Are Cleanroom Regulations Realistic?

November 30, 2010
James P. Agalloco

James P. Agalloco is the president of Agalloco & Associates, P.O. Box 899, Belle Mead, NJ 08502, tel. 908.874.7558, He is also a member of Pharmaceutical Technology’s editorial advisory board.

Pharmaceutical Technology Europe

Pharmaceutical Technology Europe, Pharmaceutical Technology Europe-12-01-2010, Volume 22, Issue 12

What are the current expectations for cleanroom operations? And are these realistic?

This article is part of a special feature on cleanrooms that was published in the December issue of PTE Digital, available at

The current expectations for cleanroom operations are those found in the FDA's 2004 Guideline on Sterile Drug Products Manufactured by Aseptic Processing and EMA's Annex 1: Sterile Medicinal Products. These documents are reasonably well harmonised with each other with respect to environmental monitoring expectations, media fill requirements and other areas, but they differ with respect to classification of the core aseptic processing environments, where the EMA employs Grades A and B, and the FDA adheres to the more general ISO classification scheme. USP is about to formalise a new chapter <1116> Microbial Evaluation of Clean Rooms and Other Controlled Environments that differs markedly in approach by eliminating numerical limits and suggesting incidence rates. USP cites analytical variability and limit of detection with respect to numerical quantification, especially in the cleanest environments as a major part of the reason for changing their approach.

Jim Agalloco

Before validating a new cleanroom facility, I think it best to first consider the functionality of the facility and then define the desired capabilities that it is intended to satisfy. It is essential to understand:

  • the types of products and the expected volumes

  • the processes necessary for their manufacture

  • the equipment to be utilised in those processes, with special attention to the extent of automation and operator involvement

  • the materials and components necessary for the manufacturing processes.

With this defined, one can progress through the design exercise in an orderly manner.

Environmental monitoring over-emphasised

With respect to environmental monitoring, the expectations of both the FDA and the EMA do not consider the realities of aseptic processing and as a consequence, they overemphasise environmental monitoring to the point where they may actually be causing more problems than they are endeavouring to prevent. There are several aspects that the regulators seem to ignore:

  • Aseptic processing is not 'sterile' processing; those terms don't mean the same thing. The environments have never been, nor do they need to be 'sterile'. We don't require a 'sterile' environment to make a 'sterile' product.

  • Methods to precisely measure the microbial level in the air or on a surface do not exist. This is particularly true in the cleanest environments.

  • You cannot sample your way to 'sterility' in a processing environment. Even the most aggressive sampling schemes fall way short and increase risk more than any insight gained.

  • Sampling is an intervention and subject to adventitious contamination.

  • There have always been (and always will be) viable but nonculturable species, we cannot detect everything, but then again we shouldn't have to.

Expectations for perfection in performance may seem reasonable considering the label claim, but is quite unrealistic and unprovable from a scientific perspective. Unfortunately, these scientifically unrealistic expectations result in impractical acceptance criteria and the arbitrary and capricious rejection of product. The cost of monitoring, investigations and identification efforts is borne by the end user, and in many instances fails to bring any real benefit in reduction of product risk.

Can sterility ever be completely assured?

Sterility can never be guaranteed, and this represents a major technical disconnect between current regulatory policy and scientific reality. The sterility test as we know it today dates to the 1930s when processes were markedly less capable. In today's aseptic processing, its utility is highly questionable. The sampling limitations are well documented and, unfortunately, unfixable. Until such time as we have a universally accepted nondestructive sterility test for products, there is simply no means to assure sterility.

The media fill test is also, as many scientists and engineers have noted for years, merely a snapshot in time and not a method by which an aseptic process can be truly validated. It is important to remind ourselves that we can neither test nor monitor sterility (an attribute that can't be analytically measured) into our aseptically produced products.

My recent paper with Jim Akers entitled "The Myth Called Sterility" reviews this in some detail. It outlines what we called 'Sterility by Design', which is a group of interrelated design concepts that can at least assure 'safety' if not 'sterility'.1 If we were honest with ourselves, that is really all we have ever needed to have with respect to parenteral products.

Regulations should not reflect narrow-minded opinions

I've always been a minimalist with respect to the need for regulation, and I also believe that all regulation should be based strictly upon science and should be vetted through a rigorous peer review process. Regulation should not reflect narrowly drawn opinions. I respect that we must have regulations, but I find they are often outofdate before they are even published.

For example there's a continued expectation for unidirectional air flow in manned cleanrooms; however, it is important to remember that there are no metrics for the assessment of the degree to which unidirectional air flow actually exist. Smoke tests — although heavily emphasised — do not actually provide definitive information regarding "sterility assurance", as is often assumed. In fact, since all production environments contain horizontal and complex surfaces, the presence of turbulence is assured and unavoidable. Also, regulations and guidance documents continue to expect air velocities of 90 FPM (0.45 m/sec) ±20%. That specification was removed from FS 209C (now replaced by ISO 14644) in late 1987. The FDA had cited FDA 209B from 1972 as the rationale for that velocity in early 1987. It was carried over into the FDA 2004 aseptic guidance and Annex 1. So why are we dealing with a 'requirement' last accepted nearly 40 years ago, and considered arbitrary and useless more than 20 years later as an expectation for performance? The entire 5 µm particle fiasco that transpired in Annex 1 was another example of regulatory over reach. There has never been a shred of evidence that 5 µm particles bore some special significance in contamination control and no one would or should attempt to use 5 µm particle counts to classify an ISO 5 environment because the counting statistics do not allow that. Finally, it is hard to imagine how anyone would deem it appropriate to set a limit of zero for any monitoring attribute or presume that a finding of a value other than zero should require an investigation when said investigation is impossible to really conduct in a meaningful manner.

I suppose my philosophy with respect to regulation is tell me what you want me to do, but don't tell me how to do it. When regulations go beyond that the result is to reward complacency, prevent innovation and accomplish little for the patient.


1. J. Aga Agalloco and J. Akers, Pharm. Tech., 34(3), S44–45 (2010).