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Pharmaceutical Manufacturing and Packing Sourcer

Plastic Fantastic

Blow-fill-seal technology is increasingly becoming the global packaging method of choice in advanced aseptic manufacturing. Compared to traditional glass vials, they reduce microbial contamination, eliminating the need for human intervention

Blow-fill-seal (BFS) technology has been used for the global packaging of sterile products for more than 30 years, specifically in the ophthalmic and respiratory markets. Additionally, the technology is commonplace in Europe and many other countries for parenteral medicines, to replace ampoules and intravenous bags. BFS holds many advantages over traditional glass vials, as it minimises the risk of particulate and microbial contamination during the filling, as well as requiring a much smaller footprint for the equipment. The process automates the aseptic filling process and virtually eliminates all human intervention in the critical fill operations. The BFS process begins by forming the body of the container, after which the product is filled. Following the fill, the stopper is automatically inserted (if desired), and finally, the vial is sealed – all within the machine and in a matter of seconds. The risk of microbial contamination is greatly reduced, as the containers are never exposed to the open atmosphere. There is no glass management or preparation of vials prior to the filling machine, as they simply do not exist. A further advantage of utilising this glass-free container closure platform includes the potential to increase safety for medical practitioners and patients, as the vials are made from plastic, so they do not shatter. Furthermore, through the inherent properties of the BFS technology, pharma companies have primary container design freedom to better fit the delivery of their molecule to the needs of the patient.

Plastic versus Glass

However, the utilisation of BFS is not just about improving the aseptic process versus traditional glass filling. The technology creates a glass-free injectable platform, driving change in the primary container closure, compared to the conventional glass vial. To prove that the technology is viable for the molecule, several key areas need to be addressed to ensure that the container closure is compatible with biological drug products – such as whether the residual heat of the vial formation or the adaptation has a detrimental effect on the molecule, or its leachables profile. Furthermore, the plastic container closure is not impervious like glass; therefore, the stability of the molecule needs to be evaluated at the proper storage conditions to determine whether there is any impact on the drug product based on permeability over time.

Packaging a large molecule product in a BFS vial is not a new concept; however, in order to extend the adoption of this technology to other products, concerns regarding their usage need to be addressed. By carrying out a side-by-side challenge experiment, with the same batch of biologic medicine being filled both into traditional glass vials, and via the BFS technology, compatibility with biological drug products can be determined.

Comparing Results

Such a study has been carried out by Catalent to test its ADVASEPT® BFS technology, using a model monoclonal antibody formulation in both glass and plastic vials. The antibody used in the test was manufactured and formulated as a liquid with polysorbate 80, sodium citrate and sodium chloride to a concentration of 10mg/ mL, and a pH of 6.5. It was filtered with a 0.2μm Nalgene filter unit, and filled into either a BFS vial or traditional glass with the same rubber stopper, and then stored at 5°C for a 24-month stability study. A protocol for a number of investigative tests and parameters at different time points was set out. Table 1 shows the highlighted tests that were considered and undertaken, with the following results recorded:

● PH: both solutions in glass and BFS-stoppered vials showed no change and were within the defined parameters of more than or equal to 0.3
● Appearance: no foreign particles were observed within the vials before or after filling, and none were visible after nine months’ storage
● Potency: a comparison of activity data at 24 months showed that the two formats had similar potency values according to a dose response curve in a complement-dependent cytotoxic assay after storage at 5°C (see Figure 1 on page 51 of article PDF)
● Stability: a number of tests using various methods were used to measure relative stability. Size exclusion chromatography (SEC) showed that aggregation increased over time for both samples. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis showed comparable heavy- and lightchain bands on both data sets (see Figures 2 and 3 on page 51 of article PDF), and capillary isoelectric focusing (cIEF) revealed no difference in charge distribution across the samples in glass and plastic vials
● Leachables: a number of methodologies were employed to investigate possible leachable contaminants after nine months of storage. Volatiles were studied using gas chromatographyflame ionisation detector (GC-FID), semi-volatiles with gas chromatography-mass spectrometry (GC-MS), polars with high performance liquid chromatography-ultraviolet (HPLCUV) and metal leachables via inductively coupled plasma mass spectrometry (ICP-MS). The leachable data indicated a comparable profile for the different vial types.
● Bioburden: results performed at t=0 for both formats were below 10 CFU/mL

Overall, this study demonstrated the compatibility of this monoclonal antibody formulation in glass to the BFS vials, and thus provides the data to show the compatibility of this technology as a potential option for large molecule manufacturing. Although this only represents a study on a single monoclonal antibody, it does begin to address the general requirements of safety and efficacy of a product within a BFS container.

Shape Shifting

There are distinct advantages to the advanced aseptic processing of BFS vials over glass vials, and now that evidence tends to support compatibility, the industry is open for further exploitation. The flexibility that BFS technology provides with respect to vial design means headspace within the vials can be minimised to reduce the potential for agitation of the products during shipment, and brand identity of products can be established through the use of various shapes and sizes.

The shape of vials can be altered to reduce packing sizes, which can minimise weight and volume, and ultimately the cost of shipping. Glass vials, which are almost exclusively round, tessellate poorly with each other, and for the practitioner handling the vial during administration, the chances of breakage increase as vials can roll off surfaces. BFS technology allows safer designs to be incorporated, reducing the risk of breakage and loss of valuable product.

Further lowering the risk to practitioners, BFS encourages the reduction of needle and sharps related injuries by building in functionality to the vial. Closure systems can be customised using BFS to eliminate the stopper and mate with a luer syringe, to allow for withdrawal of product without the use of a needle or breaking an ampoule.

Delivering Results

With product development pipelines including more biologic products than ever, how a product is transported and delivered is becoming as important as the efficacy, and BFS technology could lessen the risks of filling and provide a solution for the primary container design to fit patients’ needs.

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