The areas of greatest concern to respondents when it comes to validating a routine process simulation are operator training and aseptic technique; In particular, costs are the least affected (see Figure 2). This finding suggests that the majority of respondents understand the importance of study design – and that a high-quality approach to study design outweighs cost. Successful media filling should never be used to justify aseptic treatment practices that present unnecessary contamination risks Media filling is a simulation of the entire aseptic process of formulation and filling that replaces a microbiological growth medium with a sterile product. Media filling also makes it possible to evaluate changes in aseptic processing operations that may affect the sterility assurance of the final product and the performance of aseptic filling personnel under operating conditions. Once the process is validated and approved, the main concerns when performing routine process simulations include aseptic techniques and the introduction of materials and components (see Figure 3). The GMP facility ensures that a combination of comprehensive equipment qualification, protection of components and equipment during handling and storage, and rigorous staff training is essential for the safe manufacture of aseptically manufactured products. Each step of the aseptic filling process requires validation and control as a prerequisite for aseptic processing. Everyone is also introducing the possibility of errors that could ultimately lead to the distribution of contaminated products. Any manual or mechanical handling of the sterilized drug, components, containers and closures before or during aseptic assembly presents a risk of contamination and therefore requires careful control. The survey results suggest that the industry is looking at some key issues when it comes to validating aseptic treatment.
Respondents agreed on the use of regulatory guidance and agreed that safety and quality documentation are essential factors in the selection or qualification of a new media provider. In addition, respondents are more concerned with ensuring that quality is built into the process than controlling costs, and risk to the product and process always comes before cost and time commitments. One of the reasons why aseptic processes are difficult to validate is that they try to prove that something didn`t happen. Simulations of aseptic processes, also known as media fillings, are studies performed on the aseptic filling process, which is simulated at the actual production process, where the product is replaced by a growth medium. Growth media are selected to act as closely as possible to the properties of the product while supporting and indicating relatively low microbial contamination. This chapter focuses mainly on the principles and methods of aseptic treatment of liquid fillings, but also briefly discusses non-liquid fillings, such as powder and ointment filling and freeze-dried products. To be effective, the design of aseptic process validation must use a holistic, risk-based approach. Many process procedures and steps can be qualified or validated using standard validation methods, including those for disinfection, equipment function, sterilization, filtration, container closure integrity, inspection, labeling, and transportation.
The aseptic process validation approach may include: sterilization of products, equipment and components; staff training and certification; disinfection programs for equipment and facilities, equipment and operation of facilities; environmental controls; flows of personnel, materials and equipment; and the overall design of the process. Any strategy and control system that affects the quality of the process and product should be evaluated and tested during the validation approach. Figure 2 Survey question: What are your main concerns when validating a process simulation? The data presented represent the two best ranking selections of eight In summary, the objective of a medium filling study is to show that a manufacturer can follow the routine aseptic production process with a sterile medium instead of a drug without causing contamination. However, successful filling of media should never be used to justify aseptic treatment practices that present unnecessary risks of contamination. Therefore, regulators advocate a quality approach to study design and appropriate risk analysis when validating an aseptic production process. Since the onset of mad cow disease, the industry has been heavily focused on eliminating the introduction of transmissible spongiform encephalopathy (TSE) and bovine spongiform encephalopathy (BSE) in aseptic establishments. Despite the fact that media manufacturers are cautious in sourcing raw materials, 70-80% of all respondents are still somewhat or very concerned about the risk of these specific contaminants, especially if their products are distributed in the European Union. The control authorities keep manufacturers at very high standards of aseptic treatment.
The current regulatory requirements for media fillings are summarized in two important guidelines: the FDA Aseptic Guide (FDA 2004)1 and the PIC/S Recommendation on the Validation of Aseptic Processes (PIC/S 2011)2. All safety requirements for the relevant production areas must be met at all times. The assurance of sterility for aseptic processing during final formulation and filling cannot be measured by the sterility test alone, and it is therefore crucial to regularly challenge the actual aseptic process under the “most adverse” conditions. Aseptic treatment is challenged using microbiological growth media under simulated conditions. Figure 4 Survey question: What are the typical planned interventions during an aseptic process simulation? The goal of a media fill test is zero growth. The industry is well beyond the time when a number of positive units in a media filler would have been acceptable from a regulatory perspective. All media fill units are incubated; Those who would be invalid in a product cycle (damaged vial, position in the barrel, proximity to a major procedure, etc.) should be identified in the process simulation protocol and the results should be treated accordingly (see below). The design of the study should include the “most adverse” conditions, usually using the largest container with the widest mouth or small, high-speed bulbs and frequent jamming. Media fill tests should also be performed at different times and on different days of the week to account for the greatest possible variability. Although this is often impractical, the best approach is to accurately mimic a complete production. If the production cycle is less than 3,000 units, the actual size of the production cycle must be simulated. For production series of more than 3,000 units, the simulation can be reduced.
Finally, each media fill must evaluate a line speed, which must be justified to the regulatory authority. Anne Connors, Regional Director of Marketing, BioMonitoring, Merck Millipore and Scott Sutton, Microbiology Network, describe the regulatory requirements for simulating aseptic processes and examine some industry trends based on a recent survey Prior to assembly or aseptic processing, different parts of the final product are typically subjected to different sterilization processes, such as dry heat, moist heat and sterile filtration. The use of media filling tests for aseptic process simulations is not a new concept. The goal of media filling is to show that the manufacturer can follow the routine aseptic production process with sterile media without contamination. However, drug manufacturers and regulatory agencies are not only concerned with the results of media filling, but also with ensuring a quality approach to study design and appropriate risk analysis (FDA 2004). A successful media filling study should never be used to justify aseptic treatment practices that pose unnecessary risks of contamination. The most critical feature of a media fill test is that it mimics the routine production process as accurately as possible The most critical feature of a media fill test is that it mimics the routine production process as closely as possible. Any element that may affect the assurance of the sterility of the process must be part of the design of the study. For this reason, each study should include a protocol of defined interventions, all of which should be performed during media filling.
In particular, any study design should include the following: Three consecutive successful simulations should be performed to initially qualify the process. Each process shall be confirmed twice a year by an additional process simulation study, unless there is a significant change to the product, process or plant, in which case further validation may be required; This should be determined by the company`s change control procedures. All employees qualified to enter the aseptic processing room must participate in at least one media filling per year. Outside the scope are closed aseptic processing systems where no aseptic connection is established after sterilization and where temperature and pressure are monitored during steam sterilization in place (SIP). To better understand industry practices and trends in aseptic processing simulations (media fillings), Merck Millipore conducted a blind survey in August 2013 as part of the American Pharmaceutical Review. The results of the following survey include 59 qualified respondents who perform aseptic simulations, with a balanced representation of manufacturing and validation (63%) and quality control (37%). Figure 1 shows the types of products represented by these respondents.