What do Fuji Films, the Olympus Corporation and Hoya (Pentax Life Care Division) have in common? If you guessed, they are teaming up to make another Godzilla movie, you would be incorrect in your assumption (maybe not a bad idea though). These three Japanese entities received FDA warning letters on the very same day, August 12, 2015. Why? The establishments manufacture endoscopes that continue to make national news over reprocessing issues that have resulted in serious patient illnesses and a handful of patient fatalities. As many of the readers already know, Dr. D spent years at Boston Scientific Corporation (BSC). During the doctor’s time at BSC, I remember BSC investing heavily in the development of a disposable endoscope. The scope worked just fine; however, because of competitive pricing concerns, it never made it to commercialization. Just maybe, now might be the time to resurrect the disposable scope. For this week’s guidance Dr. D will dive into the warning letters issued by FDA and attempt to present the readers with what the doctor believes is the salient theme(s) of the letters. Heck, Dr. D figured the FDA would just cut-and-paste the same warning letter content three times, but that would be just too darn easy. Please keep in mind, the doctor recognizes that attempting to contrast three different warning letters in an effort to assess the resulting nomothetic (look-it-up) observations may be construed as misleading to the readers. However, make no mistake in the resolve of the agency to ensure that compliance issues associated with scope manufacturers are corrected and done so quickly. Enjoy!

Warning Letter One (9 Form 483 Observations) –August 12, 2015

“During these inspections investigators from the FDA determined that your firm manufactures endoscopes and endoscope accessories. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body. These inspections revealed that your firm’s devices are adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. §351(h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.”

Observation One  – “Failure to establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR 820.30. For example (Miyanodai):

a.     Your firm’s 2014 reprocessing validation for the model ED-530XT duodenoscope did not include evaluating the effects of reprocessing on the O-ring. Your firm conducted one full cycle run of ethylene oxide (EO) sterilization for validation, but did not justify how one full run is indicative of the process being consistent and reproducible.

b.     Your firm did not adequately verify that the LT-7F manual air leak tester, an endoscope accessory, was appropriate for use in performing an air leak test for all endoscope models with ventilation connectors.”

Observation Four  – “Failure, where the results of a process cannot be fully verified by subsequent inspection and test, to validate the process with a high degree of assurance and to approve according to established procedures, as required by 21 CFR 820.75(a). For example the following deficiencies were observed (Sano):

a.     Your firm did not validate the complete range of process parameters used for the (b) (4) of the duodenoscope bending section assembly. Specifically, per validation report (b) (4), your firm validated the operating parameter of (b) (4) for output; however, operating parameters of (b) (4), were used by your firm. In addition, your firm did not document the statistical rationale for the sample size used in the validation.

b.     Your firm’s EO sterilization validation and annual revalidation includes residual testing for ethylene oxide/ethylene chlorohydrin (ECH), a measure of components’ susceptibility to holding residues. However, you did not segregate or determine the worst case materials during EO/ECH residual testing as part of your sterilization validation and annual revalidation testing in order to determine proper aeration time, a critical parameter.

c.     Your firm did not conduct growth promotion tests to validate culture media; including, (b) (4), used in bioburden testing of EO sterilized accessories.

Warning Letter Two (2 Form 483 Observations) –August 12, 2015

“During these inspections investigators from the FDA determined that your firm manufactures endoscopes and endoscope accessories. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. § 321(h), these products are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body. Our inspections revealed that the duodenovideoscope Olympus TJF Type Q-180V is misbranded under section 502(t) (2) of the Act, 21 U.S.C. § 352(t) (2), in that your firm failed or refused to furnish material or information respecting the device that is required by or under section 519 of the Act, 21 U.S.C. § 360i, and 21 CFR Part 803 – Medical Device Reporting.

Observation One – “Failure to report to FDA no later than 30 calendar days after the day that your firm received or otherwise became aware of information, from any source, that reasonably suggests that a device that your firm markets may have caused or contributed to a death or serious injury, as required by 21 CFR 803.50(a)(1). For example, Complaint #GIR/OBV-11055 references 16 patients who contracted a Pseudomonas aeruginosa infection, of which some resulted in abscesses, after undergoing an endoscopic procedure with your firm’s devices. Your firm submitted one MDR (MDR #8010047-2015-00218) to account for all the patients involved in the event. Your firm failed to submit an initial MDR for each event referencing patients sustaining abscesses as a result of contracting a Pseudomonas aeruginosa infection after undergoing an endoscopic procedure involving your firm’s devices. Your firm became aware of the event on May 16, 2012. The referenced MDR and all additional MDRs associated with the event were received by FDA in 2015, which is beyond the 30 calendar day timeframe.”

Warning Letter Three (6 Form 483 Observations) –August 12, 2015

“These inspections revealed that your firm’s devices are adulterated within the meaning of section 501 (h) of the Act, 21 U.S.C. § 351 (h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformity with the current good manufacturing practice requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820.

Observation One – “Failure to establish and maintain design validation procedures to ensure that devices conform to defined user needs and intended uses, failure to include testing of production units under actual or simulated use conditions, and failure to document the results of the design validation in the device history file (DHF), as required by 21 CFR 820.30(g). For example:

a.     The validation studies conducted to support the Ethylene Oxide (EtO) sterilization and cleaning and high level disinfection (HLD) Instructions for Use (IFUs) for the currently marketed device, ED-3670TK, were conducted using different model/series endoscopes. Your firm failed to document why design validation results for the different model/series endoscopes are valid and applicable to the ED-3670TK devices [Akishima-shi, Tokyo].

b.     Labeling document (b) (4), Revision A, states that an EtO/Carbon Dioxide (80:20 gas mixture) and EtO/Carbon Dioxide (90:10 gas mixture) can be used to sterilize endoscopes. However, your firm did not use the specified gas concentrations for validation. The validation for the ED-3490TK and ED-3670TK devices was conducted with EtO/HCFC (Oxyfume 2001) (10:90 gas mixture) [Akishima-shi, Tokyo].

c.     Your firm failed to document in the DHF the protocol and the raw data associated with:

            i. The final EtO sterilization validation report, (b) (4), laboratory number (b) (4),   for the ED-3490TK and ED-3670TK devices [Akishima-shi, Tokyo].

            ii. The protocol and the raw data associated with the HLD validation report           (b) (4) were not documented in the DHF [Akishima-shi, Tokyo].

d.     Validation protocol no. (b) (4), used to support the reprocessing of the ED-3490TK and the ED-3670TK devices, does not specify the validation testing conditions. For example, the cleaning protocol requires using a syringe filled with an enzymatic detergent to flush the suction channel. However, the volume of the syringe and the type of detergent are not specified [Akishima-shi, Tokyo].”

Observation Five – “Failure to report to FDA no later than 30 calendar days after the day that Hoya Corporation received or otherwise became aware of information, from any source, that reasonably suggests that a device that your firm markets may have caused or contributed to a death or serious injury, as required by 21 CFR 803.50(a)(1). For example, Hoya Corporation, Akishima-shi, Tokyo, Japan, facility failed to submit initial Medical Device Reports (MDRs) for each patient who developed a Carbapenem Resistance Enterobacteriaceae infection after an endoscopic procedure involving your firm’s duodenoscopes. This information was reported by your firm’s importer, PAl, in MDRs#2518897-2013-00004, #2518897-2013-00005, and #2518897-2013-00006, and the associated supplemental reports. In addition, your firm failed to submit initial MDRs for each of the seven events referenced in MDR #2518897-2014-00001 and for each of the two events referenced in MDR #2518897-2014-00002 [Akishima-shi, Tokyo].”

Common Theme(s)

For those readers familiar with the reprocessing issues associated with duodenoscopes and endoscopes, the improper reprocessing of these complex devices was determined to be ineffective. In fact, FDA asked the manufacturers to revisit their reprocessing protocols earlier this year. As a result of the ineffectual reprocessing, patients became extremely ill and a few succumbed to their illnesses, leaving their loved ones, healthcare practitioners, the manufacturers, the reprocessors, and the FDA pondering what happened. Dr. D loves the FDA and strongly believes that the agency has the interest of public health at the top of its priority list. However, what happened with the issue of scope processing is puzzling to many, including Dr. D. It is the doctor’s opinion that action by the agency should have occurred at an accelerated pace. FYI, the doctor underwent a scope procedure in the summer of 2013, with no adverse events noted (as far as the doctor knows).

The common thread in these warning letters is essentially two fold. One: The FDA has thrown the validation of these devices, especially sterilization through the use of ethylene oxide (EtO), under the proverbial bus. Two: The FDA cited two establishments for their failure to report adverse events in accordance with 21 CFR, Part 803, when serious patient injuries occurred. Considering that these devices were hurting people and concerns were being noted over the effective reprocessing of scopes, or lack thereof (including the validation activities), these establishments should have taken ownership and quickly reacted to the general threat to the public health. Folks, I am sorry, but Dr. D is of the mindset that one life lost because of a product reprocessing issue is one life too many.

Takeaways

For this week’s guidance, Dr. D will leave the readers with just a couple of thoughts and no takeaways. If complex medical devices such as endoscopes and duodenoscopes cannot be reprocessed safely, then why is this practice permitted? Just maybe BSC’s disposable endoscope isn’t such a crazy idea after all. Considering some complex electrophysiology catheters can cost more than $1,000, paying $1,000 for a disposable scope might not be a bad investment. Just knowing where these scopes may have been used previously, should scare the crap (figuratively, of course) out of people. In closing, thank you again for joining Dr. D, and I hope you find value in the guidance provided. Until the next installment of DG, cheers from Dr. D. and best wishes for continued professional success.

References

1. Code of Federal Regulation. (April 2014). Title 21 Part 820: Quality system regulation. Washington, D.C.. U.S. Government Printing Office.
2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
3. Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
4. FDA. (August 12, 2015). Inspections, Compliance, Enforcement, and Criminal Investigations, Fujifilm Medical Systems U.S.A., Inc., Warning Letter. Accessed August 24, 2015. Retrieved from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm458453.htm
5. FDA. (August 12, 2015). Inspections, Compliance, Enforcement, and Criminal Investigations, Olympus Corporation of Americas. Accessed August 24, 2015. Retrieved from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm458510.htm
6. FDA. (August 12, 2015). Inspections, Compliance, Enforcement, and Criminal Investigations, Hoya Corporation. Accessed August 24, 2015. Retrieved from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2015/ucm458487.htm