One question that the doctor fields quite often is: “How many inspectional observations equate to the automatic issuance of an FDA warning letter?”

Although there is no real answer to this age-old question, Dr. D thinks 13 Form 483 observations are going to result in the awarding of a warning letter to the offending device establishment every-single time! Additionally, if the offending device manufacturer has a Quality Management System (QMS) which is that far out of whack, then no doubt claims of manufacturing and distributing adulterated product are going to vibrate through the air, quite loudly the doctor might add, like an AC/DC concert. Seriously, 13 inspectional observations, coupled with the failure to provide objective evidence of correction is always a bad thing in the eyes of our friends at the agency. In fact during an inspectional debrief, when the FDA investigator asks for the signature of the Chief Jailable Officer (CJO); no doubt the face of the CJO will contain nothing less than a “saturnine” (look-it-up) look driven by the “sardonic” (look-it-up) demeanor of the FDA investigator. Enjoy.

FDA Warning Letter – 25 June 2014

For this week’s guidance, the doctor decided to extract an entire warning letter and share it with the readers. Thirteen observations are clearly indicative of an organization that has completely missed the proverbial boat in regards to complying with the QSR; considering most of the basic elements of a QMS are missing such as:

(a) management review;
(b) process control;
(c) CAPA;
(d) purchasing;
(e) document control;
(f) calibration,
(g) audits; etc.

The doctor would like to say something sarcastic and funny like throwing out the QMS and starting over; however, it appears from the warning letter that a QMS is probably not in place; at least not an effective one.

One (1) – Failure to validate a process whose results cannot be fully verified by subsequent inspection and test, as required by 21 CFR 820.75(a). For example: You failed to validate the automated manufacturing process of the elastic orthodontic bands. You do not conduct quality checks on all of the bands manufactured. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Two (2) – Failure to establish process control procedures that describe the controls necessary to ensure conformance to specifications where deviations from device specifications could occur as a result of the manufacturing process, as required by 21 CFR 820.70(a). For example: You manufacture latex orthodontic bands from natural materials using an automated extrusion and cutting process but do not have written procedures for setting manufacturing equipment parameters, quality control sampling and testing, or setting packaging and labeling equipment parameters. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Three (3) – Failure to establish procedures to ensure that all purchased or otherwise received product and services conform to specified requirements, as required by 21 CFR 820.50. For example: You have a list of current and former suppliers; however, when our investigator asked you for documentation of the approval and qualification of each supplier, your General Manager stated that you do not have that type of documentation. The binder containing the list of suppliers does not have written specification or other quality requirements that each supplier must meet. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Four (4) – Failure to establish and maintain procedures for acceptance activities, as required by 21 CFR 820.80(a). For example: You manufacture latex elastic bands for orthodontic use. However, your General Manager told our investigator that you do not have an incoming test or examination of the rubber latex material and have never conducted any testing of the raw material. In addition, Ms. (b)(6) told our investigator that she conducts a stretch test on the orthodontic elastic bands. She stated that the bands are supposed to stretch three times their original size; however, she was unable to provide a written procedure or explain the rational for the specification. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Five (5) – Failure to establish and maintain procedures for implementing corrective and preventive action, as required by 21 CFR 820.100. For example: Your General Manager was unable to provide a copy of a corrective & preventive action written procedure. Mr. Nichols told our investigator that he thought a former employee had created a procedure but he was unable to provide a copy. Mr. Nichols has been employed by your firm for ten years and has occupied his current position for the past nine years. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Six (6) – Failure to maintain complaint files and establish procedures for receiving, reviewing, and evaluating complaints by a formally designated unit, as required by 21 CFR 820.198(a). For example: Your General Manager was unable to provide a written procedure for receiving, reviewing, or evaluating complaints. According to Ms. (b)(6), she is the person that would receive complaints, and she does not follow any written procedure. She makes an undocumented determination of which complaints require escalation. Any follow up or investigation that may occur is not documented and does not follow any written procedure. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Seven (7) – Failure to establish procedures for identifying training needs and ensuring that all personnel are trained to adequately perform their assigned responsibilities, as required by 21 CFR 820.25(b). For example: Your General Manager stated that you do not have training records or written procedures for identifying each employee’s training needs; your General Manager stated that you have no training records for the employees manufacturing the Mark 20x chairs, or the elastic bands; employee responsible for elastic band production was unable to answer questions about elastic band production. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Eight (8) – Failure to establish procedures for conducting management reviews that assess the suitability and effectiveness of the quality system at defined intervals and with sufficient frequency to ensure that the quality system satisfies the requirements of 21 CFR 820, as required by 21 CFR 820.20(c). For example: Your General Manager stated that you do not have written procedures in place to conduct management reviews and was unclear of what is required to be covered during management reviews. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Nine (9) – Failure to conduct quality audits and establish procedures for conducting quality audits, as required by 21 CFR 820.22. For example: Your General Manager stated that you do not have written audit procedures and was unable to provide documentation of any audits that may have been performed. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Ten (10) – Failure to establish and maintain procedures to adequately control environmental conditions that could reasonably be expected to have an adverse effect on product quality, as required by 21 CFR 820.70(c). For example: Printed circuit boards with sensitive electronic components are used in the production of the electronically controlled chairs, but your General Manager stated that you have no procedures for controlling or maintaining the electrostatic discharge area. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Eleven (11) – Failure to establish and maintain procedures to control product that does not conform to specified requirements, as required by 21 CFR 820.90(a). For example: Your General Manager stated that you do not document the non-conformance of in-process components, or finished products, any evaluations that may be conducted, re-work that may occur, or their disposition. Your General Manager confirmed that there are no written procedures for handling non-conforming components or finished products. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Twelve (12) – Failure to establish and maintain procedures to control all documents that are required by 21 CFR 820, as required by 21 CFR 820.40. For example: Your General Manager was unable to provide a written document control procedure. In addition, you have two documents titled, Q.A. Ortho/Exam Assembly Inspection Checklist, for use in the assembly of all Mark series chairs. The two documents lack revision dates, document numbers or other identifiers to distinguish one from the other. The adequacy of your firm’s response cannot be determined at this time. You did not include documentation of any corrections and only promise to make corrections by March 31, 2014.

Thirteen (13) – Failure to establish and maintain procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained, as required by 21 CFR 820.72(a). For example: Your General Manager was unable to provide calibration procedures for the scales, calibration weights, or grip hook weights. In addition, you failed to calibrate the (b)(4) Sealer (P/N: 470000A15) used in the packaging of elastic bands, and the grip hook weights used in the quality control testing of elastic bands have not been calibrated since February 2002.

Compliance for Dummies

Instead of focusing on one individual element requiring correction, the doctor is going to provide the readers with some fatherly advices, a.k.a.Devine Guidance. The doctor always recommends creating a QMS Matrix that maps regulatory and statutory requirements to your QMS. It is a great way to identify gaps so procedures can be scripted to close the gaps. However, if an organization has established procedures and chooses to ignore them, well that is a different organizational problem. Can you say training issues, management oversight issues, or QMS construction issues?

For example, Dr. D often sees canned QMS’s, implemented by consultants that:

• Have not been properly tailored to the medical device establishments device requirements;
• Have not been properly tailored to fit the organizations size (e.g., limited personnel resources);
• Have not been properly implemented, including training; and/or
• Are missing major chunks of compliance requirements delineated within 21 CFR, Parts 801, 803, 806, 807, 820, etc.

Additionally, the doctor strongly recommends that at least once each year, device establishments review all of the QMS-related SOPs to ensure the procedures are still compliant with statutory and regulatory requirements, including currently being appropriate for the organization. Forms should be included in this review. Even better, all procedures should be assessed at least annually to ensure they are effective and result in the organization achieving the desired outputs. For example, work instructions employed in medical device manufacturing should be reviewed from time-to-time to ensure they are still effective and capable of producing finished medical devices that are safe and effective in their intended use.

Furthermore, enough emphasis cannot be placed on training. It is imperative that each and every member of an organization, including contractors and consultants, be adequately trained. For example, if a contractor is performing bio-testing assessments in your cleanroom, the contractor should be trained to your gowning and cleanroom etiquette procedure(s). If a contractor is performing internal audits, the contractor should be trained to your internal quality audit procedure. Ensure all training is documented. Why? Because if an event or activity is not documented in writing; in the eyes of FDA, the event or activity did not happen.

Takeaways

For this week’s guidance the doctor will leave the readers with just one takeaway. We are talking about manufacturing medical devices folks and not plastic toys. In the United States, to manufacture and/or enter devices into commerce, device establishments are expected to have written procedures that are fully implemented and in compliance with the QSR and subsidiary regulations. Please do not be that organization that receives thirteen Form 483 observations because procedures have not been established. Create a matrix for mapping the QMS to statutory and regulatory requirements and use the matrix to quickly identify and close gaps.

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. (2013, April) 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. FDA’s enforcement page. (2014, July). FDA.gov Website. Retrieved July 8, 2014, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2014/ucm403055.htm