A recent draft guidance document issued by the US Food and Drug Administration (FDA) raises a "number of important concerns," said the Combination Products Coalition (CPC), a group concerned with the regulatory impact of FDA activities on combination products, in a recent response to the agency.
A glass syringe is one component of an injection device, which when fully equipped often includes a needle, needleless luer connectors, adapters and/or transfer units-collectively known as connective devices. FDA's guidance observes that the devices are "a critical aspect of patient care," and are often used for intravenous (IV) line luer connections, needleless luer locks, adapters and transfer units, and not just injections.
Such devices are cleared or approved by FDA under a wide range of pathways, including humanitarian device exemptions (HDEs), postmarket applications (PMAs) and 510(k) premarket notification. For devices that include a drug product, they can also be approved through the new drug approval (NDA), abbreviated new drug approval (ANDA), and biologics license approval (BLA) pathways.
Those devices have in recent years been subject to the International Standards Organization's (ISO) Standard 11040-4, which was deemed suitable for ensuring that a glass syringe is suitable to be connected to a connecting device.
But in April 2013, FDA released a new guidance document saying it was being made aware of too many adverse events associated with the devices, especially those related to clogs, breaks or general malfunctions. In one instance, relayed regulators, patients suffering from cardiovascular abnormalities could not benefit from pre-filled vials of adenosine because of device malfunctions.
The guidance, at its most basic, is meant to correct a compatibility problem: Syringes right now can conform to either the ISO 594-2 standard or the ISO 11040-4 standard, but devices meeting the former may not be compatible with the latter.
"The glass syringe standard, ISO 11040-4, has certain undefined key dimensions," FDA explained in the guidance. "For example, the standard lacks dimensions for the glass syringe nozzle internal diameter, thickness of nozzle wall, and barrel neck curvature. In contrast, the standard for the connecting devices, ISO 594-2, has specified dimensions in these areas."
In other words, they're interoperable for the most part, but it's not guaranteed, making it possible that a syringe meeting the 11040-4 standard might not connect with a device meeting the 594-2 standard.
In response, FDA said companies will need to ensure compatibility between the two standards, and will need to provide information on five different areas at a minimum:
- syringe inner and outer diameter
- height of the nozzle for a glass barrel syringe intended to connect to a luer lock fitting
- thickness of nozzle wall
- barrel neck curvature
- dimensions to accommodate luer locks with a center pin piercing element
"FDA recommends that sponsors submit data to demonstrate that their glass syringe has connectivity (interoperability) to connecting devices to ensure proper delivery of the drug or biological product," it explains in the guidance.
CPC: Generally Good Guidance, but Problematic in Parts
Comments on the draft guidance were due on 2 July 2013, and FDA recently posted the CPC's to its public docket website.
Their reaction: While they are "quite pleased" that FDA has drafted the guidance in response to the interoperability issues, they remained disturbed about a "number of important concerns."
Three issues in particular caught CPC's attention:
- There's no indication in the guidance, they said, about whether it will apply only to new products, or if manufacturers of already-marketed products will need to reconfigure their products as well. CPC noted that some already-marketed products have not been associated with any safety issues, implying that the manufacturers would incur a cost without adding any benefits.
- Some tests recommended in the draft guidance "do not appear to be related to connectivity issues," raising questions about why they are listed within the guidance. "It is unclear as to why [an analysis of drug/biologic dilutent delivery] was included in this Draft Guidance because there is no explanation on how such an analysis would relate to the connectivity issues sought to be addressed by the guidance," CPC wrote.
- Several other types of products outside of glass prefillable syringes also contribute to connection issues, such as needleless luer access devices (NLADs), "many of which have luer shapes and/or thread designs that do not conform to the ISO 594 standard." CPC added: "The Agency should take steps to ensure that all new luer connector devices comply with the existing ISO luer standards , especially the new ISO 80369 Standard once it is issued, demonstrate the ability to connect to all syringes on the market, or contain labeling statements regarding syringes with which they are not compatible."
CPC recommended not requiring any existing devices be required to make changes, and apply instead only to products under review or requiring a new 510(k) or PMA submission.
GFI: Glass Syringes for Delivering Drug and Biological Products: Technical Information to Supplement International Organization for Standardization (ISO) Standard 11040-4