CONTENTS

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Administrator: Irene Gray, Scottish Society for Contamination Control, Suite 20, The Atrium Business Centre, North Caldeen Road, Coatbridge ML5 4EFTel: +44 (0)844 800 7809 Fax: +44 (0)844 800 7810 e-mail: administrator@s2c2.co.uk WEBSITE: www.s2c2.co.uk

THE SCOTTISH SOCIETY FOR CONTAMINATION CONTROL

ISO 21501 – A StandardMethodology to OpticalParticle Counter Calibrationand What It Means toCleanroom Owners

How To Choose The RightDisinfectant – A Guideline ForSafe Application

Revision to Annex 1: Impact onAirborne Particle CountingMethodology

Cleanroom technology for lifescience applications Part 2:Regulatory issues, standardsand guidelines

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IntroductionISO 21501 is a new family of standardsdescribing the instruments and calibrationrequirements for determining particle sizedistribution using light interaction methods.It represents the culmination of work byinstrumentation manufacturers and industryusers and comes at a critical time for the lifescience industry with the increasing trend forreal-time air particle monitoring in cleanroomsusing light scattering air particle counters.

Air Particle Counters and ISO 21501In comparison to liquid particle counters,the calibration of air particle counterspresents greater challenges due to the needto generate air samples containingsub-microscopic particles of homogenoussize and distribution. Although thetechnology of air particle counting is wellunderstood, the ability to calibrate any twoair particle counters so that they producethe same results when sampling the same airsample has proven to be challenging,bringing into question the accuracy of theseinstruments. ISO 21501 now delivers acalibration method that can significantlyimprove the repeatability andreproducibility of air particle counters.

Liquid Particle Counters and ISO 21501ISO 21501 also applies to liquid particlecounters used for determination of

particulate contamination in infusions andinjections. Until recently, the calibrationrequirements [known as “IST” methods] forliquid particle counters used to test infusionsand injections were described in detail in theUnited States Pharmacopoeia (USP) chapter<788>. However, in the interest ofinternational harmonization of thepharmacopoeias, the details of these ISTcalibration methods have been removed inorder to simplify the text of USP <788>.ISO 21501 now offers an alternative tothese IST tests and establishes calibrationmethods to ensure accurate and repeatableperformance of liquid particle counters.

BackgroundOptical instrumentation has been used todetermine particle contamination in air andliquids in the life science industry for manyyears. In addition, the correlation betweenairborne particles and final product qualityhas long been recognized in thesemiconductor, flat panel display and harddisk storage manufacturing industries,where improvement of air quality(reduction of particulate contamination) hasled to increases in final product yield.

Differing techniques are used to determinethe number and size of particles dependingon the size of particles that are of interest.[Figure 1]

ISO 21501 – A Standard Methodology toOptical Particle Counter Calibration andWhat It Means to Cleanroom Owners

1nm 10 100 1000 10000 100000 1000000

0.1µm 1µm 10µm 100µm

CNC

Light Scattering

Light Blocking

Figure 1. Particle size range and counting techniques

Author: Tony Harrison

August 2009 Issue 61

ContinuedISO 21501 – A Standard Methodology to Optical Particle Counter Calibration andWhat It Means toCleanroomOwners

Feature

In liquid particle counting for infusions andinjections, the sizes of interest are =>10µmand =>25µm, whereas for the life scienceindustry, the sizes of interest for cleanroomair particle cleanliness are =>0.5µm and=>5µm. Higher sensitivities are requiredfor semiconductor manufacturing plantswhere cleanroom and mini-environment airis routinely monitored at 0.1 µm and lower.Hard disk manufacturers typically monitorto around 0.2 µm to 0.3 µm and flat paneldisplay manufacturing environmentsmonitor to 0.3 µm and 1.0 µm.

USP <788>, EU 2.9.19 and JP 6.07recognize that light obscuration is suitablefor liquid particle counting in infusions andinjections, whereas ISO 14644-1 recognizesthat light scattering particle counters areappropriate for determining airbornecontamination in cleanrooms.

There is a requirement to follow theguidelines in EU GMP and cGMP forcleanroom users that aseptically manufacturepharmaceutical products for the Europeanand American markets. Both documentsdefine the airborne particulate count limitsfor different cleanroom operations, butneither defines the methods required todetermine these count limits, nor do theydefine the instrument to be used and how itshould be calibrated. However, EU GMPstates that ISO 14644-1 should be used formethodology to determine cleanroom airparticle cleanliness classification and thatISO 14644-2 should be used formethodology for demonstrating continuedcompliance. The introduction inISO 21501-4 states, “Monitoring particlecontamination levels is required in variousfields, e.g. in the electronic industry, in thepharmaceutical industry, in the manufacturingof precision machines and in medicaloperations. Particle counters are usefulinstruments for monitoring particlecontamination in air. The purpose of this partof ISO 21501 is to provide a calibrationprocedure and verification method for particlecounters, so as to minimize the inaccuracy inthe measurement result by a counter, as wellas the differences in the results measured bydifferent instruments.” The scope of ISO21501-4 states, “Instruments that conform tothis part of ISO 21501 are used for theclassification of air cleanliness in cleanroomsand associated controlled environments inaccordance with ISO 14644-1”. So theimportance of ISO 21501 to cleanroomusers looking to follow the guidance inGMP is evident.

Equally the scope of ISO 21501-2 states,“Instruments that meet this standard are usedfor the evaluation of cleanliness ofpharmaceutical products (injections, water forinjections, infusions), as well as themeasurements of number/size distribution ofparticles in various liquids.”So the importance of ISO 21501 to those inthe pharmaceutical industry manufacturinginjections, water for injections or infusions isalso evident.

What Standards Exist? What IsISO 21501 Replacing?ISO 14644 is a widely used standard forcleanroom classification using opticalparticle counters. Despite the existence ofISO 14644, prior to the ratification andintroduction of ISO 21501 at the beginningof 2007, there were no ISO standardsdealing with calibration and performance ofthe optical particle counters (OPC) used toclassify cleanrooms to ISO 14644.Comprehensive non-ISO standards andcalibration methods guidelines did existhowever and have been employed by mostmajor particle counter manufacturers. Insummary, these standards are:

• ASTM F 328-98(2003) “Standard Practicefor Calibration of an Airborne ParticleCounter Using Monodisperse SphericalParticles” (withdrawn May 2007).

• IEST-RP-CC014.1 “Calibration andCharacterization of Optical Airborne ParticleCounters” (providing actual methods toperform the calibration).

• JIS B 9921:1997 “Light scattering automaticparticle counter”, a Japanese standardwhich comprehensively deals with OPCdesign performance, most notably in thearea of “counting efficiency”.

The counting efficiency parameter haspresented the most significant variablewhen it came to the actual countaccuracy of individual OPC’s, especiallyair particle counters.

Counting EfficiencyOPC’s typically feature a number of sizechannels into which particle counts arebinned, each channel being calibrated tocount particles greater than a specificparticle size. Particle sizes are typicallyexpressed in micrometers (µm). The termcounting efficiency primarily refers to theability of the OPC instrument to countparticles at a specified size. Typically,calibration involves passing a continuousstream of standard, monosized particles

through the OPC’s sensor, which results in astream of electrical pulses, each pulse beingproportional to the size of each particle.The mono-sized standard particles producea distribution of pulse heights, the median ofwhich is typically regarded as theappropriate channel calibration thresholdfor that size. Therefore, in the real world aparticle exactly the same size as a givenchannel would have a 50% probability ofbeing counted (see Figure 2a). As a result,OPC’s calibrated in this manner are said tohave a counting efficiency of 50%. Notehowever that this does not mean that theOPC will only count half of the particles inthe real world.

ISO 21501 makes use of the specification forcounting efficiency accepted in the JIS B 9921standard. This states that the countingefficiency should be 50%+/-20% (i.e.between 30%� 70%) in the first channel(Figure 2a). Additionally, particles of between1.5 X to 2.0 X the channel 1 particle sizeshould be counted with an efficiency of100%+/-10% (i.e. between 90%� 110%)in the first channel (Figure 2b.)

ISO21501 Limits50% +/- 20% (30% to 70%)

Channel 1 size (um)

OPC smallest specified size.

Noise

NISO21501 Limits50% +/- 20% (30% to 70%)

Channel 1 size (um)

OPC smallest specified size.

Noise

N

At 1.5 x to 2 x the particle counters minimum specified size all particles should be counted in the first channel. ISO21501 allowed limits are 90% to 110%

Channel 1 size (um)Noise

N At 1.5 x to 2 x the particle counters minimum specified size all particles should be counted in the first channel. ISO21501 allowed limits are 90% to 110%

Channel 1 size (um)Noise

N

Figure 2a: The 50% calibration point

Figure 2b: Verifying 100% efficiency at a higher size

2

Why Was A New StandardRequired?Prior to ISO 21501, it was not required forcounting efficiency to be checked at eachcalibration interval nor that this moreexhaustive series of tests be performed oncethe instrument was in the field, although itwas often done at the end of the initialmanufacturing process at the factory. Thereare many things that can impact countingefficiency during the lifetime of an OPC; forexample a slight optomechanicalmisalignment of the illumination source cango undetected. Therefore, the situationexists where even though a given OPC maycorrectly size particles, it may beundercounting - in effect missing some of theparticles. The new ISO 21501 standardrequires (among other elements) that theall-critical counting efficiency element bechecked during calibration. To checkcounting efficiency, it is necessary that oncecalibrated for sizing characteristics usingtraceable size standards, the OPC under testmust be run and compared to either anElectrostatic Classifier or an OPC instrumentwith higher sensitivity than the OPC undertest. This OPC is considered to be a“secondary standard”, having been formallycompared to an Electrostatic Classifier andverified as having 100% counting efficiencyat the size of interest, i.e. the channel 1 sizeof the OPC to be certified.

The full list of elements that ISO 21501requires to be tested in addition to the basicsize calibration are as follows:

What Is ISO 21501 And WhatImprovements Will It Bring?To quote from the ISO 21501 standard:

“The purpose of this part of ISO 21501 is toprovide a calibration procedure and verificationmethod for particle counters, so as to minimizethe inaccuracy in the measurement result by acounter, as well as the differences in the resultsmeasured by different instruments.”

Simply put, the ISO 21501 standard willensure that OPC instruments will size andcount particles correctly, using a traceablereference instrument. Different OPCmodels from different manufacturers willtherefore closely correlate in terms of actualparticle counts recorded. This presents asignificant step forward in providingtraceable, accurate OPC tools to classifyand validate cleanrooms to ISO 14644.

Who Should Adopt ISO 21501?Manufacturers of products requiringprocessing or assembly all goods andmaterials within a cleanroom environmentclassified under ISO 14644 should requirethat OPC instruments be calibrated to theISO 21501 standard. This is particularlyapplicable to the pharmaceuticalmanufacturing facilities employing sterileprocessing or filling lines.

Users of cleanrooms OPC’s with questionsor concerns regarding the transition toISO 21501 should contact their particlecounter supplier or cleanroom certifier.

Additional InformationThe ISO 21501 family of standards extendsbeyond air particle counters to include bothscattering and extinction type liquid particlecounters. The standard is split into fourparts and all are available from ISO athttp://www.iso.org.ISO 21501 Determination of particle sizedistribution – Single particle light interactionmethods -• Part 2: Light scattering liquid borneparticle counter

• Part 3: Light extinction liquid borneparticle counter

• Part 4: Light scattering airborne particlecounter for clean spaces

Hach manufactures a range of ISO 21501compliant particle counters and is currentlyin the process of deploying an ISO 21501field service capability for the calibration ofexisting products.

Particle counter owners and users withspecific questions or concerns regardingISO 21501 are invited to email theHach ISO 21501 support team atiso21501@hachultra.com. Through thisemail address, one can access a panel ofexperts regarding ISO 21501 and receiveprompt and accurate answers to questions.

Tony Harrison is aqualified electrical &electronic engineer, withover twenty years’involvement in processcontrol and monitoringsystems formanufacturing industries.Tony represents thePharmaceutical

Healthcare Sciences Society (formerly known asthe UK Parenteral Society) on the LBI/30committee for the British Standards Institute,working on the revisions to the ISO14644 familyof standards. LBI/30 also represents the UKinterests on changes to EU GMP Annex 1.

Tony is one of the UK technical experts onISO TC 209 Working Group 1 working on therevisions to the cleanroom standardISO 14644-1 & -2.

Tony is also acting Convenor for ISO TC 209Working Group 2 working on the revision ofISO 14698, the ISO standard for microbialcontamination in cleanrooms.

The recently published guide to continuousparticle monitoring to EU GMP Annex1 from thePHSS “Best Practice for Particle Monitoring inPharmaceutical Facilities” was produced by aworking party of PHSS members chaired by Tony.In his role as Global Life Sciences Manager forHach Lange (part of the Danaher group of

companies), working with colleagues on variousstandards groups in a world-wide network, he isresponsible for interpreting and comparing thedifferent regulatory and international standardsfor clean rooms and regulatory compliance issues.In recent years he has published papers oncompliance issues relating to the life sciencesindustry, including most recently a paper in theEuropean Journal of Parenteral & PharmaceuticalSciences. He has also been responsible forcreating validation best practice standardoperating procedures (SOP) for equipment usedto demonstrate regulatory compliance.

About the Author

3

• Counting efficiency• Sizing resolution• False count rate• Concentration limit

• Sampling flow rate• Sampling time• Sampling volume

Disinfection is a very important part of quality assurance, as it prevents the transfer of undesiredmicroorganisms. Because disinfection is such a crucial process a wide range of potentially suitableproducts are available on the market. Immediately this raises the question “Which is the rightdisinfectant for my situation?”

ObjectiveFirst of all, the goal that you wish to achieve must clearly be defined. Disinfection is theinactivation or reduction of pathogenic and product-harming microorganisms to an acceptable level,usually attained by altering either their structure or metabolism. Each individual company orlaboratory must determine this “acceptable level”, as well as the germ spectrum to which it applies.Indications of such acceptable levels for pharmaceutical manufacture are to be found in Annex 1 ofthe EU-GMP-Guideline for the Manufacture of Sterile Medicinal Products. The selected level to bereached should of course be both achievable and relevant to the situation in question (“<1 CFU”does not make sense everywhere!).

Cleaning Comes FirstIn production areas where a heavy amount of soiling is expected, cleaning is the first step to betaken prior to disinfection. In cases of low dirt loading sometimes the use of disinfectants that have acombined good cleaning effect is sufficient.

If cleaning must be undertaken it is important to know what type of soil is present, how long it hasbeen there, how much there is and how widespread it is. Organic fatty dirt, for example, requiresan alkaline cleaning agent, while calcium deposits are removed with acid cleaning agents. Older anddried-on dirt requires a higher level of mechanical cleaning, stronger chemistry and/or a longercontact time in order to loosen the dirt from the surfaces. In contrast, dirt particles that are lightlyand thinly spread on the surface can be removed with a low level of chemical application orsometimes none at all. Hence, knowledge of the dirt is decisive when selecting the right cleaningmethod, cleaning agent, use concentration, temperature and contact time.

Material compatibility is another criterion to consider when choosing a cleaning agent. Very stronglyacidic cleaning agents are usually not suitable for use on non-ferrous surfaces. Also alcohol-basedproducts are not suitable for acrylic surfaces. Generally speaking all cleaning agents and disinfectantsshould be tested for compatibility with all materials that they are likely to come into contact with.

Selection Criteria for DisinfectantsIf the microbiological goals are set, each user must be aware of the criteria that the disinfectantmust meet. These can include:

LimitsIt is often impossible to meet all the requirements of the user due to the relevant biocideregulations (e.g. impending restriction of active ingredients to be used in the future), industrial safetyconsiderations (e.g. discussion about formaldehyde) and also the chemistry of the active ingredients.Peracetic acid, for example, has a very wide spectrum of activity (e.g. against bacterial spores), butdepending on the applied concentration and contact time may also have limited materialcompatibility. In contrast, alkalis show a limited spectrum of effect but excellent cleaning powerwith high protein loading capabilities. Quaternary ammonium compounds are often used due totheir excellent cleaning effect, good material compatibility and user-friendliness - however, they arenot effective against spores. Aldehydes have a low cleaning power and protein load but a widespectrum of effect. However aldehydes in general, and formaldehyde in particular, are often

Feature

• operational stipulations• sterility• conformity with relevant biocide guidelines• microbiological efficacy, tested anddocumented in accordance with recognisedmethods (e.g. European standards) alongwith corresponding expert opinions

• type of active ingredients• any possible interaction of the activeingredients (e.g. when two disinfectants areused alternately)

• any possible interaction between cleaningagents and disinfectants

• ease of dosing, concentration & contact time• cleaning effect and dirt loading capacity• material compatibility, corrosive properties• toxicology and safety implications for bothusers and the environment

• odour• rinsing characteristics and residue-freerequirements

• cost

How To Choose The Right Disinfectant –A Guideline For Safe Application

AbouttheAuthor

Author: Phil Blundell

4

Phil Blundell is anInternational Sales Managerwith 15 years experiencewith Schülke & Mayr.

restricted for health and safety reasons despite having this high level of efficacy. Alcohols are widelyused because they can be easily sprayed, have a fast action and are residue-free on application - butthey do not have a sporicidal effect. Such conditional limitations, and the chemical properties of theactive ingredients, lead to the fact that different products are used depending on each uniquesituation and the desired spectrum of efficacy.

DevicesApart from choosing the right disinfectant, the method and type of application also influence thesuccess of disinfection procedures. A variety of devices are commonly available to apply thedisinfectants. From system trolleys for wiped or mopped disinfection of large surfaces to handyspray bottles for smaller surfaces and objects which are difficult to wipe, right up to mobile sprayingdevices for disinfecting larger plants and equipment. Dosing units are commercially available whichdilute disinfectant concentrates, thereby ensuring a constant supply of the stock solution. Thisremoves the need to buy more expensive ready-to-use pre-diluted disinfectants.

SterilityDifferent levels of hygiene are required in production areas depending on which products are beingmanufactured there. This also has implications for the requirements of the sterility of thedisinfectants to be used. For the manufacture of sterile products a sterile disinfectant isrecommended according to the legal requirement of the Supplementary Guidelines to the EUGMP-Guideline for the Manufacture of Sterile Medicinal Products. If a high quality disinfectant is required,but does not need to be sterile, a microbially filtered product is suitable. Products with normalhygiene status are usually sufficient for all other fields of application.

Quality LevelsThe chapter ‘Operational Hygiene’ in The Supplementary Guidelines to the EU-GMP-Guideline forthe Manufacture of sterile Medicinal Products, demands that: “Disinfectants and detergents used inareas of hygiene level A and B should be sterilised before use.” The user can meet thisrequirement by either sterile filtration of a pre-prepared stock solution, or by purchasing adoublewrapped sterile disinfectant [Figure 1].

Both options have advantages and disadvantages. Sterile filtration needs a high level of technicalinput and documentation when performed by the user. Ready-to-use or concentrated steriledisinfectants can only be delivered in relatively small units, thereby causing a high level of waste.On the other hand, these products are supplied with expert opinions and all the necessarycertification, so that the validation process carried out by the user is considerably morestraightforward. Moreover, the double-bagging makes it much easier to bring the product into thesterile areas.

As Much As Necessary – As Little As Possible“As much as necessary” means that the selected disinfectant can be used to successfully meet therequired criteria when used at a certain concentration. The objective to use “as little as possible”can then only be achieved by means of a well functioning, practically relevant cleaning anddisinfection program, incorporated into an effective clean room concept.

ConclusionA range of disinfection products which can be used according to the above principles, should includethe following:

Selection of the right disinfectant facilitates working in sensitive areas of the pharmaceutical industryand provides a high level of safety.

• A non-sporicidal disinfectant for daily routinedisinfection e.g. based on quaternaryammonium compounds;

• a disinfectant with a sporicidal effect (e.g.based on active oxygen), which is used atregular intervals for basic disinfection and tocounter contamination by bacterial spores;

• a cleaning agent if certain amounts of soilingare to be expected;

• products that are available as sterileconcentrates or ready-to-use products foruse in areas with the strictest hygienerequirements

• the same products should be available as anon-sterile variant for use in non-sterileareas.

ReferencesEU-Leitfaden einer Guten

Herstellungspraxis für Arzneimittel,Teil I und II (EU-GMP-Leitfaden)

Ergänzende Leitlinien zur EU-GMP-Richtlinie für die Herstellung steriler

Arzneimittel (ÜberarbeitungSeptember 2003)

Aide mémoire (AiM): Inspektion vonQualifizierung und Validierung in

pharmazeutischer Herstellung undQualitätskontrolle

Richtlinie 98/8/EG über dasInverkehrbringen von Biozidprodukten

(Biozid-Verordnung)

Finale Guidance for Industry: SterileDrug Products Produced by Aseptic

Processing – Current GoodManufacturing Practice (Leitfaden der

FDA für die Herstellung sterilerArzneimittel unter aseptischen

Bedingungen)

Figure 2: Perform-Range from Schülkefor optimised product hygiene

Figure 1: An example of adouble-bagged, sterile disinfectant foreasy introduction into the sterile area

5

1. OverviewAnnex 1 is a guidance document associated with the European GMPregarding the production of Sterile Medicinal Products. The mostrecent revision of Annex 1 has an effective date of 01 March 2009.There are several key points about the revision that will affect - andin general simplify - the methodology of non-viable airborne particlecounting:a) direct statements of requirements for classification versusmonitoring

b) linkage to ISO 14644 for classification proceduresc) relaxation of the limits of 5 micron airborne particles allowed inGrade A and Grade B

d) clarification of the need for “continuous” monitoring duringproduction process

e) clarification of the sample volume and rates needed duringproduction process

The result is that the concern with a larger sampling volume of onecubic meter applies specifically to Grade A areas and only duringclassification procedures, which, following ISO 14644-1, wouldtypically occur only every 6 months. Also the monitoring protocol isclarified to allow any sampling rate or sampling volume as long as theprocess would capture significant transient events or systemdeterioration.

2. Specific changes or additions

2.1 Direct statements of requirements for classificationversus monitoring

2.1.1 Separate sections in the document for classification andmonitoring

Note that the sub-title of Clean room and clean air deviceclassification precedes Section 4 through Section 7 whereas theinformation starting with Section 8 through Section 20 is entitledClean room and clean air device monitoring

2.1.2 classification differentiated from monitoring“Classification should be clearly differentiated from operationalprocess environmental monitoring” [Section 4]

2.2 New classification limits for airborne particles

2.2.1 The table previously was

2.2.2 The newly revised table of classification limits is

2.3 Linkage to ISO 14644-1 for classification procedures

2.3.1 Section 4 - statement of linkage“Clean rooms and clean air devices should be classified in accordancewith ISO 14644-1.” [Section 4]

2.3.2 Additional references to ISO 14644-1“For classification purposes EN/ISO 14644-1 methodology definesboth the minimum number of sample locations and the sample sizebased on the class limit of the largest considered particle size andthe method of evaluation of the data collected.” [Section 5]

2.4 For classification of Grade A areas, a full cubic meter ofsampled air required

2.4.1 Minimum Sample Volume for Grade A“For classification purposes in Grade A zones, a minimum samplevolume of 1m3 should be taken per sample location.” [Section 5]

2.5 Process conditions for classification of “in operation” status

2.5.1 Three potential activity states can qualify for “in operation”test conditions:a) normal operationsb) simulated operationsc) media fills“In operation” classification may be demonstrated during normaloperations, simulated operations or during media fills as worst-casesimulation is required for this.” [Section 7]

2.6 Establishing a program for monitoring during process

2.6.1 Use both results of previous testing and risk analysis todetermine positions“Clean rooms and clean air devices should be routinely monitored inoperation and the monitoring locations based on a formal riskanalysis study and the results obtained during the classification ofrooms and/or clean air devices.” [Section 8]

At Rest In Operation

Grade Maximum permitted number of particles/m3 equal to or above

0.5µm 5µm 0.5µm 5µm

A 3 520 20 3 520 1

B 3 520 29 352 000 2 900

C 352 000 2 900 3 520 00 29 000

D 3 520 000 29 000 not defined not defined

At Rest In Operation

Grade Maximum permitted number of particles/m3 equal to or above

0.5µm 5µm 0.5µm 5µm

A 3 500 1 3 500 1

B 3 500 1 350 000 2 000

C 350 000 2 000 3 500 00 20 000

D 3 500 000 20 000 not defined not defined

Revision to Annex 1: Impact on Airborne ParticleCounting Methodology

Feature

Author: Joe Gecsey

Joe Gecsey is currently the Life ScienceApplication Manager for the HACH ParticleCounter Unit, Joe has been involved with theparticle counting industry since 1984. First joiningMet One as an electronic design engineer, Joe hasbeen involved in both airborne and liquid particlecounter design, as well as multi-sensor systemsfor facility monitoring systems (FMS). He is partof the TC209 WG1 revision group on the main

global cleanroom certification standard, ISO 14644-1 and -2, one of thetwo Americans on the committee. One of his main focus points today isstaying abreast of changes in global standards and compendial tests usedby laboratories and production systems in the Life Sciences. Joe has beeninvolved in various standards involving particle counting in air and liquidsand gives informational seminars in Asia, Europe and South America.

About the Author

6

3. Analysis

3.1 Classification follows ISO 14644-1 except for Grade A

3.1.1 Frequency of classificationFollowing current ISO 14664-1 and 14644-2 directives, theclassification effort needs to be done at a minimum frequency ofevery 6 months in Grade A and B areas and every 12 months forGrade C and D areas.

3.1.2 Minimum number of sample points for classificationThe number of points will be determined by the area of the area tobe classified. The formula is to take the square root of the area (insquare meters) and then to round up to the next whole number. Forexample, a 200 square meter area would infer a minimum of 15sample positions because the square root of 200 is 14.14 androunding up to the next integer yields a value of 15.

3.1.3 Minimum sample volume for classificationBecause the classification effort is based on representative sampling,a minimum volume is specified in ISO 14644-1 Annex B in order toobtain a reasonable level of confidence that the sampled volumereflects - as a partial sample - the entire air quality in that immediatearea. In ISO 14644-1 Annex B, there are calculations for a minimumsample volume.

However, this revision of Annex 1 gives specific instructions for thesize of the sample volume used for classification purposes. RevisedAnnex 1, Section 5, specifically demands that the sample volume forclassification purposes for Grade A areas be at least one cubicmeter. This is a different volume than is required by followingISO 14644-1 but is considered appropriate in order to achieve ahigh level of confidence that the sample results will effectivelyrepresent these critical areas.

The table below represents the results of calculating the requiredminimum sample volumes for each of the ISO Classes at therespective particle count size channel.

3.1.4 Use of the Sequential Sampling method from ISO 14644-1Annex FInstead of adhering strictly to the minimum sample volume to obtainthe confidence level in the results, users who are doing 5-microntests to certify their cleanroom can use the Sequential Samplingmethod to limit the length of time for the sampling process.

In reading 14644-1, Appendix F, there is a table of time fragments(Table F.1) that states if observed counts (C) are less than a givenlimit within certain time fragments of the sample period, then thesample point can be presumed to meet the Class limits. Forexample, if the observed counts are still “0” after the FractionalTime, t, of 0.1922 has passed then the sample point passes.

The time, t, is based on the time needed to count 20 particles ifthere were precisely that number of particles of that size in thesample area to meet the class limit.If the wish is to classify a Grade B (ISO Class 5) area at rest, the limitis (29) 5-micron particles in a cubic meter. To gather (20) particleswould require 0.69 cubic meters or 24.3 cubic feet. For a particlecounter running at 1 CFM, this would mean a minimum sample time(t) of 24.3 minutes.

Using Table F.1, and t = 24.3,

Thus, if no counts were observed at 5 microns after 4 minutes and41 seconds, the sampling process could be stopped and the samplepoint declared to have passed at the 5- micron limit for ISO Class 5.

Or if (1) count was recorded, then if no more counts wererecorded within 5.85 minutes, again you could record a PASS.

For a flow rate of 1.77 CFM [50 lpm], the chart would then showthese times for t = 24.3/1.77 = 13.73 minutes:

However, in no case can the sample period at a location beless than 1 minute. [ISO 14644-1, Annex B 4.2.2.

3.2 Monitoring has a different philosophy

3.2.1 Intent for monitoring of Grade A areaThe revised Annex 1 does not use the word “continuous” as in theprevious versions but instead demands a monitoring protocol that,for all intents and purposes, could only be satisfied by monitoringcontinuously in the critical areas:“For Grade A zones, particle monitoring should be undertaken forthe full duration of critical processing, including equipment assembly,except where justified by contaminants in the process… The GradeA zone should be monitored at such a frequency and with suitablesample size that all interventions, transient events and any systemdeviations would be captured and alarms triggered if alert limits areexceeded.” [Section 9]

3.2.2 Intent for monitoring of Grade B areaAnnex 1 encourages the use of the same or similar airborne particlecounting system for Grade B with the allowance for a frequency ofsampling that could be not continuous and would not need tocapture all transient events:“It is recommended that a similar system be used for Grade B zonesalthough the sample frequency may be decreased… The Grade Bzone should be monitored at such a frequency and with suitablesample size that changes in levels of contamination and any systemdeterioration would be captured and alarms triggered if alert limitsare exceeded.” [Section 10]

ObservedCount

FractionalTime

Time(mins)

Time(mins)

0 0.1922 2.64 2 min 38 sec

1 0.2407 3.31 3 min 18 sec

2 0.2893 3.97 3 min 58 sec

3 etc.

ObservedCount

FractionalTime

Time(mins)

Time(mins)

0 0.1922 4.68 4 min 41 sec

1 0.2407 5.85 5 min 51 sec

2 0.2893 7.03 7 min 2 sec

3 etc.

Calculation of Vs (Single Sample Volume) in liters refer to Appendix B.4.2

0.1um 0.2um 0.3um 0.5um 1 um 5 um

ISO Class 1 2000 1000

ISO Class 2 200 833.33 2000 5000

ISO Class 3 20 84.39 196.08 571.43 2500

ISO Class 4 2 8.44 19.61 56.82 240.96

ISO Class 5 0.20 0.84 1.96 5.68 24.04 689.66

ISO Class 6 0.020 0.084 0.196 0.87 2.40 68.26

ISO Class 7 0.06 0.24 6.83

ISO Class 8 0.006 0.024 0.683

ISO Class 9 0.0006 0.0024 0.0683

7

3.2.3 Selection of sample locations for monitoringThe selection of sample locations should be based on a) previouslyacquired particle count data and b) on risk analysis of the process.Probable sample locations based on risk could be at the intersectionof exposed product and human interactions for interventions ormanipulations in the process. Also points where the productremains exposed to the environment for a period of time (forexample, on turntables) should be considered due to the increasedrisk of particulate deposition.“Clean rooms and clean air devices should be routinely monitored inoperation and the monitoring locations based on a formal riskanalysis study and the results obtained during the classification ofrooms and/or clean air devices.” [Section 8]

3.2.4 Sample volume and sample size for monitoringDue to the more frequent occurrence of monitoring - perhaps evencontinuous in critical areas - Annex 1 makes no specification of thesample volume or sample time.“The sample sizes taken for monitoring purposes using automatedsystems will usually be a function of the sampling rate of the systemused. It is not necessary for the sample volume to be the same asthat used for formal classification of clean rooms and clean airdevices.” [Section 12]

In other words, there is no need to sample a full cubic meter or toset alarm levels based on results per cubic meter. It is for the user toestablish the volume, rate and alarm levels to satisfy the informationneeded for the Grade to be monitored. (ref. Sections 9, 10 and 15)

3.2.5 Appropriate types of particle counting instrumentationThe Annex 1 leaves the decision of instrumentation type to the userto determine based on the particle size to be considered. Portable,sequential (manifold) and remote counters can all be employed at afacility to accomplish the needed tasks. The text cautions the user toconsider the effect of transport of the particles in the size range ofinterest but makes no specification for tubing dimensions, radius ofbend or maximum tubing length. (ref. Section 11)

3.3 Written procedures; establishing alarm values;corrective action

3.3.1 Alarm LimitsA written plan needs to define the sampling strategies forclassification and for monitoring; the plan also needs to detail theactions to be taken when the alarm values are exceeded.“Appropriate alert and action limits should be set for the results ofparticulate and microbiological monitoring. If these limits areexceeded operating procedures should prescribe corrective action.”[Section 20]

4. Points of Controversy

4.1 Meaning of “at rest”In ISO 14644-1, the general meaning of “at rest” for classificationpurposes is that an area has no human operators present and themachinery is present but not in operation. However, the phrasingof Annex 1 has left many to conclude that the machinery should berunning during the Annex 1 classification procedure for the “atrest” state:“In order to meet “in operation” conditions these areas should bedesigned to reach certain specified air-cleanliness levels in the “atrest” occupancy states. The “at rest” state is the condition wherethe installation is installed and operating, complete with productionequipment but with no operating personnel present.” [Section 3]

4.2 Limits or levelsMany users would prefer the use of the terms “level” whendesignating a target value for the airborne counts in a given area.Generally the term “limit” is reserved for a PASS/FAIL test that setsa mandatory boundary for a parameter. Annex 1 is a guidancedocument [“informative” not “normative”] and thus the values areintended to be significant but not mandatory.

4.3 Corrective ActionIt would be difficult to cover all reactions necessary for the widerange of potential causes of particle counts exceeding Alert orAction limits. (ref. Section 20)

5. Conclusions

5.1 Cubic meter sample volume not required except forGrade A during classificationA full cubic meter sample volume is only required for Grade A areasand only during the classification process, typically occurring at 6-month intervals. [Section 5]

Minimum sample volumes for Grades B, C and D are based on ISO14644-1 methodology. [Section 5] This infers that, as appropriate,sequential sampling, as outlined in ISO 14644-1, Annex F, could beemployed to shorten the sample times.

5.2 Number of sample positions set by ISO 14644 forclassification; by risk analysis for monitoring effortFor classification efforts, the minimum number of sample positions isset by ISO 14644-1 and is determined by calculating the square rootof the area (as measured in square meters) and rounding up to thenext integer. [Section 5]

For monitoring efforts, the number of sample positions is set by therisk analysis of the critical areas and would be determined in mostorganizations by the efforts of the QA department. [Section 8]

5.3 5-micron particle count limit now set to 20 for Grade AFor “at rest” and “in operation” conditions, the 5-micron count limitis established at 20 counts or less per cubic meter at the 5 micronand larger size channel. The latest revision modifies the 0.5 micronlimits slightly from a previous value of 3500 counts per cubic meterto 3520 counts per cubic meter in order to harmonize the limitswith the ISO 14664-1 values for this particle size and roomclassification. [Section 4]

5.4 Sample size and frequency for monitoring purposes canbe different than values used for classificationThe classification and monitoring protocols should be clearly definedand distinct. [Section 4]

The equipment used and the methodology employed can be quitedifferent than that used for classification [Section 111,12]

5.5 Written sampling procedures are needed with prescribedcorrective action plansWritten procedures need to be authored that include alert andaction limits for particulate and microbiological monitoring and theseprocedures should detail the appropriate corrective actions to beundertaken when the limits are exceeded. [Section 20]

Feature

ContinuedRevision to Annex 1: Impact on Airborne Particle Counting Methodology

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Feature

Cleanroom technology for life science applicationsPart 2: Regulatory issues, standards and guidelines

SummaryIn the first part of this article, some technical trends in thepharmaceutical industry and in the medical device field had beendiscussed. In this second part of this article, recent regulatory andstandardization trends are to be addressed. As commondenominator, the trend towards quality risk management systemspropagated in the ICH Q8-Q10 series is being implemented into, forexample, the second edition of ISO 13408-1 on the generalprinciples for aseptic processing of health care products, and intoISPE’s GAMP 5 handbook on a risk-based approach to compliantGxP computerized systems. In the world of Good Practicescompendia, the new PIC/S guide on the preparation of medicinalproducts in pharmacies is worthy of note. Only limited commentsare focussed upon the recent revision of Annex 1 to the GMP Guideof the European Union as it has already received wide attention inthe S2C2 Cleanroom Monitor and elsewhere. However, recentdevelopments in the ISO series of cleanroom technology standardswill be addressed in more detail.

Regulatory guidance: the point of departureThe point of departure of today’s GMP Guides is health legislation:generally on a national basis in countries such as the USA, Japan andthe Republic of Korea. The European Community has improvedupon this national approach: national health legislation in its membernations is guided by Directives of the European Council which hasentrusted the elaboration of regulatory compendia to EMEA - theEuropean Medicines Agency. A step in a good direction: but is thisstep good enough in the present era of globalization andconsequently global markets?

Comparing the GMP compendia of the leading pharmaceuticalnations or regions, they agree to a large extent - but not always indetail. To give an example: FDA, in its Guidance to Industry foraseptic processing1, requires room classification for particles≥ 0.5 µm and in the occupancy state “in operation” only. EMEA, onthe other hand, continues to require, in the new edition of Annex 1to the GMP Guide of the European Union (EU), published inFebruary 20082, classification also for particles ≥ 5 µm and in the“at rest” occupancy state. Not so much difference fundamentally,but leading to considerable extra cost during qualification tests andoperational monitoring.

A GMP trend to be overcomePresent GMP guidance is distinguished by its focus upon detail, andwith each new edition more detail is added. By focussing on all thisdetail, the GMP objectives may well become overlooked or, as theGermans say, the forest may no longer be perceived because of allthese trees. As a consequence, GMP tends to be interpretednegatively as “GiveMore Paper”, i.e. as the need to qualifyeverything that is capable of being qualified, instead of focussingupon the meaningful issues. Thus, qualification degenerated into thecompilation of a multitude of files distinguished by a rather lowinformation density. In addition, an over-cautious attitude started toprevail, impeding innovation. Another example: the extremelycautious attitude of FDA regarding isolator technology. As thisauthority possessed no experience with this technology, it refrainedfrom rulemaking, and industry in the Americas remained reluctanttowards this technology because of the lack of isolator-specificregulatory guidance.

Developing into a trend: quality risk managementFDA quickly perceived the above-mentioned problems, and did soin a very comprehensive way. Their initiatives towards science- andrisk-based attitudes paved the way towards a genuine paradigmchange: the principles of quality risk management were introduced,with its focus upon risk assessment as the instrument for identifyingthe core risks, concentrating upon their control and avoiding theexpenditure of too much time on risks of minor consequence.Regarding qualification of contamination control systems, this meantfocussing upon the major issues, with a positive effect upondocumentation in which irrelevant issues were no longer addressedbeyond the statement, corroborated through risk analysis, that theyare irrelevant.

For preparing the necessary fundamental guidance enablingimplementation of this new philosophy of quality risk management,the trend towards a collaborative, international approach wasfollowed: the elaboration of the fundamental guidance documentswas trusted to ICH, the International Conference on Harmonizationof Technical Requirements for Registration of Pharmaceuticals forHuman Use. ICH comprises EMEA, FDA and the JapanesePharmaceutical and Medical Devices Agency PMDA. Thus, ICH isnot as international as it could possibly be, but it comprises acollective of leading nations regarding pharmaceutical innovation andpharmaceutical quality management.

The outcome of this effort is a series of guidance documentscomprehensively covering the fundamental issues of the new qualityrisk management philosophy³:

• ICH Q8: Pharmaceutical Development, to which the Annex Q8R:Quality by Design is soon to be added;

• ICH Q9: Quality Risk Management;

• ICH Q10: Pharmaceutical Quality System.

The third document and highlight of this series, ICH Q104, wasapproved in its definite form by the ICH Standing Committee in June2008 and is now ready for incorporation into the regulatoryguidance collections of the ICH member bodies. The objective ofICH Q10 is to establish a model of a pharmaceutical quality systemdesigned for the entire product life cycle. It is based upon the qualitymanagement philosophies of the ISO 9000 series - thus finallyintegrating pharmaceutical quality systems into this wider context -and goes beyond current GMP thinking. It is expressly intended tofacilitate innovation and continuous improvement as well as tostrengthen the link between pharmaceutical development andmanufacturing activities. Together with ICH Q8/Q8R and Q9, ICHQ10 provides a common roof above the different GxP Guides suchas GMP, GLP etc. which it is not intended to replace.

A spreading philosophyThe quality risk management philosophies just explained are quicklyspreading into other compendia serving the pharmaceutical andother life-science industries.

The second edition of ISO 13408-1: Aseptic Processing of HealthCare Products - General Requirements5, published in June 2008, is agood example. Quality management system requirements are a coretopic addressed in this international standard. Regardingcontamination control, the frequent references to the ISO 14644series of cleanroom technology standards are worthy of note.

Author:Hans Schicht

A comprehensive biographical note accompanied Part 1 of this article in Issue 60 of the Monitor.

9

Another example is GAMP 5, the guideline published earlier thisyear6 (see also Martin and Perez7) on Good AutomatedManufacturing Practices for computerized systems prepared byISPE, the International Society for Pharmaceutical Engineers. Justlike ISPE itself which has, from its origins in the USA, grown into aglobal professional organisation with chapters all over the world, this352-page compendium has been prepared by a truly global team ofprofessionals: three Steering Committees were involved coveringthe Americas, Europe and Japan, as well as representatives not onlyfrom FDA, but also from the regulatory authorities of a number ofother nations. GAMP 5 explicitly encourages science-based qualityrisk management procedures as exemplified by the ICH Q8-Q10series, and is devoted to the establishment of links between thesephilosophies and compliance with the current GxP manuals.

Good Practices guidance for pharmaciesFor implementing the new quality risk management philosophies,GxP guidance documents continue to be indispensable, andadditions to them continue to be published. A recent compendiumof this kind is PIC/S PE 010-1: Guide to Good Practices for thePreparation of Medicinal Products in Healthcare Establishments8elaborated by PIC/S, the Pharmaceutical Inspection Co-operationScheme of PIC, the Pharmaceutical Inspection Convention. Itsobjective is to extend the quality philosophies of the GMP guides forindustry into the world of patient-specific individual preparations.The manufacturing task of healthcare establishments can beextremely complex and varied. Typical product classes requiringsterile preparation and therefore a well-controlled environment are:

• cytotoxics and radiopharmaceuticals with a high hazard level for theoperator preparing the product and a high risk of preparation error

• total parenteral nutrition solutions, which may be of very complexcomposition and are associated with a high risk of microbialcontamination and of preparation error

• infusions, which sometimes are administered over significantperiods of time, the temperature being at or near bodytemperature where once more the risk of microbial growth is to becontrolled, a risk sometimes aggravated by the fact that solutionsmay promote bacterial and/or fungal growth

In PIC/S PE 010-1, the specific situation of healthcare establishmentssuch as hospital pharmacies is duly taken into consideration -without compromising the stringent quality thinking. The guide is astand-alone document which requires no reference to other qualitymanagement compendia. It follows the basic structure of Part I ofthe European Community’s GMP guide for medicinal products.However, there are only two annexes: one of whichcomprehensively devoted to the preparation of sterile products.

The new PIC/S guide sometimes goes beyond the determinations ofAnnex 1 of the EU GMP guide for industrial manufacturing ofmedicinal products, for example regarding classification tests: therecommended frequencies are given in Table 1. An annual integritycheck, for instance, is required for HEPA filters - a topic surprisinglynot even mentioned in Annex 1 to the EU GMP guide.

Tables 2 and 3 present the requirements for the monitoring ofphysical and microbiological parameters. The room gradedeterminations follow exactly those established in the February2008 edition of Annex 1 to the EU GMP guide.

Annex 1 to the EU GMP guide– a minimum of commentsThe new edition of Annex 1 to the EU GMP guide has beenexhaustively commented upon in the S2C2 Cleanroom Monitor andelsewhere 9-11. Just one remark: in this age of science-basedregulatory compendia, it is difficult to understand why the terms“laminar airflow” and “laminarity” have not been replaced by thescientifically correct terms “unidirectional airflow” and “uniformityof airflow” as employed without exception both in the ISO series ofcleanroom technology standards and in the FDA Guidance forIndustry on aseptic processing of medicinal drugs.

ISO cleanroom technology standards:towards new horizonsRegarding trends in cleanroom technology standardization: therecent publication of the Draft International Standard ISO/DIS14644-9 Classification of Airborne Particulate Cleanliness12-13 opensup a new dimension to the ISO 14644 family of standards. So far,these standards have focussed upon the air cleanliness requirementsrelevant for design, construction, start-up and operation ofcleanroom systems. All determinations regarding surfaces andsurface cleanliness in Parts 1-8 of the series have a cleanroom bias.

ISO/DIS 14644-9, however, addresses surface particulate cleanlinessfrom the product perspective. In parallel to the air cleanlinessclassification scheme established in ISO 14644-114, the surfacecleanliness classification scheme is based upon a formula shown inTable 4. Table 5 presents selected surface cleanliness classes intabular form and Fig. 1 as a graph. The particle diameter rangecovered stretches from 50 nm = 0.05 µm up to macroparticles of500 µm and above. Such macroparticles are irrelevant to theclassification of airborne particles as they will sediment out of the airwithout delay. But exactly because of the sedimentation theybecome very relevant from the surface point of view.

ISO/DIS 14644-9 is soon to be followed by a standard on surfaceinteractions with airborne molecular contamination.

Summing upMany trends are apparent in the development of standards andregulatory guidance: international collaboration, increasingcomplexity and detail, new application areas such as the hospitalpharmacy. The dominating trend, however, seems to be thetriumphant advance of quality risk management systems and theirfocus upon continuous improvement and concentration on the trulyrelevant risks. This trend will certainly drive technical andprocedural progress in industry as well as progress in regulations andstandards relevant for contamination control. Wouldn’t it be great ifsuch quality risk management philosophies could also spread intothe chaotic financial world?

Feature

ContinuedCleanroom technology for life science applications Part 2: Regulatory issues, standards and guidelines

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References1. Guidance for industry: Sterile drug products produced by aseptic processing -current Good Manufacturing Practice. U.S. Department of Health and HumanServices, Food and Drug Administration, Rockville MD/USA (September 2004).2. European Commission. Eudralex: The rules governing medicinal products in theEuropean Union, vol. 4: EU guidelines to Good Manufacturing Practice - Medicinalproducts for human and veterinary use: Annex 1: Manufacture of sterile medicinalproducts. Brussels, 14 February 2008.3. Ch. Potter: Review of status of ICH guidelines. GMP Review 7 (2008) 1, 4-9.4. ICH Harmonized Tripartite Guideline Q10: Pharmaceutical quality system.European Medicines Agency, London (June 2008).

5. ISO 13408-1: Aseptic processing of health care products - Part 1: Generalrequirements. International Organization for Standardization ISO, Geneva (secondedition June 2008).6. GAMP 5: A risk-based approach to compliant GxP computerized systems. ISPE -The International Society for Pharmaceutical Engineers - in collaboration with FDAand other regulatory authorities. Tampa FL/USA (2008).7. Martin K.C., Perez A.: GAMP 5 quality risk approach. Pharmaceutical Engineering28 (2008) 3, 24-34.8. PIC/S PE 010-1: PIC/S guide to good practices for preparation of medicinalproducts in pharmacies. Pharmaceutical Inspection Co-operation Scheme PIC/S,Pharmaceutical Inspection Convention PIC, Geneva (1 April 2008).9. Eaton T.: EU GMP Annex 1:2008 & airborne particle limits - early considerationsfrom a cleanroom user. The S2C2 Cleanroom Monitor issue 59 (March 2008), p. 5-9.10. Neiger J.: Sterile medicines: Annex 1 arrives. Cleanroom Technology 15 (2008) 4,26-27.11. Schicht H.H.: Trends in pharmaceutical cleanroom technology. EuropeanPharmaceutical Review 13 (2008) 1, 53-60.12. ISO/DIS 14644-9: Cleanrooms and associated controlled environments - Part 9:Classification of surface particle cleanliness. International Organization forStandardization ISO, Geneva (July 2008).3. Anon.: Defining surface cleanliness. Cleanroom Technology 15 (2008) 6, 26-27. 14.ISO 14644-1: Cleanrooms and associated controlled environments - Part 1:Classification of air cleanliness. International Organization for Standardization ISO,Geneva (May 1999; presently in revision).

About the AuthorHans H. Schicht, Dr. sc. techn.is an independent consultant,specialising in cleanroom andcontamination control technology,based in Switzerland.

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