What is Blow-Fill-Seal Technology?

This refers to advanced aseptic manufacturing in which the containers are formed, filled, and sealed in a single continuous automated system, within a sterile and closed area. It is mainly used to produce small (0.1mL) and large volume (500mL +) liquid-filled containers. Originally developed in Europe in the 1930s, it was introduced in the United States in the 1960s, originally used to food package and industrial products but over the last 20 years, it has become more prevalent within the pharmaceutical industry and is now widely considered to be the superior form of aseptic processing by various medicine regulatory agencies including the U.S. Food and Drug Administration (FDA) in the packaging of pharmaceutical and healthcare products.

The process of creating BFS involves several steps. Pharmaceutical-grade plastic resin is heat-extruded through a circular throat to form a hanging tube called the parison. This extruded tube is then enclosed within a two-part mold, and the tube is cut above the mold. The mold is transferred to the sterile filling space, mandrels are lowered and used to inflate the plastic to form the container within the mold. After the formation, the mandrel is used to fill the container with liquid. Once filled, the mandrels are withdrawn, and a secondary top mold seals the container. All actions take place inside a sterile chamber within the machine. The product is then discharged for labeling, packaging, and distribution.

What makes Blow-Fill-Seal technology an ideal solution for pharmaceuticals?

Firstly, it reduces human intervention making it a more robust method for the aseptic preparation of sterile pharmaceuticals. It is widely used to fill vials for parenteral preparations and infusions, eye drops, and inhalation products. Secondly, the plastic containers are made up of polyethylene and polypropylene. Polypropylene is more commonly used to form containers that are further sterilized by autoclaving as it has greater thermostability. Thirdly, there is a reduced risk of particulate delamination, which could be in the case a glass packaging. Fourthly, it is a flexible solution: the resins can be melted into any shape to create the container of choice. Lastly, it is ideal for transportation as it is lighter than glass and positively influences the weight of the shipment and there is a lower risk of breakage during transport.

Should I test BFS packaging for integrity?

As with the many advantages offered by BFS packaging, there could be some downsides too, like with all containers it is certainly worth testing for container-closure defects. The EU guidelines state that “containers closed by fusions, e.g., glass or plastic ampoules should be subject to 100% integrity testing”. Thus, inspection becomes fundamental. The inspection of each unit will result in a reliable, final product examination that can identify defective units (e.g. “leakers”). There are a variety of leak-inspection technologies in the market, such as the vacuum-decay method (VDM) and high-voltage leak detector (HVLD). The vacuum-decay method (VDM) is often selected for biological manufacturing because of its zero-impact on product quality. During vacuum decay leak detection, the test article is placed inside a chamber, which is then evacuated to a known pressure. If the product container exhibits a leak, the chamber pressure will rise at a rate greater than a predetermined baseline value.

What should I consider when evaluating in-line leak detection for BFS packaging?

One of the main challenges with in-line leak detection operation is the high false rejection rate. Due to the high temperature required for plastic extrusion, the ampoules, immediately after the BFS process, are notably warmer than room temperature. When the products are immediately passed onto a vacuum-detection chamber, the heat from the ampoule can cause a slight increase in pressure which the instrument may interpret as a leaky sample, which will trigger a false rejection signal. Therefore, it is highly advisable to have the product equilibrated to room temperature prior to subjecting the product to vacuum leak detection.

What solutions does Bonfiglioli Engineering provide to combat BFS packaging leak detection challenges?

Bonfiglioli Engineering follows the procedure of Vacuum Decay Method which is Approved industry-standard “ASTM F2338-09”: “Standard Test Method for Non-Destructive Detection of Leaks in Packages” and approved by United States Pharmacopoeia – USP General Chapter «1207» “Packaging Integrity Evaluation” and EU Guidelines to GMP Medicinal Products for Human and Veterinary Use – Annex 1 “Manufacture of Sterile Medicinal Products” ; PDA Technical Report No. 27 “Pharmaceutical Package Integrity” as well as EMA Annex 11.

Handling BFS leak-detection for zero false rejections:

The measurement system adopted by Bonfiglioli Engineering comprises of application of a pressure differential into an airtight testing group enclosing the container. The test objective is to detect container leakages by measuring the reached vacuum level. It also measures the vacuum change over test time, so that a correct interpretation of the test results can be given, reducing false rejections. The PK-VS is a non-invasive and non-destructive, 100% in-line Integrity Inspection solution for BFS containers. It offers an automatic drying system for zero testing chamber contamination and offers a speed limit of up to 220 strips/cards per minute for container formats from a minimum of 40 x 40 x 6 mm to a maximum size of 150 x 80 x 15mm. https://www.bonfiglioliengineering.com/products/pk-vs/ The batch control is fast, reliable, and repeatable. The quick format change offers versatility for diverse container sizes. All this comes with remote access for machine data and exchange and real-time display of testing cycle diagrams and raw data. It also offers an automatic head exclusion.

Bonfiglioli Engineering also offers laboratory equipment for small batch testing and for feasibility studies. The LFS-11 is a Benchtop CFR21 Part 1 Compliant CCIT solution that offers Vacuum Decay Testing for various container types, with its quick format change over, including one for BlowFill-Seal. It is also equipped with a Barometric Compensation System to avoid any vacuum level reading variations and provides records storage for maintenance and statistical raw data with easy, quick, and safe remote access.

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