EMPQ Essentials for Successful Cleanroom Qualifications – Part 2

Insights from industry leaders on regulatory compliance, overcoming challenges and risks, and best practices for cleaning and disinfection during an EMPQ

In Part 1 of our blog series, we discussed the importance of microbial identification, tracking and trending in EMPQ, along with strategies for an effective qualification process. In this second installment of our series, we’ll focus on questions from our recent EMPQ Essentials webinar about disinfection and regulatory compliance and explore additional key factors to support your cleanroom qualifications.

Understanding and Complying with Regulations

The controlled environment of a cleanroom is a critical component of contamination control for the manufacture of sterile products. Because of its importance and role in brand protection and patient safety, there are many regulatory requirements surrounding cleanroom design and validation. The FDA covers cleanrooms in 21 CFR 600 through 680 for biological products, as well as the more general CFR 210 and 211 regulations covering cGMP practices. The EU GMP Annex 1: Manufacture of Sterile Medicinal Products also provides expectations for cleanrooms, but the most cited standard is the ISO 14644 series of documents. These standards provide additional details on a variety of topics from cleanroom design and construction to classification and monitoring.

In the ISO 14644 nomenclature, cleanrooms are classified as ISO 1 through 8 depending on the cleanliness of the air by particle concentration. For example, an ISO 7 room (equivalent to a Grade C room in EU GMP Annex 1) should not exceed 352,000 particles ≥ 0.5 µm per cubic meter of air. The requirements are tighter the lower the class of room, with ISO 5, 7, and 8 rooms being the most common in pharmaceutical manufacturing (with equivalents to EU GMP Annex 1 Grades A, C, and D, respectively).

A new cleanroom must be commissioned by undergoing design, installation, operational, and performance qualifications. These qualifications are a significant investment by the facility so a well thought out approach is critical. According to Annex 1, Grades A and B should be requalified at least every 6 months, while Grades C and D should be requalified at least every 12 months to demonstrate that the cleanroom is still operating under a state of control.  

Overcoming EMPQ Challenges and Risks  

EMPQs are a large undertaking, even within the scope of an entire cleanroom validation. Cleanroom projects are a large financial investment, and any delays can cost a company significant revenue. To help ensure your site comes out relatively unscathed, it is important to recognize and mitigate potential setbacks during your cleanroom qualification work. Companies may be facing limited personnel resources and lack of laboratory space for sample processing and identification, along with the pressure of getting a cleanroom up and running as efficiently and quickly as possible. These challenges can be addressed using consultants and contract personnel and identifying partnerships with pharma-focused companies providing outsourcing and technical services. The same strategies can also be used to help companies recover from unsuccessful or especially challenging EMPQs and get back on track.

It is also critical to involve members of the Quality Unit experienced in microbiology and contamination control during development of the validation plan, and especially during creation of the User Requirements Specification (URS) document. Inclusion of this additional expertise helps makes sure that the cleanroom space is designed and performs optimally during execution of the EMPQ with regards to meeting or exceeding contamination control requirements.

Another crucial aspect to ensure success is to use a risk-based approach when choosing EM sampling sites. An EMPQ forms the basis for your entire routine EM program in support of the site’s contamination control strategy, and understanding your environment, processes, and personnel and material flows within the areas being assessed is essential for a comprehensive risk assessment. If a risk is not properly addressed during the EMPQ process, it can pose contamination challenges for your manufacturing processes down the road.

There are also a number of important considerations when it comes to identifying and mitigating potential contamination risks. Special attention should be paid to items passed in and out of cleanrooms such as carts (including the wheels), bags, markers, cellphones, and boxes to ensure they have been suitably wrapped or disinfected. Items inside cleanrooms such as equipment, door kick plates, incubators, ceiling tiles, poorly maintained flooring, and vibrations from construction can also pose contamination risks. Another factor includes transfer of contaminants via personnel, where gowning can present a particular concern.

Overall, it is imperative that the data gathered during EMPQs with the use of modern microbial identification methods such as MALDI-TOF and DNA sequencing are thoroughly analyzed so that actionable and scientifically valid conclusions can be drawn. These data will be used to inform multiple aspects of your site’s contamination control strategy such as the cleaning and disinfection program, personnel gowning, and material transfer activities.

Effective Cleaning and Disinfection 

Destroying contamination in any cleanroom operation requires known vegetative cells and the spores. In the present design of a rotation system, there are two types:  

1. A single disinfectant rotated with a sporicide
2. A two-disinfectant system (rotated monthly), plus a sporicide

Both require a minimum of a monthly sporicidal application. The frequency depends on the environment. The use of a cleaning agent, such as DECON-CLEAN, is considered an optional step in controlling existing residues. This should be performed once a quarter. A final wipe down step should also be performed using an alcohol such as DECON-AHOL WFI.

Disinfectant Validation Process for Cleanrooms

Validation of disinfectants as part of cleanroom qualification is necessary to prove that the disinfectants chosen are effective at eliminating microorganisms on surfaces within your cleanroom environment. This ensures the level of microbial control within your cleanroom/controlled environment and are mandated by regulatory agencies. Validation of disinfectants for cleanrooms is done by performing disinfectant efficacy studies per regulatory guidelines. The steps include:

1. Develop a well-detailed validation protocol outlining testing.
2. Include disinfectant concentration, aging, contact time, microorganisms, surfaces and acceptance criteria.
3. Identify prevalent organisms found in your cleanroom through your environmental monitoring program.  
4. Choose surfaces that are representative samples within your cleanroom.
5. Determine appropriate inoculation of the chosen microorganisms and apply disinfectant at various contact times.
6. Choose a suitable method such as swab or rinsing to determine recovery and enumeration.
7. Determine log reduction achieved and compare it to your acceptance criteria.

It’s also important to understand the factors driving disinfection cleaning study and how to leverage existing validated strategy for new facilities. The question ‘Is it mandatory to go through a full cleanroom qualification or risk assessment is enough?’ is being asked frequently.  

It is generally not recommended to use an existing validated study to qualify another facility. There may be differences in environmental conditions, surface types, microbial populations, and cleaning practices. Depending on your industry and regulatory requirements, it may be mandatory to conduct a facility-specific validation study to demonstrate compliance.  

Important items to consider include the types of organisms that you are going to challenge, the contact time, surface type, the dilution of the disinfectant and the application method per the disinfectant manufacturer’s instructions.  

Matthew Smith, Ph.D., is Sr. Director of Sales, Jessica Rayser is Associate Director of Product Management and Doug Botkin, Ph.D. is a Scientific Portfolio Specialist II with Charles River's Microbial Services business. 

If you are seeking support with EMPQ testing and reporting, there are options available to help streamline the process and make it more resource efficient. Accugenix offers an EMPQ service bundle that could be a valuable solution for your complex EMPQ microbial ID testing, reporting, and data management needs. Additionally, Veltek Associates Inc. (VAI), with over 40 years of experience, provides a range of contamination control products, services, testing and training, ensuring high-quality and reliable solutions. 

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