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Module 01 Introduction To FdA and Quality System Regulation
- 1. Introduction to FDA andQuality System Regulations Quality System Regulations Training Module 1
- 2. Learning Objectives Gain an understanding of the history of the Food and Drug Administration Overview of the Quality System Regulation
- 3. Origins of FDA 1798 Public Health Service 1820 United States Pharmacopeia (USP) First compendium of standard drugs 1862 US Department of Agriculture Group of chemists form the beginnings of what becomes FDA
- 4. Early Regulation 1848 Drug Importation Act Customs can stop adulterated drugs What is adulterated? 1880 Congress Defeats Food & Drug Bill
- 5. Adulteration aยทdulยทterยทant (-dltr-nt) n. An additive causing an undesirable effect; impurity. TITLE 21--FOOD AND DRUGS CHAPTER 9--FEDERAL FOOD, DRUG, AND COSMETIC ACT SUBCHAPTER V--DRUGS AND DEVICES Part A--Drugs and Devices Sec. 351. Adulterated drugs and devices
- 6. 1906
- 7. Government Acts Outrage over our food source Harvey Wiley MD Conducted experiments to show food can make people sick Became first commissioner of FDA 1906 Pure Food and Drug Act Requires labeling on foods
- 8. Establishment of FDA Calls for stronger enforcement continues FDA is created in 1930 Federal Food, Drug and Cosmetic Act passed in 1938 Creates broader definition of drug adulteration New drugs require approval!! Requires reports of all investigations
- 9. Medical Devices 1976 Medical Device Amendment Classify devices FDA authority to conduct appropriate level of review โPre-amendment devicesโ grandfathered New devices Premarket approval - PMA Premarket notification - 510(k)
- 10. Class I Medical Devices โ General Controls Minimal potential for harm Only general controls are required Most are exempt from design controls, but not good manufacturing practices. Notification to FDA is required in the form of registration, proper labeling Some Class I devices do require a 510(k) Include bedpans, exam gloves, tongue depressors
- 11. Class II Medical Devices โ General and Special Controls General controls alone are not sufficient to assure safety and effectiveness Special controls may include special labeling requirements, mandatory performance standards, and postmarketsurveillance
- 12. Class II Medical Devices โ General and Special Controls Perform as indicated and will not cause injury or harm to patient or user Devices include X-Ray machines, catheters, wheelchairs, sutures, cervical plates, pedicle screws or Intervertebral Body Fusion Implants and Instruments
- 13. Class III Medical Devices โ General Controls and PMA Insufficient information exists to assure safety and effectiveness solely through the general or special controls These devices need premarket approval and a scientific review to ensure the device's safety and effectiveness Devices include heart valves, silicone-filled breast implants, pacemakers
- 14. Good Manufacturing Practices Regulation - 1978 Defined the minimum good manufacturing practices for processing, packing, or holding drug products and medical devices Organization and personnel Buildings Equipment Control of components Production and process controls Packaging and labeling Holding distribution and installation Device evaluation Records
- 15. Safe Medical Devices Act - 1990 Strengthens the Medical Device Amendment Act Followed the device failures of the 1980โs Mechanical heart valves Broadens device reporting requirements for device related adverse events Gives FDA authority over pre-production design controls
- 16. Quality System Regulation - 1996 Refines the GMPโs and Revised definition of โbecomes aware ofโฆโฆ.โ Emphasis on Design Controls
- 17. FDA Today Agency regulates products accounting for over 25% of American spending Staff of over 10,000 employees Inspect over 16,000 facilities per year Budget of 2.1 billion (2008)
- 18. What the QSRโs Mean to You What is required to comply with the FDA QSR? What does this mean for each employee?
- 19. Elements of 21 CFR 820 Quality System Each manufacturer shall establish and maintain a quality system that is appropriate for the specific medical device(s) designed or manufactured, and that meets the requirements of this part
- 20. Elements of 21 CFR 820 Management Responsibility Management with executive responsibility shall establish its policy and objectives for, and commitment to, quality. Management with executive responsibility shall ensure that the quality policy is understood, implemented, and maintained at all levels of the organization
- 21. Elements of 21 CFR 820 Quality Audit Each manufacturer shall 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.
- 22. Elements of 21 CFR 820 Personnel Each manufacturer shall have sufficient personnel with the necessary education, background, training, and experience to assure that all activities required by this part are correctly performed.
- 27. Elements of 21 CFR 820 Identification and Traceability Each manufacturer shall establish and maintain procedures for identifying product during all stages of receipt, production, distribution, and installation to prevent mixups.
- 28. Elements of 21 CFR 820 Production and Process Controls Each manufacturer shall develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications. Where deviations from device specifications could occur as a result of the manufacturing process, the manufacturer shall establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications.
- 29. Elements of 21 CFR 820 Nonconforming Product Each manufacturer shall establish and maintain procedures to control product that does not conform to specified requirements. The procedures shall address the identification, documentation, evaluation, segregation, and disposition of nonconforming product.
- 30. Elements of 21 CFR 820 Corrective and Preventive Action Each manufacturer shall establish and maintain procedures for implementing corrective and preventive action. The procedures shall include requirements for: (1) Analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product . . . (2) Investigating the cause of nonconformities relating to product, processes, and the quality system; (3) Identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems;
- 31. Elements of 21 CFR 820 Complaint Files Each manufacturer shall maintain complaint files. Each manufacturer shall establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit
- 32. Elements of 21 CFR 820 Device Labeling Each manufacturer shall establish and maintain procedures to control labeling activities.
- 33. Elements of 21 CFR 820 Device Packaging Each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, storage, handling, and distribution.
- 36. Elements of 21 CFR 820 Installation and Servicing Each manufacturer of a device requiring installation shall establish and maintain adequate installation and inspection instructions, and where appropriate test proceduresโฆ Where servicing is a specified requirement, each manufacturer shall establish and maintain instructions and procedures for performing and verifying that the servicing meets the specified requirements.
- 37. Elements of 21 CFR 820 Statistical Techniques Where appropriate, each manufacturer shall establish and maintain procedures for identifying valid statistical techniques required for establishing, controlling, and verifying the acceptability of process capability and product characteristics
- 38. Summary Medical device companies manufacturing and distributing medical devices in the U.S. are required to comply with the applicable laws and regulations administered by FDA FDA has the authority to inspect your company Issue a FDA 482 upon arrival This is your chance to demonstrate compliance to the FDA regulations
- 39. Summary A poor inspection can lead to difficulties including More frequent inspections A warning letter Other legal actions
- 40. Questions?
Editor's Notes
- Welcome to Module 1 of the Quality System Regulations TrainingAn Introduction to the FDA and the Quality System Regulations
- As you are probably already aware, the requirements associated with the QSR are extensive. In addition, the FDA dictates compliance with the many โrulesโ listed in the QSR but seldom provides much guidance as to how they expect the rules to be implemented into your organization. This training series breaks the QSR down into manageable components to help you understand how to work the FDAโs requirements into your own business processes.As part of todayโs training, we will:- Gain an understanding of the history of the Food and Drug Administration- Review the Quality System Regulations that dictate the requirements for distributing medical devices in the US
- As with most things, I think itโs best to start this training series at the beginning. For you, the relevant beginning probably represents the origins of the FDA.The beginning of federal involvement in healthcare began in 1798 as the public health service, which was established as part of The Act for the Relief of Sick and Disabled Seamen.In 1820, the United States Pharmacopeia or USP was established to protect product quality by standardizing the ingredients and formulae for common treatments. Only 217 drugs that met the criteria of "most fully established and best understood" were admittedIn 1862, the US Department of Agriculture took ownership of the USP documentation and employed chemists to document new compounds as they were developed or discovered.
- Regulations of medical products began in 1848 with the Drug Importation Act, which stated that customs officials had the authority to seize adulterated drugs.In 1880, Congress proposed legislation to create an agency that would regulate the food and drugs made and sold in the US โ but this was defeated.But back to adulterationโฆ for many of you, this may be a new word, and it is essential to many components of the Quality Systems Regulations and is fundamental to FDA law, so weโll take a moment to discuss it.
- By definition, an adulterant is an additive causing an undesirable effect or impurity. The FDA has a very long and elaborate version of Adulterated in:Title 21 CFR Chapter 9 โ the federal food, drug, and cosmetic act โ subchapter 5, which covers drugs and devices, has a section #351 entitled adulterated drugs and devices.The key point of this slide is to review just how seriously the FDA takes adulteration. The law has said that if the FDA determines that product or processes have the POTENTIAL to become adulterated, then the manufacturer of record is not complying with the Quality Systems Regulations. To reinforce this point, all the FDA has to do is feel that there is the potential for product to become adulterated. The FDA enforces this regulation through the use of 483- letters of observations, warning letters, and even worse โ fines and/or jail, which we will discuss in more detail in subsequent training modules.
- Ok โ back to the topic of the evolution of the FDA. Letโs fast forward to the early 20th century.You may be familiar with the novel The Jungle, which was written in 1906 by the socialist journalist Upton Sinclair.It was written about the corruption of the American meatpacking industry during the early 20th century. The novel depicts in harsh tones, the poverty, absence of social programs, and unpleasant living and working conditions present at the time. In addition, the novel demonstrated the horrific manufacturing conditions that a key component of the US food supply was being subjected to.
- Following the release of The Jungle, the public became outraged at the filth associated with this part of their food source.So along comes Dr. Harvey Washington Wiley. He was a noted chemist who conducted experiments to show how food can be the cause of illness, and how the conditions described in Sinclairโs expose could lead to a public health crisis. The confluence of the publicโs outrage and Dr. Wileyโs discovery of food-borne illness led Congress to evaluate the need for federal regulation of the food supply. Dr. Wiley is probably best known for his leadership in the passage of the landmark Pure Food and Drug Act of 1906, which required labeling on foods, and his subsequent work at the Good Housekeeping Institute laboratories.
- Despite the new legislation, the government did not have much authority to enforce the regulations stipulated by the Pure Food and Drug Act. Heeding the calls for stronger enforcement and following the trend for a stronger federal involvement throughout the economy, the Food and Drug Administration was created in 1930. Due to his strong leadership in the realm of protecting the food supply, Dr. Wiley was appointed the first commissioner of the FDA, and he saw it as a personal mission to reduce the incidence of food adulteration.After Dr. Wileyโs death, the government passed the Federal Food, Drug, and Cosmetic Act in 1938, which instituted a broader definition of drug adulteration. In addition, the legislation dictated that all new drugs were required to be approved by the FDA before they could be marketed and that any investigations into food or drug manufacturers had to be documented in written reports. At this point the drug manufacturer only had to show that the drug was safe for the intended patient population in order to gain approval.Believe it or not, it was not until 1962 that the Keefauver-Harris Drug Amendment was passed requiring drug applications to demonstrate proof of efficacy.
- Regulations pertaining to Medical Devices were not developed until the 1976 Medical Device Amendment to the Food, Drug, and Cosmetic Act.In the Medical Device Amendment, the FDA defines a medical device as any instrument, apparatus, or other article that is used to prevent, diagnose, mitigate, or treat a disease or to affect the structure or function of the body, with the exception of drugs. For example, a medical device includes but is not limited to ventilators, monitors, dialyzers, and any other electronic equipment, implants, thermometers, patient restraints, syringes, catheters, in vitro diagnostic test kits and reagents, disposables, components, parts, accessories, and related software.In addition, the 1976 device law established a regulatory system based on the degree of risk posed by a product, as classified by FDA. New high-risk products were subjected to a premarket procedure similar to that for new drugs โ this is commonly referred to as the PMA, which stands for pre-market approval. This procedure required FDA approval based on clinical experience before a device could be marketed. โMe-tooโ products and product modifications were not required to adhere to this process if the product as introduced or modified was substantially equivalent to a product on the market before the 1976 enactment date. This process is referred to as a 510(k) application, or premarket notification.High-risk products on the market prior to that date were โgrandfatheredโ but were supposed to be eventually subjected to premarket approval requirements. All products, regardless of the category of risk, were subject to a variety of controls, chief of which were adherence to good manufacturing practices and reporting of defects related to product malfunction or patient death or injury.The next obvious question is how does the FDA classify the devices? The answer is that there are 3 classes of devices. Weโll talk about Class I Medical Devices first.
- Class I devices present minimal potential for harm to the user and are often simpler in design than Class II or Class III devices. These devices are subject only to general controls. General controls cover such issues as manufacturer registration with the FDA, good manufacturing techniques, proper branding and labeling, notification to the FDA before marketing the device, and general reporting procedures.When these controls are deemed sufficient to provide reasonable assurance of the safety and effectiveness of the device; or when the device is not life-supporting or life-sustaining and does not present a reasonable source of injury through normal usage โ these devices do not require a 510(k) application. Devices in this category include tongue depressors, bedpans, elastic bandages, examination gloves, and hand-held surgical instruments and other similar types of common equipment. However, depending on the "stated/purported use" of a device, it may be necessary to obtain a Premarket Notification (510K) for the device, which is otherwise classifiable as a Class 1 device. Such devices are referred to as "reserved devices". The electrically powered arthroscope is an example of a reserved device.
- Class II Medical Devices require General Controls along with Special ControlsClass II devices are those devices for which general controls alone are insufficient to assure safety and effectiveness, and additional existing methods are available to provide such assurances. Therefore, Class II devices are also subject to special controls in addition to the general controls of Class I devices. Special controls may include special labeling requirements, mandatory performance standards, and post-market surveillance.
- Compared with Class I devices, devices in Class II are held to a higher level of assurance that they will perform as indicated and will not cause injury or harm to patient or user. Devices in this class may be non-invasive and include x-ray machines, powered wheelchairs, infusion pumps, surgical drapes, surgical needles and suture material, as well as acupuncture needles.Other examples of Class II devices include cervical plates, pedicle screws or Intervertebral Body Fusion Implants and Instruments.All Class II devices require a pre-market notification 510(k) at a minimum.
- Class III Devices require General Controls and Premarket ApprovalA Class III device is one for which insufficient information exists to assure safety and effectiveness solely through the general or special controls sufficient for Class I or Class II devices. Devices that are life-supporting or life-sustaining, approved for a use which is of substantial importance in preventing impairment of human health, or present a potential unreasonable risk of illness or injury, are categorized as Class III devices.Such a device needs premarket approval, which includes a scientific review to ensure the device's safety and effectiveness, in addition to the general and special controls of Class I and II. Examples of Class III devices which require a premarket approval include replacement heart valves, silicone gel-filled breast implants, implanted cerebral stimulators, implantable pacemaker pulse generators and endosseous (intra-bone) implants (with the exception of root-form endosseous dental implants which were recently reclassified as Class II).
- Between 1978 and the early 1990s,FDA actions includedEstablishing the requirement for process validation in 1987Establishing the regulation for tamper evident packaging for OTC products in 1992 based on the acetaminophen-capsule poisoning by cyanide, which caused 7 deathsThen as a result of the Shiley heart valve failures, congress passed the Safe Medical Devices Act of 1990 to strengthen the Medical Device Amendment of 1976.Medical device reporting is one of the US Food and Drug Administration's (FDA's) means of obtaining information on medical device problems and this legislation was key to providing FDA with authority to require reports of adverse events in addition to broadening the criteria for which adverse events needed to be reported. As part of this legislation, the FDA was given authority to add requirements for preproduction design controls and tracking of critical or implantable devices to CGMPs. The law also required notification of serious device problems by user facilities to FDA and the agency gained the ability to order device recalls.
- The FDA Quality System Regulation (QSR) 21 CFR Part 820 was published on Monday October 7th, 1996, and came into effect on June 1st, 1997, while the Design Control requirements came into full effect on June 1st, 1998. The FDA stated that this major revision was necessary to make medical devices safer and more effective. In effect, it imposed significant new requirements on device manufacturers. In many cases manufacturers have not satisfactorily established compliance with the regulation and have received adverse FDA inspections, Warning Letters and Import Alerts. According to FOI data in 2001, 56% of foreign medical device manufacturers inspected by FDA, were issued with a form 483 listing objectionable conditions and practices.The FDA says - The Quality System (QS) regulation indicates the required end result rather than specifically prescribing how a manufacturer is to comply with this regulation. It is the responsibility of the manufacturer to use good judgment when developing a quality system which appropriately applies the QS regulation to their specific products and operations. The manufacturer, not FDA, bears overall responsibility for the production of high-quality products.
- To give you some perspective on how far the FDA has come since its inception in 1930:The agency is responsible for regulating food, drug, and medical device products โ which together account for over 25% of Americanโs spendingThe FDA itself staffs over 10,000 employees and conducts over 16,000 facility inspections each yearIn 2008, this was all done with a budget of $2.1 billion โ and current political forces may result in an even bigger presence in years to come.
- As we have just discussed, the Quality System regulations have been in place since 1996; and even still medical device manufacturers struggle with how to meet the FDAโs expectations for compliance and at the same time operate and bring product to market quickly.Remember, the FDA has specifically stated that the QSRs are meant to impose restrictions on the end results, rather than taking a prescriptive approach at the individual process level. But how are you supposed to know what is required? What is expected? Which employee needs to know what?The rest of this module will provide an overview of the different sections of the QSR. Each slide will introduce a topic covered in one of the training modules that together comprise the Quality Systems Regulations training series.
- The first requirement that the FDA mandates is for the manufacturer to establish a quality system. The quality system must be appropriate to the devices being designed or manufactured and must encompass all of the components listed on the following slides.
- The requirement for management responsibility entails laying the groundwork for ensuring quality throughout the organization. This means establishing a quality policy and quality objectives and conducting management reviews on a periodic basis.Moreover, management has the responsibility to make sure that the quest for quality trickles down into every aspect of the business and is understood by every employee.
- The requirement for quality audits are the way the FDA ensures that companies have a process in place to examine their own quality system. The FDA expects that the results from the quality audit feed into other components of the quality system, such as corrective action measures and management review discussions.
- From a management standpoint, the FDA expects personnel staffed within the parts of the business governed by the quality system regulations to be sufficiently qualified to conduct their job functions. In addition, the FDA wants procedures to be in place that ensure that personnel receive training on both the QSRs and their specific activities to ensure product does not become adulterated.
- By the time you finish the series of Quality Systems Regulations training modules, you will have a better idea of just how much documentation is generated within the quality system.This requirement encompasses the stipulation for procedures to handle document creation, approval, distribution, and changes.
- Record control is also very important given the large number of records generated as part of the quality system.Two of the most important types of records generated are the Device Master Records (DMRโs) and the Device History Records (DHRโs). These will be discussed in more detail in the module covering record control.
- The element of the quality systems encompassing design controls were not enforced until 1998, 1 year after the other requirements began to be enforced. The reason for this is the large amount of work associated with establishing and following a design control process and handling all the documentation that is generated during the process.It is important to mention that the design control requirements differ based on the class of the device and that design control regulation also encompasses the requirements for risk management.
- The requirement for procedures enforcing the purchasing process is the way that the FDA ensures that received product and services conforms to specified requirements that will hopefully decrease the likelihood of adulterated product.Purchasing controls apply to suppliers, contractors, and consultants.
- Related to the purchasing process is the process receiving product and establishing acceptance status, which serves to control distribution of unacceptable product. This requirement entails the creation of acceptance criteria for each product and at each phase in the manufacturing cycle.
- Also related to product control is the process for identification and traceability of product. Through this requirement, the FDA expects the manufacturer to have procedures in place that dictate how product is identified at different stages in its production and how the product and its components are traced both before and after distribution.
- The requirement for production and process controls encompasses the stipulation for procedures to govern:- Production and process changes- Environmental control- Personnel- Contamination control- Buildings- Maintenance, Inspection, and Adjustment of Equipment- Manufacturing Materials- Automated processes, such as computer or data processing systemsIn addition, the regulations in this subpart cover the need to control Inspection, Measuring, and Test Equipment, through activities such as calibration; and also address process validation.The FDA expects that in cases where the process cannot be fully verified by subsequent inspection and test, companies should conduct process validation to establish with a high degree of assurance, that it is robust.
- The requirement for controlling nonconforming product is in place to sure that product that is unacceptable for distribution is identified, evaluated, segregated, and disposed of properly. In addition, the FDA expects that documentation and trending of these events is maintained.
- Corrective Actions and Preventive Actions, which are commonly referred to as CAPA serve the function for reducing the quantity of nonconforming product, and thus decreasing the chances that unacceptable product makes its way into the marketplace.The FDA wants to see that CAPAs are generated from a multitude of sources, such as nonconforming product events, internal audits, complaints, and other quality records. The FDA also wants to see that a root cause investigation is conducted and that actions are taken to prevent the occurrence or recurrence of the event. Finally, the FDA expects the manufacturer to establish that the actions were effective in correcting or preventing the problem.
- Complaint files, and the associated Medical Device Reports that are stipulated by 21 CFR Part 803 encompass the component of the QSR that deals with unsatisfactory product that makes it to the marketplace. The FDA expects each manufacturer to have a process in place for receiving and reviewing complaints and following up with the root cause investigation and product risk analysis.
- The FDA considers more than just the acceptibility of the product; it also wants companies to have procedures in place to control the product labeling. This includes the surgical technique documentation, the instructions for use and any other paperwork, as well as the product identification sticker.
- The section of 21 CFR Part 820 that deals with packaging is included to ensure that companies have a process in place for considering the type of packaging and shipping containers best suited to the device to protect it from damage and adulteration once ready for distribution or in the marketplace.
- The handling and storage regulations provide further regulations surrounding the need to ensure that product does not get mixed-up, damaged, deteriorated, contaminated, or otherwise affected, whether by the people who are moving the product, or the storage conditions that the product is placed in.This regulation also considers the need to ensure that obsolete, rejected, or deteriorated product is not moved from storage into the marketplace.
- The FDA also mandates that medical device manufacturers need to have procedures in place to ensure that only finished devices that have been approved for release are distributed and that any ambiguities or errors between the purchase order and product shipment are resolved before the devices are shipped.This regulation also considers the need to ensure that products that are expired or otherwise unacceptable are not distributed.
- For companies whose devices require installation, the FDA requires manufacturers to establish procedures for installation and inspection of installed devices. This is to ensure that the device performs as expected no matter who performs the installation.The FDA also requires manufacturers to develop instructions to perform applicable servicing activities, conduct trend analysis on service reports, and use service reports as an input to the complaints management process.
- This requirement relates to almost all of the previously discussed requirements, as it involves the statistical techniques used throughout the quality system. Some examples of statistical controls that need to be addressed include: control charts for nonconformance and complaint trend analysis; and reliability and reproducibility analyses and process capability analyses for process validation.
- To summarize this first module of the QSR training:Remember that you, as the manufacturer of record, are legally responsible for manufacturing and distributing your devices in compliance with the applicable sections of 21 CFR Part 820 โ the Quality Systems Regulations.As part of the law surrounding the QSRs, the FDA has the authority to periodically inspect your facilities. When doing so, they will issue a Form 482 upon arrival and have the right to document any gaps in your compliance on a Form 483 โ letter of observations when the inspection is complete.The FDA inspection is your opportunity to demonstrate that you are operating in compliance with the QSR.
- One of the best rules to keep in mind when faced with the prospect of an FDA inspection is โIf it looks good โ it is more likely to be goodโ โ this is something that most people, including FDA inspectors can relate to. Showing that you have your documents in order and that they are easily accessible during an inspection will leave the inspectors thinking that you are in control of your businessโฆ and as such, your product is less likely to be adulterated.Keep in mind that a poor inspection can lead to further difficulties down the road, such as more frequent inspections or a warning letter or other legal actions if your responses to the observations arenโt sufficient.
- This concludes the 1st module of the Quality Systems Regulations TrainingIf you have any questions about the History of the FDA or the Overview of the QSR, please do not hesitate to contact QA Consulting.