ISO 14644-1:2015CLEANROOMS & ASSOCIATED CONTROLLED

ENVIRONMENTS

PART 1: CLASSIFICATION OF AIR CLEANLINESS BY PARTICLE

CONCENTRATION Anwar Munjewar

Quality Assurance DepartmentBharat Serums and Vaccines Limited

ABOUT INTERNATIONAL ORGANIZATION FOR STANDARDIZATION

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HOW DOES ISO DEVELOP STANDARDS?

New Standards is proposed to

relevant technical

committee

Working group of

experts start discussion to

prepare a working draft

1st working draft shared

with technical committee and ISO CS

Draft shared with all ISO

national members, who are asked to comment

Final draft sent to ISO members

ISO Internation

al Standards

If proposal is accepted

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ISO TECHNICAL COMMITTEE 209Cleanroom associated with controlled environments

■ Participating Country : 22

■ Observing Country : 19

Secretariat: USA (ANSI) Australia (SA) Kenya (KEBS)Belgium (NBN) South Korea (KAT)

Brazil (ABNT) Netherlands (NEN)

China (SAC) Norway (SN)Denmark (DS) Phillipense (BPS)Finland (SFS) Portugal (IPQ)

France (AFNOR) Russian Federation

Germany (DIN) Sweden (SIS)Ireland (NSAI) Switzerland (SNV)

Italy (UNI) United Kingdom (BSI

Japan (JISC)

Argentina PolandBosnia and Herzegovina Romania

Bulgaria Saudi ArabiaCuba SerbiaCzeh Republic South AffricaEgypt ThailandHungary TurkeyIndia UkraineIranJamaicaMalaysia

ISO PARTS & STATUS■ Part 1: Classification of air cleanliness by particle concentration (15th

Dec 2015)■ Part 2: Monitoring to provide evidence of cleanroom performance

related to air cleanliness by particle concentration (15th Dec 2015)■ Part 3: Test Methods (DIS 2014)■ Part 4: Design, construction and start-up (2001)■ Part 5: Operations (2004)■ Part 6: Vocabulary (2006)■ Part 7: Separative devices (clean air hoods, gloveboxes, isolators and

environments) (2007)■ Part 8: Classification of air cleanliness by Chemical concentration (2013)■ Part 9: Classification of surface cleanliness by Particle concentration (2012)■ Part 10: Classification of surface cleanliness by Chemical concentration

(2013)Note: There is no Part 11 in ISO 14664, and Part 12 – Part 16 is under

process(Draft).

SCOPE■ Only particle populations having cumulative distributions based on threshold

(lower limit) particle sizes ranging from 0.1 µm to 5.0 µm are considered for classification purposes.

■ Light scattering (discreet) airborne particle counters (LSAPC) is the basis for the determination of the concentration of airborne particles equal to and greater than the specified sizes, at designated sampling locations.

■ ISO 14644 does not provide for the classification of particle populations that are outside the specified lower threshold particle size range 0.1 µm to 5.0 µm.

■ An M descriptor may be used to quantify populations of macroparticles (particles larger than 5 µm).

■ The standards also allow the addition of location to the minimum number of sampling locations.

■ Calculation for Number of location changed and 95% UCL completely removed.

ISO Class Number

Method for Classification of Air Cleanliness by Particle Concentration■ Apparatus: Light Scattering Airborne Particle Counter (LSAPC)■ Establishment of Sampling locations:

– Drive the number of sampling locations from the Table 1– Positioning the sampling locations– Sampling locations for large cleanrooms or clean zone– Establishment of single sample volume and sampling time per

locations– Processing of results– Interpretation of result

A.4.1 Sampling locations related to cleanroom areaAREA LOCATIONS AREA LOCATIONS

2 1 76 154 2 104 166 3 108 178 4 116 1810 5 148 1924 6 156 2028 7 192 2132 8 232 2236 9 276 2352 10 352 2456 11 436 2564 12 636 2668 13 1000 2772 14 >1000 Formula

A.4.2 Positioning the sampling locations Use the minimum number of sampling locations NL derived from

the Table 1 Divide the whole cleanroom or clean zone into NL section of equal

area Select within each section a sampling location considered to be

representative of the characteristics of the section Additional sampling locations may be selected for locations

considered criticalA.4.3 Sampling locations for large cleanrooms or clean zone When the area of a clean room is greater than 1000 meter

square.

NL- is the minimum number of sampling locations to be evaluated A- is the area of the clean room in meter square.

A.4.4 Establishment of single sample volume and sampling time per locations

At sample location, sample a volume of air sufficient to detect a minimum of 20 particles if the particle concentration for the largest selected particle size were at the class limit for the designated ISO class

Single sample volume:) x 1000

Where,

Vs – is the minimum single volume per location (expressed in liters)

Cn,m – is the class limit (number of particles per cubic meter) for the largest considered particle size.

20 – is the number of particles that could be counted if the particle concentration were at the class limit.

A.6 Processing of results:A.6.1 Recording of results:

– Record each sample measurements as the number of particles in each single sample volume.

– When two or more single sample volume are taken at a location, calculate and record the average number of particles per location at each considered particle size.

– For particle counters with concentration calculation mode, the manual evaluation may not be necessary. (i.e. counts per litter to counts per cubic meter)

A.6.2 Interpretation of result:– If an out-of-specification count found at a location due to an identified

abnormal occurrence, then that count can be discarded and noted as such on the test report and a new sample taken.

– If an out-of-specification count found at a location is attributed to a technical failure of the cleanroom or equipment, then cause should be identified, remedial action taken and resting performed of the failed sampling location, the immediate surroundings locations and any other locations affected. The choice shall be clearly documented and justified.

ISO 14644-1:2015(E) ANNEX■ Annex A – Reference Method For Classification Of Air Cleanliness By

Particle Concentration ■ Annex B – Examples Of Classification Calculations■ Annex C – Counting And Sizing Of Airborne Macroparticles (M

descriptor)■ Annex D – Sequential Sampling Procedure : NA■ Annex E – Specification Of Intermediate Decimal Cleanliness Classes

And Particle Size Thresholds : NA■ Annex F – Test Instruments : NA

Why Does the Pharmaceutical Industry Love 5.0 μm particles?

■ EU inspectors maintain that large particles are potential carriers (hitch-hikers) of, or are viable organisms themselves. If these particles are present in an aseptic environment, they represent an increased risk of contamination of the sterile product. Most ISO Class 5 (Grade A) clean zone shave counts of zero or one on the >= 5 μm size channel. Viable microorganisms, whose individual sizes are generally less than 1 μm, tend to form in pairs, chains, and clusters. These colony forming units together often have a size greater than 5 μm. Therefore, a particle counter is like the “canary in a coal mine”, because it provides an early warning of a potential problem.

■ It is worth while noting that USFDA cGMP 2004 does not require measurement of 5um particles in ISO Class 5.

Counting and Sizing of Airborne Macroparticles – M Descriptor

■ The test method describe the measurement of airborne particles with a threshold size ≥ 5 µm in diameter(macroparticles).

■ The number of sampling location, location selection and quantity of data required should be in accordance with A.4.

■ M descriptor format:“ISO M (a;b); C”

Where, a- is the maximum permitted concertation of macroparticles (in cubic meter)b- is the equivalent diameter associated with the specified method for

measuring macroparticles.c- is the specified measurement method.

Example : To express an airborne concentration of 29 particles per cubic meter in the particle size range ≥ 5 µm using LSAPC

“ ISO M (29; ≥ 5 µm ); LSAPC”

Annex A of ISO 14644-1:2015

■ Clause A.2 Apparatus Requirements, under A.2.2 Instrument Calibration specifies that the particle counter shall have a valid calibration certificate, the frequency and method of calibration should be based upon ISO 21501-4

■ Old ISO14644 specified calibration be performed by suitable method. New revision recognises some of the older particle counters (ex. those manufactured prior to 2011) cannot be calibrated to all of the required tests in ISO21501-4

■ Some details of this new calibration standard are given in the next two slides, a detailed presentation is available from the author.

ISO 21501-4 Calibration

■ Parameters that will now be required– Size Calibration (Using NIST traceable particles)– Size Verification– Counting Efficiency (50% and 100%)– Size resolution (equal to or less than 15%)– False Count Rate (1 or less in 15 minutes)– Maximum Concentration (before coincidence loss) – Flow Rate (Uncertainty of 5% or less)– Sample Time (Uncertainty of 1% or less)– Response Rate (0.5% or less)– Calibration Interval ( not to exceed 1 year)– Test Report (minimum information required)

SummaryISO14644-1:1999 ISO14644-1:2015

Title ChangePart 1 : Classification of air cleanliness

Part 1 : Classification of air cleanliness by particle concentration

Ultra and Macro (U,M) DescriptorsSmaller than 0.1 microns defined as U, >than 5 microns defined as M.

Smaller than 0.1 micron particles will no longer exist in ISO 14644-1. This issue addressed in ISO 14644-12 (Air cleanliness by nanoparticles).

Annex A Informative (Graphical Illustration of classes)

Annex A (normative) Reference method for determination of classificationTable E.1 of Annex E provides permitted intermediate air cleanliness classes in increments of 0.5 (3.5, 4.5, 5.5etc.)No graphical illustration

SummaryISO14644-1:1999 ISO14644-1:2015ISO Class 5, 5.0 micron – 29 Particles No more Class 5, 5.0 micron size

Sample Numbers and LocationsSquare-root method for sample numbers.Grid for sample locations

Table A.1. (Fixed numbers). Sections of equal area, within each section select location representative of characteristics of the section

Apparatus for Particle Count DPC = Discrete Particle Counter

LSAPC = Light Scattering Airborne Particle Counter

ParticleSizes in Classification TableISO Class 1: 0.2 um = 2 particles ISO Class 2: 0.5 um =4 particles ISOClass 3: 1.0 um = 8 particlesISO Class 5: 5.0 um = 29 particles

Since it is possible to classify a cleanroom at one particle size only, these low table values are removed and cannot be used for classification.

95% Upper Confidence Limit>1 & <10 sample points, 95% UCL should be calculated

95% UCL removed completely

Thank-you..!for your attention.

Have a wonderful day ahead…