FDA’s device center is sending a record number of warning letters to foreign facilities as the agency continues its efforts to more effectively oversee product manufacturing located outside the U.S.

So far this year, CDRH has sent 22 quality system-related warning letters to non-U.S. facilities – an 83-percent increase over what it issued to manufacturers during the entire 12 months of 2010, a “Silver Sheet” analysis shows. (See chart.)

“The number of warning letters and the attention being paid to foreign manufacturing of devices and device components has increased, and that’s no accident. It’s the result of a number of factors,” CDRH Office of Compliance Director Steven Silverman said.

“We are committed to stronger and increasingly effective oversight of foreign device products,” FDA’s Silverman says.

“In recent years ORA has received additional resources that it has been able to successfully dedicate to growing its inspectional force,” he said. “As an outgrowth of that area of evolution, there have been additional ORA personnel available to conduct foreign inspections and to otherwise oversee products brought into the United States from abroad.”

ORA is FDA’s Office of Regulatory Affairs, the lead office for all of the agency’s field activities.

CDRH also upped the ante by using ORA’s new Foreign Device Inspection Cadre to conduct targeted non-U.S. facility inspections.

The cadre, composed of 10 senior FDA investigators, has performed roughly 200 inspections since it was formed a year ago. In fiscal year 2010 the cadre conducted 96 of 251 foreign good manufacturing practice (GMP) inspections.

The agency expects to perform around 286 foreign device GMP inspections in FY 2011. (See chart.)

The cadre’s inspections have resulted in 22 warning letters and eight untitled letters – some linked to quality, others related to pre-market and other issues.

“That’s roughly a 30-percent enforcement rate, which we think is telling. Those warning letters come through CDRH for review, and we are quite confident in the findings of the cadre members,” Silverman told “The Silver Sheet.”

“We view the cadre as a critical component to supplement – but not to replace – ORA’s overall device investigational capability,” he said. “This is a group that, based on its experience and seniority, is able to take on varied and sometimes complex inspections, and we believe the cadre is enhancing our overall impact.”

Further, FDA’s new foreign offices have made it easier for the agency to conduct facility inspections and gather critical information that otherwise would not have been available to the center, Silverman said.

The foreign posts are located in China, India, Latin America and Europe.

“The real takeaway from what you’re seeing is FDA’s overall approach to the regulation of foreign manufacturing,” Silverman said.

“We are committed to stronger and increasingly effective oversight of foreign device products, but we can’t get the job done through ORA’s current investigatory corps,” he said. “Even with the very important addition of this cadre of foreign investigators, there are far more foreign manufacturers than there are agency personnel. We recognize this.”

Chart shows the number of QS-related warning letters issued by FDA’s device center to overseas firms. CDRH sent more letters to foreign manufacturers during the first four months of 2011 than during each of the 12-month timeframes of 2006 through 2010.

Chart shows the number of QS-related warning letters issued by FDA’s device center to overseas firms. CDRH sent more letters to foreign manufacturers during the first four months of 2011 than during each of the 12-month timeframes of 2006 through 2010.

FDA is also using other strategies to gain company compliance.

“As much as we’ve been emphasizing inspections and warning letters, we simultaneously have been emphasizing strategies that rely on our use of and exchange of information, as well as collaboration, with foreign regulatory partners,” Silverman said.

“Our openness to single-audit inspections – which has been demonstrated through initiatives such as our ISO 13485 initiative and pMAP program – as well as our very blunt expectation that manufacturers that produce devices or key components of devices outside the United States take responsibility on their own to ensure the quality and integrity of those finished products and components” are also ways the center is working to ensure foreign facility compliance.

ISO 13485 is the international quality system standard for medical device manufacturing; its requirements for device manufacturers are similar – but not identical – to the Quality System Regulation.

Under the ISO 13485 audit report program, which could become operational as soon as Oct. 1, a company may put off an FDA inspection for a full year if it recently satisfied international quality system standards. (See News In Brief.)

Meanwhile, pMAP – the pilot Multipurpose Audit Program launched in 2006 – was shuttered in November due to low participation by manufacturers (“The Silver Sheet” November 2010).

The program allowed firms to be inspected by a third-party auditor for compliance with both Canadian and U.S. regulations in a single auditing visit. The agency is currently analyzing data it gained from pMAP to better construct future shared-inspectional programs with other countries.

Regarding the new emphasis on foreign manufacturing, Silverman said FDA will be monitoring “the impact of the uptick in foreign warning letters.”

He added, “I think we’ll need to gauge, as we continue on, what that overall impact is and whether or not we’ve achieved what we hope we’ll achieve, which is a higher rate of overall compliance and the corresponding improvement in public health protection.”

However, “we’re not going to rely on inspections and warning letters as a single vehicle to achieve compliance,” Silverman said. “It is one of a number of tools that we’re going to bring to bear, and we’re going to use those tools in a complementary manner to enhance overall compliance.”

CDRH Deputy Director for Science William Maisel said FDA is challenged by the globalization of product development more and more each day.

“The agency recognizes that and has established a strategy and a program for trying to assess that,” he said May 4 in a keynote address at the MedCon medical device conference in Cincinnati.

“The device community is no different,” Maisel said. “We certainly recognize the importance of monitoring products that are coming from foreign sites, and [the value of] inspecting foreign sites.

“We’ve developed a risk-based inspection model that allows us to better target and make better use of our available resources so we can obtain a higher yield on the inspections that we do perform, and it’s that type of effort [that allows FDA] to use the resources we have most efficiently,” he added.

Foreign Inspection Cadre A Success – So Far

Formed in April 2010, the Foreign Device Inspection Cadre is organized out of ORA’s Division of Foreign Field Investigations and augments the agency’s existing foreign inspection program.

The 10 cadre members were “selected based on their knowledge and experience in conducting independent and complex inspections, and in developing compliance cases,” said Dorothy Lee, an ORA consumer safety officer who heads up the cadre.

Investigators also were selected based on their ability to speak foreign languages and understand various cultures. Further, they had to be intimately familiar with FDA processes after an inspection is completed.

“The cadre investigators conduct inspections of high-risk medical device establishments,” Lee told “The Silver Sheet.” “Upon completion of these inspections, the investigators are responsible for writing detailed Establishment Inspection Reports, which include well-documented supporting evidence for any identified observations.”

“With the continued increase in the global supply chain, the cadre will remain in existence. There is no plan for the program to be discontinued,” FDA’s Lee says.

Cadre positions are not permanent, however. Investigators will be rotated in and out of the program each year.

“It is recognized that the expectations of this position are demanding,” Lee said. “Investigators are traveling internationally every other month.”

Being in the cadre could “burn people out,” added FDA/GMP expert Kim Trautman. “It’s a fair amount of travel. Also, foreign inspections are more difficult. They have to come in and accomplish a lot in four days, and some people, even if they are a great domestic investigator, have a hard time adjusting to that compressed timeframe.”

Lee pointed out, though, that “there are provisions for cadre members to remain with the cadre. However, this decision is made by the cadre supervisor and the cadre member.”

Cadre investigators are scattered throughout FDA district offices across the United States.

“With the continued increase in the global supply chain, the cadre will remain in existence. There is no plan for the program to be discontinued,” Lee said.

Chart shows the number of FDA good manufacturing practice (GMP) inspections of foreign manufacturing facilities during fiscal years 2004 through 2011.

Chart shows the number of FDA good manufacturing practice (GMP) inspections of foreign manufacturing facilities during fiscal years 2004 through 2011.

Although Lee said there are no current plans to increase the number of investigators in the cadre, CDRH’s Silverman said the unit could grow over time.

“We’re still in the cadre’s early days, so we’re assessing both the impact of the cadre and ... how we might be able to grow it successfully,” he said.

The current 10 cadre members have high levels of device expertise.

“Because these individuals, in some cases, have quite a bit of experience and have been in the agency for some time, they’re able to take on challenging or complex inspections that might be more of a challenge for someone who was newer to FDA,” Silverman said.

But he added, “The message behind the standing up of this cadre is not a lack of confidence in other ORA investigators. I think ORA’s investigatory staff is excellent, well trained and has a high impact, but this is a subset of that very qualified group that is really able to enhance our impact.

“I would view [the cadre] as a complement to our current pool of ORA investigators. To the extent that we’re able to leverage lessons learned and experience gained by the cadre’s work abroad and use that to enhance the capability of other ORA investigators, that is a net win.”

Process Validation Troubles For Foreign Firms

FDA’s increased attention to non-U.S. manufacturing was brought about in part because of problems with tainted heparin and infant formula, pet food laced with melamine, and faulty Huber needles (“The Silver Sheet” February 2010).

But it’s not so much foreign products as foreign manufacturing processes that have caught the agency’s attention.

“I wouldn’t say that [lately] there are particular foreign products of concern,” CDRH’s Silverman said. “But I would say one area where we have seen an elevated level of concern in relation to foreign manufacturing as compared to domestic manufacturing is process validation,” Sec. 820.75 of the QSR.

“I think some international firms are still getting used to the level of detail and prescription that FDA requires in process validation,” FDA’s Trautman says.

“I would recommend that foreign manufacturers continue to pay significant attention to their process validation capabilities,” he said. “When I talk about process validation I’m talking about making sure that the manufacturing process is able to produce a finished product that operates in the manner in which it is intended. That is one of the elements of a quality system approach to device manufacturing.”

FDA’s Trautman said there are “some pretty legitimate reasons” why some foreign manufacturers are having trouble with process validation.

“If you look at the process validation requirements in ISO 13485 and you compare it to [QSR Sec.] 820.75, you’ll find that [Sec.] 820.75 is more prescriptive,” she told “The Silver Sheet.”

“Process validation showed up in ISO 13485 for the first time in 2003. It previously was not an explicit requirement like it is in FDA’s Quality System Regulation,” Trautman explained. “I think some international firms are still getting used to the level of detail and prescription that FDA requires in process validation, hence I tend to see more issues with process validation for international firms.”

Supplier Control A Problem For Foreign Firms, Too

It should come as no surprise that many foreign manufacturers grapple with supplier controls, just as domestic companies often do.

“There are manufacturing quality issues that we see that are equivalent for foreign and domestic manufacturing,” Silverman said. “Manufacturers should be vigilant about things like CAPA [corrective and preventive action] and design control.”

However, “one area of particular focus for firms that bring their products in from outside the United States and rely on foreign manufacturers has got to be purchasing controls,” QSR Sec. 820.50, he said.

“Firms that are sourcing either finished products or components from outside the United States must have a transparent view of who it is that is producing those products and have absolute confidence in their supplier’s ability to consistently produce high quality and reliable products,” Silverman said. “The public health in the United States demands that as a baseline for doing business here.”

FDA National Device Expert Phil Pontikos said he consistently sees foreign facilities struggling with supplier control issues.

Supplier controls and FDA investigator training

As FDA continues to hire and train new domestic and foreign investigators, the agency has made those new recruits aware of rampant manufacturer problems when it comes to supplier controls.

The potential investigators “are definitely being instructed to take a look at purchasing controls during each and every quality system inspection,” says FDA National Device Expert Phil Pontikos.

“I just got back from Asia. I was doing a couple of inspections and some other activities there, and I ran into this problem,” he said May 4 at the MedCon conference.

“When you start looking at the foreign supply chain, we have less information about it,” Pontikos said. “They also act in different ways than we’re used to. For example, one foreign supplier may have four or five sub-tier suppliers for a particular product. They’re not necessarily looking to meet [a foreign manufacturer’s] quality attribute. They’re looking at just being able to supply what was asked for.

“We’re aware of this as an agency,” he continued. “The burden is back on foreign manufacturers because they have to exercise the right amount of control on their suppliers.”

Johanne Hamill, director of quality and regulatory for foreign manufacturer Neoss, maker of the Neoss Dental Implant System, said ISO 13485 may also play a role in foreign companies’ confusion when it comes to supplier control.

“ISO isn’t as mandatory around the types of controls that you need to have in place,” she said. “It says you need to select your suppliers and have an identified approval process for that, but it doesn’t get into the level of detail that the QSR does.”

And because a majority of foreign suppliers are expected to comply with ISO 13485, too many non-U.S. facilities are simply taking the quality of parts and components for granted.

“There is heavy reliance on ISO 13485 certification in order to approve a supplier,” Hamill told “The Silver Sheet.”

“It’s not unusual, therefore, for a lot of foreign businesses to say to a supplier, ‘You have ISO 13485, we have a copy of your ISO certificate, we won’t audit you, and we’ll bring your product in, direct-to-line,’” she said. “The manufacturers assume that because they follow ISO 13485 that they can deliver direct-to-line and they’ll have defect-free products.”

Language can often be a barrier to ensuring proper purchasing controls.

David Jones, director of quality and regulatory for Philips Home Monitoring, agrees that foreign companies should not assume that everything is going well at a supplier’s manufacturing facility.

“Because so many medical device companies are now essentially technical specification developers and the actual manufacturing is done in other parts of the world, the most important thing is to make sure that you have purchasing controls to control all of those vendors,” he said. “Managing a supplier that is 13 hours away is a lot more difficult than managing a supplier that is down the hall in your own facility.

“One of the things we do is make sure our vendors tell us when there are component changes so we can evaluate the impact,” Jones added. “But unless you do that very rigorously, there is a tendency for manufacturers to assume that everything is going well. If you’re auditing that vendor only once a year, what are they doing the rest of the year when you’re not in their face?”

Language can often be a barrier to ensuring proper purchasing controls.

“I just sent one of my key people on a one-month trip to the Far East. He’s going to visit Singapore, Hong Kong, Shenzhen and Manila to audit foreign vendors under our supplier controls,” Jones said.

“What we find is, when we get hosted by a vendor, usually the host speaks English but most of the people in the organization don’t,” he said. “So there are two sets of quality system documents, one in English and one in the language of the country that the individuals are from.”

In addition, a foreign vendor employee “may go home after working for a company for a whole year and then send one of their family members to replace him or her,” Jones explained. Therefore, “you don’t always get the same people back with the same level of training, so training is a constant requirement for people over there.

“Training in the local language is absolutely essential and it’s ongoing because of the turnover of staff that we see in those environments.”

Catching Up With Foreign Facilities

Despite apparent gains in obtaining foreign facility compliance, it’s generally recognized that FDA still has a long way to go.

“I’ll be the first person to admit that a gap exists in terms of the current FDA resources that are available to dedicate to the oversight of foreign manufacturing, and the actual inventory that exists of manufacturers of finished devices and components outside the United States. Unquestionably we need to close that gap,” CDRH’s Silverman said.

“We have made strides to move in that direction,” he said. “We’re aware of the gap and we are actively looking for strategies that go beyond our traditional inspection model to ensure that we have appropriate oversight of foreign manufacturers.

“I can’t predict what our budget is going to look like next year or the year after, but what I can tell you is that is that we’re going to use all available resources to protect the public health,” Silverman says.

“I can’t tell you that in five years we’ll be on site in every foreign manufacturing operation annually or biannually, but what I can tell you is that in five years we will have continued to improve our understanding and oversight of foreign manufacturing,” Silverman added.

Just as the agency is beginning to make inroads with foreign inspections, could congressional budget-cutting set FDA back several steps?

“I can’t predict what our budget is going to look like next year or the year after, but what I can tell you is that we’re going to use all available resources to protect the public health,” Silverman said.

“To do this, we rely on our traditional compliance strategies and we constantly look for new strategies,” he said. “Some of those strategies may require additional resources, and there is no way to know whether those resources will or will not be available. So we also look for strategies that don’t rely on major resource investments.

“For example, take our ‘business case for compliance’ – an atypical approach that creates incentives for manufacturers to adopt best quality practices – as an example of an initiative that doesn’t require a significant sum of resources in order to have an impact,” he noted.

FDA’s business case for compliance encourages manufacturers to make quality assurance an organization-wide concern rather than the responsibility of a discrete quality assurance unit.

Under that model, an understanding of what it means to produce a high-quality product is shared throughout the company, from managers to people on the manufacturing line, and all have a chance to contribute to the dialogue about quality (“The Silver Sheet” November 2010).

Manufacturer Neoss: No FDA Inspection For Six Years; Philips Doesn’t See Much Difference

Neoss had its very first FDA inspection in 2010 – even though the company has been in operation for six years.

The agency inspects Neoss because it sells its products in the U.S. The firm is headquartered in Harrogate, U.K.

“That is quite a long time to go without being inspected – six years,” Hamill said. “I was told by the [FDA] investigator that they’re not getting to Europe as often as they need to. I know a lot of [foreign] companies out there that have gone as long as we did without an inspection.”

Although Hamill believes International Organization for Standardization (ISO) audits aren’t as strong as FDA inspections, she says one advantage of an ISO audit is that they occur more frequently.

Neoss is audited by an ISO-accredited third party twice a year for its quality management system and once a year for CE certification.

“That’s a technical audit, so they’re looking at the technical files,” Hamill said. “And then also, because we conduct sterilization, we have an annual sterilization audit by the notified body as well. So we see the ISO notified body four times a year.

“The regularity with which we see our notified body works very well,” she continued. “If we’re drifting out of control on anything, we’re never drifting out any more than six months because they come in and we can also talk to them about how we can correct [problems]. That side of it is good. Are they as strict and stringent about everything as the FDA is? Maybe not.”

Philips’ Jones said his large global firm has always been a target for foreign inspections, so he hasn’t seen a dramatic increase in agency scrutiny.

Philips has manufacturing facilities in both the U.S. and abroad.

“FDA is always coming to our foreign facilities because we’re a big firm like General Electric or Siemens,” Jones told “The Silver Sheet.”

He surmises that foreign facility inspections “have probably been expanded to the next tier of medical device manufacturers.”

Still, Jones does look across the foreign industry and sees that the agency is lagging behind.

“Even though FDA has expanded its personnel, there has just been an explosion in foreign manufacturing of medical devices in the Far East,” he said.

“There is just so much to do that if [FDA] can’t do it with its own staff, then it needs to form relationships with its foreign counterparts to be able to cover all of the firms,” Jones said. “But right now I don’t think FDA has enough people to do that, even though it has added a lot of people and added a lot of funding. There are never enough people to do everything.”

Inspection Advantages For Foreign Firms?

There are complaints by some domestic firms that FDA foreign inspections are not as difficult as those performed stateside.

This perception pervades industry because foreign inspections typically take less than one week and non-U.S. facilities are told by the agency well in advance when FDA investigators will be arriving.

Inspections of domestic companies, however, are open-ended and there is typically no warning of when one will be conducted.

“One of the concerns that continually is brought to the agency’s attention is the length of a foreign inspection. It’s pretty limited, and trip plans are arranged well in advance,” said Steven Niedelman, senior consultant for the law firm Crowell & Moring and a former FDA deputy associate commissioner for regulatory operations.

Philips’ Jones believes foreign manufacturing facilities receive a “gentler audit” than domestic firms.

FDA foreign investigators “basically get three inspections done in three weeks [because] they’re four or five days in length. Meanwhile, FDA may inspect a firm in the United States for six months, two months, eight weeks, whatever,” Niedelman said May 4 at the MedCon conference.

“There is some concern that industry expresses to the agency of an uneven playing field. Anecdotally, many manufacturers feel their foreign counterparts are not subject to the same depth and scope of inspection as they are,” he said. “That is a concern that I hear all the time. I know the agency hears it.”

Philips’ Jones thinks foreign manufacturing facilities receive a “gentler audit” than those located in the U.S.

“If it’s a foreign inspection, then it’s no longer than four or five days because the investigator needs to write everything up and then move on to his or her next geographic assignment,” he said. “I believe they’re a lot more manageable than U.S.-based [inspections], and there is less anxiety.”

Foreign facilities “are notified well in advance, they have time to prepare and the timeframe is prescribed,” Jones said, pointing out that FDA recently conducted a 13-day inspection at a U.S. Philips facility.

During that inspection, “the general manager would ask me when I thought the inspection would be done, and I couldn’t tell him,” Jones said.

“Once the site is being inspected the whole focus of the site is on meeting the investigator’s needs,” he said. “It’s all-hands-on-deck, and it takes attention away from other things that people would probably be doing, because the No. 1 objective is to meet the needs of the FDA.”

Before joining Neoss, Hamill was director of quality systems and compliance international operations for the global firm Steris, a manufacturer of surgical equipment, sterilizers, lab equipment and other products.

She recalls only one time when an FDA foreign investigator stayed longer than the prescribed four- to five-day timeframe.

“In my experience, 99 percent of the time the FDA inspection runs from the prearranged start-to-finish time. It’s very, very rare in Europe or outside of North America that [the agency runs] over that. It’s because someone is landing on a plane on such and such a date, and booked to return on a specific date,” Hamill said.

“I have had ‘sudden’ FDA [foreign] inspections – there’s a call and within four weeks they’re here. That’s considered quite quick,” she said. “My American counterparts over the years have said, ‘Hey, [FDA inspections are] nothing in Europe, because we have FDA in for 53 days, or we have them in for 27 days.’ So I think, in the industry – I wouldn’t say it’s hostility – there is kind of a pleasant ribbing over it, but nothing more than that.”

Socializing With FDA Investigators

Another perceived advantage for foreign facility managers is that they have more opportunity, if they choose, to socialize with an investigator at the end of an inspection day.

“There is a little bit more courtesy extended when the investigator is overseas as opposed to the U.S. because they’re totally out of their comfort level, especially if they’re in a non-English-speaking country,” Philips’ Jones said.

“If an investigator is in a foreign country, you can’t just dump them off at their hotel at night. You try to make them feel comfortable in the country without plying them with food and drink,” he said.

The FDA investigator pays for his or her own meals. However, “you might be in the same hotel with that investigator, and if you’re both in the dining room, you wouldn’t leave the investigator at one table if you’re at another table,” Jones said.

This is the time when company officials may become friendly with the person who is inspecting them.

“It is human nature that you would get to know the investigator,” Jones said. “Rather than being adversarial, it can be more of a courteous relationship, and actually things may be a little gentler because of that. Naturally your relationship is going to be good with that person.”

Neoss’ Hamill has taken a similar tack with FDA investigators during her career.

“If the investigator is comfortable, then yes, arrangements for social events are made for the evening,” she said. “Maybe if they have flown in over the weekend, we may have collected them from the airport and made sure they got to their room OK, and we’ve shared supper. Is that to our advantage? I would say it definitely isn’t a disadvantage. You are no doubt able to get a little bit of a feel for them as a person and you do build interrelationships a little bit.

“When you link those points together – the advance inspection warning, the inspection start and finish dates being known, and the possibility of spending some time with the investigator outside of the audit – I believe then, if I was a domestic American manufacturer, that that slightly different process was somewhat advantageous to foreign manufacturers,” Hamill added. “There is no doubt about that.”

By Shawn M. Schmitt

Warning Letters To Foreign Firms Rise; FDA Inspection Cadre Yields Big Impact

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