MAUDE Adverse Event Report: PHILLIPS MEDISIZE SYMJEPI; EPINEPHRINE

Lot Number EP0042,EP0043, EPJ0015

Device Problem Inaccurate Delivery (2339)

Patient Problem No Clinical Signs, Symptoms or Conditions (4582)

Event Date 02/15/2022

Event Type  malfunction  

Manufacturer Narrative

An interim investigation pointed to a component issue and not a product issue.The components (syringe, needle, and stoppers) are common to seven total batches of symjepi with three lots released to market, ep0042, ep0043 and epj0015.Expiration dates: nov-2022 (ep0042, epj0015); feb-2023 (ep0043).There has been zero non-functional product complaints.In an abundance of caution, all potentially impacted batches (ep0041, ep0042, ep0043, ep0044, ep0045, epj0015 and epj0016) were placed on quarantine hold pending a full investigation.An nda field alert report was submitted to fda on 18-feb-2022.Follow-up information will be provided when it is available.

Event Description

Contents on five syringes could not be emptied [device malfunction].Case description: on 15-feb-2022, adamis was notified by (b)(6) that five non-conforming results were obtained from one month (t1) and two month (t2) stability testing on epinephrine lots ep0044 (t1 40c & t2 40c) and epj 0016 (t1 25c and two more syringes at t1 30c).Neither of the two batches had been released.In accelerated, long term and intermediate stability testing (completed (b)(6) 2022, (b)(6) 2022, and (b)(6) 2022), the contents of five syringes (out of a total of 740 syringes) could not be emptied.No issues had been noted during the initial release testing.

Manufacturer Narrative

Three lots released to market, ep0042, ep0043 and epj0015.There have been zero non-functional product complaints.In an abundance of caution, all potentially impacted batches (ep0041, ep0042, ep0043, ep0044, ep0045, epj0015 and epj0016) were placed on quarantine hold pending a full investigation.An nda field alert report was submitted to fda on 18-feb-2022.After one month of stability testing, blocked syringes/difficulty in expelling the contents were detected.Brown, corrosive traces were noted at the extremity of the needles.A laboratory investigation was completed, and laboratory error was ruled out as a cause.A detailed manufacturing and component investigation was performed.The investigation was able to bracket the clogged syringe defects to catalent manufactured batches ep0042, ep0043, ep0044, ep0045, epj0015, & epj0016.The investigation identified a commonality between these batches with a specific empty needle/syringe component lot supplied by gerresheimer.A significant increase of microcavities or pitting found on the needle bevel (via sem-eds analysis) of syringe needle batch 837301 was determined as the most probable root cause for clogging due to oxidation and corrosion.Analysis of a reference needle cannula confirmed that such microcavities are not normally present on the cannula bevels.The investigation and experimental testing further corroborated that needles from the suspected batch 837301 (with microcavities) were more susceptible to salt and acid corrosion.Batches ep0044, ep0045, & epj0016 were under catalent control and were subsequently placed on qa hold.On 21-mar-2022, a voluntary recall of four product batches, ep0040/21041w, ep0042/21081w, ep0043/21102w, and epj0015/21101y was initiated.There had been two (2) technical complaints concerning three (3) syringes filed against batch ep0040/21041w in july 2021.In an abundance of caution batch ep0040/21041w was included in the recall.Although the investigation has not been completed to date, the following corrective actions have been proposed: restart production with a new syringe batch and performing heightened qc inspections at different steps of the product life cycle including perform investigative incoming qualitative testing on a minimum of ten empty syringes to assess microcavities on the needle bevel using sem-eds and place the initial batch on accelerated stability and test one thousand (1000) drug product syringes at t0, t1, and t2 months for needle appearance and performance.Direct customers were sent recall notification letters via email on 24mar2022.To date, 69 direct customers have responded to the recall, of which, 46 customers indicated that product was on-hand for return; 126 indirect customers have responded, of which, 39 customers indicated that product was on-hand for return.Five customers indicated that product on-hand (total of 12) will be destroyed.One customer previously indicated that product (20 units) would be destroyed subsequently, provided a revised response indicating that 22 units will be returned.Based on the customer responses to date, a total of (b)(4) units will be returned.To date, 637 units have been returned; an additional 785 units have been returned to ics and are currently being processed.The returned quantities for each customer will be counted, verified, and included in the detailed returns report that will be included with the next status report.The estimated completion date for recall is july 2022.Follow-up information will be provided when it is available.

Event Description

Case description: on 15-feb-2022, adamis was notified by catalent brussels that five non-conforming results were obtained from one month (t1) and two month (t2) stability testing on epinephrine lots ep0044 (t1 40c & t2 40c) and epj 0016 (t1 25c and two more syringes at t1 30c).Neither of the two batches had been released.In accelerated, long term and intermediate stability testing (completed 04-feb-2022, 10-feb-2022, and 12-feb-2022), the contents of five syringes (out of a total of 740 syringes) could not be emptied.No issues had been noted during the initial release testing.An interim investigation pointed to a component issue and not a product issue.The components (syringe, needle, and stoppers) are common to seven total batches of symjepi with continued in additional info section.

Manufacturer Narrative

Three lots released to market, ep0042, ep0043 and epj0015.In an abundance of caution, all potentially impacted batches (ep0041, ep0042, ep0043, ep0044, ep0045, epj0015 and epj0016) were placed on quarantine hold pending a full investigation.An nda field alert report was submitted to fda on 18-feb-2022.After one month of stability testing, blocked syringes/difficulty in expelling the contents were detected.Brown, corrosive traces were noted at the extremity of the needles.A laboratory investigation was completed, and laboratory error was ruled out as a cause.A detailed manufacturing and component investigation was performed.The investigation was able to bracket the clogged syringe defects to catalent manufactured batches ep0042, ep0043, ep0044, ep0045, epj0015, & epj0016.The investigation identified a commonality between these batches with a specific empty needle/syringe component lot supplied by gerresheimer.A significant increase of microcavities or pitting found on the needle bevel (via sem-eds analysis) of syringe needle batch 837301 was determined as the most probable root cause for clogging due to oxidation and corrosion.Analysis of a reference needle cannula confirmed that such microcavities are not normally present on the cannula bevels.The investigation and experimental testing further corroborated that needles from the suspected batch 837301 (with microcavities) were more susceptible to salt and acid corrosion.Batches ep0044, ep0045, & epj0016 were under catalent control and were subsequently placed on qa hold.On 21-mar-2022, a voluntary recall of four product batches, ep0040/21041w, ep0042/21081w, ep0043/21102w, and epj0015/21101y was initiated.There had been two (2) technical complaints concerning three (3) syringes filed against batch ep0040/21041w in july 2021.In an abundance of caution batch ep0040/21041w was included in the recall.The following corrective actions have been proposed: restart production with a new syringe batch and performing heightened qc inspections at different steps of the product life cycle including perform investigative incoming qualitative testing on a minimum of ten empty syringes to assess microcavities on the needle bevel using sem-eds and place the initial batch on accelerated stability and test one thousand (1000) drug product syringes at t0, t1, and t2 months for needle appearance and performance.Direct customers were sent recall notification letters via email on 24mar2022.A detailed manufacturing and component investigation was conducted and completed.A manufacturing error was ruled out.The issue was isolated to a specific needle batch.All drug product batches using the subject needle receipt and all other drug product within expiry dating were subsequently evaluated.Root cause analysis was correlated to a specific needle supplier (matsuoka) used by gerresheimer (the empty syringe manufacturer) for batch 837301 that contained a significant amount of microcavities on the 304 stainless steel needle bevels found under magnification via sem-edx (scanning electron microscopy-energy dispersive x-ray) analysis, as compared to a control batch of non­incriminated needles.Further, experimental exposure of needles from the implicated batch to an acidic solution and chloride anions led to increased corrosion.Epinephrine has a low ph range and contains chloride anions (from sodium chloride).The clogged needles were isolated to catalent manufactured batches ep0042, ep0043, ep0044, ep0045, epj0015, and epj0016.Type 304 stainless steel contains 66.5 - 67.0% iron and is designed to be resistant to oxidation.However, long term exposure in the presence of chloride solutions can result in the generation of iron oxide through a pitting mechanism (tsutsumi, et.Al., corrosion science, vol.49, issue 3, march 2007).Epinephrine drug solution has 6 mg/ml of nacl (3640 ppm) with a low ph which is favorable for stainless steel pitting oxidation (destabilization of the passivation layer).The de-passivation threshold is at ph 1.9 for 304 stainless steel.The formulated ph range of symjepi is approximately 3.2 to 4.4 which contributed, along with the chloride anions, to oxidation resulting in the clogging of the syringes.Epinephrine drug product batches using the same batch of empty syringes (gerresheimer batch 19767035/matsuoka 837301) were assessed which included ep0044, ep0045, epj0016, plus ep0041, ep0042, ep0043, and epj0015.A total of 250-1000 syringes/batch were assessed/tested.In addition, retain samples using different syringes and batches still within expiry were tested (ep0037, ep0040, epj013, and epj014).From this heightened testing, additional clogs were noted with batches epj0015 and ep0043.To date, no complaints from the incriminated syringe batches that have been distributed have been received.In conclusion, the root cause of the clogging was considered multifactorial; however, limited to a single batch of faulty stainless needles.The most likely cause was long-term contact of the filled drug product with the compromised 304 stainless steel needles causing the clogging and observed corrosion at the cannula tip.Several other contributing factors were the presence of an elevated number of microcavities on the needle batch surface and other environmental factors (e.G., high temperature/humidity exposure in the stability chambers).Corrective actions to prevent recurrence of the problem include: a new syringe batch has been sourced and will undergo a heightened product life cycle qc inspection process, the initial batch and all subsequent new needle batches will be placed on accelerated stability and testing will occur on no less than 1000 syringes at t0, t1, and t2 prior to release, and alternate needle suppliers will be evaluated as well as the feasibility of an alternate stainless steel component such as 316 ss.It was noted that 304 ss is the industry standard for needle syringes.To date, 70 direct customers have responded to the recall, of which, 47 customers indicated that product was on-hand for return; 131 indirect customers have responded, of which, 48 customers indicated that product on-hand would be returned.Seven customers indicated that product on-hand (total of 20) will be destroyed.Based on the customer responses to date, a total of 2,054 units will be returned.To date, 1489.5 units have been returned.Field alert reports were submitted on 18feb2022, 19may2022, and 03aug2022.A final report will be submitted when it is available.

Event Description

Case description: on 15-feb-2022, (b)(6) was notified by (b)(6) that five non-conforming results were obtained from one month (t1) and two month (t2) stability testing on epinephrine lots ep0044 (t1 40c & t2 40c) and epj 0016 (t1 25c and two more syringes at t1 30c).Neither of the two batches had been released.In accelerated, long term and intermediate stability testing (completed 04-feb-2022, 10-feb-2022, and 12-feb-2022), the contents of five syringes (out of a total of 740 syringes) could not be emptied.No issues had been noted during the initial release testing.An interim investigation pointed to a component issue and not a product issue.The components (syringe, needle, and stoppers) are common to seven total batches of symjepi with continued in additional info section.

• Brand Name: SYMJEPI
• Type of Device: EPINEPHRINE
• Manufacturer (Section D): PHILLIPS MEDISIZE; menomonie WI
• Manufacturer (Section G): PHILLIPS MEDISIZE; 428 technology drive east; menomonie WI
• Manufacturer Contact: 11682 el camino real; san diego, CA 92130 ; 8582843717
• MDR Report Key: 13793122
• MDR Text Key: 292365890
• Report Number: 3002919960-2022-00002
• Device Sequence Number: 1
• Product Code: PQX
• Combination Product (y/n): Y
• Reporter Country Code: BE
• Number of Events Reported: 1
• Summary Report (Y/N): N
• Report Source: Manufacturer
• Source Type: Other
• Reporter Occupation: Other
• Remedial Action: Recall
• Type of Report: Initial,Followup,Followup
• Report Date: 06/17/2022

1 Device was Involved in the Event

1 Patient was Involved in the Event

• Is this an Adverse Event Report?: No
• Is this a Product Problem Report?: Yes
• Device Operator: Other
• Device Expiration Date: 11/01/2022
• Device Lot Number: EP0042,EP0043, EPJ0015
• Was Device Available for Evaluation?: Yes
• Is the Reporter a Health Professional?: No
• Initial Date Manufacturer Received: 02/15/2022
• Initial Date FDA Received: 03/17/2022
• Supplement Dates Manufacturer Received: 05/19/2022; 07/28/2022
• Supplement Dates FDA Received: 06/17/2022; 08/26/2022
• Was Device Evaluated by Manufacturer?: Yes
• Is the Device Single Use?: Yes
• Is This a Reprocessed and Reused Single-Use Device?: No
• Type of Device Usage: Initial
• Patient Sequence Number: 1