Establishment and Feasibility Analysis of a New Method for Biocompatibility Testing of Pre-filled Syringe

LT-TSB Automatic denesting machine for prefilled syringes (3)

Establishment and Feasibility Analysis of a New Method for Biocompatibility Testing of Pre-filled Syringe

A pre-filled syringe is a novel drug packaging container that can store and administer medications. It is mainly used for packaging anticoagulant drugs, vaccines, and biopharmaceuticals. The advantages of pre-filled syringes are as follows: they have good compatibility with medications, reduce wastage caused by adsorption during storage and transfer, have more precise drug quantification through machine filling technology, avoid secondary contamination caused by repeated suction of diluents, and are easy to use, suitable for emergency patients, etc. (1). However, due to the direct contact between pre-filled syringes and blood or body fluids, attention needs to be paid to their biological safety (2). This article systematically analyzes pre-filled syringes from aspects such as manufacturing processes, materials, risks of human contact, and differences in biological evaluation standards at home and abroad, aiming to explore the feasibility of conducting biocompatibility testing of pre-filled syringes as a system.

I. Background of Pre-filled Syringes

 

1.1 Development of Pre-filled Syringes

 

Pre-filled syringes originated in the 1980s (3). The first pre-filled syringe in China was produced in 2005. With increasing emphasis on health and the numerous advantages of pre-filled syringes, such as safety and convenience, the application prospects of pre-filled syringes are becoming broader.

 

1.2 Classification and Composition of Pre-filled Syringes

 

Pre-filled syringes are classified into plastic and glass syringes based on the material of the syringe. They are further divided into syringes with and without needles. Syringes without needles can be classified into luer-lock and screw-on types. The luer-lock type consists of a glass syringe barrel, rubber plunger, luer-lock cap, and plunger rod. The screw-on type consists of a glass syringe barrel, rubber plunger, screw-on cap, screw-on head, and plunger rod (4).

II. Risks of Pre-filled Syringes

 

2.1 Stainless Steel Injection Needle

 

The stainless steel injection needle on the pre-filled syringe is mainly used for intradermal, subcutaneous, intramuscular, and intravenous injections in humans (5). UV adhesive is commonly used as the adhesive for the needle, usually composed of acrylate compounds. Acrylates have strong irritations to the eyes, skin, and respiratory tract (6-7), and UV adhesive can come into long-term contact with the medication, directly affecting the quality and safety of the medication (8). The potential hazards of injection needles mainly include biological contamination (pyrogens, bacteria) and particle contamination. According to the requirements in GB/T 16886.1-2022 “Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing within a Risk Management Process,” injection needles need to undergo biological evaluation (9).

 

2.2 Rubber Plunger

 

Rubber plungers are divided into butyl rubber plungers and bromobutyl rubber plungers, and they are further classified into snap-lock (PSL) and screw-on (PT) types. The quality requirements for rubber plungers include: no toxic soluble compounds such as lead, mercury, arsenic, and barium; no interaction with the packaged medication, which can affect the efficacy and clarity of the medication; no precipitates on the surface, such as free sulfur, wax, and other organic substances; smooth surface without cracks, bubbles, or other impurities, with a certain degree of lubricity for operation on automatic filling machines; the plunger should have sufficient elasticity, not shed after a specified number of punctures, and maintain its original sealing performance (10-11). Since the rubber plunger directly contacts the medication (or saline solution), its safety needs to be evaluated through biological testing during production and storage.

 

2.3 Syringe Barrel

 

The syringe barrels used in pre-filled syringes are divided into glass barrels (borosilicate glass) and plastic barrels (COP). Both types have their own advantages. Glass barrels have a longer history of use and are coated internally with silicone oil for lubrication, helping the plunger move during administration. However, residual silicone oil that has long-term contact with the medication may cause compatibility issues (12-13). The main advantage of plastic barrels is their lightweight and resistance to breakage. However, plastic barrels are all made of polymer materials, and their physical and chemical properties are not as stable as glass, and some polymer materials have potential biological risks (14).

 

2.4 Needle Cap

 

The needle cap is a protective device that covers the needle to prevent injury and contamination. According to relevant Chinese standards, the combination components of pre-filled syringes must include needle caps (15-16). The needle cap used in pre-filled syringes is made of rubber, mainly composed of polyisoprene, with the addition of fillers, vulcanizing agents, plasticizers, and alkali resistance additives. It should have no potential toxicity to medications or human tissues.

III. Current Status of Biocompatibility Testing of Pre-filled Syringes

 

3.1 Domestic and International Standards

 

Since 1992, various inspection standards for pre-filled syringes have been issued domestically and internationally. The National Pharmaceutical Packaging Standards (2015 edition) specify the relevant testing requirements for glass syringe barrels, rubber plungers, stainless steel injection needles, needle caps, and combination components. The ISO 11040 series of international standards provides detailed requirements for various types of pre-filled syringes but does not specify testing requirements for injection needles and caps in pre-filled syringes. The United States Pharmacopeia only has general requirements for the corresponding components of pre-filled syringes (17).

 

3.2 Comparison of Biocompatibility Testing Items at Home and Abroad

 

Currently, there are differences in biocompatibility testing items for different components of pre-filled syringes in domestic and international standards. Table 1 lists the comparison of biocompatibility testing items in national pharmaceutical packaging standards, international standards, and the United States Pharmacopeia.

IV. Establishment of a New Method for Biocompatibility Testing of Pre-filled Syringes

 

By comparing relevant regulations and standards at home and abroad, it can be seen that the current standards mostly require testing of individual components of pre-filled syringes separately, and different regulations and standards have different requirements for testing different components. For example, the National Pharmaceutical Packaging Standards require stainless steel injection needles to undergo cytotoxicity, skin sensitization, intracutaneous irritation, acute systemic toxicity, and hemolysis tests. However, the ISO 11040 series of standards and the United States Pharmacopeia do not have special requirements for stainless steel injection needles. Both the ISO 11040 series of standards and the United States Pharmacopeia require plunger testing to include intracutaneous irritation and cytotoxicity tests, but the National Pharmaceutical Packaging Standards do not require these tests for plungers. Some literature suggests that rubber plungers, as high-performance components of pre-filled syringes, come into direct contact with the packaged medication during production and storage. Therefore, the intracutaneous irritation and cytotoxicity of rubber plungers in pre-filled syringes should be tested (19-21).

 

Currently, domestic pharmaceutical packaging standards only require biocompatibility testing of individual components of pre-filled syringes and only consider the hazards caused by materials, thus ignoring the biological risks of the combination components of pre-filled syringes. Therefore, based on the clinical application of pre-filled syringes, the potential biological hazards of the combination components should be assessed as a whole, following the biocompatibility testing recommended for single-use sterile syringes in GB/T16886.1-2022. Since pre-filled syringes are mostly filled with medication to their nominal capacity during production, it is also possible to fill the extraction medium into the syringe’s cavity during sample preparation, which better simulates the clinical application of pre-filled syringes.

V. Feasibility Analysis of a New Method for Biocompatibility Testing of Pre-filled Syringes

 

Looking at the test items, including the hemolysis test, among various biocompatibility tests, the new method involves filling the extraction medium into the syringe’s cavity following GB/T16886.12-2017, extracting the medium as the test solution for various tests. For example, in the hemolysis test, 10 mL of the extraction medium can be added to rabbit blood for subsequent testing (22). This method of preparing test solutions fully considers the risks of contact between the components of pre-filled syringes and medications, as well as risks of contact with the human body, making the testing process more reasonable.

 

Among all the components of pre-filled syringes, only the stainless steel injection needle directly contacts the human body, while the needle cap, syringe barrel, and rubber plunger only come into direct contact with the medication. Therefore, during production, the additives and chemical auxiliaries used may migrate to the medication, affecting its safety and stability. Therefore, biocompatibility testing is also needed for the needle cap, syringe barrel, and rubber plunger (23-27). We randomly selected pre-filled syringe combination components from two manufacturers that passed the quality inspection and filled the extraction medium into the syringe’s cavity for sample preparation and biocompatibility testing. The results showed that both batches of pre-filled syringe combination components from different manufacturers met the corresponding standard requirements. Therefore, using the new method instead of the current testing methods is feasible.

VI. Discussion

The current national pharmaceutical packaging standards for pre-filled syringes require separate testing of the various components, and the biocompatibility testing items required for combination components are limited to acute systemic toxicity and bacterial endotoxin tests. Furthermore, different components are subjected to different testing items in different regulations and standards. This not only leads to unnecessary waste but also fails to truly reflect the clinical application risks of pre-filled syringes. Pre-filled syringes and single-use sterile syringes have many similarities in clinical application, processing, and storage. GB 15810-2019 “Single-Use Sterile Syringes” specifies that syringes should undergo tests for cytotoxicity, skin sensitization, intracutaneous irritation, acute systemic toxicity, hemolysis, and pyrogens (bacterial endotoxins). Moreover, the introduction of this standard explicitly states that when testing the chemical and biological properties of syringes with accompanying injection needles, the test should be performed with the extraction solution prepared together with the injection needle (28). Likewise, YY/T 0243-2016 “Pistons for Single-Use Syringes” also specifies testing items such as cytotoxicity, skin sensitization, intracutaneous irritation, acute systemic toxicity, hemolysis, and pyrogens (bacterial endotoxins) (29). It can be seen that the domestic standards for single-use sterile syringes have consistent testing items for components in direct contact with medications. Additionally, the comparative test results in our laboratory also indicate that testing the combination components separately or as a whole yields similar results, with no significant differences.

In summary, the established biocompatibility testing method can fully consider the risks of contact between the components of pre-filled syringes and the human body, improve testing efficiency, reduce costs, and comply with the 3R principles of animal welfare. Therefore, this method is practically feasible.

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