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In the pharmaceutical industry, there is a very thin line between beneficial and harmful. In fact, the margin can hinge on the minutest of particles. Take antibiotics for instance. Trace amounts of contaminants and suddenly you’re dealing with widespread antibiotic resistance or adverse reactions in patients. With the manufacture of injectable medications, it can cause severe infections or septic complications. Any unintended by-products during the synthesis of APIs (Active Pharmaceutical Ingredients) can alter the performance or safety of the drug involved. Like the presence of metal impurities in excipients that catalyze the degradation of the active drug.
Even the production of biologic drugs, such as vaccines or monoclonal antibodies, requires an environment free from viral and bacterial contaminants. A tiny breach in the sterile environment, like a microscopic tear in a filter, and oops! You compromise the entire batch. Now you’re faced with recalls and lawsuits for putting entire populations at risks.
The FDA reported a total of 912 drug recalls across 166 manufacturing sites in 2022, marking the highest number in five years. Reasons ranged from violations of current good manufacturing practices (CGMP), including temperature abuse and storage errors, to CGMP errors, and contaminations. Respiratory tract agents were the most affected, followed by cardiovascular agents. It’s a high-stakes world. Which is why firms use cleanrooms.
Cleanrooms 101: How They Work
These environments are closely monitored to maintain very specific levels of temperature, humidity, and particle contamination. The right temperature is needed to ensure the stability and viability of sensitive ingredients used for manufacture process. For the humidity, if it gets too high, and you risk condensation, potentially a breeding ground for contaminants; too low, and you may face static electricity, threatening delicate electronic equipment or even igniting volatile substances. There is simply no room for error.
The first step in the cleanroom design is understanding what the cleanroom will be used for, and the regulations around the particular products involved. For instance, ISO Class 5 cleanrooms are often necessary for aseptic processing. How easy will it be to clean and maintain? Are the surfaces smooth and non-porous enough to prevent microbial growth and speed up decontamination? All these are factored in.
One increasing trend in this part of the world is using modular cleanrooms. This is due to their fast installation, reconfigurability, and compliance with regulatory standards. In 2022 for instance, they were particularly prevalent in compounding pharmacies, contributing to a large revenue share of 92.9%, and had been set to grow at the fastest CAGR of 2.8% during the period.
Other considerations include:
Airflow and Filtration Systems: Proper airflow is vital in preventing contamination. The cleanroom design should ensure a unidirectional or laminar airflow, where filtered air flows in a single direction at a uniform speed, effectively removing particles and contaminants. High-Efficiency Particulate Air (HEPA) filters are also incorporated as they can remove 99.97% of particles as small as 0.3 microns, essential for maintaining the purity of the air.
Layout: The cleanroom layout should be strategically planned to minimize contamination risk. This includes defining clean zones and controlling the flow of personnel and materials. Entry and exit points must be designed to prevent air from less clean areas from entering more critical zones. For example, airlocks or gowning rooms can serve as effective transition zones. The internal layout should ensure easy and minimal movement of people and materials to lower the risk of cross-contamination.
United States Pharmacopeia (USP) standards are specifically tailored to address the unique requirements of the industry. Let’s look at two here:
USP 797 Standard: Compounding with Care
It applies to all pharmacy settings where compounded sterile preparations (CSPs) are produced, including hospitals, retail settings, and ambulatory care centers. It does this by describing clear steps for making sterile drug preparations and making sure they are made in a way that reduces the chances of contamination, infection, and errors.
The CSPs here are categorized into three risk levels based on the potential for contamination:
Low-Risk Level CSPs: These are compounded in an ISO Class 5 environment and involve simple aseptic measuring and transferring with a limited number of sterile products.
Medium-Risk Level CSPs: This category includes CSPs that involve more complex aseptic manipulations or are intended for use over multiple doses or patients.
High-Risk Level CSPs: These are compounded using nonsterile ingredients or devices, outside an ISO Class 5 environment, or when proper personal protective equipment (PPE) is not used.
Like every other regulation, USP 797 is subject to continuous review and revision to reflect the latest practices and technological advancements. Recent and proposed changes include:
Introduction of Category 3 CSPs with specific beyond-use dates and requirements for endotoxin testing, garbing practices, and cleaning procedures.
Enhanced cleaning procedures for Category 3 preparations, including the application of a sporadic agent to various areas in the compounding environment.
Continuous feedback and updates to refine and enhance the guidelines for better alignment with current practices and technologies.
USP 800 Standard: For The Drug Handling Process
According to NIOSH, approximately 8 million U.S. healthcare workers are potentially exposed to hazardous drugs (HDs). This standard establishes proper guidelines for the entire lifecycle of these drugs, from receipt to disposal in healthcare settings. It was introduced in 2016, its key components include:
Facilities and Engineering Controls: USP 800 specifies that healthcare entities must handle HDs in designated areas. These include spaces for receipt and unpacking, HD storage, and sterile and non-sterile compounding areas.
Personal Protective Equipment (PPE): The standard requires healthcare entities to develop SOPs for PPE based on exposure risk and activities performed. PPEs include gloves, gowns, head, hair, shoe and sleeve covers, eye and face protection, and respiratory protection. Disposable PPE must not be reused and that reusable PPE must be decontaminated and cleaned after use.
Risk Assessment and Cleanroom Requirements: The cleanroom requirements outlined in USP 800 are stringent and are designed to create a controlled and safe environment for compounding HDs, thereby minimizing the risk of contamination and exposure. The main elements include:
Negative Pressure Cleanrooms: Their purpose is to contain HD contaminants within the compounding area, preventing their escape into cleaner sections of the facility. They do this by maintaining a lower pressure inside the designated compounding area compared to adjacent spaces. This draws air drawn into, rather than out of, the cleanroom.
Dedicated Ventilation Systems: They control air quality and minimize HD exposure by preventing the recirculation of contaminated air. These specialized systems vent air from the compounding areas directly outside the building, effectively removing contaminants from the facility and ensuring they do not re-enter the pharmacy or adjacent areas.
External Venting within Primary Engineering Controls: PECs provide a sterile environment crucial for aseptic compounding processes. USP 800 mandates that PECs incorporate external venting mechanisms to eliminate the possibility of HD contaminants recirculating into cleanrooms or pharmacy areas, thereby maintaining an uncontaminated compounding atmosphere.
Monitoring and Maintenance: Put in place protocols regular inspections, testing, and certification to ensure the cleanrooms function correctly within the required limits of air quality and pressure differentials.
Deactivation, Decontamination, Cleaning & Disinfecting: Healthcare entities must establish written procedures for the decontamination, deactivation, and cleaning of all areas and equipment in contact with HDs. The cleaning process involves steps like deactivation (rendering compounds inactive), decontamination (residue removal), cleaning (removal of organic and inorganic material), and disinfection (destruction of microorganisms).
Spill Control and Medical Surveillance: USP 800 mandates immediate containment and cleaning of hazardous drug spills by qualified personnel wearing appropriate PPE. It also calls for medical surveillance as a crucial component of the exposure control program to minimize adverse health effects in personnel exposed to HDs.
Compliance from the Ground Up
Integrating the principles of the required standard begins at the cleanroom design phase. Every detail of the cleanroom, from the choice of materials for surfaces to the layout promoting unidirectional airflow, must aim for sterility and safety. The design should make cleaning and decontamination easy, limit places where contaminants can collect, and make sure that hazardous substances are handled and stored properly.
It’s not a once-and-done deal. After the cleanroom design and installation, regular maintenance ensures that HEPA filters function optimally, surfaces remain uncontaminated, and the environmental conditions like temperature and humidity stay within prescribed limits. Monitoring involves routine checks and documentation, ensuring every element, from air quality to personnel compliance with gowning procedures, adheres to the standards. Validation on the other hand provides assurance of a cleanroom's compliance. It's a multilayered process involving testing, monitoring, and certification.
Cleanroom Management & Best Practices for Peak Performance
For businesses in the thick of it, not only are you keeping an eye on the ever-evolving policies and regulations, but you're also dealing with the human side of things (we all have our off days, right?). Occasional lapses or inadequate training, contribute to the complexity involved, as do the demands of managing delicate mechanical systems. How do you stay on top of it all?
Ongoing Education and Professional Development: Beyond initial training, it's important to invest in educating your staff, keeping them abreast of the latest industry standards and procedures. Regular drills and assessments come in handy as well.
Stringent Monitoring and Detailed Record-Keeping: With a comprehensive system for monitoring environmental conditions and operations within cleanrooms, you will be able to identify any irregularities early, and quickly take remedial actions. Thorough documentation is not only a regulatory requirement but also a tool for traceability and continuous improvement.
Preventive Maintenance: Don’t wait for trouble to come knocking. Getting proactive with routine checks and servicing can prevent unforeseen breakdowns and ensure consistent performance.
Engaging Staff: Encourage a workplace ethos where compliance is everyone's business. When team members take personal ownership of maintaining standards, adherence becomes part of the organizational DNA. Recognize and reward those who go above and beyond. Establish clear and accessible channels for your staff to report deviations and ensure that protocols for addressing non-compliance are well understood and followed.
Keeping Your Operations Compliant
DesignTek Consulting Group understands the gravity of these responsibilities and stands ready to be more than just a service provider, but a partner in your mission to safeguard public health. With our deep industry knowledge, we are poised to assist your firm through the cleanroom design and installation of the cleanrooms. For inquiries, guidance, or a detailed discussion on how to align your operations to the required standards, free to give us a ring at (855) 203-2958 or drop us a line at info@dtcdesign.us.