What's the latest news on the ISO Standards and their implementation?

On November 29, 2001, the U.S. General Services Administration (GSA) officially announced that Federal Standard 209E, Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones, has been canceled and superseded by ISO Standards for cleanrooms and associated controlled environments, ISO14644-1 Classification of air cleanliness and ISO 14644-2 Specifications for testing and monitoring to prove continued compliance with ISO 14644-1. The GSA action was the result of a recommendation made by IEST Working Group CC-100 to “sunset” Federal Standard 209E in favor of the ISO documents.

FS 209E is NOT a document controlled by the FDA and thus the FDA was not compelled to issue a change notice (209E and the ISO standards are NOT cGMP guidance documents). The USP references 209E in <1116>, but has not issued a notice of the reference change in their Pharmacopeial Forum.

All in all ISO/TC209 has proposed twelve (12) documents which will make up the cleanroom standards. Most of these documents are either issued or at the final voting stage and can be legally used in trade.

ISO-14644-1 Classification of Air Cleanliness
ISO-14644-2 Testing and Monitoring to prove Compliance
ISO-14644-3 Metrology & Test Methods
ISO-14644-4 Design, Construction and Start-up
ISO-14644-5 Operations
ISO-14644-6 Vocabulary
ISO-14644-7 Separative Devices
ISO-14644-8 Classification of Airborne Molecular Contamination
ISO-14644-9 Clean Surfaces
ISO-14698-1 Biocontamination Control - General Principles
ISO-14698-2 Evaluation & Interpretation of Biocontamination Data
ISO-14698-3 Measuring the efficiency of processes of cleaning & disinfaction

Cleanliness class designations and quantity have changed from FS209E in 14644-1. Along with the obvious change to metric measure of air volume, ISO 14644-1 adds three additional classes - two cleaner than Class 10 and one dirtier than Class 100,000.

ISO also forces the contractual partners to specify (i) the particle size of interest, and (ii) the state of cleanroom occupancy for certification, i.e., "as-built", "at-rest", or "Operational".


ISO FEDSTD

1

2

3 1 M1.5
4 10 M2.5
5 100 M3.5
6 1,000 M4.5
7 10,000 M5.5
8 100,000 M6.5

9



What's the major impact on cleanroom testing that ISO will have?

Particle Count Tests for classifications <= ISO 5 will be required every 6 Months and for classifications > ISO 5, testing will be required every 12 Months.

Air pressure difference for all classes will be required every 12 Months as well as Airflow re-certification.

Further, installed filter leakage for all classes is recommended every 24 Months as is Containment Leakage Testing, Recovery Testing, and Airflow Visualization.


Where can I find any standards or guidelines on Airborne Molecular Contamination?

Unfortunately to-date, there has been very little published in the public domain regarding this ever more critical parameter. We predict that materials selection will become an ever more critical issue, across all industries - including life sciences!

One can start with SEMI F21-95, which provides a common catagorization system - similar to ISO for particle counts - as to the acceptable level of acids, bases, dopants and condensables permitted. However the absolute level itself must be set by the owner, user or designer, and more than 9 times out of 10, the database required to knowledgibly set the permissable level is proprietary and empirical, built up through long (and sometimes painful!) years of experience and testing of individual materials.

One can also reference the SEMATECH National Technology Roadmap for predictions as to required Wafer Environment Control and Process Critical Materials for future new technology generations. In Particle Measuring Systems (Boulder, CO) Application Note #43, , which discusses their SAW sensor technology for AMC measurement, a molecular contamination level of <0.2 ng/sq.cm./day is considered "clean", and a level of >0.6 ng/sq.cm./day is considered "dirty".

What's the difference between "offgassing" and "outgassing"?

Offgassing refers to the release of gaseous materials under atmospheric conditions, outgassing refers to release under sub-atmospheric conditions!

Is it correct to specify a minimum number of "Air Changes per Hour" for a given cleanliness class?

Air changes per hour is a DEPENDENT, and NOT an independent variable. AC/HR is simply the calculation of the air entering the room in one hour (avg. room velocity times the room area - adjusted for units of time if required) divided by the product of the room length, times the room height, times the room width.

While experience may tell us, over time and over hundreds of designs, what AC/HR could be expected to give us the proper required room performance, the AVERAGE ROOM AIR VELOCITY is really the variable of key interest to the designer and the owner.

Where do I need an airlock?

Wherever there is a need to maintain a validatable differential pressures between rooms, AND control of the directionality of flow is critical, then an air lock is normally the solution. At sea level, the Velocity Pressure that can be exerted due to pressure differential is typically equal to 4005 (a constant) multiplied by the square root of the delta P. So, as an example, for a 0.05 inches of water (gauge) differential between rooms, we can expect to see a horizontal velocity component upon door opening of approx. 896 feet per minute!

When should I recommend barrier isolation or mini-environment technology vs. a traditional cleanroom?

Process isolation should be evaluated and incorporated wherever it makes sense to do so. Frequently this is NOT a financial decision as much as it is a decision to incorporate "best available technology" and "build quality into the product". Any time you can remove a contamination source from the production process, it is an obvious plus to do so! That's certainly one of the major reasons that all new 300mm fabs will be mini-environment-based.

Whenever there is a need to protect the product, such as in aseptic filling, or the personnel and environment - such as in potent drug or live biologicals production - the application of barrier isolation is today the rule, rather than the exception. Because we still need to prove controlled conditions in the event of a breach, and have cGMP functional flows in an FDA validatable facility, most isolator-based life sciences facilities today are being designed to at least an EU Class "C" or "D" - under Operational conditions.

What's cheaper, modular construction or stickbuilt?

Every site has to be evaluated on its own merits. While "stickbuilt" is generally lower first cost (excluding architectural and engineering fees, which can be SUBSTANTIAL), so called "modular" or pre-engineered cleanroom solutions may often qualify for accelerated depreciation vs. built-in-place construction, and so on an overall evaluated basis, the modular solution is less expensive - but it takes a thoughtful analysis to ensure that the correct decision has been made...modular construction will always be faster than stick-built, and we do not know of any industries today where "time to market" is NOT money!

I've heard that Design/Build facilities delivery is faster, better, and cheaper than "plan and Spec". What exactly is the difference between the two approaches and HOW do I make sure that I get what I want in a design/build cleanroom project?

In the design/build approach, there is a SINGLE CONTRACT ONLY, between the owner and the design/builder. There are no separate, sequential contracts for architects, engineers, and construction managers or general contractors. The design/builder, and NOT the owner, is at risk for quality, schedule, and cost. Because a sustantial amount of engineering is required up-front to get accurate cost, schedule and scope prior to letting a design/build contract, this is often done via a "bridging" or conceptual design contract, in which the design/builder will prepare a complete conceptual design including an accurate (+/- 10-15%) estimate, a firm scope of work, and a realistic Gantt chart schedule.

What elements comprise a Basis of Design?

1. Process description and process flow diagrams
2. cGMP floor plan and general equipment arrangement
3. Sized major process equipment list with utilities requirements/consumption
4. Sized process support services utilities list (e.g., WFI, etc.)
5. Functionality flow diagrams (process, people, product, material, components, waste, directionality of air flows)
6. HVAC zoning and room classifications, including MICROBIAL limits
7. Budget quality cost screening estimate
8. Scope of Work matrix (design/specify/furnish/install/inspect/test/balance/certify/guaranty/challenge/qualify -i.e. identify explicity WHO is responsible for every element of the HVAC, envelope, and process)
9. Realistic project schedule from kick-off through validation
10. A listing of the appropriate/applicable regulatory authorities and jurisdictional venues for which the facility will have to be validated.