Dr. Christopher Joseph Devine, President, Devine Guidance International
Devine Guidance

Three Strikes Equals a Warning Letter

By Dr. Christopher Joseph Devine
Dr. Christopher Joseph Devine, President, Devine Guidance International

You can’t just validate processes—you have to monitor them, too.

I am sure many of the readers are familiar with the phases: (a) one and done, or (b) one, two, three strikes, you’re out. Well it appears these two phrases became a reality for a device establishment located in South Carolina, and at the same time. The offending establishment received a Form 483 observation for process validation (PV) issues. As an outsider looking in, the receipt of a Form 483 observation for PV is a relatively common occurrence. In fact, it is one of the more frequently cited violations of the quality system regulation (§820.75). However, failing at three attempts to provide the FDA with a reasonable response is troubling. After all, a well-worded response will typically result in the prevention of an agency warning letter. This is especially true when the initial observation appears to be quite innocuous. However, when the Chief Jailable Officer’s (CJO) Form 483 response is obnubilated (look-it-up) by convoluted prose, anything is possible with the FDA. This is especially true when three attempts at placating the FDA have resulted in failure. Enjoy!

Warning Letter – March 3, 2016

As mentioned in the opening paragraph, this week’s warning letter recipient received one Form 483 observation: The failure to establish procedures. So if an establishment has failed to establish procedures associated with the monitoring and control of process parameters, what is so darned difficult about telling the agency we are going to establish procedures and provide documented evidence of compliance? Seriously, the FDA expects: (a) a containment statement, (b) a realistic plan to achieve compliance, (c) actual documented evidence to support compliance has been achieved, and (d) documented evidence of the verification of effectiveness (VOE) at some point in the future (not too far in the future, however) to ensure the actions pursued are effective.

Warning Letter Excerpt

Observation One  – “Procedures for monitoring and control of process parameters for a validated process have not been established as required by 21 CFR 820.75(b). During our inspection of your facility, the following violations were observed:”

“a. Your firm’s validated cleaning process is not routinely monitored to assess contamination levels for reprocessed single-use devices subjected to the process. The most recent assessments for contamination were performed in 2012 as part of Cleaning Validation of Compressed Sleeves, Protocol #12019 (for hemoglobin and bioburden) and Cleaning Validation of Orthopedic, ENT and Laparoscopic Instruments, Protocol #12020-A (for hemoglobin and protein). However, your firm’s procedure, titled QAP008-Appendix C, Validation of Product, Equipment and Process for EO Sterilization, Rev. 1, states, “Product bioburden is controlled through the cleaning process and monitored on a quarterly basis…;.” No documented evidence was provided during the current inspection to support this requirement as required by your procedures.” 

“b. Your firm has failed to adequately identify the worst-case product used during the validation of your firm’s sterilization process. The 2014 and 2013 Performance Qualification of Sterilization Process reports both state under item #2 that “the (b)(4) devices within the load would present a bioburden challenge”. During our review of sterilization records, Sterilization Batch Record (SBR) #782 indicated that (b)(4) devices were sterilized in that load, with over (b)(4) more devices than used in the validations.”

“c. The numbers of samples chosen for use in the Cleaning Validation studies were not based on a valid statistical technique.”

“Your response letters dated December 02, 2015; December 23, 2015; and February 08, 2016, did not adequately address this violation.” 

21 CFR, Part 820.75 – Process Validation

“(a) Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedures. The validation activities and results, including the date and signature of the individual(s) approving the validation and where appropriate the major equipment validated, shall be documented.”

“(b) Each manufacturer shall establish and maintain procedures for monitoring and control of process parameters for validated processes to ensure that the specified requirements continue to be met.”

“(1) Each manufacturer shall ensure that validated processes are performed by qualified individual(s).”

“(2) For validated processes, the monitoring and control methods and data, the date performed, and, where appropriate, the individual(s) performing the process or the major equipment used shall be documented.”

“(c) When changes or process deviations occur, the manufacturer shall review and evaluate the process and perform revalidation where appropriate. These activities shall be documented.”

Compliance for Dummies

There have been so many papers and books authored on approaches to process validation in support of the device industry, so Dr. D is going to keep this really simple with just four acronyms:

  • IQ (Installation Qualification) determines, through the collection of documented evidence, that systems and equipment have been properly installed
  • OQ (Operational Qualification) establishes through the collection of documented evidence, that the process control limits for equipment meet predefined requirements
  • PQ (Performance Qualification) establishes, through the collection of documented evidence, that processes consistently produces a result that meets the predefined requirements
  • PPQ (Product Performance Qualification) demonstrates, through the collection of documented evidence, that all validated manufacturing processes produce finished devices/products that meets their defined product specifications

The first thing that the doctor would like you to notice is that an emphasis is being placed on documented evidence throughout this week’s guidance. If you have to ask why, and you are a CJO, a warning letter will be in your future. That being said, if there is no documented evidence of compliance, in the eyes of FDA, the activities never happened. Now before you validation experts begin the heap contumely on old Dr. D, the QSR fails to mention IQ, OQ, PQ, and PPQ. The only reason the doctor even mentioned this approach is because the device industry has pursued this approach for PV for years, and the FDA actually likes it. Hey Mikey, he likes it!

Additionally, it is not simply enough to validate processes. There is a requirement to actually monitor processes to ensure that they remain within some level of control. The doctor believes Juran made a small fortune off his handbook that drives home the virtues of an effective approach to PV and the management of processes.

Furthermore, whatever the approach a device establishment pursues for PV, FDA expects written procedures. These procedures should define the use of: (a) validation protocols (written, reviewed and approved), (b) validation reports, (c) qualifications of individuals performing validations, (d) sample size rationales, (e) training, (f) equipment qualifications (e.g., test method validation requirements), (g) handling deviations, and (h) requirements for repeating validations. Please do not forget the importance of risk management (e.g., EN ISO 14971:2012) when pursuing PV activities.

Finally, as the doctor previously mentioned, all of these activities shall be documented. If they are not documented, they never occurred. If you don’t want to believe Dr. D, send an email to the CJO associated with this week’s warning letter. It is public information. I am sure this individual can enlighten the readers on the level of regulatory pain the agency can unleash on violative establishments.


For this week’s guidance, the doctor will leave the readers with three takeaways. One: At some point in time every establishment will be on the receiving end of a Form 483 observation. They should be treated as opportunities for improvement. However, make no mistake, your establishment’s response better be robust. Two: PV is not rocket science. The best approach Dr. D can offer when it comes to PV is pursing the good-old-fashioned IQ, OQ, PQ, and PPQ approach. It works, and there is a boatload of data to support its effectiveness. Three: No documented evidence of compliance equates to it never happened. 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.


Code of Federal Regulation. (April 2015). Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.

Devine, C. (2011). Devine guidance for complying with the FDA’s quality system   regulation – 21 CFR, Part 820. Charleston, SC: Amazon.

Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.

FDA. (March 3, 2016). Inspections, Compliance, Enforcement, and Criminal Investigations. SureTek Medical. Accessed March 16, 2016. Retrieved from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2016/ucm489979.htm

About The Author

Dr. Christopher Joseph Devine, President, Devine Guidance International