Avoiding Contamination Risks in Aseptic Processes

Contamination is almost always related to human error, and there is a clear drive to reduce human implications in aseptic operations. This can be achieved in multiple ways. Some solutions include:

• Isolation of the operator: the use of barriers such as isolators and restricted access barrier systems (RABS) are increasingly used to separate the filling area from the operator. This trend has been reinforced by the tendency of regulatory authorities to increase their scrutiny on aseptic filling facilities that use old designs, such as cleanrooms.

• Use of disposables: disposables can reduce the cost of operations, including labor work in cleaning, cleaning validation, and Quality Assurance/Quality Control (QA/QC). The cost of disposables is, of course, higher, but the total cost is reduced.

• Reduction of exposure: exposure is recognized as a contamination risk. Few people claim that the filling environment is guaranteed contamination free. Therefore, several technologies have been developed to help reduce exposure, such as by using specialized containers. For example, many people have reported projects being launched using Blow-Fill-Seal (BFS) containers in recent years. BFS is well known to strongly minimize exposure due to the very short cycle times before the container is fully closed.

Benoît Verjans

When it comes to equipment, the main contamination risks are the contact parts, exposure risk, and operator intervention. In addition, operations such as clean-in-place (CIP) and steam-in-place (SIP)—although designed to optimize the sterility assurance level of product contact parts—remain complex and, consequently, are a source of contamination because of potential errors. Compared with these operations, the use of connectors to cross barriers and disposable sterile product paths are much simpler solutions.

Length of exposure to the environment is also an issue because the probability of contaminants entering the container is higher if the exposure time is longer. On that basis, containers that require shorter operating times are preferred. Three container bodies help minimize exposure to the environment: prefilled syringes, which are supplied sterile in tubs and immediately processed through filling and plunger placement; BFS, which is immediately filled after molding at high temperature; and closed vials, which are kept permanently closed and immediately processed to filling and laser resealing. Unfortunately for prefilled syringes, plungers used as the vial stoppers are still exposed for long periods of time in vibrating bowls.

Barriers to new technology uptake

The largest barrier hindering the uptake of new aseptic technologies is the pharmaceutical industry's reluctance to use a technology that has not been approved. There is always a small risk that a complete drug-development application using new technology will be rejected by regulators. However, this risk is minimized when both the vendor and the pharmaceutical company together build a solid scientific rationale, including robust risk analysis, to support the use of a new technology. Authorities are also open to informal presentations of new technologies and, in the author's experience, are much more open to new technologies than many believe. It would be useful if authorities provided official advice and opinions on new technologies regarding their potential acceptability and benefit to the patient. This information could significantly accelerate the development of new technologies and provide faster benefits to patients.

The future

In the coming years, the author believes that regulatory authorities will reject more aseptic solutions that do not minimize contamination risk. Instead, use of barrier systems and disposable technologies will continue to grow. Several companies now offer fully disposable solutions for biological drugs that can be used throughout fermentation, purification, and formulation and during the filling process.

Containers will also evolve. Several companies have already begun to replace glass with more robust materials, such as polymers. As a result, there will be a decreased risk of small cracks, which are a significant source of contamination. Furthermore, problems such as the recently discovered issue of glass delamination with several drugs, such as erythropoietin and methotrexate, may be avoided.

Benoît Verjans is Chief Commercial Officer of Aseptic Technologies, 7 ru C. Hubert, B-5032 Gembloux, Belgium, tel. 32 81 409 417, benoit.verjans@aseptictech.com.