What Every Foreign Medical Device Manufacturer and Importer Should Know
A review of medical device warning letters issued to foreign manufacturers by the FDA, 1997-2007, Part II
Carolyne Hathaway, John R. Manthei and Seth Mailhot, Latham & Watkins LLP
The manufacture of medical devices has become increasingly global as U.S. medical device companies contract with non-U.S. companies for their manufacturing operations and foreign device companies seek to penetrate the U.S. market. The foreign manufacture of medical devices for import into the United States presents regulatory challenges that are different than those confronted by U.S. device manufacturers.
This article continues the examination of warning letters to medical device companies between 1997 and 2007. The goal of this series, which began in the July/August issue of MPO, is to explore the qualitative and quantitative differences between warning letters issued to U.S. and foreign device companies. In particular, this review reveals that:
• More than 40 percent of warning letters issued to foreign medical device manufacturers include notice of detention without physical examination, otherwise known as automatic detention.
• A slightly greater percentage of inspections of foreign device manufacturers result in warning letters compared to inspections of U.S. medical device manufacturers.
• The rate of warning letters per inspection varies by country, with higher- than-average rates found in two English- speaking countries (Canada and the Unit-ed Kingdom).
• The types of quality system regulation (21 C.F.R. Part 820) citations identified in warning letters issued to foreign manufacturers differ in significant respects from those cited in warning letters issued to U.S. manufacturers.
• The quality system regulation (QSR) citations in warning letters issued to manufacturers in English-speaking countries differ from those given to manufacturers in non-English-speaking countries, suggesting differences in the way that the U.S. Food and Drug Administration (FDA) conducts foreign medical device inspections between English and non-English speaking countries.
• The corrective and preventive action, or CAPA (21 C.F.R. 820.100), and design control (21 C.F.R. 820.30) citations in warning letters issued to foreign countries suggest a focus on specific corrective and preventive actions and design changes, instead of a top-down review of each system.
• It takes significantly longer for the FDA to issue warning letters to foreign manufacturers than to U.S. manufacturers.
This series examines these differences and their implications for foreign device manufacturers.1 This information highlights the significant consequences of a warning letter for foreign device manufacturers. A warning letter, particularly one combined with notice of automatic detention, can effectively shut a foreign manufacturer out of the U.S. market until the issues identified in the warning letter are resolved. This resolution can take years if the FDA requires a follow-up inspection. This final part of the series includes suggestions on how to prepare for an FDA inspection and provides guidance on responding to inspectional observations in order to minimize these risks.
This series examines information from publicly available warning letters posted on “FDA’s Electronic Freedom of Information Reading Room—Warning Letters and Responses.”2 Particular focus is given to FDA warning letters involving foreign medical device manufacturers over a 10-year period (1997 to 2007).
The methodology used to generate the data presented in this series is only intended to identify general trends, and is not capable of measuring the regulatory compliance of any country or identifying any non-public FDA inspectional guidance. As noted throughout this series, there are significant gaps in the data used to compile the tables provided. For example, there is disagreement in the press as to the total number of medical device warning letters issued by FDA.3
This series reviews these warning letters on two levels. The first part examined the rates at which warning letters were issued in certain foreign countries as compared to the rate at which warning letters were issued to manufacturers in the United States. This second part examines the most frequent citations in warning letters issued to domestic and foreign manufacturers, the average time between the close of an inspection and the issuance of a warning letter and some common problems encountered by foreign manufacturers when responding to inspectional observations.
Particular focus is given to the years 2002 through 2007. This reflects the period during which FDA’s Office of Chief Counsel began a program to review all warning letters and untitled letters for legal sufficiency and consistency with FDA policy in March 2002.4Furthermore, this data begins about three years after implementation of FDA’s quality system inspection technique and five years after implementation of FDA’s quality system regulation (21 C.F.R. Part 820), which represented a paradigm shift in the way that FDA conducted inspections of medical device manufacturers.
Basis for Warning Letters Issued to Foreign OEMs
Nearly all of the warning letters issued as the result of an FDA inspection of a foreign medical device manufacturer include citations to 21 C.F.R. Part 820. Of these, nearly 70 percent include a citation to
the CAPA regulation (21 C.F.R. 820.100), and more than 55 percent cite the design control regulation (21 C.F.R. 820.30.) The frequency of citations to the CAPA and design control regulations suggests that FDA uses a bottom-up inspectional approach that focuses on specific quality problems.
Comparing quality system regulations cited between English-speaking and non-English-speaking countries suggests that certain issues are associated with manufacturers in non-English-speaking countries possibly because FDA investigators may modify their inspectional technique due to their unfamiliarity with the native language.
Most of the warning letters resulting from inspections of foreign manufacturers included observations under 21 C.F.R. Part 820. Only nine out of 239 warning letters since 1997 did not cite a violation under Part 820. Among those, six cited the lack of a premarket approval (PMA) or premarket notification under Section 510(k) of the FDCA; two involved violations of 21 C.F.R. Part 803, medical device reporting (Part 803) and 21 C.F.R. Part 806, medical devices reports of corrections and removals (Part 806); and one involved failing test results in device samples collected during a foreign inspection.
The quality system regulation at Part 820 plays a central role in FDA’s inspections of device manufacturers (including foreign manufacturers). We, therefore, reviewed the warning letters to determine which sections of Part 820 were cited most frequently. FDA’s quality system Inspection Technique focuses on four main subsections of Part 820: CAPA; design controls; production and process controls; and management controls. During a foreign inspection, FDA generally tries to cover all four of these subsystems, but almost always assigns CAPA as the highest priority and management controls as the lowest priority.5 The regulatory citations to the QSR components are summarized in Table 2.
As seen in Table 3, most warning letters issued to foreign manufacturers between 2002 and 2007 cite violations of FDA’s CAPA requirements (21 C.F.R. 820.100). Year to year, CAPA issues consistently appear most frequently in foreign warning letters, as they generally do in warning letters for all medical device manufacturers.6
Table 4 identifies the specific CAPA subsection cited in the warning letters issued to foreign device manufacturers from 2002 to 2007. These data indicate that the most common problems that FDA
identified relate to the processes of analyzing quality data to identify quality problems [21 C.F.R. 820.100(a)(1)], investigating the cause of the quality problem [21 C.F.R. 820.100(a)(2)], identifying the appropriate corrective or preventive actions [21 C.F.R. 820.100(a)(3)], and verifying or validating the corrective or preventive actions [21 C.F.R. 820.100(a)(4)]. This suggests that the CAPA violations reflect specific examples of corrective and preventive actions reviewed during the inspection. Less common are CAPA violations associated with documentation, such as the failure to establish and maintain CAPA procedures [21 C.F.R. 820.100(a)], document corrective and preventive actions [21 C.F.R.820.100(b)] and implement and record changes in methods and procedures and communicate those changes to the responsible personnel [21 C.F.R. 820.100(a)(5) and (6)]. This suggests that, in preparing for an FDA inspection, foreign manufacturers and auditors should consider focusing on recent critical corrective and preventive actions, instead of relying on a top down review of the CAPA system as would be done in an ISO-style audit.
One notable difference from warning letters issued to U.S. manufacturers is that design control violations (21 C.F.R. 820.30) are the second most frequent category cited for foreign manufacturers,
never falling lower than third place in any given year. While design control violations are usually among the five most common violations for all device manufacturers (and even ranked first in 2007), they more consistently rank high for foreign manufacturers.7 Table 5 identifies the specific design control subsection cited in the warning letters issued to foreign device manufacturers from 2002 to 2007.
Table 5 indicates that, by an overwhelming margin, the most common design control citation relates to design changes [21 C.F.R. 820.30(i)]. This is not surprising as design changes occur more frequently than new device design projects, and may reflect the inspectors’ focus on specific design changes. Thus, manufacturers should ensure that their procedures are sufficient to ensure compliance with the regulations covering changes to device design, and that any recent design changes have been appropriately documented, verified and/or validated, and approved.
The next most common design control citations are design validation [21 C.F.R. 820.30(g)], design review [21 C.F.R. 820.30(e)] and design verification [21 C.F.R. 820.30(f)]. When these design control violations extend beyond simple issues of documentation, they can be very difficult
to address. In some cases, these citations suggest the presence of a critical deficiency in the device design. In these cases, correction can require much more than modifying the underlying design control procedures. In the most extreme situations, it may be necessary to recall an entire device model or series of models.
Effect of Native Language on Warning Letter Observation
Reviewing warning letter citations based on whether or not the manufacturer is located in an English-speaking country reveals some interesting results. As noted in the previous article, two English-speaking countries (Canada and the United Kingdom) had higher than average rates of warning letters. Differences between English-speaking and non-English-speaking countries also extend into the types of violations noted on the warning letters issued by FDA.
Table 6 shows the rate of citations for acceptance activities (21 C.F.R. 820.80 and 820.86) differed most significantly between warning letters issued to manufacturers in English and non-English-speaking foreign countries. Most of these citations related either to receiving acceptance activities [21 C.F.R. 820.80(b)] or final acceptance activities [21 C.F.R. 820.80(d)]. This may reflect a tendency of FDA investigators to focus on the more uniform and data-rich documents during QSR inspections of non-English-speaking manufacturers. Foreign language documentation of incoming raw material and finished device test results are easier to understand than more qualitative or abstract records. If inspectors are focusing more intently on those documents, they will be more likely to identify deficiencies in those activities.
Paradoxically, the language barrier also may account for the relatively lower citation rate for nonconforming product (21 C.F.R. 820.90) among warning letters issued to manufacturers in non-
English speaking countries. FDA instructs its investigators to perform a “walk-through,” or tour, of a manufacturing facility at the beginning of the inspection.8Issues related to the segregation of nonconforming incoming materials and finished product are commonly documented during the walk-through of the warehouse and production areas rather than during a review of procedures and documentation. FDA investigators may find it difficult to conduct a walk-through in a facility where they do not speak the language and communication is difficult. In these cases, they may focus on document review and be less likely to identify problems with segregation.
Foreign manufacturers located in non-English-speaking countries also may be less likely than manufacturers located in English-speaking countries to handle complaints originating in the United States, due to the unavailability of staff capable of processing and reporting English language complaints. In such cases, complaint handling functions may be performed by a U.S. office or the distributor. As a result, non-English-speaking manufacturers may be less likely to be cited for violations of the Complaint Handling regulation (21 C.F.R. 820.198). The higher rate of document and record control citations (21 C.F.R. 820.40, 820.180, 820.181, 820.184, and 820.186) for non-English-speaking manufacturers, however, may stem from problems interpreting the FDA’s regulations and communicating the meaning of certain records and procedures to FDA investigators during an inspection.
Timing and Responding to a Form FDA-483, Warning Letter
FDA will typically issue a Form FDA-483, Notice of Inspectional Observations, at the close of its inspection of a medical device company. FDA directs its investigators to fax the form and a summary of findings to the Division of Field Investigations before completing an establishment inspection report
when a foreign inspection shows significant, system-wide quality system deviations.9Companies then have the opportunity to respond to the observations presented in the Form FDA-483. FDA takes this information into account in deciding whether or not to issue a warning letter.
The data on medical device inspections from 2002 to 2007 indicate that, overall, FDA took a minimum of 53 days to issue a warning letter following the close of the inspection and an overall average of 143 days (or approximately 4.8 months). Table 7 and Chart 1, summarize the data on the length of time between the close of the inspection and the issuance of a warning letter.
As noted in the first part of this article, between 2002 and 2007, approximately 6.5 percent of foreign inspections resulted in warning letters. On average, these warning letters were issued 143 days (approximately 4.8 months) after the close of the inspection. Approximately three-quarters of foreign warning letters (73 percent in 2006 and 81 percent in 2007) were issued four months or more following the close of the inspection. In contrast, only 34 percent of all device warning letters and 28 percent of U.S. warning letters in 2006, and 48 percent of all device warning letters and 40 percent of U.S. warning letters in 2007 were issued four months or later following the close of the inspection.10
Thus, foreign manufacturers should not be surprised if a warning letter is issued after several months have passed without word from FDA.
Of the 238 warning letters recorded in the database, FDA discussed the responses it had received to the Form FDA-483 in 150 of those warning letters. Nine of those 150 responses were determined to be adequate in addressing the issues identified. In the cases where responses were provided but determined to be inadequate, FDA took, on average, 12 more days to issue the warning letter.
Among the more common reasons for determining that a response, following a foreign inspection, to be inadequate was the failure to completely translate the response into English. FDA noted this problem in 12.7 percent of the warning letters for which a manufacturer had submitted a response. Even where a foreign-language document is accompanied by a general description of the contents in English, FDA will accept the document for review only if it is accompanied by a full translation.
Responses should also include ample documentation to establish that the correction has been made, including photographs or other visual representations that would assist in demonstrating the correction.11While it may be difficult for foreign companies with limited experience with FDA inspections to determine the significance of particular observations and the adequacy of proposed corrective actions, a response, even if incomplete, can be useful to open the dialogue with FDA on how to correct the particular observations in order to mitigate potential FDA enforcement.
The data provided in this series demonstrate real differences between foreign inspections and domestic inspections, as revealed through the warning letters issued to U.S. and foreign
manufacturers. These differences include the rate at which the FDA issues warning letters following an inspection, the number of days between the close of the inspection and the issuance of the warning letter, and the citations noted in the warning letters themselves. Companies should consider these differences in their pre-inspection preparations and in their responses to Form FDA-483s and warning letters.
Based on these findings, foreign device manufacturers facing an FDA inspection should consider the following steps:
• Take advantage of the extended pre-inspection notice period to prepare for an FDA inspection. The FDA typically notifies foreign manufacturers of an upcoming inspection approximately a month before
the inspection is scheduled to start. This compares to a week’s notice typically received by U.S. companies. Foreign manufacturers should take full advantage of this pre-inspection period to audit its facility, correct potential areas of noncompliance and obtain translators, diagrams, translations and other logistical support to facilitate the inspector’s understanding of the company’s products, processes and procedures.
• Prior to the inspection, conduct a “bottom-up”-style audit with emphasis on areas covered by FDA during foreign device inspections. FDA’s quality system inspection technique describes a top-down approach to conducting medical device quality system inspections.12 Nonetheless, anecdotal evidence and the CAPA and design control citations common in warning letters issued to foreign manufacturers suggest that FDA investigators frequently apply a bottom-up approach. Thus, in preparing for an FDA inspection, the auditor should include a bottom-up approach focusing on the CAPA and design control subsystems. Auditors should pay particular attention to significant corrective or preventive actions and recent design changes or design projects completed since the last inspection, or in the last few years for manufacturers that have never been inspected.
• Following the pre-inspection audit, focus on issues routinely cited by FDA in warning letters to foreign manufacturers. Following the pre-inspection audit, manufacturers should address any issues identified as significant by the audit team, with a particular focus on CAPA issues associated with quality data analysis, investigating cause and identifying appropriate actions and verification and validation of actions. Manufacturers also should address any design control issues associated with design changes, design validation and verification and design review activities. Manufacturers located in non-English- speaking countries should pay particular attention to incoming raw material and finished device testing activities, and manufacturers who handle U.S. complaints should spend time correcting any identified issues.
• Make arrangements to have an interpreter available during the inspection, and familiarize the interpreter with FDA-regulatory terminology and the manufacturer’s quality system. A disproportionate number of warning letters issued to manufacturers in non-English-speaking countries cite observations related to document and record controls. These companies should engage experienced, English-speaking translators and spend time preparing them for the upcoming inspection by familiarizing them with FDA regulatory terminology and the manufacturer’s document and record control systems. Where appropriate, companies should consider preparing English translations of key regulatory documents and procedures, such as the quality manual and the CAPA procedure.
• Address any deficiencies noted during the inspection as soon as practicable, and prepare a timely response to the Form FDA-483. Manufacturers should correct as many observations as possible before the end of the inspection to ensure that those corrections are noted in the FDA investigator’s report. Where observations will require more time to correct, the manufacturer should provide FDA with a well-documented, detailed response describing the proposed corrective actions and a timeline for the completion of those actions. Companies should endeavor to submit its proposed corrective action plan within five days of the completion of the inspection.
• Follow-up the initial response with documentation of completed action items, thoroughly translating any attachments submitted in a foreign language. FDA takes, on average, 143 days to issue a warning letter following an FDA inspection. Submission of a corrective action plan to address observations noted in a Form FDA-483 should be followed up with periodic updates on the progress of the corrective actions until completed. These updates should be provided on a monthly or bi-monthly basis, and should include photographs, data or other evidence documenting the correction. When documenting the completion of any corrective action, all documents and procedures should be translated into English. Manufacturers should not take the passage of several months without communication with FDA to mean that the Form FDA-483 observations do not warrant, or that the manufacturer’s responses mitigate a warning letter.
• Following completion of corrective actions, request a copy of FDA’s Establishment Inspection Report. Once all observations listed in the Form FDA-483 have been corrected, and information on those corrections have been provided to FDA, the manufacturer should request a copy of the FDA investigator’s report. This report, called an “Establishment Inspection Report,” or “EIR,” is provided to manufacturers when the FDA determines the inspection to be “closed.”13 An inspection is determined to be closed when a final decision has been made by FDA to not take an administrative or judicial action or when such an action has been taken and the matter has been concluded.14 Generally, a request for a copy of the EIR should be made six months after the close of the inspection.
1. Carolyne Hathaway, John Manthei and Seth Mailhot, “What You Don’t Know Can Hurt You: Understanding the FDA’s Foreign Inspection Program,” Medical Devices Litigation Reporter, Feb. 4, 2008.
2. Available at www.fda.gov/foi/warning. htm. As of the date of this series, 2008 figures could not be compiled.
3. Compare Sven Pommeranz, “Medical Devices Warning Letters Report 2008 – CAPA 1st,” European Compliance Academy (Feb. 25, 2009), available at www.gmp-compliance.org/ eca_news_01363.html with F-D-C Reports, Inc., “Changes May Be In Store For FDA’s Quality System Inspection Technique,” The Silver Sheet 8 (March 2008) (reporting different totals for the number of medical device warning letters issued per year).For the purposes of this series, calculations were based on the total number of medical device warning letters reported by the European Compliance Academy.The numbers reported by the European Compliance Academy generally were greater than those reported in The Silver Sheet.
4. FDA, Regulatory Procedures Manual, Exhibit 4-1, “Procedures for Clearing FDA Warning Letters and Untitled Letters,” Jul. 2008 (available at www.fda.gov/ora/compliance_ ref/rpm/exhibits/Exhibit_4-1.pdf).
5. This priority does not reflect the order in which FDA will cover these subsections. The quality system inspection technique was validated in the sequence: management controls, design controls, CAPA, and production and process controls. FDA, “Inspection of Medical Device Manufacturers,” Compliance Program 7382.845, Part III, p. 4 (Jun. 15, 2006).
6. Sven Pommeranz, “Medical Devices Warning Letters Report 2008—CAPA 1st,” European Compliance Academy (Feb. 25, 2009), available at www.gmp-compliance.org/ eca_ news_01363.html.
7. In fact for 2005, design control violations did not even appear in the top five most common QSR citations for all device manufacturers. Id.
8. FDA, “Inspection of Medical Device Manufacturers,” Compliance Program 7382. 845, Part III, p. 1 (Jun. 15, 2006).
9. FDA, Office of Regulatory Affairs, Field Management Directive No. 13A, Foreign Inspection Program (October 2002), available at http://www.fda.gov/ora/inspect_ref/fmd/fmd13a.htm (directing investigators to “[p]romptly notify [the Division of Field Investigations] via fax of any significant deficiencies which adversely affect the safety of products currently being shipped to the U.S. or where conditions warrant immediate center attention”).
10. F-D-C Reports, ]] Inc., “Changes May Be In Store For FDA’s Quality System Inspection Technique,” The Silver Sheet 8 (Mar. 2008).
11. FDA, Div. of Field Investigations, Guide to International Inspections and Travel, § 315.1 (November 2002), available at www. fda. gov/ ora/inspect_ref/giit/default.htm.
12. FDA, “Guide to Inspections of Quality Systems,” 7-8 (Aug. 1999), available at www. fda.gov/ora/inspect_ref/igs/qsit/QSITGUIDE. PDF.
13. FDA, “Procedure for Release of Establishment Inspection Report to the Inspected Establishment,” ORA Field Management Directive No. 145 (Feb. 21, 2001).
14. 21 C.F.R. 20.64(d)(3).