Originally published October, 1996
As members of the medical device industry eagerly await the release of the revised rule on good manufacturing practices (GMPs), there is little doubt that the new regulation will have an extraordinary impact on the device community, particularly through the extension of FDA authority to the design of medical devices. But before manufacturers can comply with the GMPs, they must understand them.
In the weeks and months following the release of this revision, FDA plans to unleash an unprecedented wave of support materials--guidances, videotapes, a guidebook, and teleconferences--designed to explain every nuance in the new regulation. Print materials will be distributed through public and private sources, and electronic versions will be put on the FDA web site.
"We feel it is a major regulation and we need to go out and assist both small and large manufacturers, but we're mostly concerned about the smaller manufacturers," says Kim Trautman, GMP/quality systems expert in FDA's Office of Compliance. "The rollout of these materials should make the point that the agency is really trying to reach out and work with industry." The reason for the major concern about small businesses, she explains, is that more than 98% of the industry is composed of small entities, according to criteria developed by the Small Business Administration. "Small manufacturers need the most help because they might not be connected with some of the major associations, or getting the information at an affordable price may not be easy," Trautman says.
The four guidances, which are currently in various stages of development, represent a shift in the thinking of FDA officials away from the development of guidance documents that inadvertently become de facto regulations. This practice has caused industry countless problems, according to David Link, executive vice president of EXPERTech (Concord, MA). "Typically inspectors take these documents to the manufacturer and look at them as a set of requirements," says Link, who also serves on the board of directors of the Medical Device Manufacturers Association. "If the methods stated in the guidance are not followed exactly, the onus is put on the company to convince the inspector that the procedure used is acceptable."
That will not be the case for the current wave of guidances planned to accompany the revised GMPs. Trautman explains that the agency is changing its thinking about guidances, moving away from the way these documents have been used. "We are looking at them as educational tools, not as regulations," she says. "They are not meant to define the way or ways that industry can meet the regulation. We want to be clear that there is no one way of doing things; rather we want to emphasize the different ways that goals can be accomplished."
The final versions of three guidances will follow almost immediately after release of the GMP revision.
Quality Systems Manual. "Medical Device Quality Systems Manual: A Small Entity Compliance Guide" will interpret the entire regulation, providing examples of procedures and forms that can be adopted and modified by manufacturers. The approximately 500-page guide, developed by FDA's Division of Small Manufacturers Assistance (DSMA), will approach GMPs from the perspective of a novice company executive seeking knowledge about the medical device industry. Andrew Lowery, associate director for quality systems at DSMA, says the guide is a compilation of different methods and concepts. For example, it explains that GMP requirements might be met by using a photograph, a drawing, or perhaps a model of the device. And while the knowledge that there is more than one right way to meet a requirement is especially important for new people entering the GMP environment, Lowery says the manual is directed toward all manufacturers, large and small.
Technically, the guide is a revision of the fifth edition, but because of the addition of design controls to the GMPs, it underwent a major rewrite. Even so, Lowery notes that it still contains certain fundamental materials, and even the description of design controls had a precedent. "The old document covered preproduction planning, which was the earlier name we used for design controls," he says. "But there was still a lot of work in molding it to fit a new regulation."
The guide first addresses the design controls needed for the development of a product. It then progresses through a description of the device and master records, and finally into production, labeling, packaging, and the design history file. "We continued in the tradition of making each chapter independent of the others," Lowery says. "In other words, you can read the guide as a reference manual. You don't have to read it like a novel."
Device Design Guidances. Two guidances will focus on what's new about the revised GMPs and of special interest to industry: medical device design. "Do It by Design: An Introduction to Human Factors in Medical Devices" will examine the significance of the human-machine interface. "Users sometimes get overly confused by the product and make errors not even logically connected to the source," says Dick Sawyer, a human factors scientist in FDA's Office of Health and Industry Programs. "The margin of error is often reduced by adequate human interface design." Sawyer has led the team in developing the human factors guidance to help decrease that margin of error. In a straightforward format, the document defines the problems and describes how they might be avoided through human factors engineering. "It is a primer. It lays out the rationale and the basics, but doesn't get into the details," says Sawyer, who wanted to avoid developing a guidance that would take on a regulatory character. "It is meant to educate industry and CDRH [Center for Devices and Radiological Health]," he says, noting that the document will be distributed to FDA staff as well as to industry.
Building safe and effective products requires that the user be considered in the design of the user interface. Sawyer hopes that the guidance will sensitize manufacturers to the problems associated with not taking the user into consideration, as well as help familiarize designers with the methodology of human factors design.
A number of sophisticated tools have been developed recently to assist designers in building a better human interface to medical equipment. One of the most important is computerized prototyping. "Computer screen simulations take the place of paper sheets," Sawyer explains. "Push a button, and a new screen with a new display shows the effect of some change." In this way, computers allow designers to generate iterative prototypes of a device.
In addition to describing some of these aids, the guidance identifies and describes resources available to help designers learn more. Included among those resources are the developers of human factors design products, as well as literature describing relevant methodology.
The "Design Control Guidance for Medical Device Manufacturers" will delve into the nuts and bolts of the regulation, assisting manufacturers in understanding the intent of the design control requirements. This guidance consists of two parts: one that reiterates the requirements contained in the GMP regulation, and another that is a discussion section focusing on points to consider. Separating the two clearly delineates the requirements from the educational discussion, says Trautman.
In the discussion section, team leader Bill Midgette places special attention on interpreting the regulation's language and explaining the underlying concepts in practical terms. "One thing we want to convey to industry is that we don't want to tell them precisely how to implement design controls," says Midgette, deputy chief of FDA's medical electronics branch, which is in the Office of Science and Technology. "There is an awful lot of work that they need to do to define exactly what is best for their particular process."
Consequently, Midgette says the guidance provides an appropriate level of detail that explains clearly what manufacturers need to know in order to have adequate design controls, yet does not restrict them to certain approaches, tools, or techniques.
Validation Guidance. A fourth guidance, entitled simply "Validation," will include discussions on design, computer, and process validation. This guidance will replace the process validation guidelines implemented in 1987 by CDRH. The 1987 guideline might remain in use by the Center for Drug Evaluation and Research, but the GMPs have changed the ground rules enough that the nine-year-old guidance is effectively obsolete in regard to devices.
The goal of the guidance is to provide an understanding of the differences among verification, qualification, and validation so that these terms are used consistently and properly. Significantly, the revision of that guidance is being conducted by private consultants working under four different contracts with FDA.
DESIGN CONTROL INSPECTION STRATEGY
FDA is also developing a "Design Control Inspectional Strategy," which will be composed of questions that FDA investigators will be asking when they go on-site to ensure compliance with the design control requirements. This strategy is not a guidance, Trautman says. "It is going to detail how FDA investigators go in and look at design controls. It will guide our investigators in regard to what is appropriate."
The questions, Trautman continues, are designed to focus the investigators on the design system, not on the particular designs of devices. They will not be of the yes/no variety, but rather will lead the investigators to draw conclusions. How these questions are phrased, therefore, will directly affect industry, which is the reason FDA plans to release a draft of the questions for comment. "We're trying to get the industry and the regulators to cooperate," Trautman says. "We believe that if we work together, we probably can do our work better than if either one of us goes off to do our own thing."
FDA plans to release drafts of both the inspection strategy and the validation guidance for industry comment this autumn, providing an example of the shift in attitude by FDA officials toward bringing industry into the feedback loop. Top officials at FDA have decided to engage industry at earlier points in the development of key regulatory materials. "For all four documents, we decided right away that we weren't going to wait for someone to tell us to get industry involved, we just did it," Trautman says.
MAKING USE OF INDUSTRY FEEDBACK
In March, FDA released draft versions of the two design control guidances being developed under the tutelage of Midgette and Sawyer. The guidances' release provided industry with its first opportunity to comment on a guidance prior to issuance. The majority of comments received from industry--particularly those concerned about the guidances being too restrictive--were incorporated into the documents.
Authors of FDA documents try to walk a thin line between being too prescriptive and not providing enough guidance. "Guidances need to get into some 'how-to' yet not give the impression that this is the only way 'how to,'" Trautman explains. The danger in being too prescriptive is that field investigators may try to hold the manufacturer to exactly what appears in the guidance.
Comments submitted to Trautman by the Health Industry Manufacturers Association (HIMA) voiced exactly that concern in regard to the first draft of "Design Control Guidance for Medical Device Manufacturers" written by Midgette and Al Taylor, a senior engineer in FDA's Office of Science and Technology. In a letter written to Trautman on May 6, 1996, Bernie Liebler, who is HIMA's director of technology and regulatory affairs, noted that "when this hap-
pens the guidance becomes a burden on, rather than an aid to, the manufacturer."
Midgette says the criticism was on target. "As the guidance was originally written, we would have forced manufacturers into adopting techniques or approaches that might not have been appropriate," he explains. "It was not intentional."
The second concern noted by HIMA was that the draft guidance "in many places addresses areas not specifically covered in the GMP regulation. . . . We do not believe that FDA should use the guidance document as a means to include details that it was unable to write into the regulation." Liebler, in an interview with MD&DI, doubted that the inclusion of this added detail was a conscious attempt to broaden the GMPs. "It has to do with the idea of completeness," he says. "You start out trying to make sure everything is covered, and you don't look back to see if something is part of the regulation."
Midgette describes the comments received from industry as essential to revising the document into the form that will be released in coming weeks. The new version still explains the principles of design control, but as a result of industry comments, includes many practical examples. "Manufacturers will be able to draw knowledge from understanding these examples and then apply that knowledge to their own case," Midgette says. "The comments we did not accept were ones where the manufacturers wanted us to provide so much detail with regard to written documentation that it would have been a cookbook of what they needed to do to meet the requirements when the investigator came to their front door."
Comments received regarding the human factors guidance developed by Sawyer focused mostly on fine-tuning. Some requested a change in emphasis, asking, for example, that devices intended for home health care be given more attention. Other comments related to wording (clarity, readability, and conciseness). "There were no fundamental changes, but the changes that were made were very constructive," Sawyer says.
Both Midgette and Sawyer describe their experiences of being in industry's line of fire as very positive. But becoming the subjects of criticism, regardless of how constructive it might be, is not easy. "The partnership issue is something that I wish industry would appreciate when we're developing guidances like this," Midgette says. "There were comments that came in that were critical without providing any indication as to how the guidance should be improved. And there were comments that had suggestions as to what should be done to make the document better. They often included examples of the situation applied to their particular company. Those were really excellent comments and I think they were very helpful in allowing us to achieve a better understanding of exactly what should be included in the document and how much detail it should have."
FDA tends to be viewed by industry as a bureaucracy, but its tasks--such as the development of guidances--are performed by individuals whose every thought, when committed to print, is microscopically examined by the best regulatory minds in industry. "It's a scary kind of thing," says Sawyer. In March, copies of the design control guidances were sent out by CDRH's Office of Compliance to various industry associations, as well as to vendors. Electronic versions were also posted on the FDA Web site.
VIDEOTAPE AND GUIDEBOOK DISTRIBUTION
Of all the FDA officials associated with the revised GMPs, Trautman has the most exposure. Not only has she been a key contact for and developer of this revision for the past six years, but she has guided the development of each of the accompanying support materials. With release of a four-hour series of videotapes collectively titled "Quality System Regulation," Trautman will also be the most visible. Throughout the tapes, her visage will be guiding the television audience through the revised GMPs section by section, providing in-depth discussion of the more important areas, such as the preamble. "This series is meant to be the initial tool to get discussion of the new regulation out," she says. "It's meant to take the place of sending me across the United States."
The videotapes will be accompanied by "The FDA and Worldwide Quality System Requirements Guidebook for Medical Devices," which will contain the entire quality system regulations from FDA, the entire text of ISO 9001-1994, the FDA guidance from the regulation's preamble, and guidance on quality systems from the global harmonization task force. The videotapes and guidebook will be put in the hands not only of industry but also of FDA's field force. Copies will be sent to district offices to be viewed by field inspectors. "It's very important that the videotapes be viewed in the context of the handbook," Trautman says.
The videotapes and guidebook are designed as a primer on the revised regulation. A teleconference, tentatively scheduled for this December, is meant as a follow-up, serving as an interactive medium for answering questions that have come up as manufacturers have begun implementing the regulation. This teleconference, entitled "Quality System Regulation," is the first of two currently planned in support of the new GMPs. The second teleconference, tentatively set for April or May 1997, will specifically address design controls and the final design control inspectional strategy. It will allow FDA to explain how the comments submitted following release of the draft inspection strategy in autumn 1996 affected the final version of that document, as well as how the final version will be implemented in the field. FDA may also hold regional workshops in May 1997 to further discuss the design control requirements and their implementation.
While these may be the most visible FDA activities to help industry understand and implement the revised GMPs, other forms of assistance in this area are also available. The agency, through DSMA, plans to continue providing guidance and holding workshops that can help small businesses with compliance activities. Similarly, agency officials will participate in industry association workshops, conferences, and meetings. This effort to involve industry, Trautman says, is the natural extension of the effort put into development of the regulation itself. "We have a lot of industry buy-in on this regulation. I think it's much more of a consensus regulation than anything that ever came out of CDRH before. And we want to continue that cooperation."