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By:  Andrea Wagner, PhD. SVP, Business Develop, Thomas Lewis, MBA, Project Manager at Berkshire Sterile Manufacturing

When performing filling or formulations that require a “sterile” area many components need to be assessed. This article is intended to give the reader a broad overview of the current options available. When performing sterile manufacturing and filling all work areas need to be qualified and validated.  There are many requirements that are published by the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) regarding documentation and frequency of re-qualification. The focus of this series is to give the reader a measurement tool to use when evaluating providers of aseptic services.

Because a manufacturer can only claim a sterility assurance level of 103 versus 106 for terminally sterilized products, aseptic handling (formulation or filling) is considered the most risky of all the types of drug product packaging. This is significant because for every 1000 vials/syringes/cartridges filled it is statistically possible that 1 unit per 1000 has contamination. Contrast this probability with terminally sterilized products and the risk drops to 1 contaminated unit per million – significantly better odds.

Therefore, it is a requirement, by all regulatory agencies, that if a process can be terminally sterilized, it must be. Many drug products can be destroyed by terminal sterilization techniques and therefore require aseptic handling and filling in order to make their way to market where their application can help improve and save lives.

In order to minimize the risk of contamination during aseptic handling, the validation and qualification of all work areas is taken to an extreme. The entire facility must be validated, including certification of air handling and filtration systems with a timetable of recertification. Operators (the people working in these rooms) need to maintain qualifications with a continued education program. To maintain the aseptic environment, a program that includes active and passive monitoring of the air and water supply, as well as plating of bacterial cultures is a requirement. The list of activities to simply operate within the current regulatory structure to claim a product is manufactured under cGMP (current Good Manufacturing Practices) is long and complex. Each of these concepts and processes deserve discussion within the organization by leveraging the many training manuals, books, conferences and blogs that have been dedicated to each aspect of cGMP.

Each area where aseptic activities take place must have a minimum International Standards Organization (ISO) 5/Grade A rating. The aseptic areas must also be surrounded by an ISO 7/Grade B space with the exception of isolators which are required to be surrounded by an ISO 8/Grade D space.  The concept is to establish a succession of lower graded areas as you approach the “sterile core (Grade A)”.  The air changes in a Grade A are at higher frequency than that of a Grade B.  This creates a positive pressure environment away from the Grade A area, decreasing the ability for the Grade A to be impacted by activities outside.

Thorough training of operators is key to the success of any aseptic program. 70% of all contaminants in a cleanroom are sourced from human beings as people shed millions of particles, daily. Bacteria are often associated with human-sourced particles and can easily travel into the production area, thus becoming a huge concern of manufacturers seeking to avoid low sterility assurance levels (SALs). While isolators may remove people from direct contact with product components, good aseptic technique and fundamentals are still required to minimize contamination. Proper operator training is extensive and qualification of operators to perform in aseptic operations is not a “read and understand” process, but, rather, the much more time-consuming and successful “show you can do it” model. For companies that do not use isolators the operators must be gown-trained for aseptic operations to demonstrate that they can perform this task without adding bacteria or normal cleanroom flora to the “sterile” core. Operators must participate in aseptic simulations of media fills prior to performing actual cGMP work. Success is based on an assessment of contaminant-free plating and media units that pass an incubation test. If an operator generates a high number of contaminant colonies on environmental plates or their media fills fail incubation tests they will not be qualified to work in the aseptic areas.

The next article in the series will discuss the different types of filling equipment and the related risks of each method. Expanding the knowledge-base of individuals at organizations in need of aseptic drug product formulation and filling will increase the current level of sterility assurance of products in the market. Increased awareness of aseptic manufacturing will spur innovation in the industry, resulting in reduced risks and improved production practices, overall.

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