Injector Failure Guidance From US FDA Aims To ‘Balance’ Reliability And Feasibility
Executive Summary
Injectors used for emergency administration of drugs such as epinephrine should be demonstrate a ‘remote probability’ of failure equating to no more than one in every 100,000 injection attempts, agency says in a new draft guidance that may have relevance for other types of emergency-use drug delivery devices.
A new US Food and Drug Administration guidance on recommendations for demonstrating that injector products will reliably deliver the drug component on an emergency basis could help head off recalls and shortages of injectors that fail to perform as expected in the postmarket setting.
Injectors used to administer drugs on a one-time, emergency basis should be demonstrated to have a “remote probability” of failure equating to no more than one in every 100,000 injection attempts, the agency said in the draft guidance, “Technical Considerations for Demonstrating Reliability of Emergency-Use Injectors Submitted under a BLA, NDA or ANDA.”
“This reliability level was found to balance appropriately the objective of ensuring the emergency-use injector performance is as safe and reliable as possible with considerations on feasibility.” – FDA
The agency recommends emergency-use injectors include design control specifications for successful injection reliability of 99.999%, with a 95% level of confidence.
This prospective target “is equivalent to post-market detection of failure to successfully inject in 1/100,000 injection attempts,” the guidance states. “This reliability level was found to balance appropriately the objective of ensuring the emergency-use injector performance is as safe and reliable as possible with considerations on feasibility.”
The agency told the Pink Sheet it published the draft guidance “to provide clarity and information to industry so they can demonstrate in their marketing application that their emergency-use injector will reliably deliver the drug or biological product as intended."
"Guidance on this topic is important for treatments where failure of the emergency-use injector may prevent adequate delivery of life-saving treatment to a patient, and the guidance provides an example of an acceptable approach that can be used to establish reliability,” the agency said.
Limited Guidance, But Potentially Broader Impacts
A June 2013 guidance provides general recommendations for technical and scientific information to be included in marketing applications for a range of injectors for various uses. That document lists the reliability of the injector in delivering the drug as one of the functional elements the FDA assesses in premarket review.
The new draft guidance goes a step further, describing the additional information and data that should be included in applications to demonstrate reliability in the setting of emergency, one-time use.
The recommendations apply to injectors marketed with an emergency-use drug as a prefilled, single-entity combination product or as a co-packaged combination product. This category includes pen injectors, auto-injectors and on-body wearable delivery systems for drugs for emergency treatment of conditions such as anaphylaxis, opioid overdose, poisoning and severe hypoglycemia.
However, the recommendations also could be relevant to demonstrating the reliability of other types of emergency-use drug delivery devices, such as intranasal sprays, inhalation devices, topical cutaneous sprays, syringes and transdermal systems, the guidance states. “Questions regarding whether these recommendations would apply to a specific emergency-use drug delivery system and proposed methods to demonstrate the reliability should be discussed with the agency early in the product development process,” the FDA said.
Furthermore, applicants developing an emergency-use injector or similar product for an abbreviated new drug application should request agency feedback on the potential applicability of the draft guidance’s recommendations, the FDA said.
Emergency-use auto-injectors have proven to be a difficult element to copy in the ANDA context.
Teva Pharmaceutical Industries Ltd.’s epinephrine auto-injector – the first generic version of Mylan NV’s EpiPen – was approved in August 2018, almost 10 years after the ANDA was submitted. (Also see "Teva To Launch First Generic EpiPen In 'Coming Months'; FDA Heralds Approval Of Complex Product" - Pink Sheet, 16 Aug, 2018.)
The generic approval came on the heels of EpiPen pricing controversies, quality-related recalls and shortages that cast the innovator product in a negative light and highlighted the challenges of bringing complex generics through the regulatory process.
Vigilance Needed Throughout Lifecycle
The guidance notes manufacturers may become aware of potential injector malfunctions, nonconformance or other related quality problems throughout product’s lifecycle. “In these cases, manufacturers must investigate the potential cause and identify any actions that may be needed to correct and prevent recurrence,” the guidance states.
Following hundreds of complaints that EpiPen products failed to operate properly during life-threatening emergencies, in September 2017 the FDA issued a warning letter to Meridian Medical Technologies Inc., a Pfizer Inc. company that manufactures the branded epinephrine injector for Mylan.
The warning letter cited Meridian for not investigating multiple serious component and product failures, including failures associated with patient deaths. The company also was cited for failing to adequately establish and maintain procedures for verifying and validating the device design.
The complaints about injector failures prompted recalls of the Mylan product. (Also see "Mylan’s EpiPen Recall: Adding Insult To An Injured Product" - Pink Sheet, 3 Apr, 2017.)
‘Remote Probability’ Standard Favored
The guidance states that in the context of an emergency-use injector, reliability is defined as the probability that the device will perform as intended, without failure, for a given time interval under specified conditions, according to the guidance.
The FDA has found emergency-use injectors to be acceptable if they would successfully inject on the first try in “one opportunity” situations, and the manufacturer must verify and validate the design of the product to ensure it works in such situations, the guidance states.
These requirements can be met by demonstrating the injector has met its design input requirements within the specified reliability targets at expiry, and design validation has been conducted on finished products to ensure reliability targets are met and that test conditions were representative of how the product would be exposed, the agency said..
In determining an acceptable level of reliability, the agency considered available information for risk assessment, including an ISO standard on application of risk management to medical devices that provides insights on probabilities of occurrence.
The agency determined that a “probable” failure detection rate of 1/10,000 events would be unacceptable. “In FDA review experience, this probable failure rate is likely associated with unacceptable rates of adverse events for emergency-use injectors that may result in product recalls,” the guidance states.
Conversely, the agency also rejected an “improbable” failure detection rate of less than 1/1,000,000 as not realistic or feasible. “Although the lowest possible failure rates are desirable, FDA believes that based on the standard rates and current technology, that the improbable rate of less than 1/1,000,000 detection rate could result in drug shortage or delayed product availability.”
Events occurring within 1/100,000 to 1/1,000,000 detection rate are considered as a “remote probability” of occurrence.
“FDA believes the detection of failure to successfully inject in 1/100,000 injection attempts is an appropriate risk management target for ensuring successful injection and treatment when there is only one opportunity to inject,” the FDA said, adding that its review of recent marketing applications demonstrates this reliability target is achievable for emergency-use injectors.
Reliability Report
The marketing application should include information to verify and validate that the emergency-use injector achieves its reliability specifications and related information. This information should be submitted in the form of a reliability report to facilitate efficient review.
The guidance discusses the following categories of information for an emergency-use injector reliability report:
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Design inputs and design outputs necessary for ensuring reliability;
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Reliability specifications;
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A model of reliability using fault tree analysis;
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Reliability verification testing;
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Total product lifecycle reliability; and
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Activities when implementing injector design or manufacturing modifications.