new section on asepticprocessing. Suitable filters for mostprocesses (removal of bacteria andfungi) have a pore size of not greaterthan 0.22 μm. The chapter addressesthis for the first time and describes the


REVISIONS MADE TO EUROPEAN PHARMACOPOEIA STERILISATION CHAPTERS continued

filtration and hydrogen peroxidevapour. The useful parts of theupdates include the (albeit brief)sections on aseptic processing andwith the validation of membranefilters used for sterilisation.

Despite the revisions the chaptersdo not remain without their problems.As stated above the classification ofhydrogen peroxide vapour as‘sterilisation’ places it at odds withcurrent inspectorate trends (andperhaps with the long-waited EU GMPAnnex 1 update). Keeping with thesame process, the brief description onthe use of biological indicators forassessing hydrogen peroxide cycleefficacy lacks the guidance that manyusers have been seeking around thecharacterisation of resistance.

Despite the omissions, note needsto be taken of the chapters. Althoughthe status of the chapters, based ontheir position in the pharmacopoeia,is as ‘general chapters’ and thereforenot mandatory, deviating from thechapter content requires a robustrationale and one that must stand-upto regulatory scrutiny. Thus, for thoseinvolved with sterile productsmanufacture becoming familiar withthese chapters is recommended.

References1 European Pharmacopoeia, Ninth Edition,Supplement 9.2, European Directorate forthe Quality of Medicines and HealthCareof the Council or Europe, Strasbourg,France

2 European Pharmacopoeia. Chapter 5.1.1Methods of Preparation of Sterile Products,Ph. Eur., edition 9.2, pp4333-4336

3 Tidswell, E. “Sterility.” In Saghee, M.R.,Sandle, T. and Tidswell, E.C. (Eds.) (2011)Microbiology and Sterility Assurance inPharmaceuticals and Medical Devices,New Delhi: Business Horizons, pp. 589-614

4 European Pharmacopoeia. Chapter 5.1.2Biological indicators and related microbialpreparations used in the manufacture ofsterile products, Ph. Eur., edition 9.2,pp4336-4339

5 Sandle, T. (2013). Sterility, sterilisation andsterility assurance for pharmaceuticals:Technology, validation and currentregulations, Woodhead Publishing,Oxford, pp263-279

6 Pflug, I.J. and Odlaug, T.E. (1986)Biological indicators in the pharmaceuticaland medical device industry. Journal ofParenteral Science and Technology, 40,242–248

Quality assessments for biological indicators must include:1.The genus and species of the microorganism.2.The culture collection reference of the microorganism.3.The batch number.4.Logarithm of the spore count (to one decimal value).5.Recovery method used.6.Type of carrier.7.Type of packaging (e.g. outer envelope).8.Composition of the recovery medium (including medium of self-contained biological indicators).

9.Type of indicator in the medium (if applicable, e.g. some media contain dyes indicating pH colour changes).

10.Sterilisation process and recovery conditions against which the biological indicator has been characterized.

11.Resistance against a specified sterilisation process, expressed as time or dose.12.Method used to determine the D-value (e.g. fractional negative approach).13.Z-values (where applicable). This is the temperature difference that leads to a ten-fold difference with the D-value.

14.Storage conditions.15.Expiry time.


tabletability (compaction pressureversus tablet tensile fracture stress)and compactibility (tablet tensilefracture stress vs solid fraction)together provide a unique insightinto formulation properties. Of these,the most useful for making productcomparisons are compactability andtabletability; compressibility hasother applications for formulationassessment which we will alsodiscuss.

Pitt et al3 compared the propertiesof tablets prepared on a laboratorycompaction system with the samematerials compacted on aproduction Fette press underproduction conditions, for bothcompactibility and compressibility.Two formulations were compared –one wet granulation and one directcompression. The laboratorycompaction was using a 100 mg, 6 mm diameter round tablet whilstthe production material was thesame product compressed using an800 mg caplet shape. Tablets werecompressed at a range ofcompaction pressures and fracturedin diametral compression. The tensilefracture stress of each tablet shapewas calculated using the formula ofFell and Newton4 σT = 2P/(πdt)(where P is the fracture stress, and dand t are the tablet diameter andthickness respectively) for the tensilefracture of flat faced circular tablets.The formula of Pitt5 was used for thecalculation of the tensile fracturestress of the capsule shaped tabletsmade under production conditions.Example data are shown in Figures 2and 3. The compactibility andtabletability of both formulationswere found to coincide.

Work performed at our in-housefacility has also evaluated the effectof tablet size on tablet properties.Studies with pre-gelled starch

PREDICTING PRODUCTIONTABLET PROPERTIES FROMSMALL SCALEMANUFACTUREby Michael Gamlen

With growing use of the laboratory press system,the ability to predict production tabletproperties from lab scale data becomes important. Inthis article, Michael Gamlen describes how this can bedone.

Developing a new tablet formulationis a difficult task based on limitedinformation about many parametersincluding the drug dose and thedesired final tablet shape – round orcapsule-shaped, large or small.There is very little publishedinformation to enable a formulatorto predict the properties of a tabletmade at one size using theproperties of a tablet made atanother (size). For example, smallscale tablet development is regularlyperformed on our laboratorycompaction system using punch anddie sizes of 4-6 mm. In this article Iwill be explaining how thesemeasurements are being used topredict Production running hardnessand compaction forces based on thematerial properties measured,providing valuable information tothe development process and thetech transfer team.

The recent publication of USP1 has spread theunderstanding of the key tabletparameters which need to becharacterised to understand tabletproperties (see Figure 1). Thecompaction triangle, first proposedby Tye and Amidon2 has greatlyassisted this process. The keyrelationships of compressibility (solidfraction vs compaction pressure),

Michael Gamlen studied for a PhD with Professor JM Newton at NottinghamUniversity and was Head of Solid Dosage Form Development at the WellcomeFoundation Ltd for 15 years. He is the inventor of the Gamlen Powder CompactionAnalysis System, and works as a consultant and trainer. He is a regular contributor ofarticles on tableting and powder compaction.

Figure 1. The compaction triangle


compressibility, and microcrystallinecellulose tabletability using 3 and 6 mm punches showed that thesesystems were also predictable fromone size to another. Recent workpublished by Schiano and Gamlen(AAPS 2017 poster) explored a muchbroader range of tablet properties(see Figures 4 and 5). Tablets ofmicrocrystalline cellulose from 3 to 8 mm diameter and ranging inweight between 20 and 250 mgshowed reproducible compactibilityand tabletability relationships whichare fully predictive from one size toanother.

The implications of theseobservations are that themeasurements of tabletability andcompactibility are related tofundamental material properties,and are therefore in a class ofmeasurements such as density andsurface area. This opens up anumber of exciting possibilities suchas whether they can be predictedfrom molecular structure, and towhat extent we can extend theprinciple to other tablet properties.Also included in Schiano’s poster isthe relationship between peaktablet ejection stress and

compaction pressure (Figure 6). Formicrocrystalline cellulose, this alsogives a strong correlation. Theejection stress increases to a valueof 3 MPa at a compaction pressureof 100 MPa, and then levels out withno further increase at compactionpressures up to 350 MPa. It wouldbe interesting to see if therelationship holds for othermaterials.

Based on these observations Ihave been considering the optionsfor predicting the running hardnessof tablets made under productionfrom the tablets made on thelaboratory press. For tablets in thenormal compaction pressureoperating range of 0 – 200 MPa, thetabletability relationship is normallylinear, occasionally with a positive x-axis intercept (which indicates thattablets do not form at all below acertain minimum pressure – areasonable observation). The slopeof this line applies independently oftablet size as the tensile fracturestress of the tablet is simply afunction of compaction pressure.

In this article I will be consideringthe simple case of predicting thetensile fracture for a round tabletfrom another round tablet. We willcall the weight of the small andlarge tablets, respectively, w and W,the radius of the tabletsrespectively, r and R, and thethickness of the tablets respectively,t and T. We need to estimate T, thethickness of the large tablet, andthen use the Fell and Newtonequation to calculate the tabletbreaking load of the large tabletfrom its thickness.

Based on the principle of densityindependence of tablet sizeoutlined above, the density of thelarge tablet will be the same as thedensity of the small tablet at equalcompaction pressure. The volume ofthe small tablet is given by

v = π*r2*t and the density of the small tablet

by d = π*r2*t/w. The volume of the large tablet is

given by V = π*R2*T

PREDICTING PRODUCTION TABLET PROPERTIES FROM SMALL SCALE MANUFACTURE continued

Figure 2. Compactability comparison - Fette and Gamlen

Figure 3. Tabletability comparison - Fette and Gamlen


PREDICTING PRODUCTION TABLET PROPERTIES FROM SMALL SCALE MANUFACTURE continuedPREDICTING PRODUCTION TABLET PROPERTIES FROM SMALL SCALE MANUFACTURE continued

Figure 4. Compactabiliy profile of microcrystalline cellulose

Figure 5. Tabletabiliy profile of microcrystalline cellulose


and the density of the large tabletby

D= π*R2*T/W. However, we know that d = D as the tablets are compressed

under equal conditions so we canrearrange the density equations tofind that

T = (W/w)*(r2/R2)*t. (Note that a similar relationship

can be derived for the capsuleshaped products, using the formuladeveloped by Pitt).

As an example, let’s assume that aformulator has developed a tabletof 5 mm diameter and acompression weight of 70 mg, andin production he plans to use a 500 mg tablet of 10 mm diameter. Ifthe tablet has a minimum

acceptable tensile fracture strengthof 2 MPa, the breaking strength ofthe 5 mm tablet is 2.4 kg (from theequation of Fell and Newton) which,using the same equation, wouldgive a breaking strength of the 800 mg caplet shaped productiontablet of 8.6 kg. If this was achievedat a compaction pressure of 200 MPa, the maximumrecommended production tabletpressure, then the compaction forcerequired to produce the tabletwould be

F = Pressure x Area = 200 * π*52 =15.7 kN.

(Note that use of millimetresinstead of metres in this formulacorrects for the unit of MPa insteadof Pa, keeping the calculationsimple).

These types of predictions areimportant and useful because theyhelp the Production to assesswhether the formulation is behavingas expected. For example if, inProduction, a force of 20 kN isrequired to produce the targetrunning hardness of 8.6 kg, then it isclear that the formulation is notperforming as well as it would beexpected based on the small scaledata. The cause of the changewould be worth investigating asother changes in the productsperformance such as dissolution orfriability may have also taken place.Making accurate measurement ofcompaction properties is becomingincreasingly important for checkingthe consistency of products duringthe scale-up process as well as on abatch- to-batch basis in Production.

References1 The United States Pharmacopeia, 36th ed.US Pharmacopeia Convention, Rockville,Maryland, 2013.

2 C.K. Tye, C.C. Sun, G.E. Amidon,Evaluation of the effects of tabletingspeed on the relationships betweencompaction pressure, tablet tensilestrength, and tablet solid fraction, J.Pharm. Sci. 94 (2005) 465–472.

3 Kendal G.Pitt. Compression predictionaccuracy from small scale compactionstudies to production presses, PowderTechnology 270 (2015) 490–493.

4 J.T. Fell and J.M. Newton. Determinationof Tablet Strength by the Diametral-Compression Test, Journal ofPharmaceutical Sciences 59 (1970) 688-691.

5 K.G. Pitt, and M.J. Heasley. Determinationof the tensile strength of elongatedtablets, Powder Technology 238 (2013)169-175.

PREDICTING PRODUCTION TABLET PROPERTIES FROM SMALL SCALE MANUFACTURE continued

Figure 6. Ejection stress profile for microcrystalline cellulose

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IIntroduction

Parmi les critères fondamentaux de qualité des médicaments injectables répondant aux exigences de pureté, innocuité, efficacité et stérilité, l’inspection des unités remplies est une étape clef dans la maîtrise de nos procédés de fabrication. Quel que soit le pays d’appartenance, les autorités de tutelle exigent que cette opération soit conduite.Les références réglementaires, tant dans la définition des moyens à mettre en œuvre (mode opératoire : cadence, sensibilité, équipement…) que dans les objectifs fixés (« pratiquement exempt de parti-cules »…), placent les industriels pharmaceutiques dans une situation délicate au regard des interpréta-tions possibles. À cet égard, les BPF indiquent : « 124. Après la répartition, les produits à usage parentéral doivent subir un contrôle individuel destiné à détecter tout corps étranger ou autre défaut. Lorsque ce contrôle est effectué visuellement, il doit être fait dans des conditions appropriées de lumière et d’arrière-plan préalablement déterminées. » Les principes d’inspection se déclinent en :- mirage visuel (manuel ou semi-automatique),- mirage automatique.

IIntroduction

Among the essential criteria of the quality of parenteral products corresponding to purity, safety, efficacy and sterility requirements, inspection of filled units is a key step in control of our manufacturing processes. This operation is required by regulatory authori-ties in all countries. Regulatory guidelines concerning the definition of the methods to be used (procedure: rate, sensitivity, equipment, etc.) and the objectives (“practically particle-free”) place pharmaceutical manufacturers in a delicate situation in view of the various possible interpretations.

For example, GMP indicate: “124. Filled con-tainers of parenteral products should be inspected individually for extraneous contamination or other defects. When inspection is done visually, it should be done under suitable and controlled conditions of illumination and background”.

The principles of inspection can be classified as:- visual inspection (manual or semiautomated),- automated visual inspection.

Qualification de l’inspection visuelledes médicaments injectables

Qualification of visual inspectionof parenteral products

L’inspection visuelle des médicaments injectables est requise aussi bien par les pharmacopées que par les bonnes pratiques de fabrication. La commission s’est proposé de présenter les différentes méthodes et équipements communément utilisés en industrie pharmaceutique pour l’inspection visuelle. Les aspects pratiques de la constitution et de la gestion des « défauthèques », les principes fondamentaux de la qualification des systèmes, le processus de qualification du personnel au mirage manuel et semi-automatique sont également couverts par les travaux de la commission.

Mots clefs : Inspection visuelle, Mirage, Qualification, Formation, Défauts, NQA, Particules.

Commission SFSTPF. Caire-Maurisier, F. Dumontier, P. Grel, C. Jolly, É. Levacher, S. Marcq, F. Sliwinski

V isual inspection of parenteral products is required by both pharmacopoeias and good manu-facturing practice. The Commission decided to describe the various methods and apparatuses com-monly used in the pharmaceutical industry for visual inspection. The Commission’s work also covered practical aspects concerning the constitution and management of defect databases, the basic principles of system qualification, and the process of qualifi-cation of personnel in manual and semiautomated visual inspection.

Key words: Visual inspection, Qualification, Training, Defects, AQL, Particles.


Notre groupe de travail s’est attaché au mirage visuel, où l’homme est au cœur du processus. Les auteurs proposent une méthodologie basée sur les re-tours d’inspection, les pratiques usuelles et abordent l’ensemble des critères complémentaires nécessaires à la mise en place d’une démarche de qualification de mirage visuel.

IID é f i n i t i o n s

L’inspection visuelle (mirage) : on entend par ins-pection visuelle ou mirage l’opération de contrôle de présence de tout corps étranger ou autre défaut pour chaque unité remplie. Bien que ce contrôle concerne 100 % des unités remplies, il ne peut garantir l’ab-sence de défauts qu’avec une certaine probabilité. L’inspection visuelle dite « manuelle » est réali-sée par l’œil humain sur un poste approprié où les opérations sont entièrement assurées par l’opérateur. L’inspection visuelle semi-automatique est réalisée par l’œil humain avec un équipement permettant l’alimentation, le défilement et l’agitation par rotation ou retournement à vitesse contrôlée. L’inspection automatique est réalisée par des systèmes de vision en dehors de toute intervention humaine. Contrôle visuel “in-process” : contrôle réalisé au cours du process en vue d’optimiser les paramètres d’exploitation des équipements en production (char-bonnage, particules, casse…). NQA (niveau de qualité acceptable) : niveau de qua-lité qui, pour le contrôle par échantillonnage sur une série continue de lots, constitue la limite acceptable pour la qualité moyenne d’une fabrication (définition issue de la norme ISO 2859-1). En d’autres termes, le recours à un contrôle statis-tique sur un lot est possible dès lors qu’il appartient à une série de lots ayant le même niveau de qualité. La constitution de l’échantillon sur ce lot doit être menée de manière représentative et répondre à une taille définie par la norme ISO 2859-1, fonction notamment de la taille du lot. Cet échantillon doit être évalué et le lot concerné sera accepté si cet échan-tillon comporte un nombre d’unités avec défauts inférieur à un nombre limite. Ce nombre limite est basé notamment sur le NQA et la taille du lot. Ainsi, le NQA est le niveau de qualité acceptable pour le lot ; il est défini par l’industriel et est fonction de la criticité du défaut. Imperfection cosmétique : défaut d’aspect ne met-tant pas en cause la qualité intrinsèque du produit. La détection de ces défauts est hors périmètre de cet article dans la mesure où les exigences sont variables en fonction des clients. Particules visibles : il serait confortable de se réfugier derrière le seuil communément admis des 80 à 100 µm, mais il s’agit plutôt d’une probabilité de détecter des particules à l’œil nu en fonction de plusieurs variables : environnement, temps d’obser-vation, opérateur, nature du produit. Tendances : suivi régulier d’indicateurs permettant de mettre en évidence une dérive progressive du

The working party examined visual inspection in which man is at the heart of the process. The authors propose a methodology based on inspec-tion feedback, usual practices and discuss all of the complementary criteria required to set up a visual inspection qualification approach.

IID e f i n i t i o n s

Visual inspection: visual inspection is defined as the control operation designed to detect the presence of any foreign matter or any other defect for each filled unit. Although this control concerns 100 % of filled units, it can only guarantee the absence of defects with a certain probability. Manual visual inspection is performed by the human eye at an appropriate viewing station, where all operations are ensured by the operator. Semiauto-mated visual inspection is performed by the human eye with equipment comprising a feeder, conveyor and agitation by rotation or inversion at a controlled speed. Automated inspection is performed by vision systems in the absence of any human intervention.

In-process visual inspection: control test performed during the process to optimize manufacturing equip-ment operating parameters (carbonization, particles, breakage, etc.). AQL (acceptance quality level): quality level that is the worst tolerable process average when a continuing series of lots is submitted for acceptance sampling (definition derived from ISO 2859-1).

In simple terms, a statistical control can be per-formed on a lot when it belongs to a series of lots with the same quality level. Constitution of the sample of this lot must be conducted according to a represen-tative process and must comply with a sample size defined by ISO 2859-1, essentially depending on the lot size. This sample must be evaluated and the lot concerned will be accepted if this sample comprises a number of defective units less than a defined limit.This limit is essentially based on the AQL and the lot size. The AQL is therefore the acceptance quality level for the lot; it is defined by the manufacturer and var-ies according to the criticality of the defect. Cosmetic imperfection: defects of appearance with no impact on the intrinsic quality of the product. The detection of these defects is beyond the scope of this article, as cosmetic requirements vary according to the customer. Visible particles: it would be tempting to use the commonly accepted cut-off of 80 to 100 µm, but this cut-off corresponds to a probability of detecting particles with the naked eye, depending on several variables: environment, observation time, operator, nature of the product. Trends: regular monitoring of indicators allowing demonstration of a progressive drift of the quality


niveau de qualité (rendement mirage, pourcentage de rebuts par type de défauts…). Limite de confiance : « risque statistique » per-mettant d’évaluer la précision de l’estimation d’un paramètre statistique sur l’échantillon (UCL, upper confident level). Méthode Knapp : approche statistique visant à comparer le mirage manuel à une méthode alternative afin d’en déterminer l’efficacité, dans le cadre de la recherche de particules en solution. Kit de référence : ensemble de spécimens ou pho-tographies représentant chaque défaut ainsi que sa criticité. Objectif : servir d’étalon primaire, approuvé par les utilisateurs et l’assurance qualité (AQ). Kit de formation : ensemble de spécimens repré-sentatif qualitativement de la production. Objectif : servir d’outil à la formation. Kit de qualification : ensemble de spécimens repré-sentatif qualitativement et quantitativement de la production. Objectif : servir d’outil à la réalisation de la qua-lification.

IIITextes réglementaires

1. Liste de textes

1.1. Textes réglementaires

Bonnes pratiques de fabrication. Good Manufacturing Practices européennes, Annexe 1. Pharmacopée européenne :- formes pharmaceutiques/0520 préparations paren-térales/préparations injectables,- monographie EP 2.9.20, contamination particu-laire : particules visibles,- monographies générales 0153 vaccins pour usages humains. FDA :- GMP Guidance on Sterile Drug Products produced by Aseptic Processing,- cGMP (2004), Chapter VI B.2, Inspection of Container Closure System. Pharmacopée américaine (US Pharmacopoeia) :- General Chapter 1 Injections, Foreign and Particu-late Matter (USP 36),- USP 788 Particule matters in injection,- USP 790 Visible particules in injections (draft). Japanese Pharmacopoeia XVI (6.06 Foreign inso-luble matter).

1.2. Recommandations

WHO, Regulation, guidance annexe 6. ANSM, fiche n° 2, signalements « particules de verre dans les injectables », éléments d’investigations à prendre en compte et mesures préventives (juin 2009).

level (visual inspection yield, percent rejects by type of defect, etc.). Limit of confidence: statistical risk used to evaluate the precision of an estimate of a statistical parameter on the sample (UCL, upper confidence level).

Knapp method: in the context of testing for par-ticles in solution, a statistical approach designed to compare manual visual inspection to an alternative method in order to determine its efficacy. Reference kit: set of specimens or photographs representing each defect and its criticality.

Objective: to be used as a primary standard, ap-proved by users and quality assurance (QA). Training kit: set of specimens qualitatively repre-sentative of production. Objective: to be used as a training tool. Qualification kit: set of specimens qualitatively and quantitatively representative of production.

Objective: to be used as a qualification tool.

IIIRegulatory texts

1. List of texts

1.1. Regulatory texts

Good Manufacturing Practice. European Good Manufacturing Practice, Appen-dix 1. European Pharmacopoeia:- dosage forms/0520 Parenteral preparations/Injec-tions,- Ph. Eur. Monograph 2.9.20, Particulate contamina-tion: visible particles,- general monographs 0153 Vaccines for human use. FDA:- GMP Guidance on Sterile Drug Products produced by Aseptic Processing,- cGMP (2004), Chapter VI B.2, Inspection of Con-tainer Closure System. United States Pharmacopoeia (USP):- General Chapter 1 Injections, Foreign and Particu-late Matter (USP 36),- USP 788 Particulate matters in injections,- USP 790 Visible particles in injections (draft). Japanese Pharmacopoeia XVI (6.06 Foreign in-soluble matter).

1.2. Recommendations

WHO Regulation, guidance appendix 6. ANSM, notification form No. 2 “Glass particles in injections” elements of investigations to be taken into account and preventive measures (June 2009).


1.3. Norme

ISO 2859-1, avril 2000.

2. Tableau de synthèse des exigences

Le tableau 1 synthétise les principales exigences réglementaires. Remarque : on peut noter l’absence d’harmonisa-tion sur le sujet… Tableau 1. Principales exigences réglementaires.

BPF/GMP Eu FDA cGMP Ph. Eur. USP JP

Objectifs - Contrôler 100 % des contenants, contaminations é t r a n g è r e s o u autres défauts

- N'importe quelles unités endomma-g é e s o u d é fe c -tueuses devraient être détectées et enlevées, pendant l'inspection finale

- Claires et pratiquement sans particules

- Chaque contenant sera inspecté autant que possible afin de détecter la présence de corps étranger et de parti-cules de matières- Garantir le produit “pour l’essentiel” avec absence de particules visibles

- Claire et libre de par ticules étrangères ai-sément détec-tables

Méthodes - Contrôler indi-v i d u e l l e m e n t , pauses répétées- Si autres mé-thodes, validation obligatoire

- Pas d’étiquettes, lavage, sé-chage de l'extérieur, retourne-ment du contenant, s’assurer qu’il n’y a pas de bulles d'air, observation environ 5 s devant le panneau blanc, répétez la procédure devant le panneau noir, enregistrez la présence de n'importe quelles particules

- Méthode d’inspection dé-crite et qualifiée- Qualification avec particules “représentatives” de la pro-duction réelle- Si le contenu ou contenant ne permet pas une totale ins-pection, il sera complété par le contrôle sur un échantillon soit reconstitué (lyophilisat) soit transféré (verre brun)

Matériels - Conditions appro-priées d’éclairage et d’arrière-plan- Si autres mé-thodes, procédé validé et équipe-ment qualifié pé-riodiquement

- Panneau noir, mat, de taille appropriée en position ver-ticale- Panneau blanc anti-reflet de taille appropriée en position verticale- Support de lampe réglable, non directe, avec source de lumière blanche et diffuseur adapté, (2 tubes de 13W avec longueur d’onde de 525 nm, intensité entre 2000 et 3750 lux mais possibilité de monter pour des contenants plastiques ou verres colorés)

- Pas d’élément grossissant- Intensité lumi-neuse à environ 1000 lux avec lampe incan-descente- Intensité environ 8000 à 10 000 lux pour les contenants en plastique

Main d’œuvre

- Contrôle régu-lier de la vue avec verres correcteurs si portés

Résultats - À enregistrer - N'importe quels défauts ou résul-t a t s e n d e h o r s des spécifications établies pour les contrôles en cours et l’inspection fi-nale doivent être investigués avec § 211.192.

- Tracer la présence de toutes particules

1.3. Standard

ISO 2859-1, April 2000.

2. Summary table of requirements

The main regulatory requirements are summa-rized in Table 1. Note the absence of harmonisation on this subject.

IVRetours d’inspections

Dans la cadre de la publication, une enquête réa-lisée auprès des industriels (2013) permet de noter que les principaux écarts et remarques relevés au cours des dernières inspections de l’ANSM portent sur les items suivants.

IVInspection feedback

In the context of the publication, a survey con-ducted among manufacturers (2013) revealed that the main defects and comments noted during the last ANSM inspections concerned the following items.


Table 1. Main regulatory requirements.

BPF/GMP Eu FDA cGMP Ph. Eur. USP JP

Objectives - Inspec tion of 100 % of contai-ners, foreign conta-minations or other defects

- Any damaged or defective units should be detec-ted, and removed during inspection of the final sealed product

- Clear and practically par-ticle-free

- Each container will be inspec-ted as far as possible to detect the presence of foreign matter and particles to essentially gua-rantee the product for absence of visible particles

- Clear and free of easily d e t e c t a b l e foreign par-ticles

Methods - Individual ins-pection repeated breaks- Validation is re-quired for other methods

- Remove any adherent labels from the container and wash and dry the outside. Gently swirl or invert the container, ensuring that air bubbles are not introduced, and observe for about 5 s in front of the white panel. Repeat the procedure in front of the black panel. Record the presence of any particles

- Method of inspection descri-bed and qualified- Qualification with particles re-presentative of real production- If the content or container does not allow total inspection, it will be completed by inspection on a reconstituted (freeze-dried powder) or transferred sample (brown glass)

Materials - Appropriate li-ghting and back-ground conditions,if other methods process must be v a l i d a t e d a n d equipment must b e p e r i o d i c al l y qualified

- A matt black panel of appro-priate size held in a vertical position- A non-glare white panel of appropriate size held in a ver-tical position- An adjustable lampholder fitted with a suitable, shaded, white-light source and with a suitable light diffuser (a viewing illuminator containing two 13 W fluorescent tubes, each 525 mm in length, is suitable). The intensity of illu-mination at the viewing point is maintained between 2000 lux and 3750 lux, although higher values are preferable for coloured glass and plastic containers

- No magnifying elementIntensity of illumi-nation of about 1,000 lux with incandescent lamp- Intensity of about 8,000 to 10,000 lux for plastic containers

Manpower - Regular vision testing with cor-re c t i ve g l a s s e s when needed

Results - Record results - Any defects or results outs ide the specifications established for in-process and final inspection are to be investigated in accord with § 211.192

- Record the presence of any particles

1. Habilitation des opérateurs et conditions de maintien

- S’assurer de la mise en place d’un kit représentatif de la production contenant des défauts en quantité définie et permettant d’habiliter le personnel.- Critères d’acceptation préalablement définis et pro-cédurés selon criticité des défauts et cela de manière reproductible.- Demande de vérification et de surveillance de l’acuité visuelle des opérateurs.- Conditions de maintien de l’habilitation et notam-ment la gestion des (longues) absences (de pratique) ainsi que la fréquence de réhabilitation.- Rendre accessible l’état des habilitations (affichage de matrice…).

1. Q u a l i f i c a t i o n of operators and maintenance conditions

- Ensure the presence of a kit representative of the production containing a defined quantity of defects, allowing qualification of personnel.- Reproducible acceptance criteria previously defined in a procedure according to criticality of defects.

- Verification and monitoring of the operators’ visual acuity.- Conditions of maintenance of qualification, espe-cially management of (long) absences (of practice) as well as requalification frequency.- Make the qualification status accessible (display of the matrix, etc.).


2. Conditions de réalisation du mirage

Au-delà des exigences définies dans les pharma-copées européenne, japonaise et américaine décrivant les fonds noirs et fonds blancs ainsi que les valeurs d’intensité lumineuse appliquées au poste, d’autres éléments doivent être envisagés :- les intervalles entre temps de travail et temps de pause ;- les cadences, qui doivent permettre de nous assurer que le mirage reste efficace au cours du temps ;- d’autre part l’éclairage de l’espace environnant, la disposition et l’ergonomie du poste qui doivent favoriser la concentration de l’opérateur et ainsi éviter tout risque de confusion.

3. Documentation et défauthèque de référence

- Opérations de mirage décrites dans des procédures détaillées (méthode, matériel, conditions opératoires, les prérequis du poste).- Défauthèque physique (les photos ne sont pas jugées suffisantes), tenue à jour régulièrement et maîtrisée, doit permettre aux opérateurs de visualiser les défauts et servir de référence en cas de doute.

4. Contrôle f i n a l et analyse des tendances

- Valider chaque opération de mirage par un contrôle a posteriori (contrôle statistique selon plan d’échan-tillonnage établi, double mirage…).

- Attente de suivi des tendances des défauts détectés au mirage afin de permettre des investigations et la mise en place d’actions préventives et/ou correctives.

VRetours d’experiences

1. Contexte/discussion

L’évaluation visuelle de la qualité des solutions parentérales, en ce qui concerne les particules visibles, peut s’appuyer sur des méthodes de contrôle alternatives à la Pharmacopée. Ces méthodes doivent néanmoins être aussi performantes que celles décrites à la monographie (2.9.20) de la Ph. Eur. Le tableau 2 identifie les principaux paramètres des modes opératoires susceptibles d’être ajustés. La profession est convaincue que le zéro défaut ne pourra jamais être atteint par le caractère probabiliste de la détection. Néanmoins, au vu de la disparité des approches des industriels, des spécifications réglementaires et des exigences des inspections de nos autorités de tutelle, un compromis alliant prag-matisme et souci de la qualité des produits mis sur le marché doit être trouvé.

2. Visual inspection conditions

Apart from the requirements defined in the Eu-ropean, Japanese and American Pharmacopoeias describing black and white panels as well as intensity of illumination applied for inspection, other elements must also be considered:- intervals between work times and break times;- inspection rates must ensure that visual inspection remains effective over time;- illumination of the environment, organisation and ergonomy of the viewing station must also promote the operator’s concentration and therefore avoid any risk of confusion.

3. Documentation and reference defect database

- The visual inspection operations described in detailed procedures (method, material, operating conditions, viewing station prerequisites).- Physical defect database (photographs are not con-sidered to be sufficient), regularly kept up-to-date and mastered, must allow operators to visualize de-fects and must constitute a reference when in doubt.

4. Final control and trend analysis

- Validate each visual inspection operation by a ret-rospective control (statistical control according to an established sampling plan, double visual inspection, etc.).- Trend analysis of the defects detected on visual inspection to allow investigations and implementa-tion of corrective and/or preventive actions.

VExperience feedback

1. Background/discussion

Visual evaluation of the quality of parenteral solutions in terms of visible particles can be based on alternative methods to those described in the Pharmacopoeia. These methods must nevertheless be as efficient as those described in the European Pharmacopoeia monograph (2.9.20). Table 2 identifies the main parameters of the op-erating procedures that can be adjusted. The profession is convinced that zero defect can never be achieved due to the empirical nature of detection. Nevertheless, in view of the various ap-proaches used by manufacturers, regulatory stan-dards and regulatory authority inspection require-ments, a compromise must be reached comprising a pragmatic approach ensuring quality of the products released onto the market.


Tableau 2. Principaux paramètres des modes opératoires susceptibles d’être ajustés.

Thèmes Impact qualité Impact industriel

Temps d’observation Probabilité de détection augmentée au regard du temps d’observation

Variable sur la productivité

Nbre unités mirées simul-tanément

Possibilité de comparaison (entre unités d’une même série observée)

Augmentation de cadence

Equipements Conception : optiques grossissantes, miroirs, éclai-rage optimisé en fonction de la nature du produit miré peuvent améliorer sensiblement le seuil de dé-tection ou élargir le champ des défauts détectables

Rejets/rebus plus nombreux, conception d'équipe-ments spécifiques (prototype), transfert ou sous-trai-tance complexe

Tendances - Seuil bas

- Seuil haut

- En continu

Détection de défaillance d’un opérateur ou d’un équipementDétection de défauts avérés (problème process amont) ou de défauts non avérés (défaillance opé-rateur et/ou équipement) Réaction immédiate

Taux de rejet usuel de 2 à 3%, trop bas pour définir un seuil d’alerte et nécessité de remirer l’ensemble du lot Notion de remirage

Arrêt pour investigation et décision de la suite

Remirage de la totalité du lot

Garanties supplémentaires Retraitement identique et/ou ciblé coûteux

Remirage partiel Ciblage sur une population à risque / sur un défaut identifié

Moins de manipulation (diminution du risque de générer des défauts lors des opérations de contrôle)Retraitement plus rapide

NQA Si mis en œuvre, moyen de mesure objectif de la qualité du lot par classification des défauts

Echantillonnage supplémentaire pour contrôle

Personnel Gestion des habilitations

Kit de formation Révision régulière des défauthèques, maintien des compétences des experts, évite la mémorisation des défauts du kit de qualification

Gestion lourde des défauthèques (stockage, mise à jour, gestion des casses et usures)

Kit de référence Pas d’ambiguïté sur la criticité des défauts Gestion du kit

Kit de qualification Vérifications régulières de sa validité Gestion du kit

Table 2. Main parameters of the operating procedures that can be adjusted.

Themes Quality impact Industrial impact

Observation time Increased probability of detection with increasing observation time

Variable impact on productivity

Number of units inspected simultaneously

Possibility of comparison (between units of the same series inspected)

Increased inspection rate

Equipment Design: magnifying lenses, mirrors, lighting opti-mized according to the nature of the product inspec-ted can considerably improve the limit of detection or broaden the range of detectable defects

Greater number of rejects, design of specific equipment (prototype), complex transfer or outsourcing

Trends- Low threshold

- High threshold

- Continuously

Detection of operator or equipment failure

Detection of documented defects (problem in upstream process) or non-documented defects (operator and/or equipment failure)Immediate reaction

Usual rejection rate of 2 to 3%, too low to define an alert threshold and the need to reinspect all of the lotReinspection concept

Process stopped for investigation and decision concer-ning continuation

Reinspection of the entire lot

Additional guarantees Expensive identical and/or targeted reprocessing

Partial reinspection Targeted to a risk population/an identified defect Decreased handling (decreased risk of generating defects during control operations)More rapid reprocessing

AQL When used, objective measurement of the quality of the lot by classification of defects

Additional sampling for controls

Personnel Qualification management

Training kit Regular revision of defect databases, maintenance of the experts’ skills, avoids memorization of defects of the qualification kit

Complex management of defect databases (storage, update, management of breakages and wear and tear)

Reference kit No ambiguity concerning the criticality of defects Kit management

Qualification kit Regular verifications of its validity Kit management


En prenant en compte l’ensemble des éléments, le groupe de travail est parvenu à un compromis à considérer comme un outil d’aide à la décision, dans vos industries respectives et avec vos spécificités.

2. Défauts

Un défaut est un élément de nature à impacter l’identité, l’efficacité, la pureté, l’usage et l’image du produit. Les critères de sélection des défauts peuvent être :- visibilité,- historique,- nature du produit et du contenant,- exigences des clients (donneurs d’ordre).

2.1. Sources

Au-delà du contrôle particulaire, l’inspection visuelle permet également la détection d’autres défauts, provenant de sources multiples :- défauts article (fournisseur),- produit,- process de fabrication,- process de remplissage,- convoyage,- lyophilisation,- stérilisation,- stockage,- mirage.

2.2. Typologie

Les défauts observés lors de l’inspection visuelle sont de différentes natures et de caractères différen-ciés (tableau 3, liste non exhaustive). Une partie de ces défauts est illustrée en annexe. Tableau 3. Principaux défauts observés lors de l’inspection visuelle.Table 3. Different types of defects observed during visual inspection.

FamilleFamily

Type Critères et remarquesCriteria and comments

Particules endogènesEndogenous particles

Suspension, protéine…Suspension, protein…

Particules exogènesExogenous particles

Verre / GlassFibre / FibreColorée / ColouredMétalliques / MetalPlastique / PlasticSilicone / SiliconePoils / HairNuisibles / Pest

Taille*, position et comportement Size*, position and behaviour

Volume Haut / HighBas / LowVide / Empty

Ces défauts seront observés par comparai-son et non par mesure, le contrôle du volume n’étant pas un objectif du mirageThese defects are observed by comparison and not by measurement, as visual inspec-tion is not designed to control volume

Défaut produitProduct defect

Couleur / ColourOpacité/limpidité / Opacity/clarityAspect du lyophilisat / Appearance of the freeze-dried powder

By taking all of these elements into account, the working party reached a compromise that can be considered to be an aid to decision tool in your respective industries and with your specificities.

2. Defects

A defect is an element likely to impact the identity, efficacy, purity, use and image of the product.

Defect selection criteria can be:- visibility,- history,- nature of the product and the container,- customer requirements.

2.1. Sources

Apart from testing for particles, visual inspection also allows the detection of other defects, derived from multiple sources:- packaging material defects (supplier),- product,- manufacturing process,- filling process,- conveyor system,- freeze-drying,- sterilization,- storage,- visual inspection.

2.2. Typology

Different types of defects with differentiated char-acters are observed during visual inspection (Table 3, non-comprehensive list). Some of these defects are illustrated in appendix.


Figure 1. Exemple de détermination de seuil : médiane 50% (fondée sur la distribution réelle des tailles de particules de plusieurs lots de production). Le principe de l’exemple consiste à mesurer l’ensemble des particules observées sur une population choisie (par exemple un nombre de défauts ou de lots défini) afin de déterminer la médiane entre les grandes et les petites particules.Figure 1. Example of determination of the limit: median 50 % (based on the real distribution of particle size of several production lots).The principle of this example consists of measuring all particles observed in a chosen population (for example a number of defects or defined lots) in order to determine the median between large particles and small particles.

FamilleFamily

Type Critères et remarquesCriteria and comments

Bouchage / CrimpingSertissage / StopperingScellage / Sealing

Absence et nombre / Absence and numberCapsule non-conforme / Non-conforming capsuleScellage / Sealing

Position / Position

Présence de liquide dans le joint / Presence of liquid in the sealErreur d’AC / Packaging material error

Etirement verre gros « picot », affaissement verre, trouStretching of large blob of glass, glass weakness, holeMal positionné (haut –bas), mal posé (à l’envers, de travers, quantité, …)Incorrectly positioned (high-low), incorrectly applied (upside down, askew, quantity, etc.)

Défaut contenantContainer defect

Eclat intérieur (larme calcinée…) / Internal chip (burnt defect…)Eclat extérieur / External chipFêlure (incisé…) / Crack (incised...)Rayure / ScratchCouleur / ColourExcroissance intérieure (aiguille de verre, ailette, perchoir…)Internal excrescence (glass splinter, rib, ledge…)Excroissance extérieure (bavure)External excrescence (smudge)Collé coupant (suite au collage de deux contenants)Sharp joint (following gluing of two containers)Bulle (bouillon) / Bubble (broth)Pli vertical / Vertical foldPli horizontal / Horizontal foldTache intérieure / Internal spotTache extérieure / External spotInclusion / InclusionEléments d’intégrité abîmés ( joint de piston, protège-aiguille, site de perfusion, bouchon, aiguille…)Damaged elements (piston seal, needle cover, infusion site, stopper, needle…)

Dimension / Dimensions

*Afin de faciliter la définition d’une taille de particule, il est possible de se limiter à deux familles (petites/grosses) selon l’exemple donné en figure 1.*To facilitate the definition of particle size, two families (small/large) can be defined according to Figure 1.

Tableau 3. Principaux défauts observés lors de l’inspection visuelle (suite).Table 3. Different types of defects observed during visual inspection (continued).

2.3. Analyse de criticité des défauts

Tous les défauts caractérisés doivent être évalués. Exemple de rationnel et de critères permettant d’établir/évaluer la criticité des défauts (tableau 4) :- un impact en termes d’efficacité/identité/sécurité (rouge) détermine un niveau critique ;- un impact d’utilisation/réclamation (orange) déter-mine un niveau majeur ;- un impact d’image/productivité (jaune) détermine un niveau mineur ;- le niveau le plus critique l’emporte. L’évaluation de la criticité des défauts se fera au regard de la connaissance du produit, de l’historique et de la politique de l’entreprise, et de données

2.3. Defect criticality analysis

All defects identified must be evaluated. Example of the rationale and criteria used to es-tablish/evaluate the criticality of defects (Table 4):- impact in terms of efficacy/identity/safety (red) determines a critical level;- impact of use/complaint (orange) determines a major level;- impact of image/productivity (yellow) determines a minor level;- the most critical level is adopted. Evaluation of the criticality of defects is based on knowledge of the product, product history and the company’s policy, and analytical data, and should


Tableau 4. Rationnel et critères. Table 4. Rationale and criteria.

Défaut constaté

Defect observed

Effi-ca-citéEffi-cacy

Iden-tité

Iden-tity

Sécurité patient (stérilité, pureté)

Patient safety (sterility, purity)

Uti-lisa-tionUse

Récla-mation

Com-plaint

Ternitimage

Impair-ed image

Produc-tivité

Produc-tivity

Rationnel

Rationale

Criti-cité

Criti-cality

Particule en solution Particle in solution

N N O/Y N O/Y O/Y N C

Capsule abîmée Damaged cap

N N N N O/Y O/Y O/Y Risque de réclamation à évaluer selon destination/clients

Risk of complaint to be evaluated according to destination/customer

M /m

Rayure Scratch

N N N N N Y N m

FêlureCrack

N N O/Y O/Y O/Y O/Y N Défaut d’intégrité avéréDocumented defect of integrity

C

Aspect gâteau inhabituel Unusual appearance

O/Y N O/Y O/Y O/Y O/Y N C

O : oui. N : non. C : critique. M : majeur. m : mineur. Un score rouge oriente une classification critique. Un score orange oriente une classification majeure. Un score jaune oriente une classification mineure. Le score le plus critique l’emporte. Y: yes. N: no. C: critical. M: major. m: minor. A red score indicates a critical classification. An orange score indicates a major classification. A yellow score indicates a minor classification. The most critical score is adopted.

analytiques, de préférence par un groupe multidis-ciplinaire. Ainsi un défaut pourra être catégorisé différemment d’une entreprise à l’autre, l’important étant de justifier la démarche de manière rationnelle.

2.4. Criticité/NQA

Défaut critique : défaut pouvant directement affec-ter l’identité, l’efficacité ou la pureté du médicament dont l’usage peut entraîner des dommages sur la santé du patient ou l’efficacité du traitement. Défaut majeur : défaut entraînant l’impossibilité – ou un problème – d’utilisation du produit. Ne présente pas de risque patient mais expose à des réclamations. Défaut mineur : ne présente aucun risque sur la qualité du produit, ni de risque utilisateur (infirmière, patient). Défaut pouvant impacter la productivité, l’image du produit ou du laboratoire. Les NQA appliqués pour ces différentes classifica-tions sont variables en fonction des industriels et des clients. Les NQA les plus observés sont les suivants :- défaut rédhibitoire : -,- défaut critique : 0,025 à 0,1,- défaut majeur : 0,25 à 0,65,- défaut mineur : 1 à 4.

2.5. Défauthèque

La notion de défauthèque recouvre les kits de référence, de formation et de qualification (tableau 5). Ces kits sont déterminés pour des objectifs dif-férents mais pour des raisons de facilité pratique et de coûts ils peuvent cependant se substituer les uns aux autres.

preferably be performed by a multidisciplinary group. A defect may therefore be classified in different ways from one company to another; however, it is impor-tant to rationally justify the approach used.

2.4. Criticality/AQL

Critical defect: defect that may directly affect iden-tity, efficacy or purity of the drug product for which use of the product can cause damage to the patient’s health or decrease the efficacy of treatment. Major defect: defect that makes the product dif-ficult or impossible to use. Does not present a risk for the patient, but may be the subject of complaints.

Minor defect: does not present any risk in terms of product quality or for the user (nurse, patient). Defect that may impact productivity or the product or company image. AQL applied to these various classifications vary as a function of the manufacturer and the customer. The most commonly used AQL are as follows:- prohibitive defect: -,- critical defect: 0.025 to 0.1,- major defect: 0.25 to 0.65,- minor defect: 1 to 4.

2.5. Defect database

The concept of defect database includes reference, training and qualification kits (Table 5). These kits are determined for various objectives, but for practical reasons and cost, they can be inter-changed.


La sélection des défauts à détecter lors de l’opé-ration de mirage repose sur :- la criticité (critique et majeure a minima, mineure),- l’occurrence d’apparition des défauts,- des spécificités clients. Dans le cas de production multiproduits, il conviendrait idéalement de constituer des kits par référence (format/produit) mais l’établissement d’un rationnel par la notion de regroupement (limpidité, type de verre, viscosité, taille, volume…) peut justi-fier la réduction du nombre de kits. La constitution des kits doit être assurée par des équipes habilitées et approuvés par l’assurance qualité.

2.5.1. Kit de référence

Utilisation :- formation d’un nouvel arrivant ou sensibilisation (apprentissage des défauts, de leurs terminologies et criticités) ;- aide à la construction des kits de formation et de qualification ;- aide à l’investigation lors de litiges ;- limiter autant que faire se peut les manipulations des échantillons. Constitution :- établir la liste la plus exhaustive en se basant sur les essais de qualification, l’historique du process, la connaissance du produit (contenu/contenant), les réclamations, etc., afin de figer la terminologie des défauts ;- associer à chaque défaut soit un échantillon soit une représentation iconographique (photos et schémas) ;- évaluer la criticité de chaque défaut selon modalités décrites au V.2 avec approbation finale par l’assurance qualité. Gestion : - les conditions de stockage doivent nous garantir l’absence d’altération et l’intégrité physique des échantillons (à l’abri de la lumière, accès contrôlé, conditions de conservation du produit à respecter…). NB : Attention, certains défauts peuvent dispa-raître et/ou apparaître au cours du temps ; de plus, la péremption du produit est à prendre en compte dans la durée de conservation du kit. Le kit devant servir d’étalon primaire, les représentations icono-graphiques sont à privilégier afin de s’affranchir de ces difficultés.

Tableau 5. Trois types de kits.Table 5. Three types of kits.

Kit de référenceReference kit

Kit de formationTraining kit

Kit de qualificationQualification kit

Présence de tous les défauts rencontrés

Presence of all defects encountered

Présence de tout ou partie des défauts, mélangés à des conformes

Presence of all or some defects, mixed with conforming elements

Présence des défauts sélectionnés, en pro-portion représentative de la production, mélangés à des conformesPresence of a proportion of selected defects representative of production, mixed with conforming elements

Apprentissage de leur typologie & criticité

Learning of their typology & criticality

Apprentissage de l’élimination des défauts

Learning of defect elimination

Validation de l’aptitude à éliminer les défauts en condition de productionValidation of the ability to eliminate defects under production condition

Selection of the defects to be detected during the visual inspection operation is based on:- criticality (critical and minimal major, minor),- defect frequency,- customer specificities. In the case of multi-product productions, kits should ideally be established by reference (format/product), but a rationale based on a grouping con-cept (clarity, glass type, viscosity, size, volume...) can justify a smaller number of kits.

Constitution of kits must be ensured by qualified teams and must be approved by quality assurance.

2.5.1. Reference kit

Use:- training of a new arrival or to increase the awareness of personnel (learning of defects, of their terminolo-gies and criticalities);- aid to the constitution of training and qualification kits;- aid to investigation in the event of litigation;- limit ha

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