ISO 14644-2:2015 Cleanroom Monitoring Frequently Asked ... · ISO 14644-2:2015 Cleanroom Monitoring FAQ infopmeasuring.com | 1 800 238 1801 Page 3 of 15 TOPIC: OTHER STANDARDS Have

Without measurement there is no control

ISO 14644-2:2015 Cleanroom Monitoring Frequently Asked Questions

Page 1 of [email protected] | +1 800 238 1801

This FAQ paper is a follow up to the webinar, “ISO 14644-2:2015 Cleanroom Monitoring”. Many thoughtful questions were asked about cleanroom practices and the recent changes to the ISO standard. Questions submitted during and after the webinar are answered below. If you have any additional queries for our experts, submit them directly here.Topics in this paper include:

• Basics

• Other Standards

• Cleanroom Classification

• Microbial Monitoring

• Particle Size

• Calibration and Verification

• Monitoring Frequency

• Tubing

• Locations and Positioning

• Applications

• Risk Assessment

• Alert and Action Limits

T O P I C : B A S I C S

What is the primary change to ISO 14644-2?The primary change to the standard is related to the emphasis of using a risk assessment approach for process monitoring.

If interested in the ISO 14644-1:2015 update, webinars and application notes concerning this topic are available on this page.

∙∙∙

http://www.pmeasuring.com/en/knowledge-center/application-notes/understanding-iso-standards-iso-14644-2-2015-c-(2)

http://pmeasuring.com/en/contact-us

http://www.pmeasuring.com/en/knowledge-center/iso-14644-1-2015

ISO 14644-2:2015 Cleanroom Monitoring FAQ


What are the key factors to keep in mind when working on a new cleanroom facility?To access materials to better address this wide-ranging topic, navigate to Particle Measuring Systems’ Knowledge Center. The following application note is a great place to start when designing a new cleanroom: Quality By Design and Single-Use Air Sampling Approaches.

If you need assistance or specific consultancies, our company offers customized service for you.

∙∙∙

Should I use cumulative or differential particle data from my instrument?All standards, including ISO, GMP, etc. always refer to cumulative particles.

Differential value can be used for investigation and troubleshooting purposes.

∙∙∙

Which parameters, other than particles, should be monitored in the cleanroom?Several operating conditions in addition to operation performance should be monitored based on your specific process and product risk evaluation. The ISO standards list parameters such as temperature, differential pressure, humidity, and ventilation performance, but you are not limited to these few.

∙∙∙

What is UDAF?UDAF stands for Uni-Directional Air Flow cleanrooms.

∙∙∙

http://www.pmeasuring.com/en/knowledge-center/application-notes

http://www.pmeasuring.com/en/knowledge-center/application-notes/quality-by-design-and-single-use-air-sampling-appr



T O P I C : O T H E R S T A N D A R D S

Have the EU GMP guidelines accepted the 2015 edition in the same way in which they accepted the prior version?

Yes, GMP guidelines refer to the ISO 14644 in many sections, but without any specific revision number or release date. This means that the latest version must be applied.

Anytime you read a GMP reference to the ISO standard, you need to consider the latest version available (current references are to the 2015 update).

∙∙∙

Is there any contradiction between EU GMP and ISO 14644?If you consider the classification standard ISO 14644-1, yes. There are now different approaches for ISO 5 particle limits and sample volumes. The GMP Annex 1 is under revision to harmonize the two standards. Expected availability is planned for the year end 2017.

∙∙∙

Does 21 CFR Part 11 apply to ISO monitoring requirements?21 CFR Part 11 dictates the requirements for correct management of data. As part of the batch release process, data collected by any monitoring system must be managed with an appropriate software system or procedure in respect to Data Integrity good practices and CFR 21 Part 11.

∙∙∙

How do I acquire documents ICH 29 and Technical Report No. 13? Here is the ICH 9 document link.

The PDA Technical report n° 13 must be purchased form this website.

∙∙∙

https://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/Step4/Q9_Guideline.pdf

https://store.pda.org/ProductCatalog/Product.aspx?ID=2347



T O P I C : C L E A N R O O M C L A S S I F I C A T I O N

Can I omit the annual cleanroom classification required by ISO 14644-1 with continuous monitoring?

No, cleanroom monitoring cannot replace annual/semi-annual classification tests.

Also, the classification process dictated by iSO 14644-1 must be performed in combination with the equipment/HVAC system test as per ISO14644-3.

∙∙∙

When doing ISO 14644-1 classification using the M Descriptor for GMP A and B (5 micron) should the coincidence error be considered? Meaning particle sizes of 1 and 5 microns should be counted then compared to LSAPC particle concentration limits?

The ISO 14644-1 requires the use of, at least, one other channel size when counting 5 microns using the M descriptor. You can choose to keep one channel, such as 0.5 micron or 1 micron, based on your need and the LSAPC capability.

∙∙∙

What if the sample volume is not defined in the SOP of the performance protocol?The sample volume depends on the class grade of your cleanroom. In the case of Grade A areas, the sample volume should not be considered and the sample duration shall reflect the entire production duration.

∙∙∙



T O P I C : M I C R O B I A L M O N I T O R I N G

Does ISO 14644-2 also consider microbial monitoring?ISO 14644 do not specifically talk about microbial contamination, but takes only care of particles. Anyway, microbial contamination must be controlled as well during production using appropriate monitoring tools. You can find additional details in the EU-GMP Annex 1, FDA cGMP and ISO 14698.

∙∙∙

Is microbial monitoring affected by the update in the same capacity as particle monitoring?

Microbiological monitoring has the same importance as particle monitoring, and might also be more important in certain environments. ISO 14644-2 refers specifically to particle contamination, but a good monitoring plan supported by a critical risk assessment will include appropriate microbiological sampling procedures (with additional identification).

∙∙∙

For microbial monitoring of ISO Class 8 or higher, is it required to record the specific bacterial or fungi family?

Refer to the following FDA cGMP extract:

Characterization of recovered microorganisms provides vital information for the environmental monitoring program. Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure, and the overall environmental picture provides valuable information for an investigation. Monitoring critical and immediately surrounding clean areas as well as personnel should include routine identification of microorganisms to the species (or, where appropriate, genus) level. In some cases, environmental trending data have revealed migration of microorganisms into the aseptic processing room from either uncontrolled or lesser controlled areas. Establishing an adequate program for differentiating microorganisms in the lesser-controlled environments, such as Class 100,000 (ISO 8), can often be instrumental in detecting such trends. At minimum, the program should require species (or, where appropriate, genus) identification of microorganisms in these ancillary environments at frequent intervals to establish a valid, current database of contaminants present in the facility during processing (and to demonstrate that cleaning and sanitization procedures continue to be effective).

∙∙∙



How has the acceptance criteria changed for surface contact plates and touch plates?Microbial acceptance criteria is not described in ISO 14644-2.

Refer to the current cGMP here for more information.

∙∙∙

T O P I C : P A R T I C L E S I Z E

Which particle sizes should be monitored in the cleanroom?The particle sizes monitored must be determined according to process and product requirements.

Generally, Pharmaceutical producers are required to monitor particle sizes of 0.5 and 5 microns.

∙∙∙

ISO 14644-1 removed the need to classify a Class 5 cleanroom for 5 micron particles. Should this particle size still be monitored?

In Pharmaceutical industries, 5.0 micron particles are still required to be monitored in ISO Class 5. A risk assessment analysis is required to support the selection of specific particle sizes to be monitored.

∙∙∙

Is the 5 micron size now void for monitoring in Grade A environments under the new 2015 edition?

No, the 5 micron size is still required to be monitored if your risk assessment considers this size dangerous to your product/process.

The removal of the 5 micron limit is only valid for classification but, in case you consider this size valuable and necessary for evaluation, ISO 14644-1 provides specific guidelines about this size with the Macro descriptor M section. This section explains how to manage the removal of 5 micron particles from the ISO 5 classification limit table.

∙∙∙

https://www.fda.gov/downloads/Drugs/Guidances/ucm070342.pdf



T O P I C : C A L I B R A T I O N A N D V E R I F I C A T I O N

What differences are there between the new ISO 21501-4 calibration standards and older revisions?

Prior to ISO 21501-4 (2007), no ISO standard existed for particle counter calibrations and instrument manufacturers were using their own procedures and methods. Harmonization and repeatability of measurements are readily managed by the new standards.

∙∙∙

How often is it necessary to verify and calibrate a particle counter?ISO 14644 refers to ISO 21501-4 for calibration requirements. This standard recommends calibration to be done at least once per year.

∙∙∙

Would it be acceptable to verify the performance of a built-in particle counter (in an ISO 5 isolator hood) with a handheld, calibrated particle counter rather than remove the built-in particle counter and send away for calibration?

Unfortunately, no. This kind of test will not provide any evidence of counting efficiency, size error, resolution, flow rate verification, etc.

All particle counters must be calibrated and “challenged” against a calibrated reference instrument (not a handheld device) in order to comply with ISO 21501-4.

∙∙∙

If we can prove the cleanroom is performing well through years of monitoring results, is there a need to do annual re-classifications?

Yes, you must run the classification at least once per year following ISO 14644-1:2015. Remember that the sample location you will monitor will most likely be less than the sample location to classify.

∙∙∙



How often is it necessary to check if the OPC function is actively working?ISO 14644 refers to ISO 21501-4 for calibration requirements. This standard recommends the calibration to be done at least once per year.

∙∙∙

What resources are available for tests and verification of critical parameters that are given in 14644-3 for requalification of cleanrooms?

The ISO 14644-3 test requirement deserves another webinar session. This suggestion will be kept in mind for future courses.

∙∙∙

T O P I C : M O N I T O R I N G F R E Q U E N C Y

Would the continuous monitoring of a Grade A area in operation for 2 hours, and then the surrounding Grade B area monitored immediately after operation, cover the ‘daily’ requirement?

Your proposed approach is sound. The Grade B area may also be sampled prior to operation for cleanliness verification and suitability for production operation.

∙∙∙

Which approach is better: Collecting 1 cubic meter at once, or with a series of 1-minute samples?

In a monitoring scenario, I would recommend the particle counter be configured to a series of 1-min samples. This method is likely to provide data more reflective of unexpected events.

∙∙∙



How often should I monitor a Grade B environment (ex. once in a day, once during a working shift, etc.)?

Grade B environments must be monitored once a day. More frequent control may be considered If your risk assessment underlines a greater need of monitoring this area.

∙∙∙

T O P I C : T U B I N G

Has a maximum tubing length (i.e. 1 m) been announced at recent ISO 14644 discussions?

ISO 14644 does not state any maximum tubing length. The standard dictates that the maximum tubing length must be left to the manufacturer’s discretion. You should refer to the instrument’s user manual or contact the instrument supplier to verify if the tubing length you are using is considered suitable.

For Particle Measuring Systems’ particle counters, we recommend a maximum length of 2 meters. This length is preferred, based on our experience, as the maximum length that guarantees an acceptable particle loss.

∙∙∙

Can I use stainless steel tubing to connect the particle counter to remote sampling locations?

Yes, stainless steel 316L tubing can be used, as well as other materials such as Tygon®, Bev-a-line or Polyurethane.

It is important to select the tubing based on the adherence characteristics, in addition to the specific internal diameter size as specified by the manufacturer.

∙∙∙

Is the allowed distance from the critical point to the particle counter valid for all types of particle counters or just for a 1 ft³ counter?

The instrument manufacturer must specify the maximum allowed tubing length in the user manual or specification sheet. In most cases, this is equal among different flowrates.

∙∙∙



Does tubing length need modification for older systems that have the OPC mounted on the outside of the machine?

Yes, tubing length must be modified to the maximum length specified by the particle counter’s manufacturer. Unless the customer has a defensible, sustainable and clear rationale to prove that no closer position is possible.

∙∙∙

T O P I C : L O C A T I O N S A N D P O S I T I O N I N G

How many locations in a cleanroom should be measured for particle counts?During the classification process, you can define the number of sample locations by referring to Table A.1 in ISO 14644-1:2015.

For monitoring purposes, you need to develop an appropriate risk assessment in order to identify the critical locations to be sampled.

∙∙∙

Do monitoring sample locations relate to the classification sampling plan in 14644-1 (i.e. same sample positions) or is it entirely different?

No, you do not need to replicate the same sample location classified as per ISO 14644-1. Most of the time, the number of positions per monitoring location are less than half of the classification requirement.

The selection of monitoring sample locations must be supported by a risk assessment.

∙∙∙

What is the correct sample height?The sample height, or sample location, must be within 1 foot from the critical zone. The sample height must always be in proximity or equal to the work height.

Particle sampling should never be done just beneath the filter, unless during a filter scanning test.

∙∙∙



Where should I position the air velocity sensor?The airflow sensor must be positioned in a representative location, based on the specific application. It may be necessary to evaluate locations to prove measurements are representative and not adversely influenced by airflow turbulence or uneven flow in ducts or other factors.

The best location is in close proximity to the work place where applicable.

∙∙∙

With continuous monitoring, what is an appropriate height to set the collecting funnel in an ampoule filling line from the filling point?

The right height will be as close as possible to the work/filling position. You first need to identify the most critical zone/point and then set the funnel (Isokinetic Probe) within a 1-foot radius from the critical point.

∙∙∙

T O P I C : A P P L I C A T I O N S

Should the fan/motor system in a clean, filtered laminar flow cabinet be turned on well before the cabinet is used to dispense pharmaceuticals?

Yes, this is typical practice to ensure the flow cabinet is in an acceptable cleanliness condition before starting the production process.

I also suggest you evaluate the recovery time following the ISO 14644-3 standard. With this method, you can define how many minutes/hours you need to run the fan prior to production activities.

∙∙∙

In an aseptic activities processing room, is it mandatory to sample 1 cubic meter at each and every ISO 6 sampling point?

For classification purposes, you need to refer to the ISO 14644-1:2015 sample volume calculation formula. This formula is based on the limit for the largest particle channel you will sample.

For monitoring of filling activities, you need to refer to the duration of the production session and sample the entire time of filling/production.

∙∙∙



For a high potency packaging facility, is it a requirement to comply with ISO 14644?This strictly depends on the grade of cleanliness you need to comply with. All cleanrooms must be classified and monitored, but the frequency will depend on the grade.

∙∙∙

In a temporary situation, can a periodic particle monitoring system be used in a continuous state? Is there any difference between the two measuring systems?

Yes, portable particle counters can be used for monitoring activities. You may contact your instrument supplier to make sure the instrument hardware is designed for continuous operation.

In you’re using a Particle Measuring Systems particle counter, you can operate it continuously without issue.

∙∙∙

We monitor our sterile services cleanroom for reusable surgical instruments quarterly against Class 8 of ISO 14644-1. The instruments are sterilized after being packed in the cleanroom. Is this sufficient?

Following the WHO table, your monitoring plan is sufficient. I would suggest the evaluation of your historical data for a risk assessment and verify if this quarterly frequency is providing you the necessary understanding of your cleanroom performance.

∙∙∙

In the Medical Device industry, do factors not critical for product manufacturing such as temperature or humidity still need to be monitored routinely?

The decision must be based on a risk assessment. You must have a defensible and clear rationale which describes the reason why these parameters are not critical.

With a written rationale, not monitoring factors such as temperature and humidity may be considered.

∙∙∙



T O P I C : R I S K A S S E S S M E N T

Should a different monitoring strategy for each process be performed in the same critical area based on risk assessment, or one strategy for each classification grade?

The specific process must be considered when developing your risk assessment. Different processes may have different risk factors that must be taken into consideration.

The most stringent monitoring plan can be used to control other production processes if you benefit by having a unique procedure.

∙∙∙

Are there example risk assessments available?Risk assessment documents are strictly customized for specific users/customers and are considered confidential and proprietary. For this reason, they cannot be shared.

If you are interested in evaluating how to produce a risk assessment document, refer to the guidelines recommended in the ISO 14644-2:2015 webinar. Otherwise, Particle Measuring Systems offers customized consultancy services for your company in order to develop a complete risk assessment document.

∙∙∙

Is it possible to reduce the number of air particle sampling points with historical monitoring data justification?

The number of sampling points has to be defined with a risk assessment. You can evaluate your historical data for this purpose, but always keep in mind that the critical point cannot be removed. All critical points must be defined again with a risk assessment, which includes a critical evaluation of your process and risk of product contamination.

∙∙∙



T O P I C : A L E R T A N D A C T I O N L I M I T S

How many samples should be used to develop alarm limits?It’s recommended to define alert and action limits based on a consistent amount of data, typically 4 to 6 months in total. This length of time provides a consistent and reliable picture to be used for limit set-up.

∙∙∙

In the case of a startup process with no historical data, how should alert and action limits be determined?

Refer to the ISO 14644-1 Classification section for your specific cleanliness class, and begin data trend collection and analysis as soon as possible.

∙∙∙

What software should be used to perform alert and action limit determination and evaluation?

I would suggest the use of data collection software in order to evaluate your particle contamination trends. DataAnalyst is offered as an accessory to the Lasair® III Aerosol Particle Counter. The use of this software will help you analyze large amounts of data with no manual input needed.

∙∙∙

Lasair® III Aerosol Particle Counter with DataAnalyst software



For ISO 5 monitoring, can a trend analysis be used for setting an alert and action limit?Yes, the trend analysis must be considered when developing your alert and action limits.

∙∙∙

Are Shewhart control charts practiced in the industry, and can they be used to derive alert and action limits?

As an analytical method, the Shewhart control chart can be used for your evaluation as well as others. There is not a preferred method in the Pharmaceutical industry.

∙∙∙

© 2017 Particle Measuring Systems, Inc. All rights reserved. Lasair® is a registered trademark of Particle Measuring Systems, Inc.Tygon® is a registered trademark of Saint-Gobain Corporation.Reproduction or translation of any part of this work without the permission of the copyright owner is unlawful. Requests for permission or further information should be addressed to Particle Measuring Systems, Inc. at 1-800-238-1801.App Note 2493/2017

Documents

ISO 14644-2:2015 Cleanroom Monitoring Frequently Asked ... · ISO 14644-2:2015 Cleanroom Monitoring FAQ infopmeasuring.com | 1 800 238 1801 Page 3 of 15 TOPIC: OTHER STANDARDS Have