Daragh D. Byrne, Ph.D.
Wyeth Biopharma
Introduction
The sterility test is one of the most fundamental tests performed within the sterile manufacturing pharmaceutical industry. It is a method to establish the presence or absence of viable microorganisms (bacteria and fungi) using defined culturing methods and is applied to all substances, preparations or articles which, according to the Pharmacopoeias, are required to be, or purporting to be, sterile [1- 3]. This includes products manufactured under aseptic conditions or terminally sterilized.
Due to the exacting nature of the test and the serious consequences that could result from a positive sterility result (i.e. batch rejection), the test is required to be performed under carefully controlled aseptic conditions. Traditionally, sterility testing was performed by personnel within a class A laminar airflow located within a class B clean room. Yet there are problems inherent with this type of set-up, e.g. unfiltered air can be exchanged with the surrounding environment, the work area can only be manually disinfected, and the test area is directly accessed by gowned personnel [4]. In recent years, however, isolator technology has emerged as a valuable alternative for the preparation and testing of sterile materials. An isolator can be defined as a containment device that utilizes barrier technology for the enclosure of a controlled workspace. Isolators offer advantages over clean rooms, the main ones being that they can be relatively easily decontaminated and they prevent the introduction of personnel borne contamination into the isolator [4].
However, isolators do present their own challenges and they require a very careful and rigorous validation program in order to meet the strict requirements of the regulatory authorities. The validation of a sterility test isolator suite is an intensive process that can take anywhere from 6 to 24 months to complete, depending on the complexity of the systems. Figure 1 gives an overview of the many stages of a typical isolator validation program. As the figure shows, even before delivery of the systems, a large amount of planning and preparation must be done. The remainder of this article will discuss in greater detail the various steps involved, and will hopefully provide some guidance to those embarking on an isolator validation program.
User Requirement Specification (URS)
In essence, the URS is a document that details what the user wants or expects the isolator(s) to do. It is written at the very outset of a project and it is of critical importance to the success of the validation program, as acceptance criteria of subsequent testing, such as the PQ, should be based on details set out in the URS. It is wise to be as precise as possible in the description, as this will also minimize the risk of subsequent misinterpretation.
There are many isolator manufacturers in the market today, each with their own slant on isolator design and configuration. The isolator should be designed to meet your specific requirements, and the URS is valuable as the basis for the tendering process. The following is a list of just some of the items that should be specified in the URS:
• Soft-wall vs. Hard-wall envelope. The majority of the isolators used for sterility testing use a soft-wall/flexible (PVC) film to form the workspace envelope, as it is relatively inexpensive and yet quite durable. For handling of cytotoxic or radio-pharmaceutical materials, where personnel protection is of primary concern, hard-wall/rigid plastic should be considered.
• Gloves vs. Half-suit. Half-suits may offer more flexibility, reach and range of movement than simple glove ports. Other ergonomic requirements or limitations (e.g. height) need also to be stated.
• Positive vs. Negative pressure. Generally for sterility testing, isolators will operate at positive pressure (at least +10Pa to surrounding environment [5]) in order to keep contaminating particles out, but in some circumstances (e.g. cytotoxics and radio-pharmaceuticals) it may be required to operate the isolators at negative pressure to protect personnel and the environment.
• The type of transfer devices for movement of materials in and out of, and between, isolators. The most common transfer device is known as the Rapid Transfer Port (RTP) and allows immediate transfer between isolators or containers without break of containment.
• Internal air quality requirements. For sterility testing, an EC GMP Grade A / US Class 100 (Iso Class 5) environment for viable organisms is a must (i.e. zero viable organisms allowed). The requirements for inlet and outlet HEPA filters (either single or double (recommended)), along with the intended air flow regime (turbulent or uni-directional, air-change rates etc.) must also be considered.
Reference:http://americanpharmaceuticalreview.com/ViewArticle.aspx?ContentID=202. Accessed in December 26,2010
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