Regulatory Pseudoscience – Myths, Opinions and Other Fantasies

Monday, April 13, 2026

By: James Agalloco, Agalloco & Associates

Introduction

We live in a society defined by laws of diverse types. There are laws established by governments to define taxation, human rights, immigration, contract management and traffic regulation. Relevant to the global healthcare industry are the regulations and guidelines established by regulators that define controls over production processes. These are administrative laws established by government agencies that define the practices intended to protect the public. These co-exist with natural or scientifically evolved laws that explain our environment and surroundings such as gravity, physics, thermodynamics and chemistry. Laws derived from science are founded in observation, analysis, experimentation and documentation with the results serving as the basis for further refinements. Opinion, conjecture and speculation are anathema to science. Consistency between regulatory and scientific can make medical product manufacturing substantially easier. Where regulation confounds science, difficulties of various sort result, and these situations can prove problematic for all.

Some 400+ years ago, Galileo Galilei postulated that the earth revolved around the sun, contradicting the strongly held opinions of the Catholic Church and Pope Urban VII. This may be the first instance of science finding itself outside the law. Imprisonment, threats of excommunication, and lifetime penalties were imposed upon Galileo. Increasing knowledge obtained through better telescopes ultimately vindicated Galileo and his theories were ultimately broadly accepted by the mid-1800’s.

The American revolution was in part based upon the principle: that government serves with the consent of the governed. Governmental laws have the goal of providing order to society in a manner that maximizes their individual freedoms. An unavoidable consequence of that goal are restrictions against behaviors that interfere with the rights of others. That the system is far from perfect should be obvious. The failure of the US Constitution to prohibit slavery when first adopted in 1789, and prohibitions against alcohol in the 18th Amendment are two noteworthy examples of failed regulations and laws.

Regrettably, the litany of failed laws is not restricted to the annals of history or settings outside the healthcare industry. There are numerous international regulations, guidances and other standards that contradict the natural laws of science. These can impose a substantial hardship on manufacturers that must endeavor to somehow overcome the inherent limitations and the resulting complications. The legalistic impositions on science can be found in FDA and EMA regulations, ISO and EN standards, pharmacopieal standards, guidelines, position papers and other regulatory and quasi – regulatory doctrines. The intrusion of regulation on science takes two different forms:

  • Overly prescriptive numerical limits which restrict operational flexibility and stifle innovation.
  • Artificial expectations for tests and practices lacking clear scientific rationale.

The following examples illustrate some of the points of conflict that stifle innovation, increase cost and in many instances add no meaningful value.

Regulatory and Compliance Overreach

  • Health Technical Monograph-10, Sterilization first issued in 1978 by the United Kingdom’s National Health Service established requirements for steam quality in which numerical limits for non-condensable gases, steam superheat and steam moisture fraction were defined. These values found their way into national and international standards and have slowed drug approvals and importations. The original limits were derived from experience with hospital sterilizers in which steam quality was established by the incidence rate of infections as it related primarily to sterilization of hospital linens. There is no data supporting the appropriateness of these values for materials other than linens, nor any correlation to an inability to sterilize other materials.1
  • Often associated with HTM-2010 expectation is ‘equilibration time’ (similar to come-up time) where a maximum lag of 15 or 30 seconds (depending upon the sterilizer size) is established for the delay between the start of the dwell period and the last penetration probe to attain that temperature. The belief is that any delay is indicative of air retention within the sterilizer and is now cited in any number of standards. This value has no referenced scientific evidence supporting its appropriateness as a definitive measure of sterilization process efficacy. Given the continued use of gravity displacement sterilizers in medical and dental offices, as well as the numerous sterilization-in-place systems where the ‘equilibration time’ can be longer there is little credibility to it. Sterilizers validated prior to the establishment of this requirement met all other validation requirements, yet full alignment with the ‘equilibrium time’ limits is considered CGMP.2,3
  • The FDA’s 2004 Guideline on Sterile Drug Products Produced by Aseptic Processing includes an example of a different sort.4 It suggests that ISO 5 systems using unidirectional (previously called laminar) air flow have a velocity of 90 FPM ± 20% (0.45 m/s). The original reference for this value can be found in FS 209B.5 The next edition, FS 209C issued in 1987 removed air velocity as a requirement in classification of environments as irrelevant to the desired state. Similarly, ISO 14644 which replaced FS 209 has no requirement for air velocity.6 While FDA acknowledges that velocities other than 90 FPM can be utilized (a guideline and not a regulation), that same value appears in EMA Annex 1 – Sterile Medicinal Products which is a regulation.7 Apparently, in the interests of harmonization, EMA adopted an arbitrary value as absolute. Unidirectional air velocities can range from 5 to 400 FPM, and while there are many different versions of how 90 FPM became the preference, all indicate the choice was one of convenience not science. The author has encountered numerous installations where air velocities above and below the expected velocity range were better able to maintain the desired particle classification.
  • Originally conceived as visual confirmation of air direction, smoke studies have become a required activity to assess operator intervention performance. ISO 14644-3: 2007 indicates “The purpose of this test is to confirm either the airflow direction or airflow pattern or both in regard to the design and performance specifications. If required, spatial characteristics of airflow in the installation may also be confirmed.”6 The extension of such a benign observation lacking any criteria into a subjective pass-fail test of design and dexterity as mandated in EMA Annex 1 presumes an infallible precision on the part of the reviewer.7 The expected frequent performance and documentation of smoke studies despite their lack of objective criteria belies any logic. Their use as definitive evidence of a satisfactory or unsatisfactory aseptic processing activity or design is wholly subjective.
  • The detection of >5 µ particles has been an obsession with many since the early 2000’s. This is linked to the belief that particles >5µ are derived from personnel and thus more likely to carry microorganisms. FS 209 and ISO 14644 have never included requirements for monitoring of >5 um particles due to the uncertainties of sampling and counting them.5,6 Nevertheless, according to Annex 1, ISO 5 environments must consider >5 um in classification and routine monitoring.7 Annex 1 indicates the following. “The occasional indication of macro particle counts, especially ≥ 5 μm, within grade A may be considered to be false counts due to electronic noise, stray light, coincidence loss etc. However, consecutive or regular counting of low levels may be indicative of a possible contamination event and should be investigated. Such events may indicate early failure of the room air supply filtration system, equipment failure, or may also be diagnostic of poor practices during machine set-up and routine operation.” There is no supportive data that supports the attention given to this unusual expectation.
  • The moist heat sterilization of components and products is temperature dependent. There are numerous applications using temperatures ranging from 100 to 150°C in which the operating conditions are chosen to best preserve the essential quality attributes. Yet, we find repeated expectations for temperatures in excess of 121°C to sterilize.8,9 That 121°C is a completely arbitrary choice rooted in the Celsius conversion of 250°F (the prevalent temperature measurement in the late 1800’s) is ignored. There are numerous well documented and regulatory approved products that are sterilized at other temperatures above and below 121°C.10
  • The regulatory obsession with environmental monitoring has grown over the two decades. Conceived to periodically assess the consistency of system design and process controls it has been transformed and amplified in criticality. EMA and FDA have made the absence of microorganisms in Grade A (ISO 5) an absolute requirement. Any detectable count is indicative of failure as the environment (and by inference, the product) is considered contaminated. This perspective belies the reality that has existed in clean environments since their inception – that absence means sterile. The reality is that absence merely means non-detected and aseptic environments have operated successfully in that state for decades. More recently, there are expectations for continuous viable monitoring of ISO 5 environments in efforts to ‘prove’ their sterility. That this entails additional interventional activity which in turn increases the microbial contamination potential is ignored.7,11,12
  • EMA’s 2022 revision of Annex 1 essentially equates the performance of various aseptic technologies from manned cleanrooms to isolators.7 While claiming support for advanced technologies, EMA imposes requirements on the best available technologies that increase their operating complexity and cost, whilst largely ignoring weaknesses in the less capable technologies it continues to tolerate. That this message undermines the adoption of improved systems is most unfortunate.13,14
  • USP has revised its’ content on microbial content of non-sterile products to further support the absence of so-called ‘objectionable’ microorganisms. This belies the extremely limited utility of sampling in non-sterile materials as evidence of microbial absence. The resources spent sampling and testing for specific microbes would be better served in efforts to reduce the microbial content of non-sterile products overall. Lowering the population of all microorganisms in these products provides patients with safer products overall, something fixation on a limited target cannot achieve.15,16

Concluding Remarks

This treatise should not be viewed as desiring less regulation or weaker standards for pharmaceutical products. That is absolutely not the author’s intent. My goal in developing this is to enlighten those who seek to regulate us that there are limitations in the imposition of standards that contradict science, logic and reason. We cannot test our way to safety regardless of how many samples are taken, but we can improve performance by being open to objective realities and common sense.

The form of regulatory and compendial decrees needs to revert to the practices of a generation past. Instead of telling industry how to do what we do best, these documents should outline what we should provide in the way of results.17,18,19,20 The expectations should be flexible enough to allow for continued improvement without artificial constraints evolved from subjective beliefs, oversimplified perspectives or outdated practices.

Postscript

“It is not the critic who counts: not the man who points out how the strong man stumbles or where the doer of deeds could have done better. The credit belongs to the man who is actually in the arena, whose face is marred by dust and sweat and blood, who strives valiantly, who errs and comes up short again and again, because there is no effort without error or shortcoming, but who knows the great enthusiasms, the great devotions, who spends himself in a worthy cause; who, at the best, knows, in the end, the triumph of high achievement, and who, at the worst, if he fails, at least he fails while daring greatly, so that his place shall never be with those cold and timid souls who knew neither victory nor defeat.”

Theodore Roosevelt –1910

References

  1. National Health Service, Health Technical Memorandum 10 – Sterilization, Her Majesty’s Stationery Office, London, 1978.
  2. BS EN 285:2015+A1:2021, Sterilization – Steam Sterilizers – Large Sterilizers, 24.2.2.11, 2021.
  3. ISO 17665, Sterilization of health care products — Moist heat, International Organization for Standardization (ISO), 2024.
  4. FDA, Guidance for Industry - Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice, 2004.
  5. Institute for Environmental sciences, FS 209B, Cleanroom and Work Station Requirements, Controlled Environments, 1973.
  6. ISO, ISO 14644, Cleanrooms and Associated Controlled Environments, 2007.
  7. EMA, Annex 1, Manufacture of Sterile Medicinal Products, 2022.
  8. European Pharmacopoeia, Section 5.1.1, Method of Preparation of Sterile Products, 2008.
  9. EMA, EMA/CHMP/CVMP/QWP/850374/2015, Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container, 2019.
  10. Agalloco, J., Akers, J. & Madsen, R., “Revisiting the Moist Heat Sterilization Myths” PDA Journal of Pharmaceutical Science and Technology, Volume 63, No.2, pp 89-102, 2009.
  11. Akers, J. & Agalloco, J., “Environmental Monitoring - Myths and Misapplications”, PDA Journal of Pharmaceutical Science and Technology, Vol. 55, No. 3, p. 176-184, 2001.9(1100)
  12. Akers, J., Agalloco, J., DeSantis, P., and Madsen, R., “What is this Thing Called Science and Who or What Owns It?”, American Pharmaceutical Review, Vol. 27, No. 6, pp. 34-39, 2024.
  13. Agalloco, J., “Paradise Lost: Misdirection in the Implementation of Isolation Technology”, Pharmaceutical Manufacturing, Volume 15, No. 4, p. 34, 2016. Continued online at Pharmmanufacturing.com. Reprinted in Aseptic Processing Trends eBook, pp 9-17, July 2017.
  14. Akers, J., Agalloco, J. & Madsen, R., “Slow Walking the Isolator – A Cautionary Tale”, published on-line at LinkedIn.com, October 2020.
  15. USP, Proposed Compendial Approach for the Implementation of <60> Microbial Examination of nonsterile Products – Tests for Bulkholderia Cepacia Complex (BCC), March 29, 2024.
  16. Agalloco, J., et al, “Refining Microbiological Control for Non-Sterile Products”, published in Pharmaceutical Forum, No. 48(2), 2022.
  17. K. G. Chapman, “A History of Validation in the United States: Part I, 15 (10), 82-96, (Oct 1991), and Part II,” Pharmaceutical Technology, 15 (11), 54-70, (Nov. 1991).
  18. Agalloco, J. “PDA letter to the editor re: Some Thoughts on the Need for Formalized Guidance on Aseptic Processing Practice,” PDA Journal of Pharmaceutical Science and Technology, Vol. 55, No. 5, p. 263-265, 2001.
  19. Agalloco, J., “Some Further Comments on Aseptic Processing Guidance or The Fool on the Hill”, PDA Journal of Pharmaceutical Science and Technology, Vol. 57, No. 5, p. 324-330, 2003
  20. Madsen, R., & Agalloco, J., “What, Not How”, published on-line on LinkedIn.com, April 2020.

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