Changes to Cleanroom and Clean Zone Standards ISO 14644 Parts

Changes to Cleanroom and Clean Zone

Standards ISO 14644 Parts 1 & 2

Are You Prepared?

ROBERT P. TOMASELLI, CONSULTANT

RPT MEDICAL PRODUCTS CONSULTING INC 1


Background – ISO 14644-1 vs. FS209E

Before 1999: U.S. General Service Administration’s standards FS209E applied worldwide

1999: global cleanroom classifications and standards adopted by ISO (International Standards Organization) – ISO 14644 series

Federal Standard 209E superseded internationally by ISO 14644-1

NOTE: EU GMP and USA GMP define airborne particle counts/m3 for each cleanliness class/grade referencing ISO 14644-1, they do not contain guidance on the cleanroom classification procedure

ISO 14644-1 FEDERAL STANDARD 209E

ISO Class English Metric

ISO 1

ISO 2

ISO 3 1 M1.5

ISO 4 10 M2.5

ISO 5 100 M3.5

ISO 6 1,000 M4.5

ISO 7 10,000 M5.5

ISO 8 100,000 M6.5

ISO 9


ISO 14644-1 and ISO 14644-2

ISO 14644-1:2015 Cleanrooms and associated controlled environments – Part 1: Classification of air cleanliness by particle concentration

• Specifies classes of air cleanliness in terms of the number of particles in air volume

• Specifies the standard methods of testing to determine cleanliness classes, including the selection of sampling locations and the use of light scattering airborne particle counters (LSAPC)

ISO 14644-2:2015 Cleanrooms and associated controlled environments — Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration

• Specifies the requirements for a monitoring plan based on risk assessment of the intended use

• Data obtained provide evidence of cleanroom or clean zone performance related to air cleanliness by particle concentration


ISO 14644 Parts 1-10

Part 1: Classification of air cleanliness by particle concentration

Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration

Part 3: Test methods (NOTE: specifies ancillary tests related to other aspects of cleanroom performance such as pressure difference, airflow, etc.)

Part 4: Design, construction and start-up

Part 5: Operations

Part 7: Separative devices (clean air hoods, gloveboxes, isolators and mini-environments)

Part 8: Classification of air cleanliness by chemical concentration (ACC)

Part 9: Classification of surface cleanliness by particle concentration

Part 10: Classification of surface cleanliness by chemical concentration


ISO 14698 – Normative* References

Also, indispensable for the application of ISO 14644 Part 1 & 2:

ISO 14698, Cleanrooms and associated controlled environments – Biocontamination controlPart 1: General principles and methods

Part 2: Evaluation and interpretation of biocontamination data

ISO 21501-4, Determination of particle size distribution - Single particle light interaction methods - Part 4: Light scattering airborne particle counter for clean spaces

*normative = must comply


ISO 14644-1:1999 to ISO 14644-1:2015

ISO/TC 209 - Systematic Review Process; changes made in response to user and expert feedback validated by international enquiry

Largely Unchanged:

• Nine cleanliness classifications retained with minor revisions to the specification limits –ISO Class N

• Table I - maximum particle concentration at various particle sizes for the nine classes

• Table E.1 - maximum particle concentration at various particle sizes for intermediate classes

• Macroparticle Descriptor concept for macroparticles (> 5 microns)


ISO 14644-1:1999 to ISO 14644-1:2015

Most significant changes:

More consistent (accurate) statistical approach to the selection and number of sampling locations and the evaluation of data collected

Elimination of 95% UCL calculation - new method, when successfully applied, assures at least 90% of the cleanroom and clean zone is in compliance at a 95% confidence limit

The minimum number of samples (in new Look-Up Table A.1) has increased compared to ISO 14644-1:1999 – replaces N-L = √A

The cleanroom or clean zone is sub-divided into a grid of sections whose number is equal to the number of sampling locations in Table A.1. A sampling location is placed within each grid section to represent that grid section (risk based approach)• Measurements taken at random from within each sub-division

• Each location should be newly randomized at each classification / re-qualification

• Additional samples should be taken at locations identified as high risk


ISO 14644-1:1999 to ISO 14644-1:2015

Most significant changes (continued):

Cleanroom and clean zone layout, equipment disposition and air flow systems should be considered in selecting sampling locations. Additional sampling locations can be added to the minimum number of sampling locations

The ≥ 5 µm particle limits for ISO Class 5 has been eliminated from Table 1 - Reasons: sampling and statistical limitations for particles in low concentrations make classification inappropriate; potential losses in the sampling system

Caution: the current EU, PIC/S and WHO GMPs still require measuring ≥ 5µm particles in Grade A and Grade B environments for both classification/re-qualification and monitoring events

• To specify the ≥ 5 µm particle size for ISO Class 5, the M descriptor may be adapted and used in conjunction with the ≥ 0.5 µm particle size


ISO 14644-1:1999 to ISO 14644-1:2015

Other changes:

Normative references: ISO 21501-1, ISO 14698-1 and -2

The annexes reordered and parts of ISO 14644-3:2005 concerning testing and test instruments have been included

NOTE: ISO 14644 cannot be used to characterize the physical, chemical, radiological, viable and other nature of airborne particles


ISO14644-1:2015 – Clause 3

Additional Terms and Definitions:

Unidirectional airflow – controlled airflow through the entire cross-section of a cleanroom or a clean zone with a steady velocity and airstreams that are considered to be parallel

Non-unidirectional airflow – air distribution where the supply air entering the cleanroom or clean zone mixes with the internal air by means of induction

Testing instrumentation - see Annex F

Instrument Specifications – LSAPC - see Annex F.1 and F.2

Macroparticle (M) Descriptor: designation for measured concentration of macroparticles per cubic meter of air. The M descriptor is an upper limit for the averages at sampling locations. It cannot be used to define ISO Classes but can be quoted independently or in conjunction with ISO Classes. See Annex C


ISO14644-1:2015 – Clause 4

Three Occupancy States:

• As-built

• At-rest

• Operational

At-rest and operational classification should performed periodically based upon risk assessment of the cleanroom and clean zone operations, typically on an annual basis

Where the cleanroom and clean zone is equipped with instrumentation for continuous or frequent monitoring of air cleanliness (airborne particles, room pressure differentials), the time intervals between classification may be extended provided that the results of the monitoring remain within the specified limits. However, in the pharmaceutical and related industries formal classification / re-qualification must be undertaken at least annually.


ISO 14644-1:2015 – Clause 5

Comprehensive Test Report and Statement of Compliance (or non-compliance):

Name and address of the testing organization and the date test was performed

Reference ISO 14644-1:2005

Identification of the physical location of the cleanroom or clean zone tested and specific designations for coordinates of all sampling locations (a diagrammatic representation)

The specified designation criteria for the cleanroom and clean zone, including the ISO Class number, the relevant occupancy state(s), and the considered particle size(s), e.g., ISO Class 5; at-rest, 0.5 µm

Details of the test methods used, with any special conditions relating to the test, or departures from the test methods, and identification of the test instrument and its current calibration certificate

The test results, including particle concentration data for all sampling locations


ISO 14644-1:2015 Annexes

Annex A (normative*)

• Sampling locations for large cleanrooms or clean zones – minimum number (Table A.1)

• Sample volume and sampling time per location

• Sampling procedure: recording results, calculating the concentration per m3

• Interpretation of results

• Reference to ISO 21501-4 – normative calibration procedure and verification method for particle counters

Annex B (informative**)

• Six examples of classification calculations

*normative = must comply with this section

**informative = additional information that compliment the user’s understand


ISO 14644-1:2015 Annexes

Annex C (informative)

• Counting and sizing of airborne macroparticles – M descriptor

• Adaptation of the M descriptor for ≥ 5 µm particle size for ISO Class 5 cleanrooms

o Express an airborne concentration of 29 particles/m3 in the particle size range ≥ 5 µm based on the use of an LSAPC as “ISO M (29 ≥ 5 µm)”

Annex D (informative)

• Sequential sampling procedure (for environments with very low particle concentrations, i.e., a count of <20 for the largest particle size)

Annex E (informative)

• Specification of intermediate decimal cleanliness classes and particle size thresholds

Annex F (informative)

• Test instrument specifications


ISO 14644-1:2015 Annex A (normative)

Recommend witnessing all classification/re-qualification events! Gowning, disinfection of equipment and surfaces, execution, data analysis, any deviations, etc.

Apparatus requirements (references: ISO 21501-4 and ISO 14644-3):

• Particle-counting instrument (LSAPC)

• Instrument calibration

Establishment of sampling locations

Deriving the number of sampling locations from Table A.1


ISO 14644-1:2015 Annex A (normative)

Positioning the sampling locations:• Use the minimum number of sampling locations

• Divide the whole cleanroom or clean zone into the number of sections of equal area (gird diagram)

• Select within each section of gird a sampling location considered to be representative of the characteristics of the section

• At each location, position the particle counter probe in the plane of the work activity or another specified point

Additional sampling locations may be selected for locations considered critical (based on risk assessment)

Non-unidirectional airflow cleanrooms or clean zones: sampling locations may be included if directly beneath non-diffused supply air

Questions?



ISO 14644-2:2000 to ISO 14644-2:2015

ISO 14644-2:2015 Cleanrooms and associated controlled environments — Part 2: Monitoring to provide evidence of cleanroom performance related to air cleanliness by particle concentration

• specifies the minimum requirements for a monitoring plan based on risk assessment of the intended use

• data obtained provide evidence of cleanroom or clean zone performance related to air cleanliness by particle concentration (in accordance with ISO 14644-1:2015)


ISO 14644-2:2000 to ISO 14644-2:2015

ISO/TC 209 - Systematic Review Process; changes in response to user and expert feedback validated by international enquiry

Largely unchanged requirements:

• Revise the monitoring plan when significant changes are made to the installation or process requirements

• Conduct periodic reviews of a monitoring plan based on data obtained and experience in use


ISO 14644-2:2000 to ISO 14644-2:2015

Most significant changes:

Major rewrite emphasizing a monitoring strategy documented in a monitoring plan, a formal risk assessment, and the use of statistical methods to detect trends

New guidance in Annex A (informative) - lists considerations when specifying a real-time particle monitoring system based on formal risk assessment, including:

• Definition of operational conditions and understanding of contamination sources and other factors

• Identification of critical sample locations

• How data collected are evaluated and reported

• Acceptance/Rejection criteria

NOTE: similar guidance is given for real-time room pressure differential monitoring systems and airflow velocity and volume monitoring

New guidance in Annex B (informative) – lists considerations for setting alert and action levels for airborne particle counts and pressure differential monitoring – references ISO 14644-3 for ancillary tests


ISO 14644-2:2015 Clause 3

Clause 3 changes:

Action Level – level of a parameter set by the user which, when exceeded, requires immediate intervention, including investigation of cause, and corrective action

Alert Level – level of a parameter set by the user giving early warning of a drift from normal conditions, which, when exceeded, should result in increased attention or corrective action

NOTES• For ISO 14644-2, the parameter in question is the concentration of airborne particles (only)

• Ensure internal procedures are consistent with these definitions


ISO 14644-2:2015 Clause 4

Clause 4.1 - Principle

Create, implement and maintain a monitoring plan:• Use appropriate risk assessment tools to understand, evaluate and document the risk of adverse

contamination events – including the identification of “critical locations”

• Develop a written monitoring plan; review and approve

• Implement the plan by performing monitoring

• Analyze the data derived form the monitoring activity, undertake trend analysis and report performance

• Implement and document actions or corrective actions required

• Periodically review the monitoring plan

NOTES• The concentration of airborne particles may be higher than the concentration observed during at-rest

classification due to various factors

• For processes that inherently produce particles as part of the process and are not a threat to the process or product, it may be appropriate to rely on periodic at-rest classification or operational classification of simulated operations, rather than monitoring in operation


ISO 14644-2:2015 Clause 4

Clause 4.2 – Risk assessment

Undertake risk assessment to:

• Develop a monitoring strategy and plan by determining factors that may affect the ability to maintain air cleanliness by particle concentration of the cleanroom or clean zone

• Determine the monitoring requirements to provide evidence of performance

See Annex A (informative)


ISO 14644-2:2015 Clause 4

Clause 4.3 – Monitoring Plan (output from the risk assessment) shall include as a minimum:

• Listing and justification of all parameters to be monitored

• Description and justification of measurement methods – see informative Annex A

• Accuracy, maintenance and calibration of monitoring instrumentation

• Identification and justification of selected monitoring locations – defined in three dimensions

• Identification and justification of monitoring acceptance criteria or limits, including a single alarm level (minimum requirement), or a dual alarm approach of alert and action levels – see informative Annex B for guidance on setting alert and action levels

• Specification of response required should data fall outside the specified limits

• Need for and frequency of periodic cleanroom or clean zone air cleanliness classification by particle concentration in accordance with ISO 14644-1:2015


ISO 14644-2:2015 Clause 4

Clause 4.3 – Monitoring Plan (output from the risk assessment) shall include as a minimum:

• Format for recording data

• Methods, including statistical methods to be used for data trending or other appropriate analysis

• Reporting requirements

• Policy and media to be used for record retention

• Frequency for review of the monitoring plan – periodic review based on knowledge gained from monitoring program


ISO 14644-2:2015 Clause 4 / 5

Clause 4.4 – Calibration:Instrumentation used for monitoring shall be adequate to perform the monitoring operations required, shall have a valid calibration certificate, and shall meet current accepted practices for the frequency and method of calibration (Reference: ISO 21501-4)

Clause 4.5 – Review and Approval

Clause 4.6 – Response to a deviation during monitoring:If monitoring results exceed the specified limit(s), an investigation shall be conducted to determine the cause, and remedial action taken as required

Clause 5 – Periodic classification of air cleanliness by particle concentrationAnnual requirement; allowance for extension based on risk assessment and monitoring data


ISO 14644-2:2015 Annex A (informative)

Points to consider when developing a monitoring plan:• Select an appropriate risk assessment tool: HACCP, FMEA/FMECA, PHA, FTA, HAZAP

• Define performance and operating conditions to monitor: various factors given

• General considerations, including

• Manual vs. automated monitoring system

• Measurement system – resolution, accuracy, calibration requirements and efficiency of collection system

• Location of monitoring system – access for maintenance and calibration

• Probe location, configuration and orientation

• Issues that could impact the monitoring system, e.g., temperature, cleaning procedures and agents, product

• Results of smoke studies

• Process-related events that could affect environmental conditions (including monitoring recovery times)

• Personnel placement and movement – number of personnel

• Data logging and management, including data integrity, storage, retrieval

• Techniques for evaluating raw data, assessing trends, and product of reports

• Acceptance criteria and setting single or dual alarm level(s)


ISO 14644-2:2015 Annex A (informative)

Points to consider when developing a monitoring plan:• Pressure differential monitoring

• Setting time delays to manage fluctuations caused by door opening, etc.

• Choice of measurement – between rooms or against a common reference pressure

• Setting alert and action levels

• Monitored by periodic observation or by automated instrumentation

• Airborne particle monitoring (real-time)

• System configuration – multiple local “point of use” particle counters vs. a single particle counter with a multiplexing manifold and sample transport tubes; probe configuration and orientation

• Air sample flow rate and volume – frequency and duration of collection

• Potential adverse impact of the sampling system on the process

• Airflow velocity and volume monitoring

• Selection of technique

• Location of measurement device


ISO 14644-2:2015 Annex B (informative)

Detailed guidance on setting alert and action levels for pressure differential monitoring and airborne particle counts

Setting alert and action levels for airborne particle counts. General guidance:• Risk assessment and evaluation of data from classification in according with ISO 14644-1 should be

used to determine the monitoring locations (critical control points)

• Use statistical process control principles to set alert and action levels based on analysis of historical data

• Care should be taken considering alert and action levels for ISO Class 5 environments –“nuisance” alarms should be avoided

• Consistence of the sampling position and orientation of the probe can have a measurable effect on counts

Establishing normal operating range for particles:• Initially measure the particle counts at designated critical control points over a significant period of time,

in both the “at rest” and “operational” occupancy states

• Use set of data to determine the expected normal performance of the cleanroom or clean zone which becomes the basis for establishment of the alert and action levels

• Repeat after a major change occurs to the design or operation of the installation

Questions?



Hidden Costs and Benefits

These revisions impacts all users of GMP cleanrooms and clean zones!

These are substantial revisions impacting the way GMP cleanrooms are classified and monitored, and the performance requirements of particle counting instruments

Changes are not extreme but demand additional testing locations and a more comprehensive monitoring plan after classification

Impact, costs, potential risks:• The number of sample locations required for (re)classification has increased

• Expanded risk based routine monitoring program (with implications for viable particle monitoring program)

• Review quality management systems and update policies, procedures and specifications, as applicable

• Increased demands for calibration requirements for particle counters

• Existing (older) air particle counters may not comply with ISO 21501-4

• Potential data errors – requires (re)programming particle counter with new cleanroom sampling program



Impacts all users of GMP cleanrooms and clean zones!

Impact, costs, potential risks (continued):• Cleanroom may not operate at the grade achieved using the old classification process,

necessitating urgent changes to cleanroom and air handling systems to bring cleanrooms into the required Class

• Manufacturers who perform their own classification/re-qualification work need to become familiar with ISO 14644-1 as existing methodology will no longer be sufficient to comply with the classification requirements

• Where a manufacturer uses a third party for classification/re-qualification, it is still the manufacturer’s responsibility to ensure that classification work is conducted according to the current standard



ISO 14644-1:2015 benefits include:• Improved statistical accuracy

• Elimination of the 95% UCL calculation (classes 2 to 9)

• Look-Up Table for the number of sample locations per cleanroom size (instead of calculation)

• Removal of the maximum allowable concentration of airborne particles/m3 ≥5µm for ISO Class 5

• Calibration procedure and verification method for particle counters

• Refine how the intervals between re-qualification may be extended, provided that automated monitoring systems show the cleanroom is under control (limited for the pharmaceutical and related industries)



ISO 14644-2:2015 benefits include:

• Simplification and clarification of the requirements and guidance tables that specify frequency and monitoring of cleanrooms used to demonstrate continued compliance with the cleanliness classification

• Provides new detailed guidance on aspects that should be considered when configuring a monitoring system – establishing a monitoring strategy

• Allowance for the use of permanent fixed systems as well as portable instruments

Questions?



Interactive Exercise

Outline elements of a risk-based monitoring program, in compliance with ISO 14644-2

Bonus MaterialComparison and impact assessment handouts


Documents

Changes to Cleanroom and Clean Zone Standards ISO 14644 Parts