Cleanroom Environmental Monitoring Regulations

Notably, the human body sheds between 30,000 and 40,000 skin cells per hour. As these dead cells flake away invisibly, they can spread microbes which, in turn, may contaminate a drug.

Various standards exist, given the importance of monitoring particles in air and conditions in a cleanroom. However, their navigation and correct interpretation might seem daunting. Please continue reading for an overview of the relevant regulations and their authority.

What are the standards?

Below, you will find the regulations and guidance that apply to industrial cleanrooms. Since their original publication, some of the details in these environmental monitoring standards have been revised, clarified, or expanded.

WHO

The World Health Organization (WHO) stipulates that the preparation and production of sterile products be in clean areas. Personnel, equipment, and materials must enter and leave through controlled airlocks, while air supplies must pass through efficient filters. There should be separate areas for preparing components, containers and closures, product preparation, filling, and sterilization. The WHO divides manufacturing methods into two categories. It differentiates between sterilizing products at the end of processes versus those that are aseptic.

Finally, the organization describes four grades of cleanliness. Grade A is a local zone for high-risk operations. Grade B is applied in aseptic preparation and filling, hence the background environment for the Grade A zone. Grades C and D are not as critical and are typical of closed systems.

FDA

In Title 21 of the Code of Federal Regulations (CFR), the American Food and Drug Administration (FDA) regulates medical manufacturers' quality management systems. Current good manufacturing practice (CGMP) regulations are referenced in Parts 210 and 211. 210 specifies drug processing, packing, and holding, while 211 details finished products.

The rules published in Part 11 deal with electronic documentation, records, and signatures. Since Part 11’s inception in 1997, electronic systems and computing capability have progressed immensely. Nonetheless, more than two decades later, the principles of CFR 21 Part 11 still apply.

ISO 14644

This ISO (International Organization for Standardization) standard offers direction on how to measure, interpret, and apply the results of particle deposition or obscuration rates on vulnerable surfaces in cleanrooms. It also details how to control contamination and reduce risk levels.

EU GMP

Published in 2008 and updated in 2020, the European Union's Good Manufacturing Practice standards (or EU GMP) Annex 1 mentions essential elements of monitoring such as particles, microbiological count, temperature, and relative humidity. In addition, its detailed guidance covers formal risk analysis, alerts, and action limits.

GMP lists various production methodologies, including blow, fill, and seal. In addition, it compares terminally sterilized and aseptic preparation techniques. Other topics covered include pharmaceutical quality systems (PQS) and quality control (QC) requirements.

As well as advocating a contamination control strategy (CCS) for each facility, the guide promotes a holistic approach to detect seemingly independent events, consider common causes, and implement appropriate corrective and preventive actions (CAPA) as necessary.

EU Annex 11 includes detailed guidelines for computerized systems and their requirements for validation and qualification.

USP 1116

Published in the US Pharmacopeial Convention, this chapter covers microbial contamination control in aseptic processing within healthcare industry environments. Its information and recommendations apply to some medical devices, sterile pharmaceutical products, intermediates, and excipients.

This publication recognizes that failures in aseptic processing environments present a higher potential risk to patient safety than manufacturing operations such as equipment and component preparation, non-sterile products, and processing of terminally sterilized products. The content describes how advanced aseptic processes avoid direct intervention with open product containers or exposed product contact surfaces, even if operators wear conventional cleanroom protective clothing.

How to Apply Cleanroom Standards

Given that the multiple guidelines and recommendations can be confusing – and in some cases even conflicting – companies that operate sterile product manufacturing facilities should pay particular attention to regional protocols for:

• Regular risk assessments and proactive management.

• Use of effective CCS, root cause, and CAPA measures.

• Optimization of monitoring systems to detect environmental contamination.

• Deployment of experienced staff.

Control strategies ought to cover the detailed management of plants and processes alike. For best results, the management of equipment, facilities, and personnel requires a commitment to continuous improvement.

Differences Between Standards

Cleanroom norms differ between the US and the EU, even though their recommendations are critical within GMP. Well-known examples include the different EU and FDA requirements relating to terminal sterilization and aseptic processes. Similar disparities apply to airborne particles greater than 5.0μmin size.

In some cases, possible misunderstandings may even pose safety risks. For instance, during the drafting of amendments to the regulations, engineering specialists questioned language relating to the functionality of and emergency escape mechanisms for interlocking doors and airlocks. In their view, the wording was imprecise.

Practical Guide on Cleanroom Monitoring

What you should know about monitoring parameters in pharmaceutical cleanroom production.

 

 

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Harmonizing the Standards

Increasingly, industry leaders suggest that guidance for GMP and cleanroom operation should be normalized worldwide based on practical experience and scientific evidence.

In this respect, apart from adoption in its home continent, EU GMP guidance provisions have gained acceptance in Russia and China to become a de facto near-global guide.

ISO Classes

This international standard categorizes cleanrooms according to air changes per hour and maximum airborne particle count. ISO Category 1 cleanrooms are the most scrupulously clean and are typical in life science environments and electronics manufacturing.

The design of cleanrooms in the biotechnology and pharmaceutical fields usually meets ISO Class 5 to Class 8 parameters. In contrast, category 9 areas are relatively clean but not subject to such exacting requirements.

Electronic Monitoring Standards

In biotech, drug manufacturing and regulated industries, monitoring standards are of particular importance. They detail the need for audit trails, electronic records, signatures, and system validations. While CFR Title 21 Part 11 applies within the USA, EU Annex 11 pertains to European companies.

CFR Title 21 Part 11

US federal regulations set out a framework for companies to:

• Ensure the safe and secure maintenance of cleanroom records and logs in the workplace.

• Use computer control systems and software correctly.

• Trace changes to data, through an electronic audit trail.

• Prevent or, if necessary, detect falsified records.

• Prevent data corruption and loss.

• Verify approval and review signatures indisputably.

Pragmatic in nature and based on common sense, the above principles represent a good practice worldwide.

EU Annex 11

Significantly, while the FDA's 21 CFR Part 11 applies only to electronic records, the EU Annex also covers software, hardware, personnel, and risk management.

Regardless of location, recommended security precautions should include a system of unique logins plus strong access passwords. In addition, computer servers ought to disconnect inactive users after ten or twenty minutes. Finally, as a precaution, user lockout should occur after three to five password failures and more than thirty days of inactivity.

Conclusion

Above, you have seen cleanroom environmental management standards and considerations in overview form. If you manage a clean production facility or laboratory, did you know that ELPRO is a leader in the pharmaceutical sector?

Around the globe, forward-thinking global pharma, biotech, life science, and healthcare companies count on ELPRO's three decades of experience to monitor critical production assets. Contact them today for support and in-depth expertise on keeping medicine safe for patients.