Cleanroom Standards and Updates

Cleanroom Standards / Environmental Guides FED-STD 209E: Established Sept, 1992: Cancelled November 2001 ISO 14644-1: Established May 1999 (replaces Fed-STD 209E, BS 5295) EU GGMP Annex 1 ISO 14644 DRAFT

Federal Standard 209E CLASS NAME FED-STD 209 0.1µM 0.2µM 0.3µM 0.5µM 5.0µM VOLUME UNITS VOLUME UNIT VOLUME UNIT VOLUME UNIT VOLUME UNIT S.I. ENGLISH (M 3 ) (FT 3 ) (M 3 ) (FT 3 ) (M 3 ) (FT 3 ) (M 3 ) (FT 3 ) (M 3 ) (FT 3 ) M1 350 9.91 75.7 2.14 30.9 0.875 10 0.283 M1.5 1 1240 35 265 7.5 16 3 35.3 1 M2 3500 99.1 757 21.4 309 8.75 100 2.83 M2.5 10 12,400 350 2,650 75 1,060 30 353 10 M3 35,000 991 7,570 214 3,090 87.5 1,000 28.3 M3.5 100 26,500 750 10,600 300 3,530 100 M4 75,000 2,140 30,900 875 10,000 283 M4.5 1000 35,300 1,000 247 7 M5 100,000 2,830 618 17.5 M5.5 10,000 353,000 10,000 2,470 70 M6 1,000,000 28,300 6,180 175 M6.5 100,000 3,530,000 100,000 24,700 700 M7 10,000,000 283,300 61,800 17,500 IEST WG 100 has recommended to the GSA (U.S. General Services Group) that they (GSA) discontinue the use and maintenance of FED-STD-209. The next step is for GSA to poll the U.S. Federal Agencies on the proposal that FED-STD-s09 be dropped and that the Federal Agencies use ISO 14644-1 and 2. Many organizations refuse to change, stating the cost of document changes are too expensive to warrant replacement of the standard. It is commonly accepted still in some facilities in the United States and in Asia.

ISO 14644-1 ISO Classification Number ISO 14644-1 Cleanroom Classification 0.1µM 0.2µM 0.3µM 0.5µM 1.0µM 5.0µM VOLUME UNITS VOLUME UNIT VOLUME UNIT VOLUME UNIT VOLUME UNIT VOLUME UNIT (M 3 ) (M 3 ) (M 3 ) (M 3 ) (M 3 ) (M 3 ) ISO 1 10 2 ISO 2 100 24 10 4 ISO 3 1,000 237 102 35 8 ISO 4 10,000 2,370 1,020 352 83 ISO 5 100,000 23,700 10,200 3,520 832 29 ISO 6 1,000,000 237,000 102,000 35,200 8,320 293 ISO 7 352,000 83,200 2,930 ISO 8 3,520,000 832,000 29,300 ISO 9 35,200,000 8,320,000 283,000

EU Guide to Good Manufacturing Annex 1 Manufacture of Sterile Medicinal Products Maximum permitted number of particles / m 3 Grade A 0.5µM 3,520 at rest equal to or above in operation 5µM 0.5µM 5µM 20 3,520 20 B 3,520 29 352,000 2,900 C 352,000 2,900 3,520,000 29,000 D 3,520,000 29,000 Not defined Not defined

Comparison ISO 14644-1 FED STD 209 1 2 3 1 4 10 EU GMP (At rest) EU GMP (Operation) 5 100 Grade A/B Grade A 6 1000 7 10,000 Grade C Grade B 8 100,000 Grade D Grade C 9

ISO 14644-1 Draft International Standard ISO Technical Committee 209 (TC 209) has been working on the revision of the basic airborne cleanliness classification standard for the last 4 years and has voted in favor of revision to update and improve the standard specifically to address the following: Simplify the classification process Remove the need to evaluate the 95% UCL for 2-9 sample locations Review the classification procedure and make it more applicable to rooms in operation. Generally update the standard as required to current thinking and industry requirements Avoid any radical change to the principles of the current ISO cleanliness classes 1-9

ISO 14644-1 Draft International Standard The DIS (draft International Standard). The revised standard has some important new and revised requirements: The classification would be based on a table (see fig.1.), With the well known formula used for the intermediate decimal classes In the current standard, the table is provided in an informative annex (see fig.3.). By using a look-up table as the basis for classification, it is easier to constrain the reader to appropriate particle sizes for specific classes

Fig.1 The basic classification table proposed in ISO DIS 14644-1:2010 ISO Classification Number (N) Maximum allowable concentrations (particles / m³) for particles equal to and greater than the considered sizes shown below a) ISO 14644-1 &- 2 Draft International Standards 0.1µm 0.2µm 0.3µm 0.5µm 1.0µm 5.0µm ISO Class 1 10 b d d d d e ISO Class 2 100 24 10 b d d e ISO Class 3 1,000 237 102 35 b d e ISO Class 4 10,000 2,370 1,020 352 83 b e ISO Class 5 100,000 23,700 10,200 3,520 832 e ISO Class 6 1,000,000 237,000 102,000 35,200 8,320 293 ISO Class 7 c c c 352,000 83,200 2,930 ISO Class 8 c c c 3,520,000 832,000 29,300 ISO Class 9 c c c 35,200,000 8,320,000 293,000 a All concentrations in the table are cumulative, e.g. for ISO Class 5, the 10 200 particles shown at 0,3 µm include all particles equal to and greater than this size. b These concentrations will lead to large air sample volumes for classification. Sequential sampling procedure may be applied; see Annex D. c Concentration limits are not applicable in this region of the table due to very high particle concentration. d Sampling and statistical limitations for particles in low concentrations make classification inappropriate. e Sample collection limitations for both particles in low concentrations and sizes greater than 1 μm make classification inappropriate, due to potential particle losses in the sampling system.

ISO 14644-1 Draft International Standard The current standard had a simple calculation for the minimum number of sample points: In DIS: The selection of number of sample locations has been based on a more rational basis intended to confirm with 95% confidence that 90% of the cleanroom will meet the intended classification.

Area of cleanroom (m²)) less than or equal to ISO 14644-1 &- 2 Draft International Standards Minimum number of sample Locations to be tested (N L ) 1 1 2 1 4 2 6 3 8 4 10 5 24 6 28 7 The selection of number of sample locations has been based on a more 32 8 rational basis intended 36 to confirm with 95% confidence that 990% of the cleanroom will meet 52 the intended classification. 10 56 11 NOTE 1 The number of 64 12 68 sample locations are based 13 72 on area units of 1, 2, and 4 14 76 15 m², to achieve 95 % 104 16 confidence that at least 90 % 108 17 116 of the total area does not 18 148 exceed the class limit. 19 156 20 192 21 232 22 276 23 352 24 436 25 500 26

Area of cleanroom (m²)) less than or equal to ISO 14644-1 &- 2 Draft International Standards The selection of number of sample locations has been based on a more 32 8 6 rational basis 36 intended to confirm with 95% 9 confidence that 90% of 6 the cleanroom will 52 meet the intended classification. 10 Comparison 8 56 11 8 DIS verse DIS 1 1 CURRENT 2 1 2 4 2 2 6 3 3 8 4 3 10 5 4 24 6 5 28 7 6 64 12 8 CURRENT. 68 13 9 72 14 9 76 15 9 104 16 11 108 17 11 116 18 11 148 19 13 156 20 13 192 21 14 232 22 16 276 23 17 352 24 19 436 25 21 500 26 24

ISO 14644-1 Draft International Standard A semi-random sampling technique is proposed based on a "hypergeometric" distribution, which is the statistical model for sampling without replacement. This is a significant change from current practice, and means that each time a zone is classified, the sample locations may be different. If a firm has determined through a risk assessment, that certain locations need to be examined specifically, then these should be designated in addition to the randomly selected locations

ISO 14644-1 Draft International Standard What about 5.0µm in Grade A and B? Recognizing that the <=5.0 micron class limit for ISO 5 has been removed in the revised standard, parties wishing to use the standard for classifying the environments EU GMP Grade A, and B "at rest" will have to use the macroparticle descriptor retained in the standard.

ISO 14644-1 International Standard Particle Counter Calibration Normative reference The following normative document contains provisions, which, through reference in this text, constitute provisions of this part of ISO 14644. Subsequent amendments to or revisions of this publication do not apply. However, parties to agreements based on this part of ISO 14644 are encouraged to investigate the possibility of applying the most recent editions of the normative document indicated below. ISO 21501-4:2007, Determination of particle size distribution Single particle light interaction methods Part 4: Light scattering airborne particle counter for clean spaces

ISO 14644-2 Draft International Standard Title Change: Old: 2000 Cleanrooms and associated controlled environments Part 2: Testing and monitoring to prove continued compliance with ISO 14644-1 New: 2010 Cleanrooms and associated controlled environments Part 2: Specifications for monitoring and periodic testing to prove continued compliance with ISO 14644-1

ISO 14644-2 Draft International Standard Frequency intervals removed 4.2 Monitoring and periodic testing plan Requires a documented monitoring and periodic testing plan Plan to be based upon an assessment of risks

ISO 14644-1 &- 2 Draft International Standards Recertification: Table One Removed Classification Maximum time interval Test method ISO Class 5 6 months Annex B ISO 14644-1:1999 > ISO Class 5 12 months Annex B ISO 14644-1:1999 NOTE: Particle Count tests will normally be performed in the operational state, but may also be performed in the at-rest state in accordance with the designated ISO classification Every Year Now for ALL Classes Table 1 --Schedule of testing to demonstrate compliance with particle concentration limits.

It s a Draft, Baby, only a Draft If you really care and want to comment: http://drafts.bsigroup.com/home/details/657 http://www.iso.org/iso/iso_technical_committee.html?commid=54874

TC 209 - Cleanrooms and associated controlled environments Participating countries: 22 Observing countries: 19 Participating Countries: 22 Secretariat: USA (ANSI) Australia (SA) Kenya (KEBS) Belgium (NBN) South Korea (KAT) Brazil (ABNT) Netherlands (NEN) China (SAC) Norway (SN) Denmark (DS) Philippines (BPS) Finland (SFS) Portugal (IPQ) France (AFNOR) Russian Federation (GOST R) Germany (DIN) Sweden (SIS) Ireland (NSAI) Switzerland (SNV) Italy (UNI) United Kingdom (BSI) Japan (JISC) Observing Countries: 19 Argentina (IRAM) Bosnia and Herzegovina (BAS) Bulgaria (BDS) Cuba (NC) Czech Republic (UNMZ) Egypt (EOS) Hungary (MSZT) India (BIS) Iran (ISIRI) Jamaica (BSJ) Malaysia (DSM) Poland (PKN) Romania (ASRO) Saudi Arabia (SASO) Serbia (ISS) South Africa (SABS) Thailand (TISI) Turkey (TSE) Ukraine (DSSU)