The Cleanroom Monitor

August 2009

Issue 61

THE SCOTTISH SOCIETY FOR CONTAMINATION CONTROL

CONTENTS ISO 21501 – A Standard Methodology to Optical Particle Counter Calibration and What It Means to Cleanroom Owners

ph 1-3

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

ph 4-5

Revision to Annex 1: Impact on Airborne Particle Counting Methodology

ph 6-8

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

ph 9-11

Advertisements

ph 11-12

0.1µm

1µm

10µm

Author: Tony Harrison

100µm

Light Blocking

Light Scattering

CNC 1nm

10

100

1000

10000

ISO 21501 – A Standard Methodology to Optical Particle Counter Calibration and What It Means to Cleanroom Owners

100000 1000000

Figure 1. Particle size range and counting techniques

Introduction ISO 21501 is a new family of standards describing the instruments and calibration requirements for determining particle size distribution using light interaction methods.

It represents the culmination of work by instrumentation manufacturers and industry users and comes at a critical time for the life science industry with the increasing trend for real-time air particle monitoring in cleanrooms using light scattering air particle counters.

Air Particle Counters and ISO 21501 In comparison to liquid particle counters, the calibration of air particle counters presents greater challenges due to the need to generate air samples containing sub-microscopic particles of homogenous size and distribution. Although the technology of air particle counting is well understood, the ability to calibrate any two air particle counters so that they produce the same results when sampling the same air sample has proven to be challenging, bringing into question the accuracy of these instruments. ISO 21501 now delivers a calibration method that can significantly improve the repeatability and reproducibility of air particle counters.

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

particulate contamination in infusions and injections. Until recently, the calibration requirements [known as “IST” methods] for liquid particle counters used to test infusions and injections were described in detail in the United States Pharmacopoeia (USP) chapter <788>. However, in the interest of international harmonization of the pharmacopoeias, the details of these IST calibration methods have been removed in order to simplify the text of USP <788>.

ISO 21501 now offers an alternative to these IST tests and establishes calibration methods to ensure accurate and repeatable performance of liquid particle counters.

Background Optical instrumentation has been used to determine particle contamination in air and liquids in the life science industry for many years. In addition, the correlation between airborne particles and final product quality has long been recognized in the semiconductor, flat panel display and hard disk storage manufacturing industries, where improvement of air quality (reduction of particulate contamination) has led to increases in final product yield.

Differing techniques are used to determine the number and size of particles depending on the size of particles that are of interest.

[Figure 1]

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

Feature Continued ISO 21501 – A Standard Methodology to Optical Particle Counter Calibration and What It Means to Cleanroom Owners In liquid particle counting for infusions and injections, the sizes of interest are =>10µm and =>25µm, whereas for the life science industry, the sizes of interest for cleanroom air particle cleanliness are =>0.5µm and =>5µm. Higher sensitivities are required for semiconductor manufacturing plants where cleanroom and mini-environment air is routinely monitored at 0.1 µm and lower.

Hard disk manufacturers typically monitor to around 0.2 µm to 0.3 µm and flat panel display manufacturing environments monitor to 0.3 µm and 1.0 µm.

USP <788>, EU 2.9.19 and JP 6.07 recognize that light obscuration is suitable for liquid particle counting in infusions and injections, whereas ISO 14644-1 recognizes that light scattering particle counters are appropriate for determining airborne contamination in cleanrooms.

There is a requirement to follow the guidelines in EU GMP and cGMP for cleanroom users that aseptically manufacture pharmaceutical products for the European and American markets. Both documents define the airborne particulate count limits for different cleanroom operations, but neither defines the methods required to determine these count limits, nor do they define the instrument to be used and how it should be calibrated. However, EU GMP states that ISO 14644-1 should be used for methodology to determine cleanroom air particle cleanliness classification and that ISO 14644-2 should be used for methodology for demonstrating continued compliance. The introduction in ISO 21501-4 states, “Monitoring particle contamination levels is required in various fields, e.g. in the electronic industry, in the pharmaceutical industry, in the manufacturing of precision machines and in medical operations. Particle counters are useful instruments for monitoring particle contamination in air. The purpose of this part of ISO 21501 is to provide a calibration procedure and verification method for particle counters, so as to minimize the inaccuracy in the measurement result by a counter, as well as the differences in the results measured by different instruments.” The scope of ISO 21501-4 states, “Instruments that conform to this part of ISO 21501 are used for the classification of air cleanliness in cleanrooms and associated controlled environments in accordance with ISO 14644-1”. So the importance of ISO 21501 to cleanroom users looking to follow the guidance in GMP is evident.

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Equally the scope of ISO 21501-2 states, “Instruments that meet this standard are used for the evaluation of cleanliness of pharmaceutical products (injections, water for injections, infusions), as well as the measurements of number/size distribution of particles in various liquids.”

So the importance of ISO 21501 to those in the pharmaceutical industry manufacturing injections, water for injections or infusions is also evident.

What Standards Exist? What Is ISO 21501 Replacing?

ISO 14644 is a widely used standard for cleanroom classification using optical particle counters. Despite the existence of ISO 14644, prior to the ratification and introduction of ISO 21501 at the beginning of 2007, there were no ISO standards dealing with calibration and performance of the optical particle counters (OPC) used to classify cleanrooms to ISO 14644.

Comprehensive non-ISO standards and calibration methods guidelines did exist however and have been employed by most major particle counter manufacturers. In summary, these standards are:

through the OPC’s sensor, which results in a stream of electrical pulses, each pulse being proportional to the size of each particle.

The mono-sized standard particles produce a distribution of pulse heights, the median of which is typically regarded as the appropriate channel calibration threshold for that size. Therefore, in the real world a particle exactly the same size as a given channel would have a 50% probability of being counted (see Figure 2a). As a result, OPC’s calibrated in this manner are said to have a counting efficiency of 50%. Note however that this does not mean that the OPC will only count half of the particles in the real world.

ISO 21501 makes use of the specification for counting efficiency accepted in the JIS B 9921 standard. This states that the counting efficiency should be 50% +/-20% (i.e. between 30% 70%) in the first channel (Figure 2a). Additionally, particles of between 1.5 X to 2.0 X the channel 1 particle size should be counted with an efficiency of 100% +/-10% (i.e. between 90% 110%) in the first channel (Figure 2b.)

• ASTM F 328-98(2003) “Standard Practice for Calibration of an Airborne Particle Counter Using Monodisperse Spherical Particles” (withdrawn May 2007).

• IEST-RP-CC014.1 “Calibration and Characterization of Optical Airborne Particle Counters” (providing actual methods to perform the calibration).

• JIS B 9921:1997 “Light scattering automatic particle counter”, a Japanese standard which comprehensively deals with OPC design performance, most notably in the area of “counting efficiency”.

The counting efficiency parameter has presented the most significant variable when it came to the actual count accuracy of individual OPC’s, especially air particle counters.

Counting Efficiency OPC’s typically feature a number of size channels into which particle counts are binned, each channel being calibrated to count particles greater than a specific particle size. Particle sizes are typically expressed in micrometers (µm). The term counting efficiency primarily refers to the ability of the OPC instrument to count particles at a specified size. Typically, calibration involves passing a continuous stream of standard, monosized particles

N ISO21501 Limits 50% +/- 20% (30% to 70%)

OPC smallest specified size.

Noise

Channel 1 size (um)

Figure 2a: The 50% calibration point

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%

Noise

Channel 1 size (um)

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

Why Was A New Standard Required?

Prior to ISO 21501, it was not required for counting efficiency to be checked at each calibration interval nor that this more exhaustive series of tests be performed once the instrument was in the field, although it was often done at the end of the initial manufacturing process at the factory. There are many things that can impact counting efficiency during the lifetime of an OPC; for example a slight optomechanical misalignment of the illumination source can go undetected. Therefore, the situation exists where even though a given OPC may correctly size particles, it may be undercounting - in effect missing some of the particles. The new ISO 21501 standard requires (among other elements) that the all-critical counting efficiency element be checked during calibration. To check counting efficiency, it is necessary that once calibrated for sizing characteristics using traceable size standards, the OPC under test must be run and compared to either an Electrostatic Classifier or an OPC instrument with higher sensitivity than the OPC under test. This OPC is considered to be a “secondary standard”, having been formally compared to an Electrostatic Classifier and verified as having 100% counting efficiency at the size of interest, i.e. the channel 1 size of the OPC to be certified.

The full list of elements that ISO 21501 requires to be tested in addition to the basic size calibration are as follows: • Counting efficiency • Sampling flow rate • Sizing resolution • Sampling time • False count rate • Sampling volume • Concentration limit

What Is ISO 21501 And What Improvements Will It Bring?

To quote from the ISO 21501 standard: “The purpose of this part of ISO 21501 is to provide a calibration procedure and verification method for particle counters, so as to minimize the inaccuracy in the measurement result by a counter, as well as the differences in the results measured by different instruments.”

Simply put, the ISO 21501 standard will ensure that OPC instruments will size and count particles correctly, using a traceable reference instrument. Different OPC models from different manufacturers will therefore closely correlate in terms of actual particle counts recorded. This presents a significant step forward in providing traceable, accurate OPC tools to classify and validate cleanrooms to ISO 14644.

Who Should Adopt ISO 21501?

Users of cleanrooms OPC’s with questions or concerns regarding the transition to ISO 21501 should contact their particle counter supplier or cleanroom certifier.

Additional Information The ISO 21501 family of standards extends beyond air particle counters to include both scattering and extinction type liquid particle counters. The standard is split into four parts and all are available from ISO at http://www.iso.org.

ISO 21501 Determination of particle size distribution – Single particle light interaction methods • Part 2: Light scattering liquid borne particle counter • Part 3: Light extinction liquid borne particle counter • Part 4: Light scattering airborne particle counter for clean spaces Hach manufactures a range of ISO 21501 compliant particle counters and is currently in the process of deploying an ISO 21501 field service capability for the calibration of existing products.

Manufacturers of products requiring processing or assembly all goods and materials within a cleanroom environment classified under ISO 14644 should require that OPC instruments be calibrated to the ISO 21501 standard. This is particularly applicable to the pharmaceutical manufacturing facilities employing sterile processing or filling lines.

Particle counter owners and users with specific questions or concerns regarding ISO 21501 are invited to email the Hach ISO 21501 support team at iso21501@hachultra.com. Through this email address, one can access a panel of experts regarding ISO 21501 and receive prompt and accurate answers to questions.

Tony is one of the UK technical experts on ISO TC 209 Working Group 1 working on the revisions to the cleanroom standard ISO 14644-1 & -2.

companies), working with colleagues on various standards groups in a world-wide network, he is responsible for interpreting and comparing the different regulatory and international standards for clean rooms and regulatory compliance issues.

In recent years he has published papers on compliance issues relating to the life sciences industry, including most recently a paper in the European Journal of Parenteral & Pharmaceutical Sciences. He has also been responsible for creating validation best practice standard operating procedures (SOP) for equipment used to demonstrate regulatory compliance.

About the Author Tony Harrison is a qualified electrical & electronic engineer, with over twenty years’ involvement in process control and monitoring systems for manufacturing industries.

Tony represents the Pharmaceutical Healthcare Sciences Society (formerly known as the UK Parenteral Society) on the LBI/30 committee for the British Standards Institute, working on the revisions to the ISO14644 family of standards. LBI/30 also represents the UK interests on changes to EU GMP Annex 1.

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

The recently published guide to continuous particle monitoring to EU GMP Annex1 from the PHSS “Best Practice for Particle Monitoring in Pharmaceutical Facilities” was produced by a working party of PHSS members chaired by Tony.

In his role as Global Life Sciences Manager for Hach Lange (part of the Danaher group of

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Feature How To Choose The Right Disinfectant – A Guideline For Safe Application Author: Phil Blundell

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

Objective First of all, the goal that you wish to achieve must clearly be defined. Disinfection is the inactivation or reduction of pathogenic and product-harming microorganisms to an acceptable level, usually attained by altering either their structure or metabolism. Each individual company or laboratory 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 of the EU-GMP-Guideline for the Manufacture of Sterile Medicinal Products. The selected level to be reached should of course be both achievable and relevant to the situation in question (“<1 CFU” does not make sense everywhere!).

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

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

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

Selection Criteria for Disinfectants If the microbiological goals are set, each user must be aware of the criteria that the disinfectant must meet. These can include: • operational stipulations • sterility • conformity with relevant biocide guidelines • microbiological efficacy, tested and documented in accordance with recognised methods (e.g. European standards) along with corresponding expert opinions • type of active ingredients • any possible interaction of the active ingredients (e.g. when two disinfectants are used alternately)

• any possible interaction between cleaning agents and disinfectants • ease of dosing, concentration & contact time • cleaning effect and dirt loading capacity • material compatibility, corrosive properties • toxicology and safety implications for both users and the environment • odour • rinsing characteristics and residue-free requirements • cost

Limits

About the Author Phil Blundell is an International Sales Manager with 15 years experience with Schülke & Mayr.

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It is often impossible to meet all the requirements of the user due to the relevant biocide regulations (e.g. impending restriction of active ingredients to be used in the future), industrial safety considerations (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), but depending on the applied concentration and contact time may also have limited material compatibility. In contrast, alkalis show a limited spectrum of effect but excellent cleaning power with high protein loading capabilities. Quaternary ammonium compounds are often used due to their excellent cleaning effect, good material compatibility and user-friendliness - however, they are not effective against spores. Aldehydes have a low cleaning power and protein load but a wide spectrum of effect. However aldehydes in general, and formaldehyde in particular, are often

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

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

Figure 1: An example of a double-bagged, sterile disinfectant for easy introduction into the sterile area

Sterility Different levels of hygiene are required in production areas depending on which products are being manufactured there. This also has implications for the requirements of the sterility of the disinfectants to be used. For the manufacture of sterile products a sterile disinfectant is recommended according to the legal requirement of the Supplementary Guidelines to the EUGMPGuideline 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 normal hygiene status are usually sufficient for all other fields of application.

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

Figure 2: Perform-Range from Schülke for optimised product hygiene

Both options have advantages and disadvantages. Sterile filtration needs a high level of technical input and documentation when performed by the user. Ready-to-use or concentrated sterile disinfectants 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 necessary certification, so that the validation process carried out by the user is considerably more straightforward. Moreover, the double-bagging makes it much easier to bring the product into the sterile areas.

As Much As Necessary – As Little As Possible “As much as necessary” means that the selected disinfectant can be used to successfully meet the required 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 and disinfection program, incorporated into an effective clean room concept.

Conclusion A range of disinfection products which can be used according to the above principles, should include the following: • A non-sporicidal disinfectant for daily routine disinfection e.g. based on quaternary ammonium compounds; • a disinfectant with a sporicidal effect (e.g. based on active oxygen), which is used at regular intervals for basic disinfection and to counter contamination by bacterial spores; • a cleaning agent if certain amounts of soiling are to be expected;

• products that are available as sterile concentrates or ready-to-use products for use in areas with the strictest hygiene requirements • the same products should be available as a non-sterile variant for use in non-sterile areas.

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

References EU-Leitfaden einer Guten Herstellungspraxis für Arzneimittel, Teil I und II (EU-GMP-Leitfaden) Ergänzende Leitlinien zur EU-GMPRichtlinie für die Herstellung steriler Arzneimittel (Überarbeitung September 2003) Aide mémoire (AiM): Inspektion von Qualifizierung und Validierung in pharmazeutischer Herstellung und Qualitätskontrolle Richtlinie 98/8/EG über das Inverkehrbringen von Biozidprodukten (Biozid-Verordnung) Finale Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice (Leitfaden der FDA für die Herstellung steriler Arzneimittel unter aseptischen Bedingungen)

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Feature Revision to Annex 1: Impact on Airborne Particle Counting Methodology Author: Joe Gecsey 1. Overview

2.2 New classification limits for airborne particles

Annex 1 is a guidance document associated with the European GMP regarding the production of Sterile Medicinal Products. The most recent revision of Annex 1 has an effective date of 01 March 2009.

There are several key points about the revision that will affect - and in general simplify - the methodology of non-viable airborne particle counting: a) direct statements of requirements for classification versus monitoring b) linkage to ISO 14644 for classification procedures c) relaxation of the limits of 5 micron airborne particles allowed in Grade A and Grade B d) clarification of the need for “continuous” monitoring during production process e) clarification of the sample volume and rates needed during production process

2.2.1 The table previously was

The result is that the concern with a larger sampling volume of one cubic meter applies specifically to Grade A areas and only during classification procedures, which, following ISO 14644-1, would typically occur only every 6 months. Also the monitoring protocol is clarified to allow any sampling rate or sampling volume as long as the process would capture significant transient events or system deterioration.

2. Specific changes or additions 2.1 Direct statements of requirements for classification versus monitoring 2.1.1 Separate sections in the document for classification and monitoring

At Rest Grade

In Operation

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

2.2.2 The newly revised table of classification limits is At Rest Grade A

In Operation

Maximum permitted number of particles/m3 equal to or above

0.5µm

5µm

0.5µm

5µm

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

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 accordance with ISO 14644-1.” [Section 4]

2.3.2 Additional references to ISO 14644-1

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

“For classification purposes EN/ISO 14644-1 methodology defines both the minimum number of sample locations and the sample size based on the class limit of the largest considered particle size and the method of evaluation of the data collected.” [Section 5]

2.1.2 classification differentiated from monitoring

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

“Classification should be clearly differentiated from operational process environmental monitoring” [Section 4]

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

About the Author Joe Gecsey is currently the Life Science Application Manager for the HACH Particle Counter Unit, Joe has been involved with the particle counting industry since 1984. First joining Met One as an electronic design engineer, Joe has been involved in both airborne and liquid particle counter design, as well as multi-sensor systems for facility monitoring systems (FMS). He is part of the TC209 WG1 revision group on the main global cleanroom certification standard, ISO 14644-1 and -2, one of the two Americans on the committee. One of his main focus points today is staying abreast of changes in global standards and compendial tests used by laboratories and production systems in the Life Sciences. Joe has been involved in various standards involving particle counting in air and liquids and gives informational seminars in Asia, Europe and South America.

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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 operations b) simulated operations c) media fills “In operation” classification may be demonstrated during normal operations, simulated operations or during media fills as worst-case simulation 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 to determine positions “Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.” [Section 8]

3. Analysis 3.1 Classification follows ISO 14644-1 except for Grade A 3.1.1 Frequency of classification Following current ISO 14664-1 and 14644-2 directives, the classification effort needs to be done at a minimum frequency of every 6 months in Grade A and B areas and every 12 months for Grade C and D areas.

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

3.1.3 Minimum sample volume for classification Because the classification effort is based on representative sampling, a minimum volume is specified in ISO 14644-1 Annex B in order to obtain a reasonable level of confidence that the sampled volume reflects - as a partial sample - the entire air quality in that immediate area. In ISO 14644-1 Annex B, there are calculations for a minimum sample volume.

However, this revision of Annex 1 gives specific instructions for the size of the sample volume used for classification purposes. Revised Annex 1, Section 5, specifically demands that the sample volume for classification purposes for Grade A areas be at least one cubic meter. This is a different volume than is required by following ISO 14644-1 but is considered appropriate in order to achieve a high level of confidence that the sample results will effectively represent these critical areas.

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

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

The time, t, is based on the time needed to count 20 particles if there were precisely that number of particles of that size in the sample area to meet the class limit.

If the wish is to classify a Grade B (ISO Class 5) area at rest, the limit is (29) 5-micron particles in a cubic meter. To gather (20) particles would require 0.69 cubic meters or 24.3 cubic feet. For a particle counter running at 1 CFM, this would mean a minimum sample time (t) of 24.3 minutes.

Using Table F.1, and t = 24.3, Observed Count 0

Fractional Time 0.1922

Time (mins) 4.68

Time (mins) 4 min 41 sec

1

0.2407

5.85

5 min 51 sec

2

0.2893

7.03

7 min 2 sec

3

etc.

Thus, if no counts were observed at 5 microns after 4 minutes and 41 seconds, the sampling process could be stopped and the sample point declared to have passed at the 5- micron limit for ISO Class 5.

Or if (1) count was recorded, then if no more counts were recorded within 5.85 minutes, again you could record a PASS. For a flow rate of 1.77 CFM [50 lpm], the chart would then show these times for t = 24.3/1.77 = 13.73 minutes: Observed Count 0

Fractional Time 0.1922

Time (mins) 2.64

Time (mins) 2 min 38 sec

1

0.2407

3.31

3 min 18 sec

2

0.2893

3.97

3 min 58 sec

3

etc.

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

3.2 Monitoring has a different philosophy

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

3.1.4 Use of the Sequential Sampling method from ISO 14644-1 Annex F Instead of adhering strictly to the minimum sample volume to obtain the confidence level in the results, users who are doing 5-micron tests to certify their cleanroom can use the Sequential Sampling method 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 given limit within certain time fragments of the sample period, then the sample point can be presumed to meet the Class limits. For example, if the observed counts are still “0” after the Fractional Time, t, of 0.1922 has passed then the sample point passes.

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

3.2.2 Intent for monitoring of Grade B area Annex 1 encourages the use of the same or similar airborne particle counting system for Grade B with the allowance for a frequency of sampling that could be not continuous and would not need to capture all transient events: “It is recommended that a similar system be used for Grade B zones although the sample frequency may be decreased… The Grade B zone should be monitored at such a frequency and with suitable sample size that changes in levels of contamination and any system deterioration would be captured and alarms triggered if alert limits are exceeded.” [Section 10]

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Feature Continued Revision to Annex 1: Impact on Airborne Particle Counting Methodology

3.2.3 Selection of sample locations for monitoring The selection of sample locations should be based on a) previously acquired particle count data and b) on risk analysis of the process.

Probable sample locations based on risk could be at the intersection of exposed product and human interactions for interventions or manipulations in the process. Also points where the product remains exposed to the environment for a period of time (for example, on turntables) should be considered due to the increased risk of particulate deposition.

“Clean rooms and clean air devices should be routinely monitored in operation and the monitoring locations based on a formal risk analysis study and the results obtained during the classification of rooms and/or clean air devices.” [Section 8]

3.2.4 Sample volume and sample size for monitoring Due to the more frequent occurrence of monitoring - perhaps even continuous in critical areas - Annex 1 makes no specification of the sample volume or sample time.

“The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of clean rooms and clean air devices.” [Section 12]

In other words, there is no need to sample a full cubic meter or to set alarm levels based on results per cubic meter. It is for the user to establish the volume, rate and alarm levels to satisfy the information needed for the Grade to be monitored. (ref. Sections 9, 10 and 15) 3.2.5 Appropriate types of particle counting instrumentation The Annex 1 leaves the decision of instrumentation type to the user to determine based on the particle size to be considered. Portable, sequential (manifold) and remote counters can all be employed at a facility to accomplish the needed tasks. The text cautions the user to consider the effect of transport of the particles in the size range of interest but makes no specification for tubing dimensions, radius of bend or maximum tubing length. (ref. Section 11) 3.3 Written procedures; establishing alarm values; corrective action 3.3.1 Alarm Limits A written plan needs to define the sampling strategies for classification and for monitoring; the plan also needs to detail the actions to be taken when the alarm values are exceeded.

“Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded 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 classification purposes is that an area has no human operators present and the machinery is present but not in operation. However, the phrasing of Annex 1 has left many to conclude that the machinery should be running during the Annex 1 classification procedure for the “at rest” state: “In order to meet “in operation” conditions these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy states. The “at rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present.” [Section 3]

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4.2 Limits or levels Many users would prefer the use of the terms “level” when designating a target value for the airborne counts in a given area.

Generally the term “limit” is reserved for a PASS/FAIL test that sets a mandatory boundary for a parameter. Annex 1 is a guidance document [“informative” not “normative”] and thus the values are intended to be significant but not mandatory.

4.3 Corrective Action It would be difficult to cover all reactions necessary for the wide range of potential causes of particle counts exceeding Alert or Action limits. (ref. Section 20)

5. Conclusions 5.1 Cubic meter sample volume not required except for Grade A during classification A full cubic meter sample volume is only required for Grade A areas and only during the classification process, typically occurring at 6month intervals. [Section 5] Minimum sample volumes for Grades B, C and D are based on ISO 14644-1 methodology. [Section 5] This infers that, as appropriate, sequential sampling, as outlined in ISO 14644-1, Annex F, could be employed to shorten the sample times.

5.2 Number of sample positions set by ISO 14644 for classification; by risk analysis for monitoring effort For classification efforts, the minimum number of sample positions is set by ISO 14644-1 and is determined by calculating the square root of the area (as measured in square meters) and rounding up to the next integer. [Section 5] For monitoring efforts, the number of sample positions is set by the risk analysis of the critical areas and would be determined in most organizations by the efforts of the QA department. [Section 8] 5.3 5-micron particle count limit now set to 20 for Grade A For “at rest” and “in operation” conditions, the 5-micron count limit is established at 20 counts or less per cubic meter at the 5 micron and larger size channel. The latest revision modifies the 0.5 micron limits slightly from a previous value of 3500 counts per cubic meter to 3520 counts per cubic meter in order to harmonize the limits with the ISO 14664-1 values for this particle size and room classification. [Section 4] 5.4 Sample size and frequency for monitoring purposes can be different than values used for classification The classification and monitoring protocols should be clearly defined and distinct. [Section 4] The equipment used and the methodology employed can be quite different than that used for classification [Section 111,12] 5.5 Written sampling procedures are needed with prescribed corrective action plans Written procedures need to be authored that include alert and action limits for particulate and microbiological monitoring and these procedures should detail the appropriate corrective actions to be undertaken when the limits are exceeded. [Section 20]

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

Author: Hans Schicht

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

Summary

Developing into a trend: quality risk management

In the first part of this article, some technical trends in the pharmaceutical industry and in the medical device field had been discussed. In this second part of this article, recent regulatory and standardization trends are to be addressed. As common denominator, the trend towards quality risk management systems propagated in the ICH Q8-Q10 series is being implemented into, for example, the second edition of ISO 13408-1 on the general principles for aseptic processing of health care products, and into ISPE’s GAMP 5 handbook on a risk-based approach to compliant GxP computerized systems. In the world of Good Practices compendia, the new PIC/S guide on the preparation of medicinal products in pharmacies is worthy of note. Only limited comments are focussed upon the recent revision of Annex 1 to the GMP Guide of the European Union as it has already received wide attention in the S2C2 Cleanroom Monitor and elsewhere. However, recent developments in the ISO series of cleanroom technology standards will be addressed in more detail.

FDA quickly perceived the above-mentioned problems, and did so in a very comprehensive way. Their initiatives towards science- and risk-based attitudes paved the way towards a genuine paradigm change: the principles of quality risk management were introduced, with its focus upon risk assessment as the instrument for identifying the core risks, concentrating upon their control and avoiding the expenditure of too much time on risks of minor consequence.

Regarding qualification of contamination control systems, this meant focussing upon the major issues, with a positive effect upon documentation in which irrelevant issues were no longer addressed beyond the statement, corroborated through risk analysis, that they are irrelevant.

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

Comparing the GMP compendia of the leading pharmaceutical nations or regions, they agree to a large extent - but not always in detail. To give an example: FDA, in its Guidance to Industry for aseptic processing1, requires room classification for particles ≥ 0.5 µm and in the occupancy state “in operation” only. EMEA, on the other hand, continues to require, in the new edition of Annex 1 to the GMP Guide of the European Union (EU), published in February 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 and operational monitoring.

A GMP trend to be overcome Present GMP guidance is distinguished by its focus upon detail, and with each new edition more detail is added. By focussing on all this detail, the GMP objectives may well become overlooked or, as the Germans say, the forest may no longer be perceived because of all these trees. As a consequence, GMP tends to be interpreted negatively as “Give More Paper”, i.e. as the need to qualify everything that is capable of being qualified, instead of focussing upon the meaningful issues. Thus, qualification degenerated into the compilation of a multitude of files distinguished by a rather low information density. In addition, an over-cautious attitude started to prevail, impeding innovation. Another example: the extremely cautious attitude of FDA regarding isolator technology. As this authority possessed no experience with this technology, it refrained from rulemaking, and industry in the Americas remained reluctant towards this technology because of the lack of isolator-specific regulatory guidance.

For preparing the necessary fundamental guidance enabling implementation of this new philosophy of quality risk management, the trend towards a collaborative, international approach was followed: the elaboration of the fundamental guidance documents was trusted to ICH, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ICH comprises EMEA, FDA and the Japanese Pharmaceutical and Medical Devices Agency PMDA. Thus, ICH is not as international as it could possibly be, but it comprises a collective of leading nations regarding pharmaceutical innovation and pharmaceutical quality management.

The outcome of this effort is a series of guidance documents comprehensively covering the fundamental issues of the new quality risk 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, was approved in its definite form by the ICH Standing Committee in June 2008 and is now ready for incorporation into the regulatory guidance collections of the ICH member bodies. The objective of ICH Q10 is to establish a model of a pharmaceutical quality system designed for the entire product life cycle. It is based upon the quality management philosophies of the ISO 9000 series - thus finally integrating pharmaceutical quality systems into this wider context and goes beyond current GMP thinking. It is expressly intended to facilitate innovation and continuous improvement as well as to strengthen the link between pharmaceutical development and manufacturing activities. Together with ICH Q8/Q8R and Q9, ICH Q10 provides a common roof above the different GxP Guides such as GMP, GLP etc. which it is not intended to replace.

A spreading philosophy The quality risk management philosophies just explained are quickly spreading into other compendia serving the pharmaceutical and other life-science industries.

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

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Feature Continued Cleanroom technology for life science applications Part 2: Regulatory issues, standards and guidelines

Another example is GAMP 5, the guideline published earlier this year 6 (see also Martin and Perez7 ) on Good Automated Manufacturing Practices for computerized systems prepared by ISPE, the International Society for Pharmaceutical Engineers. Just like ISPE itself which has, from its origins in the USA, grown into a global professional organisation with chapters all over the world, this 352-page compendium has been prepared by a truly global team of professionals: three Steering Committees were involved covering the Americas, Europe and Japan, as well as representatives not only from FDA, but also from the regulatory authorities of a number of other nations. GAMP 5 explicitly encourages science-based quality risk management procedures as exemplified by the ICH Q8-Q10 series, and is devoted to the establishment of links between these philosophies and compliance with the current GxP manuals.

Good Practices guidance for pharmacies For implementing the new quality risk management philosophies, GxP guidance documents continue to be indispensable, and additions to them continue to be published. A recent compendium of this kind is PIC/S PE 010-1: Guide to Good Practices for the Preparation of Medicinal Products in Healthcare Establishments8 elaborated by PIC/S, the Pharmaceutical Inspection Co-operation Scheme of PIC, the Pharmaceutical Inspection Convention. Its objective is to extend the quality philosophies of the GMP guides for industry into the world of patient-specific individual preparations.

The manufacturing task of healthcare establishments can be extremely complex and varied. Typical product classes requiring sterile preparation and therefore a well-controlled environment are: • cytotoxics and radiopharmaceuticals with a high hazard level for the operator preparing the product and a high risk of preparation error • total parenteral nutrition solutions, which may be of very complex composition and are associated with a high risk of microbial contamination and of preparation error • infusions, which sometimes are administered over significant periods of time, the temperature being at or near body temperature where once more the risk of microbial growth is to be controlled, a risk sometimes aggravated by the fact that solutions may promote bacterial and/or fungal growth In PIC/S PE 010-1, the specific situation of healthcare establishments such as hospital pharmacies is duly taken into consideration without compromising the stringent quality thinking. The guide is a stand-alone document which requires no reference to other quality management compendia. It follows the basic structure of Part I of the European Community’s GMP guide for medicinal products.

However, there are only two annexes: one of which comprehensively devoted to the preparation of sterile products.

The new PIC/S guide sometimes goes beyond the determinations of Annex 1 of the EU GMP guide for industrial manufacturing of medicinal products, for example regarding classification tests: the recommended frequencies are given in Table 1. An annual integrity check, for instance, is required for HEPA filters - a topic surprisingly not even mentioned in Annex 1 to the EU GMP guide.

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Tables 2 and 3 present the requirements for the monitoring of physical and microbiological parameters. The room grade determinations follow exactly those established in the February 2008 edition of Annex 1 to the EU GMP guide.

Annex 1 to the EU GMP guide – a minimum of comments The new edition of Annex 1 to the EU GMP guide has been exhaustively commented upon in the S2C2 Cleanroom Monitor and elsewhere 9-11. Just one remark: in this age of science-based regulatory compendia, it is difficult to understand why the terms “laminar airflow” and “laminarity” have not been replaced by the scientifically correct terms “unidirectional airflow” and “uniformity of airflow” as employed without exception both in the ISO series of cleanroom technology standards and in the FDA Guidance for Industry on aseptic processing of medicinal drugs.

ISO cleanroom technology standards: towards new horizons Regarding trends in cleanroom technology standardization: the recent publication of the Draft International Standard ISO/DIS 14644-9 Classification of Airborne Particulate Cleanliness12-13 opens up a new dimension to the ISO 14644 family of standards. So far, these standards have focussed upon the air cleanliness requirements relevant for design, construction, start-up and operation of cleanroom systems. All determinations regarding surfaces and surface cleanliness in Parts 1-8 of the series have a cleanroom bias.

ISO/DIS 14644-9, however, addresses surface particulate cleanliness from the product perspective. In parallel to the air cleanliness classification scheme established in ISO 14644-114, the surface cleanliness classification scheme is based upon a formula shown in Table 4. Table 5 presents selected surface cleanliness classes in tabular form and Fig. 1 as a graph. The particle diameter range covered stretches from 50 nm = 0.05 µm up to macroparticles of 500 µm and above. Such macroparticles are irrelevant to the classification of airborne particles as they will sediment out of the air without delay. But exactly because of the sedimentation they become very relevant from the surface point of view.

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

Summing up Many trends are apparent in the development of standards and regulatory guidance: international collaboration, increasing complexity and detail, new application areas such as the hospital pharmacy. The dominating trend, however, seems to be the triumphant advance of quality risk management systems and their focus upon continuous improvement and concentration on the truly relevant risks. This trend will certainly drive technical and procedural progress in industry as well as progress in regulations and standards relevant for contamination control. Wouldn’t it be great if such quality risk management philosophies could also spread into the chaotic financial world?

About the Author Hans H. Schicht, Dr. sc. techn. is an independent consultant, specialising in cleanroom and contamination control technology, based in Switzerland.

References 1. Guidance for industry: Sterile drug products produced by aseptic processing current Good Manufacturing Practice. U.S. Department of Health and Human Services, Food and Drug Administration, Rockville MD/USA (September 2004).

2. European Commission. Eudralex: The rules governing medicinal products in the European Union, vol. 4: EU guidelines to Good Manufacturing Practice - Medicinal products for human and veterinary use: Annex 1: Manufacture of sterile medicinal products. 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: General requirements. International Organization for Standardization ISO, Geneva (second edition June 2008).

6. GAMP 5: A risk-based approach to compliant GxP computerized systems. ISPE The International Society for Pharmaceutical Engineers - in collaboration with FDA and other regulatory authorities. Tampa FL/USA (2008).

7. Martin K.C., Perez A.: GAMP 5 quality risk approach. Pharmaceutical Engineering 28 (2008) 3, 24-34.

8. PIC/S PE 010-1: PIC/S guide to good practices for preparation of medicinal products 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 considerations from 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. European Pharmaceutical 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 for Standardization 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).

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