Medical Device Quality Management Systems: Strategy and Techniques for Improving Efficiency and Effectiveness

QMS.

Part I

An effective quality system

Outline

Chapter 1 Regulatory requirements

Chapter 2 Increasing expectations

Chapter 3 Establish and maintain

Chapter 4 QMS structure

Chapter 1

Regulatory requirements

Abstract

The era of modern device regulation began in 1906 with the Pure Food and Drug Act. A history of specific issues shaped the regulations that medical device manufacturers must comply with today. The Food, Drug, and Cosmetic Act of 1938 and subsequent amendments are the basis of the regulations we know today in the United States. In order to meet the requirements of the regulations, medical device companies must establish and maintain an effective quality management system (QMS) to prevent adulterated or misbranded products. The QMS consists of the organizational structure and resources, skills and capabilities, a network of connected processes documented in policies and procedures, and the necessary enabling infrastructure. An effective QMS is the foundation for how medical device manufacturers ensure that their products are both safe and effective. An effective QMS requires ongoing effort and is always ready for a Food and Drug Administration inspection.

Keywords

Quality management system (QMS); compliance; quality; effective; regulation; Food and Drug Administration (FDA); customer; establish; Food Drug and Cosmetic Act; Pure Food and Drug Act; patent medicines; Great American Fraud; adulterated; misbranded; quality system regulation (QSR); Code of Federal Regulations; Medical Device Amendments; FD&C Act; appropriate; advertising; adulterated; misbranded; ISO13485; ISO14971; Snake Oil; Electropoise; Mrs. Winslow’s Soothing Syrup; Safe Medical Devices Act; Medical Device Amendments Act; preamble to the quality system regulation; classification panels; appropriate; good manufacturing practices (GMPs); Form 483; warning letter; recidivist warning letter; consent decree; injunction; recall; criminal prosecution; civil money penalty; internal audit; management responsibility; management review; behavior; MEDICS; Corrective and Preventive Action (CAPA); import detention; enforcement; International Medical Device Regulators Forum (IMDRF); Advamed; AAMI; Medical Device Innovation Consortium (MDIC)

Today, medical devices are highly regulated with a long history of regulations going back to the Pure Food and Drug Act of 1906. Prior to this, medical products were unregulated, promised to cure a wide variety of vague ailments, and were often ineffective or even hazardous. Patent medicines originated in England and were associated with proprietary medicines or concoctions that arrived in North America with the first settlers. The term patent medicine is a bit confusing and does not always mean medicines that have been patented. The phrase patent medicine comes from medical elixirs of the late 17th century when those who found favor with royalty were issued letters patent that allowed the use of royal endorsement for advertising.

Patent medicines, also known as nostrums, were products that were proprietary in nature, unproven, and marketed directly to the public. Patent medicines were sold with interesting names, bogus claims, and using advertising games. Pioneer (aggressive) advertising techniques with distinctive trademarks and packaging were common. Products were promoted as cure-alls and panaceas for all sorts of ailments. Entrepreneurs began to bottle and sell old family recipes with no proof of efficacy or safety. Networks of unscrupulous traveling salesmen sprang up and turned patent medicines into big business. Profit-making took priority over safe and effective products.

These quack medicines were often not effective and did not contain the ingredients specified. Even worse, they were sometimes deadly. Often, they had high (and undisclosed) alcohol content which may explain why they were so popular. Ingredients were unregulated and could include those that were addictive and lethal. They often contained addictive ingredients such as morphine, opium, cocaine, or heroin. Mercury and arsenic were found in some products. One product containing opium, alcohol, and chloroform together promised to cure everything from toothache in 5 minutes to colds in 24 hours and deafness in 2 days! Even worse, patent medicines were frequently marketed as infant soothers and teething cordials for fussy, teething, or colicky babies, but caused tragic results. Mrs. Winslow’s Soothing Syrup claimed that it was likely to soothe any human or animal.

Newspapers became filled with advertisements promising quick, cheap cures for all ailments both dreadful and mundane. Advertisements for patent medicines were everywhere and referred to vague disorders such as female complaints and dyspepsia. Advertising cards (trade cards) were colorful, imaginative, and displayed distressing before pictures (when the card was closed) and happier after pictures when the card was opened. Testimonials were a common advertising technique.

Sellers made broad claims about patent medicines curing a variety of ailments. These concoctions were sold to the unsuspecting public with no controls. Salesmen often used innovative techniques to attract attention to their sales offerings. At the 1893 World Expo in Chicago, Clark Stanley, the rattlesnake king, caused a stir by publicly killing rattle snakes and processing their bodies to collect snake oil to stop pain, reduce swelling, remove inflammation, and oil dry joints.

Note

A visit to the Smithsonian Institution's National Museum of American History in Washington, DC or the Hagley Museum in Wilmington, Delaware provides many fascinating examples of patent medicines and their colorful bottles, advertisements, and quack claims. Items include:

• Stetketee’s Neuralgia Drops

• Aubergier’s Pastilles of Lacucarium

• Kickapoo Indian Sagwa Renovator

• Renne’s Magic Oil

• One Minute Cough Cure

By the early 1900s, some physicians and medical societies were recognizing problems and becoming critical of these medicines. At this time, there were estimates of 50,000 patent medicines being manufactured and sold in the United States. Journalists began exposing injuries as well as proprietary formulas. American journalist and author, Samuel Hopkins Adams wrote a series of 11 articles in 1905 to 1906, The Great American Fraud, that called attention to these issues.

Other changes were occurring, and Upton Sinclair described the unsanitary conditions of meat-packing plants in The Jungle. This led to widespread public outrage and demand for regulation of food and drug products. With the strong support of President Theodore Roosevelt, the Pure Food and Drug Act was passed in 1906 and started an era of regulation to ensure that medical products were both safe and effective.

In 1917, the Bureau of Chemistry (later known as the Food and Drug Administration or FDA) seized a shipment of Stanley’s Snake Oil and found that it contained no snake oil at all. It was mainly mineral oil, red pepper, and turpentine. Clark Stanley was fined $20. The term snake oil was now well-established as a quack concoction marketed as a patent medicine. Even today, the term snake-oil salesman still conjures the image of a seedy salesman peddling his wares on a soapbox in a traveling show.

In 1911, the American Medical Association published Nostrums and Quackery, describing hundreds of products linked to serious injuries and deaths. Mrs. Winslow’s Soothing Syrup was featured in a section titled Baby Killers. By this time, there were also concerns about misleading advertising, quackery, and mechanical products (the early medical devices). An entire chapter was devoted to the advertising techniques of con men and quacks.

A chapter titled Mechanical Fakes, voiced concerns about unproven new medical devices. It is sometimes hard to decide which is greater—the impudence of the quack or the credulity of his victims. The comparative ease with which the medical faker is able, by the most preposterous of claims, to separate the trusting from their money indicates the enormous potentialities in advertising. It might well be supposed that an individual who set out to sell, as a panacea for all the ills of the flesh, a piece of brass pipe with one or two wires attached to it, would commercially speaking have a hard and rocky road ahead of them. But such supposition would be incorrect. Not only would the enterprising faker find customers for his gas pipe, but there would be such a demand for this most inane of ‘therapeutic’ device that two or three imitators would immediately enter the market. This described the Electropoise device, originated by one Hercules Sanche, who modestly described himself as the ‘Discoverer of the Laws of Spontaneous Cure of Disease’. The book goes on to state that, in order to minimize legal issues and maximize financial gain, Sanche finally hit on a device that was negatively harmless—and positively worthless—and yet theatrical enough to make the purchaser feel that he was getting something for his money. Advertisements for Electropoise made wild claims, even saying that it could cure previously determined incurable diseases. It was time for improved regulation to protect the public health.

The Pure Food and Drug Act of 1906 regulated only drugs and food and did not include medical devices. It was replaced in 1938 by The Food, Drug, and Cosmetic Act (FD&C Act). The FD&C Act (sometimes referred to in medical device regulations as the Act) provides the framework for the regulations we know today. The FD&C Act, along with various amendments, forms our current regulatory requirements. The FD&C Act included the following provisions:

• Extended control to cosmetics and medical devices

• Gave the FDA formal authority to inspect factories, warehouses, or establishments

• Required drugs to be shown as safe before marketing (premarketing conditions)

• Added injunctions to the previous penalties of seizures and prosecutions

• Clarified the concept of prescription vs over-the-counter drugs in the Durham Humphrey Amendment of 1951

• Required, via the Kefauver Harris Amendment of 1962, efficacy as well as safety data before a drug could be marketed and instituted stricter agency controls. It also transferred regulation of advertising from the Federal Trade Commission to the FDA. And it established Good Manufacturing Practices (GMPs).

At the time the FD&C Act was approved, medical devices were very simple instruments such as scalpels and stethoscopes. By the 1960s and 1970s, there was a significant increase in the number, complexity, and risk of medical devices. But, the FDA’s limited resources were focused on dealing with quack devices. The Cooper Commission report of 1970 determined that more than 700 deaths and 10,000 injuries were attributed to medical devices. This resulted in the Medical Device Amendments to the FD&C Act signed into law by President Ford in 1976. This Act included:

• Authority for FDA to regulate and control the release of medical devices into interstate commerce

• Requirements for device listing, establishment registration, and adherence to GMPs

• A three-tiered classification scheme for products based on risk

• Provided procedures for authorization for distribution which include 501(k) premarket notification and premarket approval (PMA);

• Provided authority for the FDA to ban devices

The Safe Medical Devices Act of 1990 (SMDA) included:

• The first requirements for medical device reporting (section 803) to the FDA

• Requirements for device tracking and post-market surveillance

• Allowed the FDA to temporarily suspend approval of PMAs for new products

• Allowed civil money penalties for violations

• Added Humanitarian use provisions

• Provided FDA with the authority to add preproduction design controls to the cGMP (current Good Manufacturing Practices) Regulation.

The SMDA defined a medical device as "any instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part or accessory which is:

• Recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them,

• Intended for use in the diagnosis of disease or other conditions, or the cure, mitigation, treatment, or prevention of disease, in man or other animals, or

• Intended to affect the structure or function of the body of man or other animals,

• And which does not achieve its primary intended purposes through chemical action within or on the body of humans or other animals and which is not dependent on being metabolized for the achievement of any of its primary intended purposes."

This definition provided a clear distinction between medical devices and other regulated medical products such as drugs and biologics.

The Medical Device Amendments of 1992 clarified medical device reporting requirements with expectations for user facilities, manufacturers, importers, and distributors.

In 1996, the cGMP (current Good Manufacturing Practices) was revised to add design control requirements and achieve some alignment with international standards. This resulted in the Quality System Regulation (QSR) found today in the Code of Federal Regulations (CFR) Title 21 Part 820. The preamble to the QSR provides very useful information and interpretation of the FDA’s rationale and thinking at the time. It is recommended that all quality and compliance professionals read the entire preamble to enhance their understanding of the QSR.

This short history gives a framework for our current medical device regulations in the United States. It helps understand the issues that shaped the laws we know today. Many details in the laws were in response to specific events or problems that highlighted the need for regulation.

As a consumer, I am personally grateful for the all work and effort it has taken to create the laws and the regulations aimed at protecting the public health. I know that these regulations ensure the safety and efficacy of medical devices. And as a quality and compliance professional in the medical device industry, I find the history fascinating in understanding the complexities of that industry. The history provides context and interpretation of the specific issues that led to the laws and the changes over time. The regulations continue to develop and throughout this book we will discuss current issues and future trends.

Many medical device manufacturers also design, manufacture, sell, distribute, and service their devices in other countries. It is impossible to exhaustively cover the laws and regulations for other countries. But, International Standard ISO 13485 Medical devices—Quality management systems—Requirements for regulatory purposes is an important standard to understand. ISO 13485 is the basis for complying with the Medical Device Directive (MDD) enacted by European Parliament. Compliance with the MDD is signified with the CE (European Conformity) mark on products. CE marks are granted by notified bodies (e.g., TüV, BSI, or KEMA), private companies accredited by country governmental bodies. The 2003 version of ISO13485 is still in use at the writing of this book. However, many medical device manufacturers are in the process of transitioning to the 2016 version to meet the required 2019 deadline. We will discuss changing expectations for the medical device industry further in Chapter 2, Increasing Expectations.

There are many similarities and a few differences between the QSR and ISO 13485. We discusses some important distinctions throughout this book. The International Medical Device Regulators Forum (IMDRF) is an important organization that seeks to accelerate international medical device regulatory harmonization and convergence. IMDRF was started in 2011 and now includes Australia, Brazil, Canada, China, Europe, Japan, Russia, Singapore, the United States, and the World Health Organization. IMDRF built on the work of a previous organization called the Global Harmonization Task Force (GHTF) on Medical Devices. The IMDRF website is a very useful resource. It contains many important and useful guidance documents, including GHTF