According to Margaret A. Hamburg, M.D. (Commissioner, FDA), in a comment made during the August 6, 2009 FDLI Conference, “FDA’s enforcement arm is back in business.” In short, violations of the Act are going to result in a strong enforcement response from the agency. FDA issues warning letters when (a) Form 483 responses are seriously deficient; (b) an organization has failed to respond to a Form 483; or (c) violations of the Act are so egregious, that FDA has decided to move rapidly to warning letter.
In fact, the warning letter signifies the beginning of some serious regulatory hurt being unleashed by FDA. Dr. D likes to call this FDA Purgatory, where an immediate impact to their business is quickly realized. The agency is no longer obliged to review and approve new product submissions. Additionally, letters needed by foreign governments for product exportation, a.k.a., FDA Export Certificates are no longer reviewed, approved, and signed. For medical device manufacturers, these certificates are formally known as: (a) Certificate to Foreign Government; and (b) Certificate of Exportability. The impact to an organization’s bottom line can be severe, as these certificates begin to expire.
If the responses formulated and sent to the agency lack depth and detail, and FDA believes the responses are inadequate or ineffective, the time spent in the proverbial “land of lost opportunities” can be years. Dr. D strongly recommends the pulling out of all stops so organizations can quickly extricate themselves from FDA Purgatory.
What is a Warning Letter?
Just because an organization receives a Form 483, it does not necessarily translate into a warning letter. Upon conclusion of an inspection, the FDA investigator is tasked with writing the Establishment Inspection Report (EIR), which will be reviewed at the local district office. If the reviewer believes the content and evidence depicted in the EIR points to serious deficiencies in an establishment’s quality system, then a warning letter will be issued.
Additionally, as of April of 2009, the agency has adopted a policy of automatically issuing warning letters to establishments failing to respond to a Form 483 within the allotted 15-days. There will be no susurrous (look-it-up) opening phrases in the initial paragraph of the warning letter; in fact, the opening paragraph will typically commence with, “During an inspection of your firm” and end with “Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken.”
According to FDA, the issuance of a warning letter is one of the tools in their FDA enforcement bag. The primary purpose of the warning letter is to attempt to extract a voluntary correction of objectionable conditions by the agency; it is not the final regulatory action available to the agency. In fact, Dr. D’s position is the warning letter is the proverbial warning shot, but it can result in significant interruptions in the day-to-day activities of the recipients.
What happens after a Warning Letter is received?
The good news is that the US Marshalls have not shown up at your establishment’s doorstep to chain and padlock the doors. The even better news is that a warning letter, although painful, is a recoverable event and can make an organization stronger.
Dr. D strongly recommends that if the organization does not have the expertise to respond to the warning letter or does not retain legal counsel that understands the entire process, this expertise be acquired immediately. Many consultant firms specialize in assisting establishments extract themselves from FDA Purgatory.
One thing organizations must remember is that the warning letter is not an overnight fix. These typically result in a protracted period where corrections to the objectionable conditions are achieved. The more observations depicted in the warning letter, the longer the stay in FDA Purgatory. In penning Devine Guidance (DG) week after week, the doctor has reviewed hundreds of warning letters awarded to device manufacturers. In one case, an offender received a warning letter with 19 observations (reference next section). Dr. D will probably retire before this establishment finds itself back in the good graces of the agency.
Sample Warning Letter
On multiple occasions throughout 2010, the doctor has made multiple references back to a device manufacturer that was on the receiving end of a 19-observation warning letter. For those readers of DG that have never had a chance to truly appreciate the power of the agency and their resolve to enforce compliance with the Act, this is an excellent example of a warning letter. Obviously, the device manufacturer was not happy with their award; however, compliance to the QSR is only a small piece of the price of admission into the medical device industry. One final note: Dr. D has taken the liberty to redact the organization’s name and the name of their CEO.
Dr. Redacted CEO and Chairman
Dear Dr. Redacted:
During an inspection of your firm located in Towson, Maryland on September 28, 2009, through November 6, 2009, an investigator from the United States Food and Drug Administration (FDA) determined that your firm manufactures electrogastrogram (EGG) devices. 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.
This inspection revealed that these devices are adulterated within the meaning of section 501(h) 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 (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (C.F.R.), Part 820. These violations include, but are not limited to, the following:
1. Failure to establish and maintain adequate procedures to ensure that the design requirements relating to a device are appropriate and address the intended use of the device, including the needs of the user and patient, as required by 21 CFR 820.30(c). For example procedures for Version (b)(4) EGG machine in (b)(4) or for the upgrade made to the Research Version device in (b)(4) which included a new Research Waterload Version and a Waterload Version.
2. Failure to establish and maintain adequate procedures for defining and documenting design output in terms that allow an adequate evaluation of conformance to design input requirements, as required by 21 CFR 820.30(d). For example:
3. Failure to establish and maintain adequate procedures to ensure that formal documented reviews of the design results are planned and conducted at appropriate stages of the device’s design development, as required by 21 CFR 820.30(e). For example, procedures were not established to ensure formal documented reviews of the design during the design planning process.
4. Failure to establish and maintain adequate procedures for verifying the device design and documenting the results of the design verification, including identification of the design, method(s), the date, and the individual(s) performing the verification, as required by 21 CFR820.30(t). For example:
5. Failure to establish and maintain adequate procedures for validating the device design, as required by 21 CFR 820.30(g). For example:
6. Failure to establish and maintain procedures for the identification, documentation, validation or where appropriate verification, review, and approval of design changes before their implementation, as required by 21 CFR 820.30(i). For example:
7. Failure to document all activities required under 21 CFR 820.100, Corrective and Preventive 21 CFR 820.100(b). For example:
8. Failure to establish and maintain procedures that address the identification, documentation, evaluation, segregation, and disposition of nonconforming product, as required by 21 CFR 820.90(a). For example, there is no defined method of identifying, documenting and evaluating nonconforming product and any investigation associated with the nonconforming product. Specifically, email correspondence between the dates of June 29 and July 6, 2009, indicate the need to correct a problem with the data entry field on the waterload software version; however, no further documentation is available addressing this issue.
9. Failure to validate computer software for its intended use according to an established protocol when computers or automated data processing systems are used as part of production or the quality system, as required by 21 CFR 820.70(i). For example, when requested no validation documentation to support the commercial off-the-shelf program (b)(4) used to capture complaints, returned merchandise and service requests was provided.
10. Failure to establish and maintain adequate acceptance procedures, where appropriate, to ensure that specified requirements for in-process product and finished device acceptance are met as required by 21 CFR 820.80(c) and (d). Finished device acceptance includes ensuring that each product, run, lot, or batch of finished devices meets acceptance criteria. For example, electrogastrograrn machine components and finished product acceptance and/or rejection criteria have not been established.
11. Failure to establish and maintain procedures for identifying product during all stages of receipt, production, distribution, and installation to prevent mixups, as required by 21 CFR 820.60. For example, there is no procedure or mechanism for identifying individual equipment components, software, or finished device. Specifically, there are three versions of the EGGSAS software all identified as Version (b)(4): (1) a waterload version; (2) a research – waterload version; and (3) a research version.
12. Failure to establish and maintain procedures for control and distribution of finished devices to ensure that only those devices approved for release are distributed and to maintain distribution records which include or refer to the location of (1) the name and address of the initial consignee; (2) the identification and quantity of devices shipped; (3) the date shipped; and (4) any control number(s) used, as required by 21 CFR 820.160. For example, when requested, procedures for controlling and distributing finished devices and distribution records for products released into distribution for 2008 and 2009 were not provided.
13. Failure to establish and maintain device master records (DMR’s), as required by 21 CFR 820.181. For example, when requested, no DMR for the EGGSAS software used in the three Redacted Med Devices Electrogastrogram versions: Research, Research Waterload, and Waterload was provided.
14. Failure to maintain adequate device master records that include, or refer to the location of, device specifications including appropriate drawings, composition, formulation, component specifications, and software specifications, as required by 21 CFR 820.181(a). For example, when requested, the software specifications for the software update that occurred in (b)(4) or the software updates that occurred between (b)(4) could not be located.
15. Failure to establish and maintain procedures to ensure that device history records (DHR) for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the device master record and the requirements of 21 CFR Part 820, as required by 21 CFR 810.184. For example:
16. Failure to establish and maintain procedures to control all documents that are required by 21 CFR Part 820, as required by 21 CFR 820.40. The procedures should designate an individual(s) to review for adequacy and approve prior to issuance all documents established to meet the requirements of 21 CFR Part 820. For example:
17. Failure of management with executive responsibility to review the suitability and effectiveness of the quality system at defined intervals and with sufficient frequency according to established of 21 CFR Part 820 and the manufacturer’s established quality policy and objectives, as required by 21 CFR 820.20(c). For example, when requested no documentation to support management reviews are conducted was provided.
18. Failure to establish procedures for quality audits and conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system, as required by 21 CFR 820.22. For example, when requested, procedures for quality audits were not provided. Quality audits have not been conducted since 2003.
19. Failure to establish procedures for identifying training needs and ensure that all personnel are trained to adequately perform their assigned responsibilities, as required by 21 CFR 820.25(b). For example, when requested, documentation that training was performed according to the design plan for the upgraded device from Version (b)(4) to Version (b)(4) could not be located. A troubleshooting chart was scheduled to be created; however, it could not be located; and training materials and a training class were to be provided/conducted on Customer Service and Sales/Marketing according to the Design Plan; however, the training materials or documentation that the training was conducted could not be located.
Our inspection also revealed that your electrogastrogram devices are 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 C.F.R. Part 803 Medical Device Reporting (MDR) regulation. Significant deviations include, but are not limited to, the following: Failure or refusal 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 803 – Medical Device Reporting (MDR) regulation. For example, when requested procedures for MDR reportable events were not provided.
You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the Quality System regulation deviations are reasonably related will not be approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.
Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.
Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Inspectional Observations, Form FDA 483 (FDA 483), issued at the closeout of the inspection may be symptomatic of serious problems in your firm’s manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.
Please send your reply to the U.S. Food and Drug Administration, Attention: Anne Aberdeen, Compliance Officer, 6000 Metro Drive, Suite 101, Baltimore, MD 21215. If you have questions regarding any issues in this letter, please contact Ms. Aberdeen at (410) 779-5134.
How to respond to a Warning Letter
Similar to a Form 483, upon receiving a warning letter, an organization has 15 working days to respond. The doctor strongly recommends that legal council review all correspondence with the agency. Once again, the recipient of the warning letter should draft a cover letter with all correspondences back to the agency. Meticulous records of each submission should be kept.
In responding to the warning letter, the doctor recommends the following information should be considered in the response:
- A restatement of the Form 483 Observation;
- The proposed corrective action or plan (ensure past, current, and future states influenced by the observation are assessed);
- Reference to the specific CAPA number;
- Ensure root cause is determined and addressed;
- Potential impact to product;
- Potential impact to the quality system; and
- The targeted date for completion.
What Not to Do
Dr. D shares a few watch-outs with the readers:
- Never, never, never, never complain that FDA has singled out your company and is intentionally picking on you. The argument will never fly.
- Never fail to respond to the agency, within the 15 days allotted or committed dates made by your organization as part of the correction activities.
- Do not pursue the Utah Medical approach, arguing the law. Why? FDA is the keeper of the law, so most arguments are futile.
- Remember, the agency will verify objectionable conditions have been closed prior to lifting the warning letter, so ensure all correction activities are closed prior to scheduling a follow-up visit by the agency.
- Always provide the agency with sufficient detail and supporting documentation that reflects the actions pursued in support of the corrections.
- If the corrections are going to take a significant amount of time, give FDA reasonable timetable for correcting all objectionable conditions. Ensure that status updates are routinely provided to the agency.
- Never downplay or minimize the seriousness of the observation. Remember, FDA would not have issued the warning letter if they did not believe the enforcement action was warranted.
Takeaway: Warning Letters are life-changing events
Yes, warning letters are life-changing events for device manufacturers; however, they are recoverable. Dr. D recommends getting legal counsel and industry experts involved when responding to a warning letter, reviewing subsequent correspondences to the agency, and taking actual steps to correct the objectionable conditions. Remember, FDA is not picking on you but they have a responsibility to protect public health. It is the agency’s position that the objectionable conditions delineated within each waning letter could have an adverse effect on public health.
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, when Dr. D will provide some guidance and insight into consent decree (the next level of FDA pain) – cheers from Dr. D. and best wishes for continued professional success.
Code of Federal Regulation. (2010, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U. S. Government Printing Office.
Cooper, R. & Fleder, J. (2005). Responding to a form 483 or warning letter: A practical guide. Food and Drug Law Journal, 60(4).
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Devine. C. (2009, July). Exploring the effectiveness of defensive-receiving inspection for medical device manufacturers: a mixed method study. Published doctoral dissertation. Northcentral University. Prescott Valley, AZ.
Garvey, J. (2010, January). FDA form 483 & warning letter response & planning. Compliance Architects Website. Retrieved December 8, 2010, from http://www.compliancearchitects.com
Godshalk, J. (2009). Best practices: Responding to FDA form 483. Retrieved November, 27, 2010, from http://fdanews.com/ext/conference
Lookabaugh, M. (2006, May). Responding to FDA 483s and warning letters – dpresentation to Parenteral Drug Association. Parexel Consulting. Lowell, MA.
Taylor, N. (2009, February). Ignore a form 483? Not wise say FDA. Retrieved November 27, 2010, from http://www.in-pharmatechnologist.com