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Using Closed-Vial Technology in Aseptic Filling
Aseptic filling remains a risky process with multiple contaminations occurring each year that have serious consequences. Analysis of an outbreak database shows that, among 1537 patients contaminated by parenteral product from 1990–2005, the mortality rate was 15%. While the majority was due to product preparation at the hospital pharmacy or the practices of the hospital staff, 20% of these contaminations were due to the pharmaceutical manufacturing process (1).
This high contamination risk leads authorities to regularly reevaluate their requirements, thus making aseptic filling one
of the most complex processes in the pharmaceutical industry. A continuous improvement approach, however, has led to major
innovations, and the rate of contamination has been significantly reduced during the past 50 years. The innovations listed
below involve both the container and filling technologies:
These innovations improve product quality but also add complexity to the aseptic-filling process. As a result, aseptic filling is expensive, demands complex quality control, and has many potential opportunities for mistakes. Closed-vial technology, however, can improve product quality and simplify the aseptic-filling process (3, 4).
Closed-vial process summary
Advantages of closed-vial technology
Closed vials can offer three main advantages compared with traditional glass vials.
Increased patient safety. In glass vial technology, the vial stays open for more than 30 minutes between exiting the depyrogenation tunnel and stoppering. Stoppers may remain in a stopper bowl for several hours, in which direct contact with surfaces increases the risk of transferring a contaminant to the vial. A closed vial, however, remains permanently closed except during needle penetration, thereby reducing the risk of contaminant entering the vial by two logs (5).
Simplified manufacturing process. The closed vial is delivered clean and sterile, allowing the pharmaceutical manufacturer to eliminate container-component preparation, including water for injection (WFI) washing, steam sterilization, and hot-air depyrogenation. High speed stoppering and aluminum cap crimping are also eliminated. The break-resistant polymer material reduces vial breakage inside the filling area and during the supply chain.
Closed vial container design
The following sections describe a typical closed-vial container and the manufacturing and filling process. These sections also explain how the container design and the manufacturing process provide a solution for challenges in aseptic filling.
Vial body. In this closed-vial system, cyclo-olefin copolymer (COC) (Topas, Topas Advanced Polymer) was selected for the vial body because it does not create high particle levels during molding. Low particle generation is a requirement for avoiding WFI washing after manufacturing in an ISO5 clean room. COC is already used in some injectable products (Metalyse, Boehringer-Ingelheim), and is widely used in blister packaging. COC is a clear, transparent polymer that allows good light transmission and has a high barrier to water vapor. In addition, it can be gamma-irradiated without degradation or a visible change of color at standard irradiation doses. COC is shock resistant, which reduces the risk of loss during production and transportation.
Stopper. The stopper should reseal when heated by the laser to ensure reclosing of the puncture trace. The stopper must be able to absorb the laser energy with a good profile of heat distribution. Second, the stopper should be highly flexible and easy to pierce with a large needle without generating particles of significant size or amount and without material loss. Third, to ensure optimal resealing process after liquid fill and after lyophilization, the stopper should have good elastic memory. It is crucial to have both sides of the piercing trace in tight contact to ensure optimal laser resealing. Finally, the stopper material used should not release deleterious leachables. A thermoplastic elastomer (TPE) has these features, and the polymer can be engineered using a color pigment to ensure optimal absorption of laser energy.
Vial head. The vial head is equipped with a top ring to secure the assembly of the vial body and the stopper, as shown in Figure 3. In this design, the vial head has also been equipped with a snap-fit, high density polyethylene (HDPE) cap. This design eliminates the complex and particle-generating crimping process necessary with an aluminum cap. A small rib on the internal surface of the cap adds closure integrity by isolating the central part of the stopper from the environment until use by the doctor.
Closed-vial manufacturing process description
The major innovation of the closed-vial technology is the production of the vial components in an ISO5 clean room. As a result, the components are ready-to-use and do not require the complex cleaning process that is mandatory for glass vials and rubber stoppers.
Ensuring cleanliness. To ensure the cleanliness of the vial components, various conditions have been imposed on the process. First, the molds should not contain lubricating additives that are sometimes used to ease removal of the part from the mold. Second, once the room is qualified for operation, the operators cannot enter. Vial conveying must be fully automatic and should not create particles above the specified level. Vial transportation is performed by robots as shown in the first step of Figure 1. Such robots are already widely used in the ISO4 or ISO3 cleanrooms in the electronic industry as well as in the pharmaceutical industry for applications such as syringe filling.
Because the robots can achieve high precision, the stopper is designed to come straight to the vial body, which avoids the presence of a recess area when the vial is upside-down for liquid collection. Therefore, all the liquid will reach the bottom of the vial and be collected (see Figure 3). As a result, vial overfill can be reduced, thus leading to significant savings of API.
Ring assembly. After assembly of the two components, top and bottom rings are added. Each step is checked by visual sensor control or mechanical challenge before moving to the next operation. This complete PAT ensures that the vial is fully and properly assembled.
Sterilization. Because the TPE used for the stopper is sensitive to heat, the only classical sterilization procedure suitable for the closed vial is irradiation. Gamma irradiation is preferred to beta irradiation because it is available worldwide and can process a complete pallet at once.
Closed vials are provided ready-to-fill. The five most frequently used methods for loading are:
Using ready-to-fill vials eliminates component preparation and thus has a huge impact on the entire facility. Equipment for vial washing, a hot-air tunnel, and equipment for stopper washing/sterilization is not needed, and clean room space is reduced. WFI for formulation and equipment cleaning can be sourced from a much smaller WFI loop, or containers may be purchased from external sources.
Another change to the filling process is that a needle must pierce the vial stopper before filling, and the hole must be reclosed after filling. The vial must be held in a fixed position during piercing, filling, and removal of the needle. The vial must also be held in position under the laser head to be resealed, and the laser must ensure complete coverage of the piercing trace, so the laser has a uniform energy beam on a 6 mm diameter surface. After resealing, a snap-fit cap is pressed in place.
The advantage of the CVFS over the traditional isolator is its simplicity, in that it can be sanitized with classical sporicidal agents and does not require vapor hydrogen peroxide sanitization. The CVFS uses unidirectional, HEPA-filtered laminar airflow that exits through the bottom of the system, which helps maintain laminar flow and prevent turbulence. Isolators are still mandatory when the safety of the operator must be ensured (i.e., with highly potent drugs such as cytotoxics). Such isolators must be installed in an ISO9 cleanroom.
The advantage of the CVFS versus the Restricted Access Barrier System (RABS) is that in the CVFS, operator access is only possible via gloves, and the barrier environment is never compromised by door opening. Material entry is limited to secured processes such as rapid transfer ports, airlocks, and e-beam irradiation units. With these limitations, an ISO8 clean room environment for the surroundings is sufficient to ensure the ISO5 quality inside the barrier.
Lyophilization with closed-vial technology
The lyophilization cycle with closed vials is very similar to that of glass vials, except that the primary drying phase is longer. Tests show that closed-vial technology produces an improved cake surface, suggesting that the lyophilization process is more homogeneous. In the closed vial system, vials are more stable than in glass vial systems. The bee-nest assembly increases vial stability and the absence of contact between the shelves and the stoppers prevents stopper sticking. These factors reduce the risk of a vial falling down and knocking other vials on the shelf over.
Changes to the container design and process that occur when using closed-vial technology must be validated. To ensure that the technology is suitable for product approval, a series of tests that meet the required standards from Pharmacopeia and International Conference Harmonization (ICH) guidelines should be performed on the container materials, the properties and characteristics of the container closure, the processing technology, and the performance of media fill.
Closed-vial technology can provide a safer solution for the patient, in which the permanently closed container reduces the risk of external contamination, and an easier solution for the pharmaceutical manufacturer, in which ready-to-fill containers eliminate preparation steps. It can be used for any classical aseptic filling product. In addition, highly potent drugs (e.g., cytotoxics and immune-modulating drugs) and biohazard products (e.g., recombinant viruses) can benefit from the reduced breakage and spillage risks in the closed-vial technology. Other products that can benefit are lyophilized products, products that are susceptible to adhesion on glass, expensive drugs that can benefit from lower residual volume and lower breakage risk, and products with limited differentiation (e.g., generic drugs) in which the closed vial offers a solution to end-users. Closed-vial technology can also improve production capacity, and can be useful for setting up local filling from global bulk production. Some companies are investigating closed-vial technology in order to avoid issues with glass (e.g., delamination) (9).
Regulatory authorities appear to be open to innovations supported by a clear scientific rationale, as demonstrated by the acceptance of closed-vial technology for a pneumococcal vaccine by the European authorities in July 2011 (GSK Biologicals, Synflorix). A key driver for the approval was that the container is produced in an ISO8 environment but is kept permanently closed, which significantly reduces the risk of contaminant entry.
Aseptic Technologies benefits from grants given by the Region Wallonne and the Agence Wallone à l'Exportation (AWEX). Initial technology has been licensed by Medical Instill Technologies.
Benoît Verjans is chief commercial officer at Aseptic Technologies, 7 rue C. Hubert, B-5032 Gembloux, Belgium, tel. 32 81 409 417, email@example.com
1. R.P. Vonberg and P. Gastmeier, J. Hosp. Infect. 65 (1), 15-23 (2007).
2. J. Lysfjord, Ed. Isolators for the Aseptic Manufacture of Parenterals, Practical Aseptic Processing – Fill and Finish (Davis Healthcare International Publishing, River Grove, IL, 2009), pp. 247-272.
3. B. Verjans, J. Thilly, and C. Vandecasserie, "Aseptic Processing" supplement to Pharm. Technol. 29, s24–29 (2005).
4. J. Thilly, D. Conrad, and C. Vandecasserie, Pharm. Eng. 26 (2), 66-74 (2006).
5. B. Verjans and C. Reed, Biopharm. Intl. 25 (3), 46-58 (2012).
6. B. Verjans, "Innovation in Aseptic Processing: Case Study through the Development of a New Technology," in Advanced Aseptic Processing Technology, J. Agalloco and J. Akers, Eds. (InformaUSA, New York, 2010), pp. 438-444.
7. Aseptic Technologies, "Closed Vial Filling System" www.aseptictech.com/aseptic/en/8908-closed-vial-filling-system.html (accessed April 2, 2012).
8. J. Thilly and Y. Mayeresse, "Advances in Sterile Manufacturing and Aseptic Processing" supplement to Pharm. Technol. 32, s38–42 (2008).
9. FDA, Advisory to Drug Manufacturers: Formation of Glass Lamellae in Certain Injectable Drugs (Silver Spring, MD, Mar. 2011).