European Journal of Parenteral & Pharmaceutical …...European Journal of Parenteral &...

THE JOURNAL OF THEPHARMACEUTICAL AND HEALTHCARE SCIENCES SOCIETY (PHSS)

the pharmaceutical& healthcaresciences society

over 25 years of advancing pharmaceutical and healthcare sciences

2015 Volume 20 Number 3

European Journal

of Parenteral

& Pharmaceutical

Sciences

International Circulation

Prepared by the PHSS Bio-contamination Special Interest Group

the pharmaceutical& healthcaresciences society

over 25 years of advancing pharmaceutical and healthcare sciences

Bio-contamination

Technical Monograph No.20

Bio-contamination characterisation, control, monitoring and deviation management in controlled / GMP classified areas.

A comprehensive review

and best practice guidance:

Technical monograph no. 20

To order this monograph please go to

PHSS Publications on www.phss.co.uk

Bio-contamination CHARACTERISATION, RISK PROFILING, CONTROL, MONITORING AND DEVIATION MANAGEMENT.PREPARED BY A PHSS SPECIAL INTEREST GROUP FROM THE PHARMACEUTICAL INDUSTRY, NHS, SUPPLIERS AND SPECIALIST CONSULTANTS.

REVIEWED BY THE MHRA.

APPLIES TO CONTROLLED ENVIRONMENTS IN GMP AND NON STERILE APPLICATIONS WHERE BIOBURDEN CONTROL IS REQUIRED.

ON SALE NOW

Overview of content

Section 1. Introduction and scope includes a review of the challenges and requirements for Bio-contamination control and cross contamination control with a holistic approach to monitoring and proactive investigations in response to increased risk from changes in bio-contamination profiles.

Section 2. Bio-contamination characterisation and risk profiling. Methodologies and strategies that profile bio-contamination through establishing control, in operations and holistic monitoring.

Section 3. Bio-contamination control principles and best practice guidance considering Quality by Design, different processes, control attributes, background environments and Barrier technologies.

Section 4. Bio-contamination monitoring including classical and Rapid Micro Methods (RMM).

Section 5. Bio-contamination Deviation management including considerations and guidance in completing investigations and undertaking corrective and preventative actions (CAPA).

PRICE: Members £125 / Non members £175

EDITORIAL BOARDCHAIRMAN OF THE PHSSJames DrinkwaterF Ziel GmbH, UK

EDITOR-IN-CHIEFKay O’HaganTecmac UK Ltd, UK

M Gerard LeeHook, Hampshire, UKBengt LjungqvistChalmers University of Technology,Gothenburg, SwedenTim SizerSouthmead Hospital, Westbury-on-Trym,Bristol, UK

MANAGING EDITORSue BriggsT: +44 (0)1295 688028E: [email protected]

PUBLISHEREuromed CommunicationsPassfield Business CentreLiphook, Hampshire GU30 7SBT: +44 (0)1428 752222 F: +44 (0)1428 752223E: publisher@euromedcommunications.comwww.euromedcommunications.comINTERNATIONAL REVIEW BOARDRosamund BairdUniversity of Bath, UKStephen DenyerUniversity of Brighton, UK Gordon FarquharsonCritical Systems Ltd, UKMichael JahnkeHaupt Pharma Wulfing GmbH,Gronau/Leine, GermanyBrian MatthewsSouth Croydon, Surrey, UKSimon McEwenITH Pharma Ltd, UKDidier MeyerDMCompliance, FranceStephen Moss University of Bath, UKGerry ProutKennet Bioservices Ltd, Swindon, UKBerit ReinmullerChalmers University of Technology,Gothenburg, SwedenKirit Sanghani Siemens Healthcare, UKDavid SherwoodUCB Group, Slough, UK

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ISSN: 0964-4679

The European Journal of Parenteral & Pharmaceutical Sciences is the quarterly journal of the Pharmaceutical andHealthcare Sciences Society (PHSS). The journal provides a forum for publishing original peer reviewed papers,editorials, reviews and science & technology articles on all aspects of pharmaceutical and healthcare sciences. Paperswill normally be published within six to nine months of acceptance.

The European Journal of Parenteral & Pharmaceutical Sciences will also contain articles based on theproceedings of the Confederation’s scientific meetings, symposia and workshops. All submissions are subject topeer review by members of the editorial board and external referees. Advice to contributors is available from themanaging editor. The journal is published quarterly and is indexed in Scopus (http://info.scopus.com) and Embase(http://www.embase.com). It is provided free of charge to full and associate members of the PHSS. For non-members the annual subscription is £90 (personal rate) or £180 (institutional rate), plus annual postage costs of£12. Back issues are available at £25 each (abstracts of back issues can be viewed on our website atwww.euromedcommunications.com). Cheques (drawn on a UK bank) should be made payable to EuromedCommunications. Subscription orders should be sent to the publishers’ office.

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© 2015 Pharmaceutical and Healthcare Sciences Society

ContentsEditorial: Annex 1 revision - guidance, rules andinterpretation 83

Validation of the Growth DirectTM system to perform pharmaceutical waterbioburden analysis 85K. Nguyen, A. Mills, A. Sage and D. JonesAssessment of the disinfection of impaction air sampler heads using 70% IPA, as part of cleanroom environmental monitoring 94Tim Sandle and Ravikrishna Satyada

Requirements and environmental monitoring in pharmaceutical productionversus operating rooms in hospitals with focus on airborne particles andmicroorganisms 100Catinka Ullmann, Bengt Ljungqvist and Berit Reinmüller Regulatory review 104Malcolm Holmes PHSS activity and initiatives report 112

Instructions for authors in this issue or from our website: www.euromedcommunications.com

Peer-reviewed Papers

Science and Technology Features

A publication of the Pharmaceutical and Healthcare Sciences SocietyThe journal is published quarterly and indexed in Embase and Scopus

European Journal

of Parenteral

& Pharmaceutical

Sciences2015 Volume 20 Number 3

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European Journal of Parenteral & Pharmaceutical Sciences 2015; 20(3): 83-84© 2015 Pharmaceutical and Healthcare Sciences Society

Editorial: Annex 1 revision - guidance, rules andinterpretation

In the annual PHSS conference, a senior Medicineand Healthcare Products Regulatory Agency(MHRA) inspector and lead in the PharmaceuticalInspection Cooperation Scheme (PIC/S) WorkingGroup on Annex 1 revision went through theproposed changes in Annex 1. These will bediscussed within this journal when it is actuallyfinalised, but the comments of the inspector mademe think about cultural (company and national)differences in interpretation of regulatorydocuments. The inspector describes how the EUGuidelines to Good Manufacturing Practice(GMP) has a wide spectrum of interpretation. Insome cultures, it is considered as optional bestpractice (COULD do) and in others as “word forword” mandatory (MUST do). The guidance needsto be worded so that it best fit this wide spectrum ofinterpretation.Annex 1 in the 1983 Guidelines to Good

Manufacturing Practice (Orange Guide) was asingle page. This consisted of a table mainlyreferencing existing British and US Food and DrugAdministration standards for cleanrooms. The earlyDepartment of Health Orange Guides wereconsidered applicable in the UK market only. Thiswas in the days before the EU guidelines existed(joint documents started in 1992) whenpharmaceutical companies tended to manufacturemany dosage forms for their national market. The Orange Guide, and later the EU Guidelines

to Good Manufacturing Practice has always beentermed guidance and not regulations. While it isGMP guidance, it is enshrined in UK law. Thecurrent EU GMP guidance is the joint CompetentAuthority’s interpretation of the EU Directives andassociated local laws.The Medicines Control Agency/MHRA has

always started GMP from the point of perspectiveof patient safety and there was always some scope

for interpretation of the words in the “guidance”provided patient safety was the prime concern andthe route taken is justified and validated. In aculture where GMP = patient welfare, the site GMPtraining will also focus on the drug product, what isit used for and how “we” help patients. Ask anoperator in a site that is patient focused why they dowhat they do – nine times out of 10 the first thoughtwill be “helping/curing the patient”. A minority willhave regulatory compliance as their first thought.These could be argued as the same thing but itindicates a difference in core thinking.The “patient help” is a way of thinking that will

question processes and procedures if the operatorfeels empowered to do this and that they will belistened to. Questioning is indicative of a culturethat understands or at least tries to understand theprocesses they are working with.Where “compliance” is the core thinking, the

assumption is that everything approved is correctand the operator just has to do exactly as instructedfor the compliant process/product to be made.While GMP is about following exactly what isapproved – some cultures encourage and arereceptive to questioning while others are not.Typical of the compliance core culture is “learningby deficiencies” rather than a basic understandingof the processes.An example of this difference in core thinking is

given in the response to an audience questionregarding the introduction of the use of rapidmicrobiology methods (RMM) into Annex 1. Theanswer was most definitely not, because somecultures would interpret this as an instruction whileothers would see it as a viable alternative. It wasconsidered that including RMM in Annex 1 wouldcause confusion between could do and must do. An example that exists currently within Annex 1

is the recommended limits for microbial

84 Editorial

contamination table where the statement “(a)these are average values” exists. If the site has acore thinking of patient safety, it will be wellunderstood that any Grade A viable countpresents an unacceptable risk to the patient. Anyculture where the core thinking is compliancemight average out-of-specification results togive a result of less than 1 colony formingunit/unit of measure and consider themselves tobe in compliance.Now that we have such a global

manufacturing base and companies have centresof excellence for particular dosage forms, theEU GMP guidance is about what country theend product is marketed in more than the

country the product is manufactured in. Thismeans that the guidance has to be correctlyinterpreted by all cultures and realise that whatmay work in Europe might not work in the US,China or India for example.The fact that PIC/S are involved in the

revision of Annex 1 is refreshing. This meansthat 46 countries will have a similarinterpretation of the guidance. This willhopefully reduce the spectrum of could do tomust do interpretation of EU GMP guidance.

Kay O’Hagan

CALL FOR PAPERS& ARTICLES

Dear Colleagues,We live in a world of change and the pharmaceutical andhealthcare industry is rapidly changing. Regulations,technology, diseases and user expectations mean that whatwas obviously correct years ago is not quite so concrete now. This is your opportunity to drive that change. We needarticles and scientific papers that test, disseminate, validateand publicise these changes. The areas that the EJPPSspecialises in are the parenteral and pharmaceuticalsciences. It is about where and how we makepharmaceutical products and medical devices, how andwhere we test them, how and where we use them and theregulatory environment we work within. It is also about thehospital sector. Increasingly, this is where we make and testproducts but, more importantly, it is where we use theproducts we make.

There are a number of aspects to the journal, includingpeer-reviewed scientific papers. Scientific papers shouldfocus on scientific experimentation and reference otherscientific literature to create and test a hypothesis. Theseare peer reviewed by subject matter experts from theInternational Review Board.The other section is the Science and Technology Features.This includes reviews of regulatory updates, book reviews,conference reviews, technology reviews, industry reviews,best practice reviews and updates on the PHSS SpecialInterest Groups. These are reviewed for publication but donot always require subject matter expert reviews.We call for papers and articles that you would like to seeincluded in your journal. This is your opportunity to drivethe changes in the world we work in.Thank you for your continued support

Kay O’HaganEditor-in-Chief, EJPPS

85

*Corresponding author: David Jones, Director of Technical Services,Rapid Micro Biosystems, 1001 Pawtucket Blvd West, Lowell 01854, Boston,Massachusetts, USA; Email: [email protected]

European Journal of Parenteral & Pharmaceutical Sciences 2014; 20(3): 85-932014 Pharmaceutical and Healthcare Sciences Society

K. Nguyen, A. Mills, A. Sage and D. Jones*Rapid Micro Biosystems, Lowell, Boston, Massachusetts, USA

Validation of the Growth DirectTM system toperform pharmaceutical water bioburdenanalysis

IntroductionPharmaceutical water testing comprises a significantpercentage of the workload in the quality control department.Each water sample test is divided into two phases: firstsampling/setting up the test and secondly reading andrecording the test result(s). The second phase involves ahighly trained analyst performing the very repetitive task ofdata collection and collation for which they may beoverqualified. A reduction in the analyst involvement on thetesting effort would be a benefit to the department in thatother higher value activities could be performed by the sameperson. The introduction of automation to this process wouldadd significant benefit. The Growth Direct™ (GD) system isan automated colony counter that can be linked into a two-way LIMS system to upload sample work-lists and downloadresults, thus removing automatically these time-consuming,laborious tasks from the analyst. This paper describes thevalidation of the system as an automated colony counterapplied to pharmaceutical water testing.

GD technologyThe GD system uses a proven technology that is based on thesame principles and procedures as that defined in the

European Pharmacopoeia (Ph. Eur.) monographs for purifiedwater and highly purified water using R2A at 30–35°C1. Thesystem automates the compendial incubation and visualcolony counting method for water testing by replacingdetection by the human eye with sensitive digital imaging.The technology uses the same media and sampling methodsas the current water testing methods and is able to deliverfaster results by detecting microscopic colonies well beforethey become visible to the naked eye. This is achieved byimaging the intrinsic cellular auto-fluorescence of thebacterial colony. The growth of microscopic colonies aredetected by the GD system by detecting and tracking theincrease in their inherent auto-fluorescence over time. Thetechnology is based on the fact that all microbial cells emityellow-green fluorescence when illuminated by blue light at460–490 nm due to the presence of fluorescent biomoleculesinclusive of (ribo)flavins and flavoproteins2. Like adenosinetriphosphate or DNA, these molecules are ubiquitous in livingsystems in all the kingdoms of life including microorganisms.This permits the detection of the same broad range of speciesas are detected by the visual colony counting method.

Growing micro-colonies exhibit increasing auto-fluorescence and size over time which the system detects andrecords. The system discriminates growing microbialcolonies from inanimate fluorescent debris as these objects donot change in signal intensity or size.

The imaging method does not harm the cells and, as such,is a non-destructive method, thus the micro-colonies can grow

The validation of the Growth Direct system is described for the automated incubation and countingof microbial colonies on R2A media plates derived from a water bioburden test. The validationstrategy and sample data are given to demonstrate that the technology is accurate for enumeratingmicroorganisms, accurate and precise for microbial recovery and equivalent to the currentcompendia test for water testing.

Key words: Rapid Micro Method, water validation, Growth Direct, TR33.

86 K NGUYEN, A MILLS, A SAGE, D JONES

into visible colonies for use in subsequent microbialidentification.

Validation rationaleThe GD technology uses standard mixed cellulose–ester0.45 µm filtration membranes and standard media (R2A)and incubation parameters for microbial growth to allow acolony-forming unit (CFU) to grow into a colony and becounted. As the methods are comparable to thecompendial method, this technology can be viewed as arapid micro method rather than an alternative method.Effectively, the GD system performs as an automatedincubation and colony counting system. The keyfunctional parts are, therefore, only the qualification of theincubators and the qualification of the colony countingtechnology.

The new release of the PDA Technical Report TR332013 Evaluation, Validation and Implementation ofAlternative and Rapid Microbiological Methods containsthe following text3.

"Some alternative or rapid technologies may beconsidered as automated traditional orcompendial microbiological test methods,especially when the results are in colony formingunits (CFU). These technologies may be qualifiedfor their intended use without the need fordemonstrating certain method validationrequirements as specified in Section 5.0 of thisTechnical Report. For these technologies, at leastaccuracy and precision assessments should beperformed, in addition to method suitability andequivalence/comparability studies. A riskassessment should be performed to determine therequired testing that would support the validationof the alternative or rapid technology."

The validation steps of the GD system can be divided intofive sections.

1. The Installation/Operational Qualification (IOQ)phase concentrates on the validation of the system’shardware and software components to confirm thatthey are all functioning according to the designspecification. This includes the calibration andtemperature mapping of the incubators.

2. The Performance Qualification (PQ) is subsequentlycarried out to validate the growth promotion propertiesof the media in association with the accuracy of colonyenumeration by the software.

3. The Time to Result Qualification (TTRQ) phaseconsists of the determination of the timepoint atwhich the system result is shown to be comparable tothe compendial test method. For this work, thenatural flora from the facility should to be testedrather than the United States Pharmacopeia(USP)/Ph. Eur. organisms that are favoured duringthe PQ. The USP/Ph. Eur. defined organisms growvery quickly and are not indicative of the organismsseen in the facilities’ water system. Some of these

may have a long lag phase and slow doubling timethat could lead to false negatives if the TTR was setfrom the speed of the pharmacopoeial organismgrowth rates. During this testing, it is alsorecommended to include some examples of stressedorganisms to ensure the worst case scenario formicroorganism detection are met.

4. The method suitability for the product evaluatesinterference, either to the growth of the organisms orinterference of the product on the detection system ofthe GD system itself.

5. The final phase of the validation is the verification ofequivalence to the traditional method by running bothtests in parallel for a defined period of time.

Table 1. IOQ content.10.0 INSTALLATION QUALIFICATION DATA SHEETS 910.1 System Indentification Verification Sheet 910.2 SOP Verification Data Sheet 1110.3 Document Verification Data Sheet 1210.4 Network and Peripheral Connection Verification 13

Data Sheet10.5 Utility Verification Data Sheet 1510.6 Environmental Requirements Verification Data 16

Sheet10.7 Program Files, Data Base Verification Data Sheet 1710.8 Antivirus Verification Data Sheet 1910.9 Incubator Verification Data Sheet 2010.10 Optical Module Verification Data Sheet 2111.0 OPERATIONAL QUALIFICATION DATA SHEETS 2211.1 Email Notifications Verification Data Sheet 2211.2 User Role Settings and Touchscreen Calibration 24

Varification Data Sheet11.3 User Setting Verification Data Sheet 2611.4 General Settings 3011.5 IT Settings Verification Data Sheets 3411.6 Incubator Settings Verification Data Sheet 3811.7 System Shutdown and Restart Test Verification 40

Data Sheet11.8 Maintenance Options Verification Data Sheet 4411.9 Incubator Temperature Mapping Study Verification 43

Data Sheet11.10 Method Menu Verification Data Sheet 4411.11 Action and Alert Level Verification Data Sheet 4811.12 Handling Rules Verification Data Sheet 5111.13 Samples Verification Data Sheet 5411.14 Worklist Verification Data Sheet 5711.15 Compressed Air Verification Data Sheet 5911.16 Power Loss and Recovery Verification Data Sheet 6011.17 Barcode Printer, Scanner and Test Loading 62

Verification Data Sheet11.18 Condensation Removal Unit Verification Data 65

Sheet11.20 Sample Import, Assay Timing, and Interlocks 67

Verification11.21 Test Approval, Alarms and Robotic Accuracy 72

Verification Data Sheet11.22 Cancel/Retrieve Test Verification Data Sheet 7411.23 Lid Height Detection Verification Data Sheet 7711.24 Temperature Excursion and Alarm Verification 7911.25 Test Report Verification Data Sheet 8211.26 Lot/Batch Results Verification Data Sheet 8411.27 Audit Report Verification Data Sheet 8611.28 User Activity Data Table 8811.29 Disaster Recovery Verification 90

VALIDATION OF THEGD SYSTEM TO PERFORM PHARMACEUTICAL WATER BIOBURDEN ANALYSIS 87

Sections 3, 4 and 5 can be merged into the sameexperimental design if required. This paper describes theapproach used and data generated during the performanceof a water test validation on the GD system.

Installation/Operation Qualification(IOQ)The component testing performed during the IOQ areshown in Table 1. The majority of the testing focuses onthe performance of the software to verify the correct stepsand sequences. The key hardware test consists oftemperature mapping of the two incubators. The mappingwas performed with 10 Ellab temperature probes (Ellab,Hillerød, Denmark) placed throughout the incubator withboth a full and empty load pattern of test cassettes. Thetemperature profiles for the empty incubator at 22.5 and32.5°C are shown in Table 2. The temperature range seenfor both incubators over 24 hours at all test points was0.7°C. The same range was seen when testing the full loadpattern.

Performance Qualification (PQ)The PQ phase of the validation utilises microorganismsfor the qualification of growth promotion, systemaccuracy for colony detection and precision of thecolony detection. The organisms are presented in aneutral buffer such as Fluid A, buffered saline or peptonebroth to take out any inhibitory actions on the organisms.The USP/Ph. Eur. suite of organisms can be used asexamples of the spectrum of organisms required to betested (Table 3).

The accuracy of the CFU count is determined byfiltering the organisms through the GD filtration kit,transferring the membrane filter onto the GD R2Acassettes and running the cassettes on the GD system togenerate a system CFU count. The cassettes are thenremoved and the colonies on the membrane surfacecounted by the analyst. Due to analyst to analyst variationin enumeration of colonies, the cassette colony count isperformed by three analysts and the mean value obtainedis then compared to the GD system count. The results of

Table 2. Temperature mapping profiles for the two incubators at their specified set points.

13-14560: set at 22.5°C empty 13-14413: set at 32.5°C empty

Mean Minimum Maximum Mean Minimum Maximumtemperature temperature temperature temperature temperature temperature

Probe location (°C) (°C) (°C) (°C) (°C) (°C)

H8 S1 Front 22.5 22.4 22.6 32.4 32.3 32.4

H6 S1 Right front 22.5 22.5 22.6 32.5 32.5 32.5

H4 S1 Right side 22.5 22.5 22.6 32.5 32.4 32.6

H10 S1 Left front 22.5 22.5 22.6 32.6 32.5 32.6

H2 S1 Right back 22.6 22.5 22.7 32.6 32.4 32.7

H10 S13 Left front 22.6 22.6 22.7 32.6 32.6 32.6

H6 S13 Right front 22.6 22.6 22.7 32.6 32.6 32.6

H12 S13 Left back 22.7 22.6 22.7 32.6 32.6 32.6

H12 S1 Left back 22.7 22.6 22.7 32.6 32.6 32.6

H14 S1 Back 22.7 22.6 22.7 32.6 32.5 32.7

H2 S13 Right back 22.7 22.7 22.7 32.6 32.6 32.7

H8 S13 Front 22.8 22.7 22.8 32.7 32.7 32.7

H4 S13 Right side 22.8 22.8 22.8 32.7 32.6 32.8

H2 S25 Right back 22.8 22.8 22.8 32.8 32.7 32.9

H6 S25 Right front 22.8 22.8 22.9 32.8 32.8 32.9

H4 S25 Right side 22.8 22.8 22.9 32.9 32.8 33.0

H14 S25 Back 22.9 22.8 22.9 32.9 32.8 33.0

H10 S25 Front 23.1 23.0 23.1 32.9 32.8 33.0

Global mean 22.8 22.4 23.1 32.7 32.3 33.0


the GD system count and the mean of the analyst countcan then be directly compared.

The accuracy and precision of the method isdetermined using six replicates for each of the organismsof choice, run in three independent tests (Table 3). For thecontrol, a parallel run is also performed using the standardin-house method. Incubation was for 5 days at 30–35°C.

System count accuracyThe results for the enumeration accuracy are listed inTable 4 and the correlation shown in Figure 1. A verygood correlation is seen on the 1:1 line between themanual and system count for the test organisms that growto a discrete colony shape that is easy to count. For thespreading organisms, A. brasiliensis and B. subtilis, thedifference in counts is seen with the GD system giving

higher CFU counts. The graph also shows the 1 standarddeviation bars around the operator visual counts that arewide due to the variability in accurately counting mergingcolonies. The accuracy of the GD system was verified byinterrogating the image series created at 4-hour intervalsfor each plate and visually verifying that each colonydetected by the system was in fact a discrete entity. Usinglower spike numbers and counting earlier in theincubation period would help improve the accuracy of thehuman read.

Method accuracyThe results for the test methods, plate count and GD areshown in Table 5. The mean CFU count for each series ofsix replicates was calculated and the percentage recoverydetermined and then compared to the control method. Theacceptance criteria were set to a recovery of ≥70%. Allorganisms passed recovery testing.

PrecisionPrecision estimates are usually stated as a standarddeviation or a coefficient of variation (CV) and the % CVare listed in Table 6. All the CVs were well below thebenchmark of 35% as described in TR33; however, six ofthe GD and nine of the plate count sets failed thespecification of ≤15% stated in USP 12234 and Ph. Eur.5.1.65 with the maximum CV at 27%. Due to the well-known difficulty of obtaining a homogenous distributionof microorganisms in a test sample, it is not surprisingthat some tests failed the 15% CV value. However, asboth the compendial and the GD methods show similar

Table 3. USP/Ph. Eur. test organisms for use in the PQ.

Test microorganism ATCC* number3

Bacillus subtilis 6633

Staphylococcus aureus 6538

Escherichia coli 8739

Pseudomonas aeruginosa 9027

Candida albicans 10231

Aspergillus brasiliensis 16404

* ATCC: American Type Culture Collection.

Figure 1. Correlation of system CFU counts compared to the mean CFU count and standard deviation of three analysts on the samecassette.


Table 4.Accuracy and precision raw data.

Method Operator Replicate B. subtilis S. aureus A. brasiliensis P. aeruginosa C. albicans E. coliCFU CFU CFU CFU CFU CFU

GD 1 1 53 57 54 29 40 37GD 1 2 38 48 49 33 40 42GD 1 3 61 64 54 39 57 55GD 1 4 60 51 52 37 44 57GD 1 5 55 55 57 32 57 54GD 1 6 56 57 57 36 52 35GD 2 1 56 58 56 33 42 42GD 2 2 56 40 60 39 39 56GD 2 3 47 53 57 39 56 47GD 2 4 64 56 67 34 57 54GD 2 5 66 50 43 36 44 48GD 2 6 65 42 49 46 50 50GD 3 1 69 58 81 41 65 53GD 3 2 57 73 85 34 46 62GD 3 3 56 61 84 34 48 61GD 3 4 50 60 72 38 50 43GD 3 5 54 55 78 30 53 54GD 3 6 62 63 60 46 52 49GD 4 1 63 55 51 30 44 47GD 4 2 63 72 57 30 55 50GD 4 3 69 54 46 42 55 38GD 4 4 66 54 64 39 48 45GD 4 5 53 46 48 46 53 41GD 4 6 51 65 47 38 39 62PC 1 1 56.0 61.3 52.7 47.3 48.0 47.0PC 1 2 51.0 48.0 55.3 43.0 29.0 55.0PC 1 3 44.0 45.0 42.7 32.0 35.0 56.0PC 1 4 48.0 52.7 57.0 44.0 52.7 50.0PC 1 5 34.0 50.0 50.0 42.7 44.0 50.3PC 1 6 60.0 47.3 67.3 28.7 53.3 50.3PC 2 1 59.0 49.7 54.0 37.0 50.7 43.3PC 2 2 63.0 40.0 54.0 30.7 36.3 49.7PC 2 3 52.3 39.0 43.3 39.0 47.0 52.0PC 2 4 68.3 38.3 78.7 59.7 52.0 53.0PC 2 5 44.7 47.0 60.0 32.7 51.0 42.7PC 2 6 52.0 44.7 62.0 35.0 41.0 44.0PC 3 1 47.0 56.0 56.7 41.0 53.0 48.3PC 3 2 72.3 52.0 56.7 42.0 43.0 59.7PC 3 3 54.3 46.0 62.0 40.3 56.0 53.7PC 3 4 64.7 67.3 52.0 44.7 57.3 42.0PC 3 5 60.0 65.7 53.0 47.3 52.6 61.0PC 3 6 57.3 59.0 49.3 47.7 54.3 44.3PC 4 1 53.0 51.0 76.7 24.7 45.0 47.7PC 4 2 54.0 71.7 63.0 40.0 47.3 46.7PC 4 3 63.3 84.3 66.0 32.3 62.0 43.3PC 4 4 53.7 53.7 51.6 27.7 57.7 35.3PC 4 5 60.7 53.0 61.3 29.0 71.3 54.7PC 4 6 38.7 55.7 65.0 38.7 61.0 49.3

PC: plate count.Note: the PC data are averages of counts by three operators


numbers of excursions, there is no evidence that one isbetter or worse than the other.

An alternative recommended test is the F-test used tocompare the repeatability variances of both test methods inTable 6. No significant difference in repeatability precisionbetween test methods was found for any of the sixmicroorganisms. The p-values were calculated by means ofthe FDIST function in Excel using the variance ratio and thedegrees of freedom for each variance as entries for theFDIST function (PDA J Pharm Sci Technology, In press).

Time to result qualificationFollowing confirmation of the efficacy of the performanceof the instrument, the time required to confirm a negativeresult was defined. In order to do this, a TTR qualificationwas carried out.

The USP <1231> states that plates for water testingshould be incubated for between 48 and 72 hours,however, the Ph. Eur. states that this time should begreater than or equal to 5 days at 30–35°C, therefore, thesetimings should form the basis for the TTR qualification.

A broad range of pharmacopeial organisms,environmental isolates and contaminated water sampleswere used, including stressed samples, e.g. stressed bytemperature, pH, etc. Each analysed sample consisted of5–150 CFU of the test organism for each test. The testsamples were repeated in triplicate using both GD R2Acassettes and traditional R2A Petri plates.

The Petri plates were read at 7 days per standardoperating procedure, GD cassettes were incubated for up

Table 6. Precision: summary statistics by method, operator and microorganism (six replicates).

Method Operator Average (CFU)

B. subtilis S. aureus A. brasiliensis P. aeruginosa C. albicans E. coli

GD 1 53.8 55.3 53.8 34.3 48.3 46.7GD 2 59.0 49.8 55.3 37.8 48.0 49.5GD 3 58.0 61.7 76.7 37.2 52.3 53.7GD 4 60.8 57.7 52.2 37.5 49.0 47.2PC 1 48.8 50.7 54.2 39.6 43.7 51.4PC 2 56.6 43.1 58.7 39.0 46.3 47.5PC 3 59.3 57.7 55.0 43.8 52.7 51.5PC 4 53.9 61.6 63.9 32.1 57.4 46.2

Method Operator Coefficient of variation (%)

B. subtilis S. aureus A. brasiliensis P. aeruginosa C. albicans E. coli

GD 1 15 10 6 11 17 21GD 2 13 15 15 12 16 10GD 3 11 10 12 15 13 13GD 4 12 16 13 17 13 18PC 1 19 11 15 19 23 7PC 2 15 11 20 27 14 10PC 3 15 14 8 7 10 15PC 4 16 22 13 19 17 14

Table 5.Accuracy of method.

Operator GD count Plate count % recovery

B. subtilis 53.8 48.8 110.259 56.6 104.258 59.3 97.860.8 53.9 112.8

S. aureus 55.3 50.7 109.149.8 43.1 115.561.7 57.7 106.957.7 61.6 93.7

A. brasiliensis 53.8 54.2 99.355.3 58.7 94.276.7 55 139.552.2 63.9 81.7

P. aeruginosa 34.3 39.6 86.637.8 39 96.937.2 43.8 84.937.5 32.1 116.8

C. albicans 48.3 43.7 110.548 46.3 103.752.3 52.7 99.249 57.4 85.4

E. coli 46.7 51.4 90.949.5 47.5 104.253.7 51.5 104.347.2 46.2 102.2


to 5 days. The colony detection profiles from the GDsystem were downloaded and analysed as the percentagerecovery compared to the control method. The TTR can,therefore, be considered as the point at which the recoveryis greater than 70% of the manual reference method. Forthe test samples in the study, the TTR determined to be 84hours as shown in Figure 2. The data demonstrates that inthe natural flora present in the water samples, there were aspectrum of organisms that had lag times ranging from 6to 60 hours.

To add extra confidence, a later time point was takenand 96 hours was selected for the GD system TTR. Thistime gives equivalent results in approximately 60% of thetraditional method incubation time.

Method suitabilityMethod suitability was performed as described in Ph. Eur.2.6.126 and USP chapters <61>7 and <1227>8. The testingcan be split into two separate procedures whenconsidering water testing, growth promotion verificationand equivalence verification.

Growth promotion verificationGrowth promotion verification was performed byinoculating water samples characteristic of the testingsites in their testing volume of 1 or 200 mL with USP/Ph.Eur. organisms and specific local environmental isolates

at <100 CFU. The strains were filtered by the GD methodand the traditional method, membranes placed on theappropriate R2A agar cassette or Petri plate, and incubatedat 30–35°C for 96 hours on the GD system and 7 days forthe control method. At the end of incubation, the CFUcounts were collected and the percentage recoverycalculated for the GD system result versus the traditionalmethod. Acceptable recovery of the inoculated organismson the GD of 70% or greater mean CFU of that obtainedby the compendia method was exhibited for each teststrain (see Figure 3).

Equivalence verificationIn the last stage of validation, actual water sample testingwas performed side by side between the GD systemversus the manual method. Ten test sites were sampled atleast 20 times to give at least 200 results. The test methodwas the same as described in the Growth Promotionsection. Acceptance was deemed to be 50% to 200%recovery of the control media as defined in Ph. Eur.2.6.12, total viable aerobic count where a factor >2 isdefined.

For the water site shown (Figure 4), the agreementbetween CFU levels and trend detection was excellentwith all GD results >50% of the side-by side control. Nineother sample sites were followed for 20 days and allexhibited equivalent detection between the two methodsat 96 hours final incubation for the GD.

Figure 2. Estimation of TTR from all test samples run on the GD system. Each line represents the colony detection curves for eachindividual test sample expressed as a percentage of the control count for the same sample.


DiscussionThe paper introduces the validation strategy for the GDsystem, an automated colony counter, for the analysis ofwater samples in a pharmaceutical environment. As thesystem is based on the compendial test method for water,

Figure 3. Growth promotion of inoculated organisms on the GD system versus the compendial method show comparable results. Datashows the percentage recovery of the GD method compared to the traditional method.

Figure 4. Water trending for a reverse osmosis sample site. CFU/200mL water sample size using the control method at 7 days and the GDmethod at 96 hours end point.

the validation focuses primarily on those components thatare different, e.g. the colony detection and enumerationalgorithms and the automated incubation step. For theverification of the method, a simple approach to test theaccuracy and precision of the method was chosen as


suggested in the current PDA TR33 document.The data show that the camera detection and associated

algorithms accurately enumerate the microorganismcolonies on the membrane surface and that the R2A mediarecovers organisms from both standard diluents and realworld samples at equivalent levels to the standard method.The precision of the enumeration method is equivalent toor better than that seen with the traditional method.

With the GD system, a faster result can be obtainedby 96 hours rather than the 7 days used in the traditionalin-house method at the site. If the action level were 1CFU, then detection of an issue could be determined in<60 hours and would be flagged by the system to theanalyst.

In summary, the GD system has used a provenvalidation strategy that uses a minimal validationapproach following the process defined in the PDA TR33report.

References1 European Directorate for the Quality of Medicines and Healthcare,

Council of Europe. Water highly purified. EuropeanPharmacopoeia 6.3. London, UK: EMA; 2009, p. 4342.

2 London R, Schwedock J, Sage A, Valley H, Meadows J, WaddingtonM and Straus D. An automated system for rapid non-destructiveenumeration of growing microbes Public Library of Science ONE2010;5(1):e8609. doi: 10.1371/joumal.pone.0008609

3 Parenteral Drug Association. PDA Technical Report No. 33 (Revised2013). Evaluation, Validation and Implementation of Alternativeand Rapid Microbiological Methods. Bethesda, MD: PDA; 2013.

4 US Pharmacopeial Convention. General Chapter <1223> Validationof alternative micro methods. USP 37–NF32. Rockville, MD, USA:US Pharmacopeial Convention; 2014, pp. 1153–1155.

5 European Pharmacopoeia Working Group. EP 5.1.6 Alternativemethods for the control of microbiological quality. EuropeanPharmacopoeia 5.5. London, UK: EMA; 2006, p. 4131.

6 European Pharmacopoeia Working Group. EP 2.6.12Microbiological examination of nonsterile products: total viableaerobic count. European Pharmacopoeia, 5.6. London, UK: EMA;2007, p. 4398.

7 US Pharmacopeial Convention. General Chapter <61>Microbiological examination of nonsterile products: microbialenumeration tests. USP 37–NF32. Rockville, MD, USA: USPharmacopeial Convention; 2014, pp. 57–62.

8 US Pharmacopeial Convention. General Chapter <1227> Validationof microbial recovery from pharmacopeial articles. USP 37–NF32.Rockville, MD, USA: US Pharmacopeial Convention; 2014, pp.1163–1166.

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94

*Corresponding author: Tim Sandle, Head of Microbiology, Bio ProductsLaboratory, Dagger Lane, Elstree, Hertfordshire, UK. Email:[email protected]

European Journal of Parenteral & Pharmaceutical Sciences 2015; 20(3): 94-992015 Pharmaceutical and Healthcare Sciences Society

Tim Sandle1* and Ravikrishna Satyada21 Bio Products Laboratory, Elstree, Hertfordshire, UK2 Microbiology, Gland Pharma Limited, Hyderabad, India

Assessment of the disinfection of impaction airsampler heads using 70% IPA, as part ofcleanroom environmental monitoring

IntroductionContamination control is a necessary part of pharmaceuticalprocessing to avoid microbial contamination of theenvironment or product1. This is achieved through goodcleanroom design (air filtration, air movement, air changes,and pressure differentials) and through the correct gowningand training of personnel2. Once contamination control hasbeen established, physical and microbiological tests can beundertaken to verify cleanroom cleanliness. These tests rangefrom formal classification (primarily the assessment ofairborne particulates) of cleanrooms to scheduledenvironmental monitoring.

An effective environmental monitoring programme will berisk based, with the locations selected and frequency ofsampling based on some form of assessment; moreover, theprogramme will include a range of sampling methods. Whilerapid microbiological methods are promising (such asspectrophotometric particle counters)3, the majority ofmethods are comprised of the classic culture-basedtechniques: settle plates, active air sampling, surface

sampling by contact plates and swabs; with personnelmonitoring by finger dabs and gown plates, depending uponthe cleanroom grade and nature of operations.

Each of the environmental monitoring methods is variableand, despite a long history of use, the meteorology has a widerange of tolerance and is, to an extent, poorly understood. Oneof the greatest variabilities is with active air samplers.

Microbial air samplers are used to collect a predeterminedvolume of air and operate in a way to capture themicroorganisms onto an agar-based growth medium. Thereare different models of active air sampler available for theachievement of this task. These are, in terms of widespreaduse, impaction, centrifugal or filtration4. An air sampler with asieve-like impaction head functions by the aspiration of airthrough small holes on the sieve. Below the sampler head is amechanical fan which draws air in through the lid. The air isforced to directly impact onto a Petri dish containingmicrobiological agar. Any microorganisms in the air streamare deposited onto the surface of the agar. A centrifugal airsampler draws air into the sampler head through a rotatingvane mechanism. The vane causes microorganisms to bethrown out of the air and onto the agar through the effect ofthe centrifugal force. For filtration air samplers, air is sucked

Active (volumetric) air-sampling is an important component of the environmental monitoring ofcleanrooms. It is important that the results of such monitoring are accurate. One aspect of ensuringthat the result is ‘valid’ is through minimising cross-contamination. The ‘at risk’ part of the sampleris the head. There are three alternatives to control cross-contamination during active air samplingcontamination control: using multiple air samplers, autoclaving the sampler head in-betweensamples, or disinfecting the sampler head intermittently. This paper summarises a study where adisinfectant (70% isopropyl alcohol) was used to disinfect the head of an impaction air samplerbetween sampling sessions (spray-and-wipe technique). The study examined two factors: disinfectantdecontamination effectiveness and the potential for the inhibition of microbial growth. Withdecontamination effectiveness, successive operations of an air sampler were examined withindifferent cleanroom grades; with microbial growth inhibition studies, different disinfection timepoints were assessed. The paper concludes that this method of contamination control is effective andapplicable to most cleanroom monitoring situations: it is unlikely to allow carry-over of microbialcontamination and it is not shown to cause inhibition of microbial growth.

Key words: Environmental monitoring, active air sampling, biocontamination control, disinfection,cleaning, sanitisation, alcohol, culture media, microbiology.

ASSESSMENT OF THE DISINFECTION OF IMPACTION AIR SAMPLER HEADS USING 70% IPA 95

through a filter and any microorganisms are captured ontoa membrane filter, which is then transferred to the surfaceof a culture medium and this is then incubated5.

Variables that affect the collection efficiency relate tothe sampler itself; the environment within which itoperates, the culture medium used and incubationconditions, and the distribution of microorganisms in theenvironment. These factors form a necessary part of thequalification of environmental monitoring samplingmethods6.

Differences between samplers are expressed in termsof collection efficiency, which is a factor of the physicalparameters of the sampler and the d50-value (cut-off sizefor particle collection)7,8. Collection efficiency relates tovariables: inlet (or extraction efficiency), which relates torepresentative collection and transport of particles to thegrowth medium; and separation efficiency (separation andcollection of the particles drawn into the device)9. Thefocus on particles is important given that fewmicroorganisms in cleanrooms are found ‘free floating’;the majority originate from personnel and they areattached to rafts of skin detritus or dust10,11. With themodel selection, although no single model or type hasuniversal acceptance and each model has strengths andweaknesses12, in this study was a Merck-Millipore MAS -100 NT air sampler. This is an impaction sampler, withtechnology traceable to the pioneering AndersonDisposable Sampler13.

In relation to the environment, some samplers performless well within unidirectional airflow. With this, somesamplers are less effective at collection or the sampleritself can disrupt the airflow, triggering a potentialcontamination control risk as well as resulting in thecollected data being unrepresentative14. With culturemedia, the medium itself will be limited by what it canrecover, even with a ‘universal’ medium like tryptone soyagar; a secondary variable is the temperature rangeselected for incubation and the time that plates remain inthe incubator for15.

With distribution, there will always be a degree ofinaccuracy because microorganisms are not evenlydistributed in air and several factors, such as moisture,temperature, electrostatic charge, light, air movement, andso on, influence the distribution16,17.

Whilst the issue pertaining to sampler selection andoperation are important, ensuring that the results obtainedare valid is also equally important. Here ‘valid’ isdiscussed in the context of the result obtained reflecting aproportion of the microorganisms collected from thecleanroom air rather than a facet of contamination beingcarried over between sampling sessions.

The use of an air sampler for multiple samples within agiven sampling session is commonplace. When anoperator undertakes environmental monitoring, it istypical to sample more than one location within a givencleanroom and for more than one cleanroom to besampled. Here, it is important to ensure that the head ofthe sampler, especially the region within that has madecontact with microbiological culture media, isdecontaminated between each sample. The design of the‘head’ varies with the model of sampler. A sieve-like head,

for example, is commonly used with impaction samplers;whereas a rotor-head is used with a centrifugal sampler.

Most impaction air samplers are fitted with metal heads(typically fashioned from stainless steel or aluminium,with stainless steel necessary where autoclaving isrequired). An alternative is irradiated antistatic resinplastic disposable heads, although these are not suitablefor all models of air sampler and they are relativelyexpensive compared with re-using a head. The use ofmetal heads allows the heads to be sterilised viaautoclaving. Regular autoclaving of sampler heads isimportant, especially when an air sampler is transferredbetween areas of different cleanroom classes, and it is asensible practice when monitoring areas where theexpected recovery of airborne microorganisms is minimal(such as an EU good manufacturing practice (GMP)Grade A/ISO class 4.8 environment, as would be used forthe aseptic filling of medicinal products).

Outside of this, the autoclaving of heads is relativelyimpractical, especially when two or more samples need tobe taken from the same cleanroom. An alternative practiceis to decontaminate the head between sampling sessionsthrough the use of disinfectant. The choice of disinfectantis important. Some disinfectants will be unsuitable for thistask: they will corrode or causes ‘pitting’ of the metal(such as chlorine-based chemicals) or they might present asafety concern to the operator (as with chlorine andhydrogen peroxide). A safer alternative is 70% isopropylalcohol (IPA) or IUPAC 2-propanol with water, which arenon-toxic to the operator and do not present a skin orinhalation risk. Moreover, IPA is commonly used for thedisinfection of cleanroom gloves. A 70% volume/volumesolution in water is the recommended concentration foruse as a hand sanitiser18. Water is necessary to open upmembrane pores of bacteria; the opening of the poresfunctions as a gateway to allow the ingress of isopropyl,which is toxic to many bacteria19.

It is important to establish that the method ofdecontamination is effective at eliminating commoncleanroom microbiota20 and that it does not lead to theinhibition of microbial growth. This paper presents theresults of such an examination.

Materials and methodsFor the study, a Merck-Millipore MAS – 100 NT modelair sampler was used. With this device, air is aspiratedthrough a perforated lid and impacted onto the surface ofgrowth media. The sieve-like head of the sampler has300 x 0.6 mm holes. This type of sampler uses 90 mm agarplates.

The first part of the study was to determine that thedecontamination method was effective. With this, activeair samples were taken within a Grade D cleanroom. Thiscleanroom formed part of a wash-bay within apharmaceutical facility. Previous experience had shownthat this area contained a level of microorganisms with amean recovery of 50 colony forming units (CFU) percubic metre of air (below the EU GMP maximal value of200 CFU/m3, but sufficiently high to allow thedecontamination method to be assessed).

96 TIM SANDLE, RAVIKRISHNA SATYADA

In order to assess the decontamination, samples weretaken individually within the Grade D area. For this, 10samples of one cubic metre were collected ontomicrobiological culture media (tryptone soy agar with 1%glycerol) and incubated for 3 days at 20–25°C followed by2 days at 30–35°C (a dual incubation regime designed torecover bacteria and fungi).

The formulation of the agar was:

• pancreatic digest of casein (15.0 g),• enzymatic digest of soya bean (5.0 g),• sodium chloride (5.0 g),• agar (15.0 g),• glycerol (1g),• pH adjusted to 7.3 ± 0.2 @ 25°C.

Following sampling, the plates were removed andtransported for incubation. The air sampler head wasthen subjected to the decontamination step using 70%IPA. The decontamination step involved spraying theinside and outside of the head with the disinfectant andthen wiping down the surfaces with a sterile lint-free cleanroom wipe. The wiping process tookapproximately 5 seconds; with a 30-second contact timeapplied.

The sampler was then transported into a Grade A (ISOclass 4.8) environment within an isolator. Experience hasshown that the mean recovery of microorganisms was 0CFU/m3. The aim here was to determine ifmicroorganisms within the isolator were recovered and,if this was the case, whether there was similaritybetween the species recovered by comparing the isolatesusing microbiological identification with those found inthe Grade D area. The inference here was that if theGrade A results were 0 or 1 CFU/m3, then this isindicative of the decontamination process beingsuccessful; however, if the results were higher and therecovered organisms were similar, then this wasindicative that the decontamination procedure wasunsuccessful. For this assessment, the activity wasundertaken 10 times in order for the results to bereproducible. The method used to identify themicroorganisms was an automated phenotypic systemcalled OmniLog®21.

The second part of the study examined whether theprocess of decontamination affected the validity of theresults in terms of microbial inhibition. The risk with thedecontamination process was that residues of the 70% IPAcould remain and this could inhibit microbial growth,leading to the results obtained from the second use of theair sampler being invalid. This was assessed throughgrowth promotion.

For this study, the air sampler was decontaminatedusing the same procedure for the decontamination study:spraying the inside and outside of the head with thedisinfectant and then wiping down the surfaces with asterile lint-free cleanroom wipe. The wiping process tookapproximately 5 seconds. In order to assess the effect ofprolonged exposure to the disinfectant and to assessevaporation rates, the sampler was run for a standardvolume after different time points. At different time

points, agar plates were taken and subjected to growthpromotion testing. The time points selected were 30seconds, 60 seconds and 120 seconds.

To determine inhibition, the following microorganismswere used for growth promotion:

• Staphylococcus aureus (ATCC 6538)• Bacillus subtilis (ATCC 6633)• Pseudomonas aeruginosa (ATCC 9027)• Candida albicans (ATCC 10231)• Aspergillus brasiliensis (ATCC 16404)• Escherichia coli (ATCC 8739)• Staphylococcus epidermidis (Environmental isolate)

ATCC is a reference to the American Type CultureCollection. These microorganisms were selected becausethey are commonly used for the quality control testing ofculture media. They also form part of the recommendedUS and European Pharmacopoeia panel for methodsuitability testing for the sterility test and the qualificationof media used for the Microbial Limits Test. Theorganisms also covered a wide range of morphologicaltypes: Gram-positive coccus, Gram-positive rods, Gram-negative rods, yeast-like fungus, and filamentous fungus.In addition to these, the panel was complemented by anenvironmental isolate. This was S. epidermidis. Thisorganism was recovered from a cleanroom and it is ahuman skin commensurable.

With the growth promotion, agar plates at the differenttime points were challenged with not more than 100 CFUof each organism. The method used to inoculate the agarwas the spread plate method where 0.1 mL of thechallenge is deposited onto the agar plate and evenlyspread using a sterile implement across the agar surface.Control plates using agar not used in an air sampler wereprepared at the same time to verify the challenge count. Anegative control plate was performed with a sterilisedsieve. All agar plates were incubated at 20–25°C for 3days followed by 30–35°C for 2 days. The acceptancecriteria were as follows.

• No inhibition – test plates to be recovered within 50–200% of the control plates.

• Inhibition – failure of the test plates to recover themicrobial challenge within 50–200% of the controlplates.

• Negative control – no growth should be observed.

Results

Decontamination studyThe results from the decontamination study are shown inTable 1. The microbial counts obtained are summarised inTable 2. The results from the study show that thedecontamination method was effective. Nomicroorganisms were recovered from the air samplers runwithin the Grade A environment within the isolator.Because no microorganisms were recovered from theGrade A environment, no comparative identificationswere required.


Growth promotion studyTable 3 shows that each of the challenge microorganismswas recovered at each time point. The microbial controlcounts fell within the not more than 100 CFU target range.The recovery of the challenge count for each organism wasnot affected by the waiting time, as shown in Figure 1.

DiscussionFrom the results of the study, two things can be concluded.

a) The decontamination of impaction model air samplerheads with 70% IPA is effective in that contaminationis not transferred between sampling sessions.

b) The act of decontamination does not lead to theinhibition of microbial growth.

With the results obtained, considering the

decontamination part first, it should be noted that while 0counts were recorded within the Grade A area, the datarelates to a given cleanroom and to the variation ofmicroorganisms in the air at a particular time point. Pastexperience has shown that the cleanroom had a typicalairborne concentration of microorganisms of 50 CFU/m3.This was borne out with the results collected (mean count49 CFU/m3). What is not known is whether the samedecontamination effect would occur if higher counts wererecovered. A second limitation is with the types ofmicroorganisms recovered (n = 27). With this study, theoverwhelming majority of microorganisms were thosetransient or residential to human skin (see Table 4).

Although the profile is generally consistent with whichwill commonly be detected from cleanrooms20, thedecontamination step is limited by the types ofmicroorganisms recovered. Had, for example, highnumber of Bacillus species been recovered, then the

Table 1. Results of the decontamination study.

Sample Result from Grade D Identified microorganisms Result from Grade Anumber cleanroom (CFU/m3) (ISO class 4.8) isolator

environment (CFU/m3)

1 55 Kocuria rhizophilia, Micrococcus luteus, Staphylococcus 0arlettae, Staphylococcus warneri

2 40 M. luteus, Staphylococcus cohnii ss cohnii 0

3 12 M. luteus, Staphylococcus saprophyticus, Cladosporium spp. 0

4 20 K. rhizophilia, Rothia mucilaginosa 0

5 67 S. warneri, Staphylococcus epidermidis 0

6 101 M. luteus, S. arlettae, Micrococcus lylae, S. epidermidis 0

7 63 M. luteus, S. cohnii ss cohnii, Microbacterium maritypicum 0

8 42 M. lylae, Corynebacterium spp. 0

9 71 M. luteus, K. rhizophilia 0

10 17 M. luteus, M. lylae, S. epidermidis 0

Table 2. Descriptive statistics for the microbial counts obtained.

Sampling condition Range (CFU/m3) Mean count (CFU/m3) Standard deviation

Grade D cleanroom 12–101 49 28.1

Grade A (ISO class 4.8) isolator environment 0 0 0

Table 3. Results of the inhibition study, table displaying growth promotion counts (mean of two replicate tests).

Time Microorganism (CFU)

E. coli P. aeruginosa B. subtilis S. aureus A. brasiliensis C. albicans Environmentalisolate

(S. epidermidis)

30 seconds 41 43 44 40 38 44 45

60 seconds 44 45 46 44 42 41 48

120 seconds 42 45 50 46 39 46 42

Control plate 43 46 45 44 40 43 46count

98 TIM SANDLE, RAVIKRISHNA SATYADA

decontamination process may not have been as effective.IPA is not a sporicidal disinfectant. Although the recoveryof high numbers of Bacillus species would be a sign of aproblematic cleanroom or production process, it would beprudent should this occur with regularity, to considerautoclaving the air sampler head.

With the inhibition study, the results showed that theusage of 70% IPA and the method of decontaminatingthe head did not cause microbial inhibition. Similarlevels of recovery of the challenge organisms wereobserved across the three time points. While this part ofthe study was satisfactory and the results consistent,further studies could be attempted using moreenvironmental isolates. In addition, other methods ofdecontamination could be attempted (such as the use of apre-saturated cleanroom wipe). A further variable is the

time taken for the 70% IPA to evaporate. The time pointsused in this study – 30 to 120 seconds – may needmodifying in different cleanrooms with different rangesof relative humidity.

In drawing the two sets of observations together, themethod of running the air sampler appears to be sufficientto decontaminate it and leaves the air sampler with littleresidue of disinfectant (or at least a sufficiently low levelof disinfectant) so as not to cause inhibition of the growthof a range of microorganisms.

Whether the results would extend to other types of airsampler heads, such as centrifugal samplers, is unknown.The study described in this paper used impaction headswith sieve-like holes. Given the method of application(wiping) and the expected profile of microorganisms,there is a strong likelihood that similar results would be

Table 4.Microorganisms recovered that are transient or residential to human skin.

Recovered genera Number recovered Proportion of isolates (as a percentage)

Micrococcus 10 37%

Staphylococcus 10 37%

Kocuria 3 11%

Corynebacteria 1 4%

Cladosporium 1 4%

Microbacterium 1 4%

Rothia 1 4%

Per

cent

age

reco

very

120

100

80

60

40

20

0

30 seconds 60 seconds 120 seconds

Microorganism

Environmentalisolate

E. coli P. aeruginosa B. subtilis S. aureus A. brasiliensis C. albicans

Figure 1. Chart showing percentage recovery of the challenge microorganisms across three time points.


obtained. However, this would require separateassessment.

It also cannot be inferred that other alcohols, such asethanol or IPA at different concentrations, would achievethe same level of microbial kill. In terms of these twotypes of alcohol, earlier studies have shown IPA to beslightly more bactericidal than ethanol when measuredagainst some bacteria22,23. Based on this, the use of ethanolshould be assessed separately. With concentration, theoptimum bactericidal concentration, for both ethyl alcoholand IPA is 60%–90% solutions in water(volume/volume)18. A 70% concentration is a standardpreparation for pharmaceuticals and healthcare.

Therefore, the method of decontamination is effective.In practicing such measures, it is important that there isconsistency of practice, in terms of the volume of 70% IPAapplied and the run time. It is also important that heads areautoclaved periodically between disinfection sessions.This interval will need to be determined by the user andsuch a practice is recommended if samplers are removedfrom cleanrooms for service or calibration, and whentransferring samplers between different cleanroom grades.

References1. Sandle T. Contamination control risk assessment. In Contamination

Control in Healthcare Product Manufacturing, Volume 1, MasdenRE and Moldenhauer J, Eds. River Grove, IL, USA: DHIPublishing; 2013, pp. 423–474.

2. Sandle T. Cleanroom design. In Environmental Monitoring: aComprehensive Handbook, Volume 7, Moldenhauer J, Ed. RiverGrove, IL, USA: DHI Publishing; 2015, pp. 3–28.

3. Sandle T, Leavy C and Rhodes R. Assessing airborne contaminationusing a novel rapid microbiological method. European Journal ofParenteral & Pharmaceutical Sciences 2014;19(4):131–142.

4. Sandle T. Selection of active air samplers. European Journal ofParenteral and Pharmaceutical Sciences 2010;15(4):119–124.

5. Der EF, Stablein JP and Coleman DA. Comparative evaluation ofthree active air samplers. Pharmaceutical Technology 2006;April:110–116.

6. Noble NH. Validation of environmental monitoring methods andlevels. PDA Journal of Pharmaceutical Science and Technology1993;47:26–28.

7. Ljungqvist B and Reinmuller B. Monitoring efficiency ofmicrobiological impaction air samplers. European Journal ofParenteral Sciences 2008;13(4):93–97.

8. De Abreu C, Pinto T and Oliveira D. Environmental monitoring: acorrelation study between viable and nonviable particles in cleanrooms. Journal of Pharmaceutical Science and Technology2004;58(1):45–53.

9. Whyte W, Green G and Albisu A. Collection efficiency and designof microbial air samplers. Journal of Aerosol Science 2007;38:101.

10. Whyte W, Green G and Albisu A. Collection efficiency and designof microbial air samplers. Journal of Aerosol Science2007;38(1):97–110.

11. Buttner MP and Stetzenbach LD. Monitoring airborne fungal sporesin an experimental indoor environment to evaluate samplingmethods and the effects of human activity on air sampling. AppliedEnvironmental Microbiology 1993;59(1):219–226.

12. Ljungqvist B and Reinmuller B. The sampling of airborne viableparticles in controlled environments: comparative study of commoninstruments. European Journal of Parenteral Sciences1998;3(3):59–62.

13. Turner AG and Hill NF. Calibration of the Anderson 2000disposable air sampler. American Industrial Hygiene AssociationJournal 1975;36(6):447–451.

14. Ljungqvist B and Reinmuller B. The biotest RCS air samplers inunidirectional flow. Journal of Parenteral Science and Technology1994;48(1):41–44.

15. Sandle T. Examination of the order of incubation for the recovery ofbacteria and fungi from pharmaceutical cleanrooms. InternationalJournal of Pharmaceutical Compounding 2014;18(3):242–247.

16. Ljungqvist B and Reinmuller B. Interaction between air movementsand the dispersion of contaminants: clean zones with unidirectionalair flow. Journal of Parenteral Science and Technology1993;47(2):60–69.

17. Probert S, Sinclair CS and Tallentire A. Air sampling for use inmonitoring viable and non-viable particulate air quality underdynamic operating conditions of blow/fill/seal processing. PDAJournal of Pharmaceutical Science and Technology 2002;56:267–276.

18. Ali Y, Dolan MJ, Fendler EJ and Larson EL. Alcohols. InDisinfection, Sterilization, and Preservation, Block SS, Ed.Philadelphia, PA, USA: Lippincott Williams & Wilkins; 2001, pp.229–254.

19. Morton HE. The relationship of concentration and germicidalefficiency of ethyl alcohol. Annals of the New York Academy ofScience 1950;53:191–196.

20. Sandle T. A review of cleanroom microflora: types, trends, andpatterns. PDA Journal of Pharmaceutical Science and Technology2011;65(4):392–403.

21. Sandle T, Skinner K, Sandle J, Gebala B and Kothandaraman P.Evaluation of the GEN III OmniLog® ID system microbialidentification system for the profiling of cleanroom bacteria.European Journal of Parenteral & Pharmaceutical Sciences2013;18(2):44–50.

22. Coulthard CE and Sykes G. The germicidal effect of alcohol withspecial reference to its action on bacterial spores. PharmaceuticalJournal 1936;137:79–81.

23. Morton HE. Alcohols. In Disinfection, Sterilization, andPreservation, Block SS, Ed. Philadelphia, PA, USA: Lea & Febiger;1983, pp. 225–239.

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Science and Technology Feature

*Corresponding author: Catinka Ullmann, Industri Ventilator AB, Stockholm, Sweden; Email:[email protected]

Catinka Ullmann1,2*, Bengt Ljungqvist2 and Berit Reinmüller21 Industri AB Ventilator, Stockholm, Sweden2 Building Services Engineering, Chalmers University of Technology, Göteborg, Sweden

Clean areas used for aseptic manufacturing of sterile medicinal products are subject to governmentalrequirements and guidelines in order to minimise risks of particulate and microbiologicalcontamination. High cleanliness is also a necessity in hospital environments to ensure safe conditionsfor the patients. The requirements for premises within the pharmaceutical industry are compared tothose of the hospital, e.g. operating rooms including environmental monitoring with a focus on particleand microorganism levels.

Key words: Environmental monitoring, ultraclean air operating room, aseptic sterile production area.

Requirements and environmental monitoring inpharmaceutical production versus operatingrooms in hospitals with focus on airborne particlesand microorganisms

IntroductionThe safety of the patient is the main focusfor both the pharmaceutical industry andthe operating room. The distinctionbetween the branches is theconsequences of one single failure oraccident. For the pharmaceuticalindustry, one single failure might affect alarge number of people, whereas a failurein the operating room might affect onlyone person, the patient. However, overtime, lack of necessary cleanliness maycause serious harm to many patientswithin healthcare and it is always atragedy for each single person regardlessof how many people suffer from a failure.The requirements for environmentalmonitoring within the pharmaceuticalindustry are based on standards,guidelines and risk assessments. Thescope, threshold limits and appropriate

test intervals for environmentalmonitoring within hospitals are generallynot developed compared to those of thepharmaceutical industry and they mayalso vary between different hospitals.This paper compares the pharmaceuticalindustry and the Swedish operatingrooms with a focus on cleanlinessrequirements (airborne particles andmicroorganisms) for premises, includingenvironmental monitoring. Premises foraseptic production, Grade B areas, in thepharmaceutical industry and ultracleanair operating rooms for surgery prone toinfection – such as orthopaedic surgery –in hospitals have been chosen for thiscomparative study.

PremisesThe following premises and theirconditions were compared.

Aseptic production areas in thepharmaceutical industryGrade B is the background environmentfor a Grade A zone, where asepticallyproduced sterile products are filled andclosed. The air in a Grade B area ishigh-efficiency particulate air (HEPA)-filtered and the movements of the airare turbulent mixing. Entry and exit to the Grade B room isthrough airlocks for personnel andseparate airlocks for equipment andmaterials. Operators in Grade B wearsterile cleanroom garments, hood,coverall, cleanroom socks, long boots,gloves and high quality face masks,and these would be sterile newclothing systems for each entry.

Ultraclean air operating rooms (Premises used for orthopaedic surgeryare also described as ultraclean airoperating rooms. Orthopaedic surgeryis normally classified as an infection-prone surgery and maintaining high

REQUIREMENTS AND ENVIRONMENTAL MONITORING IN PHARMACEUTICAL PRODUCTION VERSUS OPERATING ROOMS 101

cleanliness in the operating room is,therefore, very important.Today, ultraclean air operatingrooms are supplied with HEPA-filtered air and often equipped with aunidirectional airflow ceiling, seeFigure 1. However, there are alsoultraclean air operating rooms wherethe movements of the air areturbulent mixing, see Figure 2. Entry into and exit from theoperating rooms are seldom throughan airlock. The layout variesbetween different hospitals; someoperating rooms are directly adjacentto a corridor, often against an outerwall. There are often doors to thepreparation room and the corridor.Sterile equipment is taken into theoperating room through the doorbefore the start of surgery; duringongoing surgery, transport ofmaterial is through a locker. Duringsurgery, all staff in the operatingroom wear non-sterile clean air suits(trousers and blouse with cuffs and adisposable hood), gloves and facemasks. Furthermore, the surgicalteam wear sterile gowns, and extragloves.

Requirements andguidelines The manufacturing ofpharmaceutical products is controlledby governmental requirements andguidelines. Good manufacturingpractice (GMP) provide guidance formanufacturing and ensures thatproducts are consistently producedand monitored to the qualitystandards appropriate to theirintended use and as required by themarketing authorisation. The EUGuidelines to Good ManufacturingPractice – Medicinal Products forHuman and Veterinary Use. Annex 1– Manufacture of Sterile MedicinalProducts1 is valid in all countries thatare part of the European Union.Cleanliness requirements (airborneparticles and microorganism) forultraclean air operating rooms and theprocedure for environmentalmonitoring differ between countries inEurope. For example, in Sweden thelevels of airborne particles and colonyforming units (CFUs) are monitoredduring ongoing surgery in theoperating room while other countriesmonitor the operating rooms at rest.

The SIS TS 39:2015. MicrobiologicalCleanliness in the Operating Room –Preventing Airborne Contamination– Guidance and FundamentalRequirements2 is the Swedishtechnical specification for microbialcleanliness in operating rooms andthe specification has some similaritiesto the EU Guidelines to GMP.

Airborne particles andmicroorganisms –requirements andguidance levelsThe EU Guidelines to GMP1 givesinformation/directions/requirementsof limits and levels for airborneparticles and CFUs for environmentswithin the pharmaceutical industry.For the background environment ofaseptic preparation and filling, theGrade B area, the limit for microbialcontamination is ≤10 CFU/m3. Therecommended level for microbialcleanliness for ultraclean air operatingrooms is the same as for Grade Benvironments in the pharmaceuticalindustry, i.e. ≤10 CFU/m3. This levelshould not be exceeded during anongoing operation.

Figure 1. Operating room with unidirectional airflow.

102 CATINKA ULLMANN, BENGT LJUNGQVIST, BERIT REINMÜLLER

Limits for maximum permittedairborne particles do not exist for theoperating room, unlike for the GradeB environment where maximumpermitted airborne particles arespecified for two different particlesizes at rest and in operation. Table 1summarises the differentrequirements of Grade B areas andultraclean air operating rooms.In addition to the recommendation ofairborne microbial cleanliness, theSwedish technical specification, SIS-TS 39:20152, also provides guidance

for the design of operating rooms(layout and heating, ventilation andair conditioning), environmentalmonitoring, garments systems,cleaning, etc.

Environmental monitoringThe purpose with periodicalenvironmental monitoring is toconsistently, over time, showcompliance of environmentalrequirements. The main tests aremeasurements of airborne particles

and microorganisms. In the SIS TS39:20152, there are also someadditional technical tests that oughtto be performed in order to assure theenvironmental conditions.According to the EU Guidelines toGMP1, the monitoring of airborneparticles should frequently beperformed both at rest and inoperation, i.e. during themeasurement, the area should be withand without personnel present. Therequirements for microbialcleanliness are valid during operation

Figure 2. Operating room with turbulent mixing air

Table 1. Summary of the limits for a Grade B environment (EU Guidelines to GMP1) and ultraclean air operating rooms (SIS-TS39:20152) regarding airborne particles and microbial contamination.

Airborne contaminant Grade B (background environment Ultraclean air for aseptic preparation and operating room filling in a Grade A zone)

At rest (maximum permitted particles/m3)≥0.5 µm 3520 3520≥5 µm 29 29

CFU/m3 Not defined ≤1

Operational (maximum permitted particles/m3)≥0.5 µm 352,000 Not defined≥5 µm 2900 Not defined

CFU/m3 10 10

REQUIREMENTS AND ENVIRONMENTAL MONITORING IN PHARMACEUTICAL PRODUCTION VERSUS OPERATING ROOMS 103

but usually in the pharmaceuticalindustry the monitoring ofmicroorganism controls arefrequently performed both in at restconditions and when operational.The technical controls should also beperformed on a frequent basis.Visualisation of airflow patterns incritical areas and recovery tests areperformed before a new or a rebuiltarea is used.

Discussion Is it possible to accomplish andmaintain the same airbornecleanliness when the differences inactivities in the compared premisesare much greater than thesimilarities?A common remark within thehospital is that it is not possible toapply cleanroom requirements andtransfer experience and knowledgefrom pharmaceutical production tothe ultraclean air operating room.There are several parameters thatdiffer between the areas, forexample, the layout, surfacematerials, type and amount ofequipment in the room, the quantityof personnel present in the room,gowning requirement, and workingprocedures. But the fundamentalconditions are the same for bothtypes of clean environment andprocesses; they require highdemands of cleanliness (the

microbial air cleanlinessrequirements/recommendations arethe same) and the procedures(infection-prone surgery and asepticsterile production) can both bedefined as a kind of asepticprocessing. The question should,therefore, instead be; could thesafety of the patient within theultraclean air operating roomincrease by adopting appropriatecleanliness knowledge andexperience from the pharmaceuticalindustry?It seems to be a general reluctancewithin the hospital to adopt newprocedures. Changes and upgradingwithin the pharmaceutical industryare based on risk assessment and thechanging process is usually fast.Within hospitals, changes andupgrades mostly have an evidence-based approach and the changingprocess seems to be slower than thatof the pharmaceutical industry. The requirements for thepharmaceutical industry have beenadopted for one kind of processwithin hospitals; the areas used forthe processing of human tissues andcells should fulfil the requirementsfor airborne particles andmicroorganisms according to limitsspecified in the EU Guidelines toGMP1 according to EuropeanDirectives4,5.For hospital pharmacies, the EUGuidelines to GMP1 for the

pharmaceutical industry is alsoapplicable.

References1. European Commission. EudraLex. The

Rules Governing Medicinal Products inthe European Union. Volume 4: EUGuidelines to Good ManufacturingPractice – Medicinal Products for Humanand Veterinary Use. Annex 1 –Manufacture of Sterile MedicinalProducts. Brussels, Belgium: EuropeanCommission; 2008.

2. Swedish Standards Institute. SIS TS39:2015. Microbiological Cleanliness inthe Operating Room – PreventingAirborne Contamination – Guidance andFundamental Requirements. Stockholm,Sweden: SIS; 2015.

3. International Standards Organization.EN/ISO 14644-3:2005. Cleanrooms andAssociated Controlled Environments –Part 3: Test Methods. Geneva,Switzerland: ISO; 2005.

4. The European Parliament and the Councilof the European Union. Directive2004/23/EC of the European Parliamentand of the Council of 31 March 2004 onsetting standards of quality and safety forthe donation, procurement, testing,processing, storage and distribution ofhuman tissues and cells. Official Journalof the European Union 2004;7 April:48–58.

5. The Commission of the EuropeanCommunities. Commission Directive2006/17/EC of 8 February 2006implementing Directive 2004/23/EC ofthe European Parliament and the Councilas regards certain technical requirementsfor the donation, procurement and testingof human tissues and cells. OfficialJournal of the European Union 2006;9February:40–52.

Table 2. Example of environmental monitoring methods mentioned in the EU Guidelines to GMP1 for Grade B areas and in the SIS TS39:20152 for operating rooms.

Test Description

Airborne particles Active sampling of airborne particles/m3

Airborne viable particles Active sampling of airborne viable particles, CFU/m3

Supply airflow/air changes Measurement of supply airflow/calculation of the number of air changes related to the supply airflow and the volume of the roomPressure difference Pressure difference between different areas with closed doorsLeakage test of HEPA-filter Installed filter leakage test according to the ISO 14644-3:2005 Test Methods3

Air velocity Determination of air velocity in unidirectional airflow according to the ISO 14644-3 Test Methods3

Ingress of air in clean zone Challenge test of the ingress of airborne particles into the clean zoneAirflow patterns Visualisation of airflow patterns in critical areasRecovery test Determine the “clean up” period in an unmanned state after completion of operations (based on particle limits) according to the ISO14644-3 Test Methods3


Regulatory Review

IntroductionSadly, in this edition, we report on legal actions taken againsttwo UK-based companies following supply of defectivemedicines, one of which resulted in the death of a patient.There is also a report of the shut down by regulators of aEuropean Union (EU) manufacturing facility for goodmanufacturing practice (GMP) violations. Developments inthe “regulation” of the pharmaceutical industry since our lastreview include the following.

Europe• Medical Devices – proposal for a regulation of theEuropean Parliament and of the Council

• Fast track routes for medicines that address unmet medicalneeds

• Concept paper on new guidance for importers of medicinalproducts (new Annex 21)

• TxCell manufacturing facility in Besançon, France shutdown following inspection by the French Agence Nationalede Sécurité du Médicament et des Produits de Santé(ANSM)

• UK-based companies sentenced for supplying hospitalswith defective pre-filled syringes

• Medicines and Healthcare Products Regulatory Agency(MHRA) to fully adopt use of the common repository forcentralised procedures

• New MHRA Inspectorate blog• MHRA blog – Inspecting clinical trials – the trial masterfile (TMF)

• MHRA advises the Cell Therapy Catapult on emergingclinical grade induced pluripotent stem (iPS) cells bankregulation

• MHRA helps to future-proof mammalian cell culturemanufacturing facility

• MHRA 2015/16 business plan • MHRA seeking views on draft guidance on re-manufactureof single-use devices

• Verification for authentication of medicines in Europe• EU good distribution practice (GDP) guidelines valid inSwitzerland

• EU and Swiss regulators sign confidentiality arrangement

USA• Request for Quality Metrics – Guidance for Industry• Allowable Excess Volume and Labelled Vial Fill Size inInjectable Drug and Biological Products

• Size, Shape, and Other Physical Attributes of GenericTablets and Capsules

• Dissolution Testing Immediate-Release Solid Oral DosageForms Containing Biopharmaceutics

• Botanical Drug Development• Guidance – For Entities Considering Whether to Registeras Outsourcing Facilities Under Section 503B of the FederalFood, Drug, and Cosmetic [FD&C] Act

• Endotoxin Testing Recommendations for Single-UseIntraocular Ophthalmic Devices (IODs)

• Food and Drug Administration (FDA) warns aboutprescribing and dispensing errors resulting from brandname confusion

• Analytical Procedures and Methods Validation for Drugsand Biologics

• Naming of Drug Products Containing Salt Drug Substances• Pregnancy, Lactation, and Reproductive Potential:Labelling for Human Prescription Drug and BiologicalProducts

• USP <671> Containers – Performance Testing: Use ofWater-Filled Test Containers for Water VaporTransmission Rate Determinations

International• National strategy and plan of action for pharmaceuticalmanufacturing development in Ethiopia (2015–2025)

International Conference on Harmonisation (ICH)• ICH Q7 Q&As

Products• Many addictive drugs lacked statutory packaging seal• First malaria vaccine receives positive scientific opinionfrom European Medicines Agency (EMA)

Europe

European Commission (EC)

Medical Devices – proposal for a regulation of theEuropean Parliament and of the CouncilFollowing on from the Poly Implant Prothèse breast implantscandal, this revised proposal would, if adopted, amendDirective 2001/83/EC, Regulation (EC) No 178/2002 andRegulation (EC) No 1223/2009. Of particular interest toreaders might be Article 13, which refers to the requirementfor and duties of the “Person responsible for regulatorycompliance” (this was the qualified person (QP) in the initialdraft).This section requires, amongst other things, that

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manufacturers shall have available within theirorganisation, at least one person responsible for regulatorycompliance activities who possesses expert knowledge inthe field of medical devices. The expert knowledge shallbe demonstrated by either of the following qualifications.

• A diploma, certificate or other evidence of formalqualification awarded on completion of a universitydegree or of a course of study recognised as equivalentby the Member States concerned, in medicine,pharmacy, engineering or another relevant discipline ofsciences, and at least 2 years of professional experiencein regulatory affairs or in quality management systemsrelating to devices.

• Professional experience of 5 years in regulatory affairsor related to devices, including experience in qualitymanagement systems relating to medical devices.

It is formally stated that “The person responsible forregulatory compliance shall suffer no disadvantage withinthe manufacturer’s organisation in relation to the properfulfilment of his duties”.

EMA

Fast track routes for medicines that address unmetmedical needsThe EMA has revised its guidelines on the implementationof accelerated assessment and conditional marketingauthorisation, two key tools in the European legislation toaccelerate patients’ access to medicines that address unmetmedical needs.The public consultations on the revised guidelines are

open until 30 September 2015. Accelerated assessment andconditional marketing authorisation are intended forinnovative medicines that target a disease for which notreatment is available, or that provide patients with a majortherapeutic advantage over existing treatments.Based on the experience gained in implementing

accelerated assessment and conditional marketingauthorisation in recent years and taking into accountdiscussions on the optimisation of the use of these tools atthe European Commission Expert Group on Safe andTimely Access to Medicines for Patients (STAMP), theEMA has revised its guidelines to improve these existingframeworks. The updated guidelines are expected tooptimise the use of these tools by medicine developers andconsequently allow more medicines that address unmetmedical needs to reach patients earlier.

Concept paper on new guidance for importers ofmedicinal productsThe increased complexity of supply chains and theobservation that most GMP non-compliance statementsuploaded into EudraGMDP pertain to third countrymanufacturers have created new areas where furtherguidance is desired by both the regulators and the industry.In particular, the requirements applicable to importers ofmedicinal products and concerning the application of GMPrequirements, which are traditionally orientated to activities

performed at true manufacturing sites.Importation of a pharmaceutical finished product

manufactured in a third country requires amanufacturer/importer licence (MIA), for the site whereQP certification occurs and the site that imports and teststhe batch. Associated with import testing are some otheraspects, such as sampling and the segregation between the‘physical importation site’ versus ‘testing and/or batchrelease site’, that have become issues subject to discussionby regulators wishing to agree a harmonised approachacross the EU.Annex 16, Certification by a Qualified Person and Batch

Release, has been revised to, among other matters, addressQP involvement when the testing site is not the releasingsite. Additionally, the term ‘import’ can be particularlycomplex in the context of global commercial activities andthere may be little-known implications in this regard evenwhen the physical location of medicinal products remainswithin the EU.In view of these issues the GMP/GDP Implementation

Working Group (IWG) agreed to draft a specific guidancefor import authorisation holders. This document most likelywould take the form of a new annex (Annex 21). The scopeof the project will be focused on importation activities notaddressed in detail in the GMP guide and annexes.

TxCell manufacturing facility in Besançon, Franceshut down following inspection by the French ANSMA non-compliance report has been published in theEudraGMDP Database for this facility. The action taken issuspension of manufacturing operations of new batches,including release and distribution, suspension of releaseand distribution of pending batches, suspension ofdistribution of released batches. The agency reported that22 deficiencies were observed, including 7 majordeficiencies.

(This serves as a reminder that EU regulatoryauthorities will not hesitate to take action againstmanufacturers when serious GMP deficiencies are notedat inspection – MH.)

MHRA

Companies sentenced for supplying hospitals withdefective pre-filled syringesA major healthcare company and a sister company that solda range of ready-to-use pharmaceutical products itmanufactured have been sentenced for supplying hospitalswith defective pre-filled syringes that contributed to thedeath of a diabetic patient. A patient died at the NorthernGeneral Hospital in Sheffield in November 2010 afterbeing treated with a batch of intravenous insulin syringesthat actually contained no insulin. The patient sufferedmulti-organ failure triggered by a serious episode ofdiabetic ketoacidosis because his body was deprived ofinsulin for more than 13 hours. The faulty syringes were supplied to Sheffield Teaching

Hospitals NHS Foundation Trust by Fresenius Kabi Ltd asa licenced wholesaler for Calea UK Ltd, whichmanufactured the product. Both companies, based at thesame address in Runcorn, Cheshire, were fined at Sheffield

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Crown Court (9 July 2015) after being prosecuted by theMHRA. Fresenius Kabi was convicted for its role in a‘medicinal failure’ that a coroner had earlier ruled was a‘major contributory factor’ in the death of the patient.The court heard that supplying faulty syringes wasn’t

an isolated incident and that Calea also manufactured abatch of pre-prepared Tobramycin syringes – used to treatinfections – that were administered to a patient with cysticfibrosis at the Royal Shrewsbury Hospital in August 2011.On this occasion, the syringes, which were prepared anddelivered direct for the patient by Calea, were each foundto contain three times the prescribed daily dose. The overmedication came to light after the patient reported anadverse reaction, although there were no lasting effects.The court was told the two incidents followed a series

of inspections by MHRA officials that highlighteddeficiencies at the Runcorn site where Calea and FreseniusKabi operated. They included concerns that there was noinvestigation regime in place to identify potential defectsand prevent future recurrence when defective productswere detected. Fresenius Kabi Ltd, of Eastgate Way, Manor Park,

Runcorn, was fined a total of £500,000 and ordered to paya further £5900 in costs after pleading guilty to breachingSections 64(1) and 67(2) of the Medicines Act 1968. CaleaUK Ltd, of the same address, was fined £50,000 with£5900 costs after also pleading guilty to similar breaches.

(Thankfully we do not often see cases where GMPfailures bring about such tragic consequences. This, likethe previous item, should serve as a reminder to companiesfalling under MHRA jurisdiction that EU regulators eithercentrally and nationally will not hesitate to takeenforcement action in such cases – MH.)

MHRA to fully adopt use of the common repositoryfor centralised proceduresFrom 1 July 2015, centralised applications submitted to thecommon repository do not need to be sent separately to theMHRA. Any centralised submission received directly bythe MHRA after this date will not be processed and will bedisposed of securely.

New MHRA Inspectorate blogThe MHRA Inspectorate blog is aimed at thoseorganisations that are inspected by the MHRA and need tokeep up to date with the latest thinking and guidelines. Itwill give MHRA inspectors a chance to speak directly tothe organisations they inspect and get feedback from themon topics they would like to hear more about. Areas theblog will cover include the following.

• Compliance management approaches.• Data integrity.• Preventing drug shortages.• Significant findings from MHRA inspections.• Supporting innovation and work with the MHRAInnovation Office.

• Upcoming learning opportunities.

The first article, from Mark Birse, Group Manager of theInspectorate at the MHRA, introduces the new platform

and gives users an idea of what to expect from the blog.

MHRA blog: Inspecting clinical trials – the TMFThe TMF is the collection of essential documents whichallows the conduct of a clinical trial to be reconstructed andevaluated. It is basically the story of how the trial wasconducted and managed. This blog highlights some of theissues which have been experienced by sponsors andinspectors attempting to manage and review the largeamounts of documentation that exist in support of a trial.

MHRA advises the Cell Therapy Catapult onemerging clinical grade iPS cells bank regulationUsing iPS cells in new therapeutic products is an excitingnew development, which sees medicine go beyond itstraditional boundaries. iPS cells are developed by takingspecialised adult dividing cells (e.g. skin cells) and‘reprogramming’ them back to stem cells. These stem cellsare considered to be ‘pluripotent’, meaning that they canbe used to make any type of cell in the body. The MHRAhelped the organisation as follows.

• Providing advice on the standard required forprocurement of cells from outside the UK for use as astarting material for advanced-therapy medicinalproducts which will meet European regulatoryrequirements.

• Reviewing global advice on iPS cell lines to providepragmatic solutions to quality control issues, such assuitable release strategy and stability programmes.

• Advising on suitable characterisation, preclinical andclinical testing for the iPS bank and products derivedfrom it – this is particularly challenging for thedeveloper as it requires raw materials and methods thatare not part of conventional GMP processes.

MHRA helps to future-proof mammalian cell culturemanufacturing facilityFujifilm involved the MHRA early on to meet regulatoryexpectations to reduce risk of any late or costly changes.They wanted to include as much feedback from the MHRAinto the design of the facility as possible. The process for the manufacture of this cell culture is

the basis for developing and manufacturing monoclonalantibodies as well as other biotechnology products thattackle illnesses, such as cancer and heart conditions. Suchbiopharmaceuticals contract manufacturing operations areseen as a growth area for the company. The MHRA helpedFujifilm meet its goals of future-proofing the design of thenew facility, including against potential changes inregulations that could have subsequently cost significanttime, and lost revenue. Experts at the MHRA helped thecompany think through the project as follows.

• Reviewing the facility layout and providing steer for“future proofing” the layout in anticipation of potentialchanges and updates to the regulatory landscape.

• Confirming regulatory expectations for qualification ofthe facility and the process equipment based on using asingle-use technology platform throughout themanufacturing chain.


• Advising on appropriate cleanroom classificationsbased on process risk profile.

MHRA 2015/16 business planThe plan highlights the key areas where the MHRA willfocus its efforts this year, and supports the delivery of its2013/18 Corporate Plan.

MHRA seeking views on draft guidance on re-manufacture of single-use devicesA number of manufacturers who have a CE mark for a re-manufactured single-use device (SUD) want to put themon the market in the UK. These companies have been re-manufacturing SUDs for a number of years and suchdevices are widely used in some countries. Over the last 2years, the MHRA has carried out a detailed review of re-manufacturers, assessing their technical, regulatory andclinical processes.Following the review, the MHRA has developed a draft

guidance document on re-manufacturing SUDs andexpectations around their use for:

• healthcare professionals,• manufacturers, and • any provider of medical devices.

The draft document is now available for review and theMHRA is seeking comments, which will be taken intoaccount when finalising the guidance.

European trade organisations

Verification for authentication of medicines in EuropeThrough the engagement of the whole pharmaceuticalsupply chain and with the support of new partners, theEuropean Medicines Verification Organisation (EMVO)has taken a major step to secure the legitimate supply chainand to prevent falsified medicines from reaching patients.The EMVO believes that the agreement with new partnersbrings them a step forward in the fight against falsifiedmedicines and would like to encourage nationalstakeholders to follow suit and sign up by establishingNational Medicine Verification Organisations, and signingup with one of the EMVO selected service providers.

(Note: the EMVO is a not-for-profit organisation basedin Luxembourg set up by five European Tradeorganisations – EU regulators are not members of EMVO– MH.)

Switzerland

EU GDP guidelines valid in SwitzerlandThe EU Guidelines on Good Distribution Practice ofMedicinal Products for Human Use became effective in theEU Member States on 8 September 2013. It was unclear,however, what validity these guidelines have inSwitzerland within the framework of the EU–Swiss MutualRecognition Agreement (MRA). The EU GDP guidelinesbecame effective in Switzerland on 1 July 2015 with a 6-month implementation period.

EU and Swiss regulators sign confidentialityarrangementThe EC’s Directorate General for Health and Food Safety(DG SANTE) and the EMA have agreed with the SwissAgency for Therapeutic Products (Swissmedic) and theSwiss Federal Department of Home Affairs to share non-public information on the safety, quality and efficacy ofmedicines, already authorised or under review, both inSwitzerland and in the EU in order to enhance public healthprotection.The arrangement supports efforts by European and

Swiss regulators to improve the oversight of medicines forhuman and animal health. The arrangement builds on aprevious cooperation of the EMA and Swissmedic duringthe 2009/2010 H1N1 pandemic and on the MRA signed in2002. The arrangement came into effect on 10 July 2015,it is valid for 5 years and may be renewed.

USA

The US FDA

Request for Quality Metrics – Guidance for IndustryThis draft guidance includes an explanation of how theCenter for Drug Evaluation and Research (CDER) and theCenter for Biologics Evaluation and Research (CBER)intend to collect data and use quality metrics to help ensurethat their policies and practices continue to supportcontinuous improvement and innovation in thepharmaceutical manufacturing industry.Quality metrics are used throughout the pharmaceutical

industry to monitor quality control systems and processesand drive continuous improvement efforts in drugmanufacturing. These metrics can also be used by the FDA:to help develop compliance and inspection policies andpractices, such as risk-based inspection scheduling of drugmanufacturers; to improve the Agency’s ability to predict,and, therefore, possibly mitigate, future drug shortages; andto encourage the pharmaceutical industry to implementstate-of-the-art, innovative quality management systemsfor pharmaceutical manufacturing.This guidance outlines the FDA’s authority to require

owners and operators of establishments involved in themanufacture, preparation, propagation, or processing ofhuman drugs, including oversight to ensure quality, offinished dosage forms of covered drug products or activepharmaceutical ingredients (APIs) used in the manufactureof covered drug products, to provide upon request recordsand information to the FDA.Manufacturers can expect that reported quality data may

be verified during on-site inspections. If inconsistencies areidentified, the integrity of the report may be questioned andused as an additional factor in the FDA risk-based or for-cause inspection scheduling. The failure to report requested quality data may elevate

an establishment’s predicted risk in FDA’s prioritisation ofinspections and may lead to an earlier inspection. Inaddition, products associated with an establishment thatdoes not report as required may be deemed adulterated andsubject to enforcement action. Data to be reported would


include the following.

• The number of lots attempted of the product.• The number of specification-related rejected lots of theproduct (rejected during or after manufacturing).

• The number of attempted lots pending disposition formore than 30 days.

• The number of out-of-specification (OOS) results forthe product, including stability testing.

• The number of lot release and stability tests conductedfor the product.

• The number of OOS results for lot release and stabilitytests for the product which are invalidated due tolaboratory error.

• The number of product quality complaints received forthe product.

• The number of lots attempted which are released fordistribution or for the next stage of manufacturing theproduct.

• If the associated Annual Product Reviews (APRs) orProduct Quality Reviews (PQRs) were completedwithin 30 days of annual due date for the product.

• The number of APRs or PQRs required for the product

Allowable Excess Volume and Labelled Vial Fill Sizein Injectable Drug and Biological ProductsThis guidance provides the pharmaceutical industry withthe CDER’s and CBER’s current thinking on allowableexcess volume and labelled vial fill size in injectable drugand biological products. It replaces the draft of the samename that was published on 14 March 2014. Specifically,the guidance clarifies the FDA regulatory requirements andrecommendations pertaining to allowable excess volumein injectable vials and describes when justification isneeded for a proposed excess volume in these injectabledrug products. This guidance also discusses the importanceof appropriate fill volumes for injectable drug products andrecommends that labelled vial fill sizes be appropriate forthe intended use and dosing of the drug product. The guidance also addresses withdrawable volume and

labelled vial fill size for injectable drug products that arepackaged in vials and ampules, including products thatrequire reconstitution. It does not address injectable drugproducts in other packaging types (e.g. pre-filled syringepackage systems and intravenous infusion bags) or non-injectable products, because there may be uniqueconsiderations for these packaging configurations. Therecommendations in this guidance apply to new drugapplications (NDAs), abbreviated new drug applications(ANDAs), biologics license applications (BLAs), as wellas supplements or other changes to these applications fornew packaging or other changes that may affect the fillvolume.

Size, Shape, and Other Physical Attributes of GenericTablets and CapsulesWhile generic formulations of these drug products arerequired to be both pharmaceutically and therapeuticallyequivalent to a reference listed drug (RLD), the FDA is alsoconcerned that differences in physical characteristics (e.g.size and shape of the tablet or capsule) may affect patient

compliance and acceptability of medication regimens orcould lead to medication errors. These patient safetyconcerns are important, and the FDA recommends thatgeneric drug manufacturers consider physical attributeswhen they develop Quality Target Product Profiles for theirgeneric product candidates.The recommendations in this final guidance apply to

ANDAs and their supplements for additional strengths thatare submitted to the Office of Generic Drugs.This guidance does not apply to approved ANDAs

(generic drugs) already on the market. However, if theAgency determines that an approved product should bemodified because the size or shape of a product poses a riskto public health, it will notify the holder of the ANDA.

Dissolution Testing Immediate-Release Solid OralDosage Forms Containing Biopharmaceutics This draft guidance is developed to provide manufacturerswith recommendations for submission of NDAs,investigational new drug (IND) applications, and/orANDAs, as appropriate, for immediate-release (IR) tabletsand capsules that contain highly soluble drug substances.The guidance is intended to describe when a standardrelease test and criteria may be used in lieu of extensivemethod development and specification-setting exercises. When final, this guidance will supersede the Guidance

for Industry – Dissolution Testing of Immediate ReleaseSolid Oral Dosage Forms (August 1997) forbiopharmaceutics classification system class 1 and 3 drugsubstances in IR drug products that meet the criteria in thisguidance. For class 2 and 4 drug substances, applicantsshould still refer to the August 1997 guidance.

Botanical Drug DevelopmentThis draft guidance describes the CDER’s current thinkingon appropriate development plans for botanical drugs to besubmitted in NDAs and specific recommendations onsubmitting IND applications in support of future NDAsubmissions for botanical drugs.In addition, it provides general information on the over-

the-counter drug monograph system for botanical drugs. Itspecifically discusses several areas in which, due to theunique nature of botanical drugs, the Agency finds itappropriate to apply regulatory policies that differ fromthose applied to non-botanical drugs.After it has been finalised, this guidance will replace the

previous June 2004 guidance. The general approach tobotanical drug development has remained unchanged sincethat time; however, based on improved understanding ofbotanical drugs and experience acquired in the reviews ofNDAs and IND applications for such drugs, specificrecommendations have been modified and new sectionshave been added to better address late-phase developmentand NDA submission for botanical drugs.For the purposes of this document, the term botanicals

means products that include plant materials, algae,macroscopic fungi, and combinations thereof. It does notinclude the following.

• Products that contain animals or animal parts and/orminerals, except when these are a minor component in


a traditional botanical preparation.• Materials derived from botanical species that aregenetically modified with the intention of producing asingle molecular entity (e.g. by recombinant DNAtechnology or cloning).

• Products produced by fermentation of yeast, bacteria,plant cells, or other microscopic organisms, includingplants used as substrates, if the objective of thefermentation process is to produce a single molecularentity (e.g. antibiotics, amino acids, and vitamins).

• Highly purified substances, either derived from anaturally occurring source (e.g. paclitaxel) orchemically modified (e.g. estrogens synthesised fromyam extracts).

Due to the heterogeneous nature of a botanical drug andpossible uncertainty about its active constituents, one ofthe critical issues for botanical drugs is ensuring that thetherapeutic effect for marketing drug product batches isconsistent. In general, therapeutic consistency can besupported by a “totality of the evidence” approach,including the following considerations.

• Botanical raw material control (e.g. agricultural practiceand collection).

• Quality control by chemical tests and manufacturingcontrol (e.g. process validation).

• Biological assay (e.g. a biological assay that reflects thedrug’s known or intended mechanism of action) andclinical data.

Guidance – For Entities Considering Whether toRegister as Outsourcing Facilities Under Section503B of the Federal Food, Drug, and Cosmetic ActThis guidance is intended for entities considering whetherto register with the FDA as an outsourcing facility undersection 503B of the FD&C Act. The FDA has receivedquestions about whether entities engaged in various typesof activities (e.g. a facility that is compounding only non-sterile drugs or only repackaging biological products)should register as an outsourcing facility. The FDA isissuing this guidance to answer some of these questionsand to provide potential registrants additional informationabout the regulatory impact of registering as an outsourcingfacility.

Endotoxin Testing Recommendations for Single-UseIntraocular Ophthalmic DevicesNational outbreaks of toxic anterior segment syndrome(TASS) have been associated with single-use IODs andsingle-use intraocular ophthalmic surgicalinstruments/accessories that are contaminated withendotoxins. These devices can become contaminated aspart of the manufacturing, sterilisation, or packagingprocesses. This guidance document providesrecommendations for endotoxin limits as well as endotoxintesting to manufacturers and other entities involved insubmitting premarket applications or premarketnotification submissions (510(k)s) for different categoriesof IODs to mitigate future outbreaks of TASS.

FDA warns about prescribing and dispensing errorsresulting from brand name confusionThe FDA is warning healthcare professionals and patientsthat reports of confusion between the antidepressantBrintellix and the anti-blood clotting medication Brilintahave resulted in the wrong medication being prescribed ordispensed. The FDA has determined that the main reasonfor the confusion between these two medications is thesimilarity of their brand (or proprietary) names. None ofthe reports indicate that a patient ingested the wrongmedication; however, reports of prescribing and dispensingerrors continue. As a result, the FDA is alerting the publicabout this safety issue.Healthcare professionals can reduce the risk of name

confusion by including the generic name of the medication,in addition to the brand name, and the indication for usewhen prescribing these medications. Patients should checktheir prescriptions to ensure that the correct medication wasdispensed.

(There are parallels in the pharma manufacturingindustry. Similar names for products and or ingredientscan also lead to manufacturing errors/mix ups, as canpacks with a common image which may be desirable froma marketing standpoint, but can be a major headache froma GMP standpoint and also later in the supply chain –MH.)

Analytical Procedures and Methods Validation forDrugs and BiologicsThis guidance supersedes the draft of the same namepublished on 19 February 2014 and replaces the 2000 draftGuidance for Industry – Analytical Procedures andMethods Validation and the 1987 Guidelines for SubmittingSamples and Analytical Data for Methods Validation. Itprovides recommendations on how applicants can submitanalytical procedures and methods validation data tosupport the documentation of the identity, strength, quality,purity, and potency of drug substances and drug products.It will help applicants assemble information and presentdata to support analytical methodologies. Therecommendations apply to drug substances and drugproducts covered in NDAs, ANDAs, BLAs, andsupplements to these applications. The principles in thisguidance also apply to drug substances and drug productscovered in Type II Drug Master Files (DMFs).This guidance complements the ICH guidance Q2(R1)

Validation of Analytical Procedures: Text andMethodology for developing and validating analyticalmethods.

Naming of Drug Products Containing Salt DrugSubstancesThis final Guidance for Industry is intended to helpsponsors understand how products with active ingredientsthat are salts may be affected by CDER’s implementationof the United States Pharmacopeia (USP) policy entitled,Monograph Naming Policy for Salt Drug Substances inDrug Products and Compounded Preparations (the USPSalt Policy). The implementation of this policy helps toensure drug product naming that is consistent with the USPSalt Policy, which became effective on 1 May 2013.


This guidance addresses prescription drug productsapproved under the FD&C Act but does not addressimplementation of the USP Salt Policy for non-prescriptiondrug products or biological products licensed under thePublic Health Service Act.The USP Salt Policy is a naming and labelling policy

applicable to drug products that contain an active ingredientthat is a salt. The policy stipulates that the USP will use thename of the active moiety, instead of the name of the salt,for such a drug product when creating a drug productmonograph title. The USP Salt Policy also states that theUSP will base the strength of the product on the activemoiety. The policy allows for exceptions under specifiedcircumstances. The USP Salt Policy became effective on 1 May 2013,

and the USP is now applying it to all new drug productmonographs for products that contain an active ingredientthat is a salt. It affects the development of new drugproducts, because a USP monograph title for a new drugproduct, in most instances, serves as the non-proprietary or“established” name of the related drug product. Readersshould note that a drug product with a label or labellingthat contains a name that is inconsistent with theapplicable monograph title risks being misbranded.The USP Salt Policy only applies to the monograph

titles for drug products. The policy will not apply to thetitles of monographs for drug substances (activeingredients). Accordingly, the names of active ingredients(e.g. salts) will not be affected.

Pregnancy, Lactation, and Reproductive Potential:Labelling for Human Prescription Drug andBiological Products This guidance is intended to help small businesses betterunderstand and comply with the new content and formatrequirements of the “Pregnancy”, “Lactation”, and“Females and males of reproductive potential” subsectionsof Labelling for Human Prescription Drug and BiologicalProducts. On 4 December 2014, the FDA published thefinal rule “Content and Format of Labelling for HumanPrescription Drug and Biological Products; Requirementsfor Pregnancy and Lactation Labelling, referred to as the“Pregnancy and Lactation Labelling Rule” (PLLR, or finalrule, 79 FR 72064). The final rule requires that the former“Pregnancy”, “Labour and delivery”, and “Nursingmothers” subsections of the USE IN SPECIFICPOPULATIONS section of the Labelling for HumanPrescription Drug and Biological Products be replaced bythe three subsections entitled “Pregnancy”, “Lactation”,and “Females and males of reproductive potential”.

USP <671> Containers – Performance Testing: Useof Water-Filled Test Containers for Water VaporTransmission Rate Determinations This Stimuli article proposes the use of water as analternative test-sample fill medium for water vapourtransmission rate (WVTR) determinations described ingeneral chapter Containers—Performance Testing <671>for container-closure systems for solid oral drug products.The use of water as the test-sample fill medium eliminatesproblems with the handling of desiccants and also

maintains a constant vapour pressure difference across thecontainer wall for the duration of the study, therebyreducing bias and variability in the WVTR determinations.Use of water-filled test containers is already provided inthe chapter <671> method for the determination of weightloss for multiple-unit containers and unit-dose containersfor liquids, but has not been extended to the determinationof the WVTR of bottle and blister container closuresystems for solid oral drug products.

International

Ethiopia

National strategy and plan of action forpharmaceutical manufacturing development inEthiopia (2015–2025)The development of the Ethiopian local pharmaceuticalsmanufacturing sub-sector has been very much limited interms of production capacity, technology acquisition,creation of employment opportunity and investment. Mostof the local manufacturers are not compliant withinternational GMP, and no single product has beenprequalified by the World Health Organization.The growth and development of the Ethiopian

pharmaceutical manufacturing sector will be based on the‘value chain’ approach, which is a spectrum of progressfrom the exclusive import of finished pharmaceuticalproducts to a research-based pharmaceutical industry.The Government proposes also to adopt some initiatives

that deliver significant returns and help local companiesbecome competitive, e.g. pooled procurement to minimisethe cost of importation of APIs for the pharmaceuticalmanufacturing industry.There are approximately 200 importers of

pharmaceutical products and medical consumables inEthiopia. The local industry comprises 22 pharmaceuticaland medical suppliers and manufacturers, with nineinvolved directly in the manufacture ofpharmaceutical products. Most of the manufacturersoperate below their capacities and supply only about 20%of the local market. In 2014, local pharmaceuticalcompanies supplied products to the value of US$ 44.2million. Local manufacturers have limited productportfolios and are thought to be able to supply only 90 ofthe more than 380 products on the national essentialmedicines list. Around 35–40% of their total output issupplied to the private sector at a price premium of 10%.The annual private pharmaceutical market in Ethiopia isestimated to be worth US$ 100 million.Some of the aims of the document are to facilitate GMP

manufacturing, including of APIs, which in turn willincrease access to medicines, help curtail counterfeitingand promote innovation within the industry.

ICH

ICH Q7 Q&As The ICH Q7 Q&As (Questions and Answers) on GMP forActive Pharmaceutical Ingredients reached Step 4 of the


ICH Process in June 2015 and now enters theimplementation period (Step 5).Experience gained with the implementation of the ICH

Q7 Guideline since its finalisation in 2000 shows thatuncertainties related to the interpretation of some sectionsexist. Technical issues with regard to GMP of APIs – alsoin context with new ICH Guidelines – are addressed in thisQ&A document in order to harmonise expectations duringinspections, to remove ambiguities and uncertainties andalso to harmonise the inspections of both small moleculesand biotech APIs.The Pharmaceutical Inspection Co-operation Scheme

(PIC/S) contributed to this document by selecting andreviewing relevant Q&As that had been collected fromtraining sessions since the implementation of Q7 andtransferred the output of these reviews to the ICH Q7 IWGfor consideration and consolidation, as appropriate.Additional questions were developed based on responsesfrom an ICH survey. PIC/S further contributed to thedevelopment of the document as an ICH Interested Party.Of particular interest might be section 4 of the Q&As

which deals with buildings and containment, specifically.

• When are dedicated production areas expected?• To what extent can quality risk management be used inestablishing appropriate containment measures toprevent cross-contamination?

It is noted that ICH Q7 should be applied in combinationwith the principles laid down for development andmanufacturing in ICH Q11. GMP principles as described in ICH Q7 should be

applied regardless of which approach is taken inpharmaceutical development and manufacturing. ICH Q7also describes principles of GMPs to be applied in themanufacture of APIs for use in clinical trials and for APIsmanufactured by cell culture/fermentation

Products

Many addictive drugs lacked statutory packaging sealThe Danish Health and Medicines Authority’s laboratoryhas found that 70 of 229 addictive drugs in the Danishmarket lacked the statutory packaging seal on the outerpackaging. The seal makes it easy to determine whether the

package has been broken before it reaches the end user.The aim is to prevent abuse. The regulator found that 17out of 35 companies had not ensured their packagescontaining addictive drugs had the required seal (cf. section14 of Executive order no. 849 of 25 June 2013 on thelabelling etc. of medicinal products).

(Denmark is a relatively small market – it may be thata single supply takes a long time to run through the pipeline. This would not be the first time that such an event hasoccurred leaving packs on the market that are out ofcompliance with regulations following a mandatory packchange. Companies need to be particularly vigilant insmall/low off-take markets that this is catered for. Failureto do so can result in market recalls and regulatory censure– MH.)

First malaria vaccine receives positive scientificopinion from EMAThe EMA’s Committee for Medicinal Products for HumanUse has adopted a positive scientific opinion for Mosquirix(Plasmodium falciparum and hepatitis B vaccine), for useoutside the EU.The malaria vaccine Mosquirix, also known as

RTS,S/AS01, was submitted to the EMA under aregulatory procedure (Article 58) that allows the EMA toassess the quality, safety and efficacy of a medicine orvaccine and its benefit–risk balance, although it will not bemarketed in the EU. This means that the EMA can helpfacilitate access to new medicines for people living outsidethe EU.Mosquirix is intended for use in areas where malaria is

regularly found, for the active immunisation of childrenaged 6 weeks to 17 months against malaria caused by thePlasmodium falciparum parasite, and against hepatitis B.After decades of research into malaria vaccinations,Mosquirix is the first vaccine for the disease to be assessedby a regulatory agency.

Further information on these and other topics can befound in recent versions of the “GMP Review News”circulated to subscribers by Euromed Communications andon the websites of the relevant regulatory bodies andinternational organisations. In addition a list ofuseful websites can be obtained [email protected]

European Journal of Parenteral & Pharmaceutical Sciences 2015; 20(3): 112© 2015 Pharmaceutical and Healthcare Sciences Society

PHSS Activity and Initiatives Report

This year’s PHSS Annual Conference at University CollegeLondon (UCL) School of Pharmacy brought together therecent initiatives to develop and grow the PHSS membershipand provide key information that can be shared via thewebsite to those not in a position to attend UK conferences. The important revision of GMP Annex 1 will be closely

followed by the PHSS, as it is important to engage with theprocess of change, both to influence and prepare for thefuture. The PHSS Annual Conference featured two sessionson the Annex 1 revision; firstly a presentation by AndrewHopkins, Senior Medicines and Healthcare ProductsRegulatory Agency (MHRA) Good Manufacturing Practice(GMP) Inspector and head of the European MedicinesAgency (EMA) Working Group (WG) on the Annex 1revision. The presentation was followed by a discussion panelthat included heads of working groups that have proposedrevisions to the EMA WG on Annex 1, including the PHSS,the Parenteral Drug Association (USA and Europe), A3PFrance, R3 Nordic, the International Society forPharmaceutical Engineering (ISPE) and the EuropeanCompliance Academy. The key points from the presentation and Q&A in the

discussion panel were documented and will be published onthe PHSS website and in the next issue of the EJPPS.In addition, the Annual Conference had three key note

presentations that had audio recording and again these will beshared on the PHSS website.

• Data Integrity – Di Morris, ex-MHRA Senior GMPInspector and GlaxoSmithKline Compliance AuditManager.

• Changes in GMP Chapters and Impact – Malcom BHolmes, GMP Consultant and Freelance Writer/Editor onGMP and regulations.

• Overview of Final Draft of ISO14644 – GordonFarquharson, Chair BSI LBI030, Chair CEN TC243,Convenor ISO TC209 WG1, and member of ISPE Sterileand HVAC CoP, Consultant Critical Systems.

It was also announced at the Annual Conference that thePHSS Bio-contamination Special Interest Group (whoprepared Bio-contamination Technical Monograph 20) are to

reform (including new group members) to prepare workedexamples on risk-based environmental monitoring andcontrol (disinfection) plans. The environmental monitoring plans are to include four

risk-based programs for: Classification and characterisation,Media fills/process simulations, Risk-based environmentalmonitoring in routine production/preparations, and End ofbatch/campaign. Guidance on bio-contamination control, via disinfection

steps, will include both manual and gaseous-automaticdisinfection programs. Following the Special Interest Groupagreement on the format and risk assessment model, variousscenarios will be worked through and published (on the PHSSwebsite) as worked examples that will provide practicalguidance to support the baseline guidance already provided inTechnical Monograph 20.As previously announced, the PHSS are reducing the

amount of yearly conferences, but are focusing on two high-level events together with Special Interest Groups that willagain have information to share on the PHSS website tosupport the full membership, including overseas.The next major PHSS conference will be within the first

quarter of 2016, again free to PHSS members to attend, with atheme of sterile product manufacture and preparation. Theconference will include key issues of regulation,manufacturing (formulation and filling) and pharmacy asepticpreparations. The collaboration of the PHSS with the UCL School of

Pharmacy Q3P course for qualified person (QP) qualificationis building strength, which is facilitating the joint annualconference, with 148 attendees, and also linking to supportgroups such as the PHSS QP Forum.In this time of change in GMP chapters, revision of GMP

annexes and revision of the ISO 14644 (Cleanrooms andClean Air Devices) and ISO 14698 (Bio-contamination), thePHSS remain committed to keeping their members informedand engaged so the impact of changes can be managed.

James L DrinkwaterChairman of the PHSS

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