Creating Safe Pharmaceuticals, Aseptically
Sterilization is an essential process for pharmaceutical manufacturers. Sterilization cannot be achieved through one specific action; effective sterilization is the result of a number of variables. In no sterilization process are these variables more apparent than in the process of aseptic filling, which requires that containers, formulations, and the environment be sterile. If one component does not meet sterile criteria, it can contaminate the entire batch.
Aseptic filling is not a fool-proof, inexpensive, or particularly simple method, but it is essential. It is the method of choice for any product that cannot withstand terminal sterilization, making it the go-to method for sterilizing vaccines, injectable products, infusions, protein-based products, and other delicate products.
Filling a Need
The FDA requires that aseptic processing be used for any product that cannot be sterilized using a terminal method. “If the product can be terminally sterilized, this is clearly the best way to ensure [a] microbial-free product,” explains David Cousins, Director of Sales for the Pharma Liquid division of Robert Bosch Packaging Technology, Inc.
For products that cannot withstand terminal sterilization, Cousins explains that aseptic processing fills “the need to ensure the product is filled in a manner where there is a minimal chance for contamination by microbes, either from contacting the product contact surfaces (i.e. pumps, tubing, nozzles, containers, or closures), or from the environment itself.”
Targeted therapies that feature lower doses of active compounds require a high level of dosing accuracy and process control. Photo courtesy of Optima Group Pharma, GmbH.
Dr. Dale Charlton, Director of Business Development for Optima Group Pharma GmbH, explains that aseptic filling is important because “many products can only be administered to humans or animals as an injection or infusion bypassing the body’s normal defense barriers.” When a product that cannot be terminally sterilized bypasses these normal defense barriers, it must be filled under aseptic conditions to ensure safety.
Aseptic Filling and the FDA
FDA regulations regarding aseptic processing have undergone a number of changes throughout the years, adapting to the changing pharmaceutical manufacturing environment.
“There has been a clear focus in the past decade to ensure the safety of injectable products by increasing the efforts to separate the operators, the main sources of microbial contaminants, away from the filling environment,” says Cousins. “This has been effectively accomplished with the use of barrier systems and isolator systems, and by implementation of RABS (remote access barrier systems) SOPs (standard operating procedures).”
Charlton notes that the FDA is still the “leading light” for the industry, ensuring that products are produced in safe conditions and that the resulting product is equally safe for the patient. “A number of key initiatives have been proposed by the FDA, including fast track applications and orphan drug files to speed up the development of new drugs in the ‘unmet need’ category, especially.” He adds that “the FDA has continued to improve … new initiatives such as PAT and QbD. Both are aimed to improve process-control and built-in safety by design.”
Reducing Human Intervention
An ever-present objective in aseptic filling is to further reduce human interaction. Therefore, it is not surprising that the experts agree that aseptic filling is becoming increasingly automated. The experts note that the removal of human intervention provides a number of benefits.
Charlton explains that processes are, undoubtedly, becoming more automated, and that this increase in automation is occurring “for a variety of different reasons.” He says that processes are becoming more automated not only to remove “the obvious source of potential contamination: the human,” but also to “remove human error and provide a detailed, accurate trace of the production process in electronic form for records or regulatory submissions.” Additionally, it seems that automation is becoming more readily accessible: “Machine technology has also advanced to allow otherwise non-automatable processes to be automated.”
“The best way to ensure operators cannot possibly contaminate the aseptic filling environment is by automating the steps that operators [performed] in the past,” says Cousins. He explains that “this includes: loading and handling of containers and closures, in-process controls (check-weigh, removing rejects, environmental monitoring, etc.), and automatically detecting various steps during the fill process.”
Chuck Reed, Director of Sales and Marketing for Weiler Engineering, Inc., explains that this automation is the reason behind the increased popularity of blow/fill/seal machinery. He says that manufacturers want “people out of the process environment” and that “processes like blow/fill/seal technology lend themselves to that, because they are highly automated.”
Ever-Changing Manufacturing Methods
The experts say that they have noticed the emergence of more versatile machines, an increase in RABS and other machines that limit human interaction, and the continued popularity of CMOs.
Many companies are “looking at progressive blockbuster drugs in their pipeline or more high-value drug products with smaller batch size or throughput requirements,” says Charlton. “I see no letup in the use of CMOs as outsourcing partners for many companies, from small biotech to large pharma,” he adds. Both of these factors “require facilities to be more versatile and thus, the machinery required for filling is adapting accordingly.”
Reed explains that, for liquid products, “blow/fill/seal and RABS are the preferred technologies for processing.” He adds that for “any of the types of filling processes that are done aseptically, the regulatory agencies are seeking to put them under isolators.”
Weiler Engineering’s blow/fill/seal machines deliver a finished package in five steps.
Cousins notes similar trends: “The industry has advanced significantly in ensuring operators are not contaminants in the aseptic fill zone, and these efforts continue with advancements in isolator barrier technology and RABS processes.” He continues: “Now that the operators are removed as potential contaminants, there appears to be a trend towards focusing on minimizing the potential for other contaminants getting into the container, i.e. glass particles by minimizing the potential glass-to-glass contact through the container handling process from washing, to sterilizing, to fill and seal.”
Charlton explains that the increase in the use of RABS “means that manual activities may be performed via gloves; in such, exchange or tubing, needles, intermediate filling vessels, etc., may need to be redesigned to take into account the restricted arm reach and accessibility of a gloved port system.”
A Mutually Beneficial Future
Single-use components, ready-to-use containers, in-process control, new container designs, and new trends in terms of the actual products being processed all seem to be popular developments that are likely to become more prevalent.
“Development pipelines are drying up or becoming more heterogeneous … the concept of personalized medicine is courting favor in many quarters,” says Charlton. Therefore, “there are an increasing number of therapies in development for smaller, more targeted populations as well as more potent, active compounds with thus, lower doses.” He explains that “in order to maintain the benefit and accuracy of low-dose filling, we see increased need for in-process control (IPC) on even the smaller, entry-level machine platforms to ensure accuracy of fill-dose.” Additionally, he says that he believes that “many drug producers will want to differentiate themselves from the market with perhaps more innovative designs and ‘instantly recognizable devices’ for their drug products.”
“The actual filling process itself is undergoing a radical change with the increasing use of disposable needles/tubing and even disposable supply tanks and pumping systems, which can be disposed of safely without the need for clean-in-place or sterile in place activities and unnecessary exposure of operators to potential hazards,” Charlton adds.
Cousins believes that single-use technologies and ready-to-use containers (such as pre-washed and pre-sterilized vials), both of which offer increased sterility, will become increasingly popular. He also says that “the use of improved accuracy peristaltic pump dosing has [grown] and will continue to grow in acceptance.”
Aseptic filling is “trending forward in a direction that it’s been going for the last 5 to 10 years, where there’s more emphasis on the risk to the patient and reducing the risk to the patient,” says Reed. “That’s going to result in a push to replace legacy systems with more advanced technologies.”
Looking toward the future, it seems that these opportunities for growth have the potential to positively impact every aspect of the pharmaceutical manufacturing process: providing new areas of innovation for machinery manufacturers, more effective machines for pharmaceutical manufacturers, safer working environments for manufacturers, and safer medicines for patients.