Letters Q&A written on wooden irregular blocks. Questions and answers concept.


Challenging the “Norm” – Process Engineering Q&A with Norm

Seeking answers regarding your biomanufacturing operations? Look no further. Our President, Norman Goldschmidt, is answering your questions regarding sterility, safety, quality, and efficiency. If you have one for us to post, please use the form below and reference “Challenging the Norm.”

Norm has more than 35 years of experience in engineering management, planning, design and construction in the pharmaceutical and biotech industry. His two-decade tenure at Bristol-Myers Squibb culminated in the role of Executive Director, Global Engineering. An expert in drug development facilities and processes, Norm holds four patents, serves as an ISO Author/Expert, and contributes significantly to industry organizations such as ISPE, ASHRAE, NSF, FDA, HCA, and TGA.



Question: In sequential airlocks (e.g., Grade C airlock followed by B airlock for entering Grade B), should gowning take place in the same cleanliness class you are entering (e.g., in Grade B)?

Answer: The cleanliness classification surrounding gowning operations depends on your Environmental Monitoring (EM) philosophy. Genesis AEC applies gowning activities that liberate the most particles, like putting on coveralls over scrubs, best applied in the lower-class space. Why? It simplifies the EM.

Imagine trying to put on aseptic coveralls over your regular attire in a Grade B cleanroom. You’d probably breach the cleanliness limits, at least briefly. This is especially true in small airlocks, where you’re close to the cleanroom door. You essentially step into Grade B without being properly gowned for it.

If the first stage of Grade B gowning occurs in Grade C, you are unlikely to fail in either Graded space. If your EM program is setup to accept the spike on the “dirty side” of the Grade B airlock, then you can do all gowning in Grade B.

So, if the first stage of your Grade B gowning takes place in Grade C, you’re less likely to exceed limits in either cleanliness class. If your EM program allows for a spike in particle counts on the “dirty side” of the Grade B airlock, you can do all of your gowning right in Grade B.

Question: Seeking forum feedback on interventions during aseptic process simulations. Our procedure clears the line of open vials before the intervention, and if first air is interrupted or units are overlaid by the isolator glove, vials are removed. Should units be filled post-intervention or remain open during the intervention?

Answer: Filling your removed units may not be indicative of your process. Clearing units, if needed, aligns with guidance. The key is ensuring removed units mimic routine production discards after similar interventions. The emphasis is on understanding the process and assessing contamination risks. Filling and incubating may reinforce process adequacy but isn’t mandatory based on the guidance provided.

Question: Can you provide guidance on the current standards for Controlled Not Classified (CNC)? Also please confirm, is CNC a European Union (EU) vs. International Society for Pharmaceutical Engineering (ISPE) standard?

Answer: CNC originated from industry practices rather than regulations. It serves as a buffer between uncontrolled spaces and ISO 8, the lowest FDA-classified environment. Over the years, it has been known by various names like “pharmaceutical clean” or “Gray.” ISPE  aimed to provide a consistent definition. In my opinion, the best definition can be found in the Biopharma Guide 2nd Edition:

CNC areas are designed with HVAC systems to reduce airborne contaminants below ambient levels. They tightly control temperature and humidity, with installation qualification common. These areas, sometimes called “pharmaceutical” or “clean” areas, make no specific claim for particulate control. Typical systems have heating, cooling, and filtration meeting MERV 13 or better.

The 3rd edition of the sterile guide offers a simpler definition: CNC refers to a non-classified room environment where closed processes and their immediate support systems may be located. It is cleanable, access-controlled, and receives filtered ventilation air. Procedural controls and personnel garment upgrades may be applied at the Owner’s discretion. In the biopharmaceutical industry, CNC is replacing the term “Gray Space.”

Question: Did the World Health Organization (WHO) mandate the requirement for an oRAB (open restricted access barrier) to have its air supply located above the ophthalmic filling line and fed from fresh air, with a separate AHU (air handling unit) to avoid turbulent flow?  I couldn’t find WHO guidance or scientific justification supporting this requirement.

Answer: There is no known requirement from the WHO mandating an oRAB to have its air supply located above the ophthalmic filling line and fed from fresh air, with a separate AHU to avoid turbulent flow. I have not viewed such guidance in the WHO sterile guide (TRS 1044 Annex 2) or the older sterile guidance (TRS 961 Annex 6).

The effectiveness of  AHUs is based on the cleanroom meeting the specifications of ISO-14644. Filtering air that is already clean is generally more effective. The suggestion for a separate AHU may be one potential solution, but it’s not the only solution. We have successfully tied active RABS to low returns in the room for almost two decades, enhancing room performance.

Question: Our intervention procedure states that the line must be cleared of open vials by the filling machine before an intervention, whenever possible.  During an intervention, vials are removed if first air is interrupted or units are overlaid by the isolator glove .

What is the recommended approach for aseptic process simulation interventions involving isolator gloves, specifically regarding the presence of open vials on the line? Should units be filled after the intervention, ensuring the line is cleared during the intervention, or is it acceptable for open units to be present on the line during the intervention, and subsequently filled with media to qualify for the intervention? Seeking feedback and insights based on practical experiences in the absence of specific guidance in Annex 1.

Answer:  I’d call your attention to what IS in the guidance, cited below:

  • “All integral units from the APS should be incubated and evaluated, including units with cosmetic defects or those that have gone through non-destructive in-process control checks.
  • If units are discarded during the process simulation and not incubated, these should be comparable with units discarded during a routine fill.
  • Only if production standard operating procedures specify that units must be removed under the same circumstances (e.g., type of intervention, line location, and specific number of units removed).
  • No units should be removed during an APS intervention than those that would be typically cleared during a production run. Examples may include those that must be discarded during routine production after the set-up process or following a specific type of intervention.
  • To fully understand the process and assess contamination risks during aseptic set-up or mandatory line clearances, these units would typically be incubated separately, and would not necessarily be included in the acceptance criteria for the APS.”

Since the units you propose to dispose of are not integral and represent units that would typically be discarded after an intervention, I believe you are on solid ground to neither fill nor incubate these. If you did choose to, it would be to reinforce the adequacy of your process.

If you have a question, please use the form below and reference “Challenging the Norm” and we’ll post the answer here, or if you prefer, reach out to you personally.

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About Genesis AEC

Genesis AEC – an award-winning consulting, architecture, engineering, and construction management firm – has partnered with life sciences companies for more than 25 years to complement the scientific expertise of our clients as they usher in the next generation of life-saving therapies, treatments, and technologies. Whether it’s providing AE support for existing sites; commissioning, validation, and qualification (CQV) for specific processes or equipment; or turnkey design-build solutions, our team blends sound science and technical expertise with quality assurance and safety measures to deliver unparalleled results.