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In an effort to treat more complex diseases, the injectables market has seen high-value molecules dominate clinical pipelines. As modern molecules continue to gain market share, it is becoming the norm for drug manufacturers to plan containment system compatibility earlier in their drug development process due to the sensitivities of their complex molecules. With packaging systems becoming an integral part of the drug development and research process, a challenge drug manufacturers face is the plentitude of choice.
When considering the added complexities of administration of these sensitive molecules and whether to use a traditional vial format or a combination product, drug manufacturers must consider the strategic and cost implications in the earliest stages of development. However, considering that more than half of the top 20 injectable drug products on the market today are delivered in prefilled syringes,1 there seems to be a preference towards use of prefillable syringes. The efficiency and ease of use of not needing to withdraw drug product from vials, with the benefit of significantly reducing dosing errors, spurred the uptake of unit-dose prefillable syringes. The prefillable syringe market is set to exceed USD 6.2 billion in 2024 with a compound annual growth rate of approximately 11% from 2024-2028.2 Sales of prefillable syringes have increased globally, making them a top choice for modern molecule containment.
However, the next, more critical question drug manufacturers must ask themselves is whether to choose glass or polymer syringes. While traditional glass syringes are still widely used, they are not always the best choice when dealing with the sensitive requirements of modern molecules. Certain molecules do not react well with glass and can result in drug interactions with glass packaging.
Glass syringe disadvantages include:
Therefore, greater scrutiny in selecting syringe packaging system material is needed considering drug interaction with packaging, drug stability, particulate burden, breakage, silicone sensitivity, and tungsten sensitivity are among the top challenges for drug manufacturers to overcome.
With the shortfalls of glass, polymer syringes are quickly gaining increased attention from drug manufacturers due to their attractive benefits. The two most prevalent polymers used in prefillable syringes are Cyclic Olefin Polymer (COP) and Cyclic Olefin Copolymer (COC). COP syringes have been the primary choice for modern molecule drugs to date,3 and are designed to overcome the deficiencies of glass syringes and protect sensitive molecules.
Daikyo Crystal Zenith® COP syringe advantages are outlined below.
Attributes that contribute to product quality:
Attributes that enhance performance:
Figure 1. Daikyo Crystal Zenith® (CZ) syringe versus Glass Particle Formation by End-Over-End Rotation of IgG Samples.
The new Daikyo Crystal Zenith® 2.25 mL Insert Needle syringe meets the needs of sensitive molecules intended for subcutaneous delivery that require larger volumes with its higher volume capacity. As drug manufacturers evaluate their packaging strategy earlier in their drug development process, the Daikyo Crystal Zenith® 2.25 mL Insert Needle syringe offers a new larger volume option to enable patient choice, as these syringes are compatible with next generation autoinjectors.
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Crystal Zenith® is a registered trademark of Daikyo Seiko, Ltd. Crystal Zenith® syringe technology is licensed from Daikyo Seiko, Ltd.
References:
Guidance Issuing Office
Office of the Commissioner, Office of Clinical Policy and Programs, Office of Combination Products
This guidance document is being distributed for comment purposes only.
April 2013
FDA has recognized International Organization for Standardization (ISO) Standard 11040-4 for glass syringes that are intended to deliver drugs or biological products.2 FDA has become aware of adverse events and product quality events related to connectivity problems when certain glass syringes are used with connecting devices, including connecting devices that conform to the FDA-recognized ISO 594-2 standard. "Connecting devices" include needles, needless luer connectors, adapters, and transfer units. Accordingly, FDA has determined that, for glass syringes, demonstrating conformity with the ISO 11040-4 standard alone does not ensure that the glass syringe can be properly connected to connecting devices. Therefore, this guidance identifies additional, technical information that should be submitted by sponsors who seek to rely on conformity to ISO 11040-4 for a glass syringe product.
The recommendations provided in this guidance document are applicable to the sponsor of an IDE, HDE, 510(k), or PMA for the following glass syringe products, and to the sponsor of an IND, BLA, NDA, or ANDA3 for a drug or biological product that is delivered with such a glass syringe product:
This document focuses mainly on connectivity issues between the glass syringe and connecting device(s). It should be used in conjunction with the following FDA guidance documents:
FDA guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, these guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
Glass syringes intended to deliver drugs or biologics to a patient are a critical aspect of patient care. Typically, glass syringes are intended to connect to other devices such as needles for injection, intravenous (IV) line luer connections, needleless luer locks, adapters, and transfer units.
In November 2010 and May 2011, FDA issued Stakeholder or Safety Alerts advising of adverse events and product quality events related to connectivity problems when certain prefilled needleless glass syringes are used with some needleless IV access systems. (See FDA Drug Safety Communication: Connection problems involving certain needleless pre-filled glass syringes containing adenosine and amiodarone.) These events could cause a delay in the administration of medication in emergency situations, and potentially result in serious harm to patients. The reported events occurred upon attempted connections between the needleless glass syringe and certain needles or needleless pin activated luer connectors. These events included syringe tips breaking upon injection, needles detaching during injection, and syringes breaking or jamming the IV lines or other patient use lines.
Because of these glass syringe connection events and associated adverse events, FDA has recognized that demonstrating conformity to the ISO 11040-4 standard alone does not ensure that the glass syringes can be properly connected to connecting devices. Therefore, sponsors who seek to rely on conformity to the ISO 11040-4 standard in submissions for glass syringe products should also submit information from supplemental tests to demonstrate that the glass syringe can be properly connected to connecting devices. The purpose of this guidance document is to identify the supplemental tests that should be performed, and to recommend possible design modifications, to ensure that glass syringes are properly connected to connecting devices.
A. What are the key ISO standards related to glass syringes and connecting devices and why is conformity to these standards not sufficient?
There are two key ISO standards related to glass syringes and connecting devices, ISO 11040-4 (Prefilled Syringes - Part 4: Glass barrels for injectables and ready-to-use prefillable syringes) and ISO 594-2 (Conical fittings with 6% (Luer) taper for syringes, needles and certain other medical equipment - Part 2: Lock fittings). Both standards are currently recognized by FDA.4 FDA expects all glass syringes intended to deliver drug or biological products that meet the ISO 11040-4 standard have, as applicable, design features to connect to connecting devices.
Prior to the occurrence of the adverse events described above, the general assumption was that glass syringes that conform to the ISO 11040-4 standard would ensure connectivity (interoperability) with any connecting devices that conform to the ISO 594-2 standard. However, the glass syringe standard, ISO 11040-4, has certain undefined key dimensions. 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.5 Therefore, it is possible that a glass syringe that meets the ISO 11040-4 standard may not properly connect to a device that conforms to the ISO 594-2 standard.6 More specifically, conformance to ISO 11040-4 alone cannot ensure connectivity to connecting devices without breakage or other product performance failure as described above.
B. What other glass syringe dimensions are critical in addition to those specified in ISO 11040-4?
Generally, the dimensions for glass syringes that are not specified in ISO 11040-4 but that are important for the connection to connecting devices include the following:
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. To achieve this, the glass syringe design and validation data should include information beyond the information needed to conform to ISO 11040-4. Recommended design or re-design options are listed in subsection A. The general types of data and information the Agency recommends in the premarket or investigational submission for glass syringes are listed in subsection B.
A. What are the recommended design or re-design options?
B. What data and information does the Agency recommend be included in premarket submissions?
FDA notes that the above items focus specifically on the glass syringe connectivity aspects of development. For additional recommendations for product development, you should refer (as appropriate) to the following FDA guidance documents:
A. What is the regulatory pathway for submitting a marketing application for a prefilled glass syringe or a co-package of glass syringe with a drug or a biological product?
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Glass syringes prefilled with drug or biological products are combination products under 21 CFR Part 3. Specifically, they meet the combination product definition under 21 CFR 3.2(e)(1). A co-package of a drug or biological product and an empty glass syringe (“co-packaged glass syringe”) also meets the definition of a combination product under 21 CFR 3.2(e)(2).
Combination products are assigned to a lead center based on the primary mode of action as defined in 21 CFR 3.2(m). For a prefilled or co-packaged glass syringe with a drug or biological primary mode of action (PMOA), CDER (Center for Drug Evaluation and Research) or CBER (Center for Biologics and Research) is the lead center. Applications requesting approval to conduct clinical trials or to market these products are generally submitted under an IND, BLA, NDA, or ANDA. The device information may be included in these submissions or it may be provided in a device master file.9 There are also general use empty (unfilled) syringes for injection of unidentified drug/biological products. These are marketed under a device premarket notification, 510(k).10
Regardless of submission type, when a master file is used, the master file submitter should provide a letter to the application holder to authorize master file cross-reference. FDA does not approve the master file; FDA regulatory action is on the investigational or marketing application. FDA will, however, notify the master file holder of any deficiencies related to the master file only. As with other medical products, the overall application holder is responsible for resolution of any product specific deficiencies. To that end, for applicants with prefilled or co-packaged glass syringes, FDA recommends that the applicant work closely with their manufacturers and suppliers to address the issues described in this document.
B. Does FDA recommend early interactions with the Agency?
We recommend that you have early discussions with FDA if you are developing a glass syringe or injector that uses the type of glass syringe described in this document. If you are uncertain about the type of technical and scientific information that may be appropriate or necessary for your submission, FDA encourages you to request a joint meeting with the involved FDA centers (CBER/CDER and CDRH) and appropriate product representatives (the applicant, the device manufacturer if not the applicant, etc.). In these meetings we recommend that you outline your proposed steps to ensure the connectivity of the glass syringe when connected to connecting devices. For a glass syringe prefilled or otherwise intended for use with a specific drug or biological product, drug/biologic-specific information is available from the CDER or CBER review division. Additional general device information is available from the CDRH, General Hospital Devices Branch at 301-796-2585. For combination product policy, procedures, and regulatory questions you may contact the Office of Combination Products by email to combination@fda.gov. General guidance information and links to the different center documents are accessible at https://www.fda.gov/combination-products.
C. What are the related guidance and FDA recognized standards?
Many of the concepts described in this document are detailed further in other agency documents. The following FDA guidance and informational documents may be useful when developing a glass syringe.
1. This guidance was prepared by the Office of Combination Products in the Office of the Commissioner in conjunction with the Center for Devices and Radiological Health, the Center for Drug Evaluation and Research, and the Center for Biologics Evaluation and Research.
2. The FDA database of currently recognized versions of these ISO documents is accessible at http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm. This website identifies the currently recognized version and any addition guidance information.
3. These submission abbreviations refer to the following: IDE is an investigational device exemption; HDE is a humanitarian device exemption; 510(k) is a premarket notification; PMA is a premarket application; IND is an investigational new drug application; BLA is a biologics license application; NDA is a new drug application; and ANDA is an abbreviated new drug application.
4. Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet and Related Injectors Intended for Use with Drugs and Biological Products (June 2013), available at: http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM147095.pdf
5. Guidance for Industry, Container Closure systems for Packaging Human Drugs and Biologics (May 1999), available at; http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070551.pdf.
6. Guidance on the Content of 510(k) submissions for Piston Syringes (April 1993), available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm081324.htm
7. Needleless Pre-filled Glass Syringes: Stakeholder Advisory - Compatibility Problems with Needleless Intravenous Access Systems; https://www.fda.gov/drugs/drug-safety-and-availability/letter-stakeholders-update-certain-needleless-pre-filled-glass-syringes
8. FDA Drug Safety Communication: Connection problems involving certain needleless pre-filled glass syringes containing adenosine and amiodarone; http://www.fda.gov/Drugs/DrugSafety/ucm254215.htm
9. See footnote 2.
10. Plastic syringe ISO standard 7886 has internal dimensions that are compatible with the ISO 594-2 standard.
11. For example, assume a given pin-piercing needleless connector complies with ISO 594-2. FDA has received reports that when such a pin-piercing needleless connector is mated with a glass syringe, the pin could jam and break the glass syringe when threaded together.
12.Guidance for Industry and FDA Staff - Medical Devices with Sharps Injury Prevention Features (August 2005), available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071663.htm
13. Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products (November 1994), available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm072171.pdf
14. See footnote 2. For further recommendations on device sterility, you may consult FDA’s guidance document, Guidance for Industry and FDA Staff: Submission and Review of Sterility Information in Premarket Notification (510(k)) Submissions for Devices Labeled as Sterile (January 2016), available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/submission-and-review-sterility-information-premarket-notification-510k-submissions-devices-labeled
15. 21 CFR 820.30(c).
16. Guidance for Industry and Food and Drug Administration Staff - Applying Human Factors and Usability Engineering to Optimize Medical Device Design (February 2016), available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/applying-human-factors-and-usability-engineering-medical-devices. See also FDA’s “Human Factors and Medical Devices” webpage, available at: https://www.fda.gov/medical-devices/device-advice-comprehensive-regulatory-assistance/human-factors-and-medical-devices.
17. See footnote 4.
18. See footnote 5.
19. See footnote 6.
20. See FDA’s “Introduction to Master Files for Devices (MAFs),” available at: https://www.fda.gov/medical-devices/premarket-approval-pma/master-files
21. Empty glass syringes marketed in isolation for general use are under regulated under 21 CFR 880.5860. See also Guidance on the Content of Premarket Notification [510(K)] Submissions for Piston Syringes (April 1993), available at http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm081324.htm.
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
Comments and suggestions regarding this draft document should be submitted within 90 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register.
Additional copies are available from:
Office of Combination Products
Office of Special Medical Programs
Office of the Commissioner
Food and Drug Administration
10903 New Hampshire Avenue, WO-32 Hub 5129
Silver Spring, MD 20993
(Tel) 301-796-8930
(Fax) 301-796-8619
http://www.fda.gov/CombinationProducts/default.htm
For questions regarding this document, contact the Office of Combination Products at combination@fda.gov or Patricia Y. Love, MD at 301-796-8933 or patricia.love@fda.hhs.gov
U.S. Department of Health and Human Services
Food and Drug Administration
You can submit online or written comments on any guidance at any time (see 21 CFR 10.115(g)(5))
If unable to submit comments online, please mail written comments to:
Dockets Management
Food and Drug Administration
5630 Fishers Lane, Rm 1061
Rockville, MD 20852
All written comments should be identified with this document's docket number: FDA-2013-D-0362.
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