Regulatory (483) Observations Related to Microbiology: a Q&A with Ziva Abraham
Microbial Solutions
Rachael Kerr

Regulatory (483) Observations Related to Microbiology: a Q&A with Ziva Abraham

The CEO of Microrite on avoiding problems with lab audits

Ziva Abraham is the President and Founder of Microrite, Inc. with over 30 years of academic, research, clinical and industrial experience in microbiology and quality assurance. Ziva has received her master’s degree in microbiology with a focus on mycology, and has conducted research on developing microbial insecticides using entomogenous bacteria and fungi towards her Ph.D. degree.

She has trained personnel from various industries in microbiology techniques and methods. She uses her extensive experience to teach why assessing risk of microbial contamination should be in the forefront of any company that has products for human/veterinary use. Her experience in clinical laboratories has provided her with the framework to understand the effects of microbial contamination in products from a patient safety perspective.

From your perspective, with SOPs, protocols, and guidelines in place, where are facilities running into the greatest risk of 483 observations during an audit situation?

Ziva: Recent trends in 483s related to microbiology denote multiple failures in environmental monitoring (EM) programs, investigations, media fill gaps, sterility test failures, and more. Often, the root cause of these issues points to facility design flaws, and inadequate cleanroom qualification (e.g., poorly performed smoke studies) as well as microbiology laboratory design and operational deficiencies. Cleanroom facilities and barrier system designs are not optimized from a holistic contamination control effect perspective. This common oversight has led to increased regulatory scrutiny.

In 2019, 81 warning letters were issued worldwide by the USFDA, the most in any year since 2015. Microbiological contamination is on the forefront of many of the 483 observations, eluding to the fact that contamination control is not addressed holistically by companies. Microbiological contamination investigations have also been found to be prominent in the 483s issued to companies. Often, the microbiologist tasked with the investigation has limited knowledge of the facility, process, patient population, and risk. Thus, investigations are not knowledge or science based and the remedial action becomes just a paper exercise.

Personnel training and qualification is also seen as a gap in the current 483 trends. Aseptic technique is more than just aseptic manipulations. Aseptic operators as well as QC microbiologists are responsible for making and testing medicinal products, often without adequate tools and training to perform their critical function. Paper based training fails time after time, as key aseptic personnel do not have the knowledge of facility, process, and holistic contamination control.

Disinfection and cleaning is a science, and performing disinfection qualification studies ensures control of microorganisms. Understanding cleanroom design, material, personnel, and airflows in combination with a risk-based monitoring program is key to microbial contamination control. Gown selection, management, and procedures are also an important component of microbial contamination control. This is another area of concern that has led to 483 observations.

A holistic approach to contamination control starting from facility design to product release should be adapted to mitigate such observations.

In your experience, what are common process-related contamination issues?

Ziva: Sterility tests should not be taken as an absolute assurance for terminally sterilized or aseptically manufactured products. Media fills are conducted to ensure that the process does not allow ingress of contamination into the product. A proactive assessment of contamination sources in the process greatly helps in assuring the quality and sterility of the product. Adequacy of facility, equipment, equipment cleaning, monitoring of contamination, and understanding the source of contamination are key to controlling contamination throughout the process and subsequently in the product.

What key suggestions do you have to offer the industry to proactively prevent 483 observations from being issued to them?  

Ziva: Developing a knowledge-based risk management program and identifying the possible microbial contamination risks associated with a product or process can help reduce product failures as well as regulatory observations.

The only alternative to risk management is crisis management, and crisis management is more expensive, reactive, time consuming, and embarrassing. Risk management is not about creating long, complex, and bureaucratic arrangements and piles of paper; it is about identifying what can go wrong and establishing practical steps to protect the patient.

Hazard identification and risk assessment methodologies vary greatly across industries, ranging from simple assessment to complex quantitative analyses with extensive documentation. There is no magical tool that will identify all risks. Without adequate understanding of the product or process and firm subject matter expertise in specific disciplines, small risks may receive unwarranted attention, while large ones are neglected. A science and knowledge-based approach to microbial contamination risk assessment is a step in the right direction for avoiding regulatory scrutiny.

You are welcome to access Ziva Abraham’s webinar on demand as she discusses 483 observations in further detail and the reasons behind these issues from a cleanroom, process, testing, and knowledge perspective.