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Cynthia A. Challener, PhD, is a contributing editor to BioPharm International.
Both empty and filled syringes must pass a range of tests to meet quality standards for biopharmaceutical drugs.
Prefilled syringes offer advantages to the manufacturer, caregiver, and patient. With fewer handling steps and ease of use compared with empty syringes, prefilled devices can help reduce medication errors. They do, however, pose challenges in manufacturing and require extensive testing.
Testing of empty syringes must be performed at the site where filling will be completed as part of incoming quality control efforts. And, filled syringes (combination of the syringe and drug product) must also be subjected to release testing.
Knowledge and understanding of the various tests involved is essential for ensuring patient safety. “The development of robust drug products based on prefilled syringes as primary containers requires an integrated holistic approach,” asserts Thomas Schoenknecht, head of R&D within the drug product services unit at Lonza Pharma & Biotech. “Aspects including formulation, process, packaging, device integration, analytics/quality control, and intimate knowledge of the user needs all must be taken into account,” he explains.
Similar to other sterile products, prefilled syringes must be sterile and free from pyrogens. In addition, according to Gregory Sacha, senior research scientist at Baxter BioPharma Solutions, they must be chemically, physically, and biologically stable with no change in performance over the intended storage and use time. In general, the regulatory requirements for testing prefilled syringes need to comply with the US and European pharmacopeias, notes Nicolas Eon, global product manager for syriQ prefillable syringes at Schott Pharmaceutical Systems.
Testing must be compliant with existing test and release methods for empty containers and for containers filled with the drug product solution. As such, both drug and device regulations apply to prefilled syringes. The regulatory landscape for combination products is complex and product/country specific, according to Schoenknecht. In the United States, for example, several parts of 21 Code of Federal Regulations (1) (211 cGMP for finished pharmaceuticals, 314 drugs, 600 biologics, and 800 devices) are applicable. There are separate requirements outlined in the European Union (EU) Medical Directives (2) and proposed revisions to EU GMP guidelines Annex 1 (3).
While International Organization for Standardization (ISO) standards are important instruments for harmonization, health authorities do not necessarily support or enforce them, but use them as a guidance for internal regulation development, according to Schoenknecht. “As an example, FDA guidance on GMP requirements for combination products (4) cites several ISO standards, such as ISO 11040,” he says.
In general, test methods are defined in ISO 11040-4, Part 4 (Glass barrels for injectables), Part 5 (Plunger stoppers for injectables), Part 6 (Plastic barrels for injectables), and Part 8 (Requirements and test methods for finished prefilled syringes). Other tests are outlined in ISO 80369 for small bore connectors for liquids and gases in healthcare applications: Part 1 (Small bore connectors) and Part 7 (Connectors for intravascular or hypodermic applications, which have replaced ISO 594-1 and -2), according to Eon.
For glass prefilled syringes for biologics, the requirements are based on technical report number 73 from the Parenteral Drug Association (5), Eon adds. With respect to inspection of prefilled syringes, ISO 2859 (Sampling procedures for inspection by attributes package) and ISO 3951 (Sampling procedures for inspection by variables) are applicable. “The PDA technical report comes from industry, with key users of prefilled syringes in the pharmaceutical community teaming up with the vendors of those containers to create a document that serves the industry as a white paper. It describes in broad detail what needs to be considered for the successful combination of a prefilled syringe with biologics and what enables combination with a drug-delivery device,” says Schoenknecht, who is one of the co-authors of the report.
Given that so many different tests must be conducted on empty syringes and syringes filled with product, it isn’t surprising that there are many opportunities for these complex systems to fail to meet quality requirements.
Cosmetic defects such as scratches are common. These units are rejected because it can be difficult to determine if a scratch is only at the surface of the material or if it is a crack. Insufficient container siliconization can result in failure during break-loose and extrusion-force measurements and actual product use. For needle syringes, insufficient needle pull-out forces can occur due to weak needle assembly and imperfect adhesive polymerization control.
For filled syringes, failures depend on the drug product design (e.g., the formulation), the syringe process design, and the careful assessment of interplays, according to Schoenknecht. “One point of concern being controversially discussed as a major risk for product development is subvisible particles. However, failing subvisible particles requirements on stability is a negligible risk for most protein formulations containing polysorbate and given adequate particle characterization,” he observes. The presence of leachables and API impurities can be further challenges.
Other failures concern patient-related issues. “Patients can have difficulty using the combination product (user handling), and these issues should be considered as testing failures,” Schoenknecht says. High injection forces, long injection times, and general issues with gripping the syringe are examples.
Testing empty syringes prior to filling presents a few challenges that largely relate to the fact that only one part of the combination product (sterile barrel) is being tested, according to Eon. “The impact of the drug product on the functionality of the syringe cannot be evaluated prior to filling, but testing is still needed to confirm the intended purpose for the combination drug product,” he explains.
Specific tests that should be performed on empty syringes include:
Retention volume and deliverable volume are also tested for prefilled syringes. The retained volume is important because it will affect the fill volume and filling tolerances during manufacturing, according to Sacha. This method can be challenging to implement, however, because variances in the values obtained during testing occur between analysts and are affected by how the tip cap is treated during the test.
“All of these tests give only information about the quality and performance of the container itself, though,” agrees Schoenknecht. “Final proof of a specific container closure system for a given drug product, consisting of the container with closures and liquid fill (drug formulation), suited to fulfill the requirements can be made using tests performed on the final combination product,” he asserts.
Schoenknecht also stresses that device development should be driven by human factor studies (user requirement studies) that lead to design input requirements. “Performance tests such as breakout- and extrusion-force measurements should be executed against the user requirements, which should take into account the capabilities of the intended patient population/group,” he explains.
Functionality testing (e.g., gliding force, mechanical resistance, opening force, etc.) involves examination of the force required to initiate movement of the plunger and the pressure required to maintain the movement; the test is usually destructive. As a result, it is only performed with a reduced inspection plan (S-4) and limited sample population, which leads to a higher beta risk for the customer, according to Eon.
Carrying out these tests requires a clear understanding of the testing requirements listed in the cited ISO standard and the capability to implement and qualify the test methods in accordance to GMP standards, according to Schoenknecht. “Injection-force, break-loose force, and glide-force measurements can be particularly challenging because they depend closely on the inner diameter of needle, which can vary within tolerances,” he says.
A key source of failure in functional tests is insufficient application of silicone oil in the barrel of the syringe, according to Sacha. “Insufficient application of the oil can make it difficult to start movement of the plunger and can cause the plunger to halt during movement through barrel, which is known as chattering,” he explains.
“Sterility is the most important critical quality attribute of a parenteral/sterile drug product. Container closure integrity (CCI) testing (ISO 11040-4) is one of key tests to be performed to ensure the combination product is in full GMP compliance, guaranteeing sterility,” asserts Schoenknecht. CCI is required to ensure microbiological quality and thus sterility until point of use.
CCI testing evaluates the adequacy of container closure systems to maintain a sterile barrier against potential contaminants. Currently, regulatory guidance around CCI testing is ambiguous and provides limited details on how to properly assess CCI, according to Eon. He does note, however, that revisions to regulations (e.g., the new EU Annex 1) are being made to ensure a common understanding of expectations in relation to CCI testing.
Schoenknecht adds that the limitations of the individual technologies need to be understood and the most suitable methods selected and qualified for a given product. “The best solution is to have a holistic sterility/CCI strategy that follows a quality-by-design approach and comprises a phase-appropriate testing strategy,” he observes.
Issues with existing methods vary depending on the method. Some, such as dye-penetration testing, leak testing, and microbiological ingress testing, are destructive to the samples being tested. “These probabilistic methods also rely on a statistically representative number of samples from the batch and assume that any defect is uniformly present throughout the batch. All decisions are therefore made based on the small number of samples removed from the batch,” Sacha comments.
With others it can be difficult to demonstrate the sensitivity of the CCI test method, particular with respect to the positive control, according to Eon. Traditionally dye ingress, which is probabilistic, also has poor sensitivity, according to Schoenknecht.
Deterministic methods are non-destructive and can be used to test every unit from the batch. These methods include vacuum/pressure decay testing, high-voltage leak detection, and analysis of the head space within the syringe, according to Sacha. New technologies on the horizon for 100% CCI inspection based on x-ray imaging analysis or online leak testing are creating some excitement, according to Eon. The implementation of such online test methods might be extremely challenging and costly, though, according to Schoenknecht.
He points to an alternative approach that involves precise process validation of the filling process using the helium leakage method to ensure selected process parameters correlated to robust process performance. After much discussion within the industry, there seems to be consensus that the helium leak test method is one of the best methods for CCI. Lonza has developed proprietary CCI technology based on helium leakage testing in which prefilled syringes can be assessed in a very sensitive way, according to Schoenknecht. Helium gas leakage from samples is detected by mass spectrometry, with the ion counts proportional to the leak rate and thus quantifiable. The test can be used for vials, syringes, and other drug product formats at a range of temperatures, including with Lonza’s method down to -80 °C.
Automatic inspection equipment is used to check the product for particles, for cosmetic defects, and for proper placement of the plunger, says Sacha. With automatic inspection, Eon notes, companies can enact 100% inspection instead of statistical process control (SPC), which is limited by the sample error. “Using 100% inspection ensures the lowest customer risk, enables parts per million quality level, and acts as a tool for process optimization and capability analysis,” he asserts.
Schoenknecht agrees that automatic control can ensure a 100% inspection of all syringes/containers per production batch following a robust reliable and reproducible testing process. “As such, a higher quality standard than for visual-only inspected syringes can be reached by calculating performance data out of the data pool of syringes coming out of the glass converting process and following handling steps at the syringe vender, helping to understand the robustness of the production process applied at the place of syringe production. However, inline CCI testing of the filled container usually has quite low sensitivity, and thus it is arguable if product quality is improved by using current CCI technologies on-line,” he observes.
It is important to note, though, that visual inspection of prefilled syringes is required under GMP. In addition, automated inspection instruments/methods need to be qualified/validated and the automated inspection system should perform as well as a human operator regarding failure detection rates, according to Schoenknecht. False-positive detection and creating too many false rejects can occur, and users of automatic inspection systems should be aware of the potential for such issues. He also notes that for smaller batches, such as for clinical studies, manual inspection is often preferred.
1. Code of Federal Regulations, Title 21, Food and Drugs (Government Printing Office, Washington, DC).
2. EC Regulation 2017/745, Medical Devices (Brussels, 5 April 2017).
3. European Commission, EudraLex, Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products, December 2017.
4. FDA, Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products, (CDER, January 2015).
5. PDA, Prefilled Syringe User Requirements for Biotechnology Applications, Technical Report No. 73 (2015).
Vol. 32, No. 3
When referring to this article, please cite it as C. Challener, “Test Methods and Quality Control for Prefilled Syringes," BioPharm International 32 (3) 2019.