The Quality System Regulations RMRAS - June, 2016

Introductions

Brian Schwarz Senior Manager Quality Management Systems, Terumo BCT Brian oversees the Audit (Internal, External, and Supplier), CAPA, and Management Responsibility processes.  Prior to joining Terumo BCT, he spent 10+ years as Quality Engineering Manager for Becton Dickinson, where he managed a team focused on validation, incoming and in-process QA, new product / process development, and Continuous Improvement.  Brian is a Six Sigma Master Black Belt, and has extensive experience in Quality Engineering and compliance readiness and remediation. 

Matthew Bickford Quality Manager, Terumo BCT Matthew is a Colorado native with a diverse background in the Pharma, Biotech, and Medical Device industries.  After graduating with a degree in Molecular, Cellular, and Developmental Biology and Biochemistry, his career began in pharmaceutical manufacturing and product development.  He then moved into biotech as a validation professional before his current role as Quality Manager at Terumo BCT, where he works within the Quality Management System group and specifically oversees the global recall and adverse event processes.  Matthew has 15+ years of experience in FDA regulated product industries and has a graduate degree in Engineering Management with an emphasis in new product ventures and process development. 

Rod Lenoble Senior Quality Manager, Terumo BCT Rod has over 25 years of experience in the medical device and pharmaceutical industries, focusing on Quality Management Systems (development, implementation, and management), laboratory management (chemistry, microbiology, and calibration), and FDA and ISO compliance.  Over his career, he has gained substantial experience in developing and improving quality system processes for compliance with FDA and ISO. Rod has developed, implemented, and managed CAPA systems, Non-conformance systems, Training systems, Global QMS systems, and has set up and managed numerous chemistry, microbiology, and calibration laboratories.  Rod received his Masters of Business Administration from the University of Phoenix and his Bachelor of Science in Chemistry from State University of New York College at Oneonta.  Prior to joining Terumo BCT, Rod was the Technology Director for Hauser Inc, an Active Pharmaceutical Ingredients manufacture.  

Participant Introductions Name Company Position Specific section of the regulation that you are especially interested in or have specific questions.

Introduction to the Quality System Regulation Course

Course Contents 21 CFR 820 Quality System Regulation Overview course Basic understanding and knowledge of each section of the regulation. Interpretation of the regulations Practical recommendations for compliance. Consequences of non-compliance.

Not included in Course Content There are many FDA and international regulatory requirements beyond 21 CFR 820 that medical device companies must comply with: 21 CFR 4 cGMP Requirements for Combination Products 21 CFR 11 Electronic Records; Electronic Signatures 21 CFR 801 Labeling 21 CFR 803 Medical Device Reporting 21 CFR 806 Corrections and Removals 21 CFR 807 Establishment Registration, Device Listings, 510(k) Premarket Clearance 21 CFR 809 In Vitro Diagnostics 21 CFR 810 Medical device recall authority 21 CFR 812 Investigational device exemptions 21 CFR 814 Premarket approval of medical devices 21 CFR 821 Medical device tracking requirements 21 CFR 822 Postmarket surveillance ISO 13485 Medical devices - Quality management systems ISO 14971 Medical devices - Application of risk management to medical devices ISO 17025 General requirements for the competence of testing and calibration laboratories Reference may be made in our presentations, but in depth discussion is beyond the scope of this course.

Quality System Regulation vs. ISO 13485 Although the Quality System Regulation is “harmonized” with ISO13485, the interpretation and compliance expectations of the FDA are dramatically different from your notified body. FDA Performs inspections for the purpose of determining compliance to federal regulations. FDA inspectors carry badges. FDA has many legal actions they can take to enforce compliance. Do not assume that having ISO 13485 certification and successful ISO audits means that you will meet FDA’s compliance expectations.

Conventions Used in Presentation

Conventions Used in the Presentation Regulations Interpretation and recommendations for compliance

Conduct of the Course Interactive Course Materials Provided Participation is expected and encouraged Course Materials Provided Slides 21 CFR 820 Quality System Regulation

Quality System Regulation -Background and History

Food and Drug Administration (FDA) Department of Health and Human Services (HHS) Food and Drug Administration (FDA) Center for Devices and Radiological Health (CDRH) Office of Compliance Field Inspections Recalls Enforcement

FDA Responsibilities Protecting the public health by assuring the safety, efficacy and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation. Advancing the public health. Regulating the manufacturing, marketing and distribution of tobacco products. Counterterrorism: Ensuring the security of the food supply. Fostering development of medical products to respond to deliberate and naturally emerging public health threats.

FDA Enforcement Actions - Authority to Protect Public Health Inspection Voluntary Corrections FD-483 Notice of Observations Untitled Letters Warning Letters Mandatory Corrections Mandatory Recall Injunctions/ Seizures Consent Decrees Legal Action Civil Money Penalties Criminal Indictments

FDA Inspections and QSIT QSIT – Quality System Inspection Technique Inspectional process that is used to assess a medical device manufacturer’s compliance with the Quality System Regulation and related regulations. 4 Major Subsystems Management Controls (MGT) Design Controls (DES) Corrective and Preventive Actions (CAPA) Production and Process Controls (P&PC)

FDA Inspections and QSIT Within each subsystem, provides: Inspection Objectives Decision flowchart Narrative The QSIT Manual is available on the FDA website: www.fda.gov/iceci/inspections/inspectionguides/ucm074883.htm

CTQ Inspection Technique Suplements the QSIT Technique Focus on key attributes of a product (CTQ’s) How are user needs identified, incorporated into design, and managed through product life cycle?

Regulatory Hierarchy Federal Laws Federal Regulations (CFR) Guidance Documents

Federal Law Enacted by Congress Federal Food Drug and Cosmetic Act (FFD&C) Civil and Criminal act Violations of the Act can be tried in Civil or Criminal court Both Companies and Individuals can be held liable for violations of the Act.

Code of Federal Regulations (CFR) Implementation of Federal Laws Written by the governing agency Published in the Federal Register Proposed Rule Notice and Comment Period Final Rule Preamble to the Final Rule 21 CFR 820 Quality System Regulation www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Postmarke tRequirements/QualitySystemsRegulations/ucm230127.htm Intent of Congress and FDA Purpose of the Regulation Response to Comments- provides insight into FDA interpretation Legally binding in a court of law

Guidance Documents Do not have the legal force of Law or Regulation “Contains Nonbinding Recommendations” “FDA's guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.” Informative Express the Agency’s position Interpretation of the regulations Roadmap for compliance

Quality System Regulation - History The quality systems regulations for medical devices were originally known as current good manufacturing practices (cGMP’s). cGMP requirements for medical devices were first authorized by the 1976 Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act. 21 CFR 820, prescribing cGMP requirements for medical devices, became effective in 1978. Only governed the manufacturing of medical devices. No authority over the design of medical devices.

Quality System Regulation - History Safe Medical Devices Act of 1990 Authorized revisions to cGMP Design Controls 44 percent of the quality problems that led to voluntary recall actions during 1983-1989 were attributed to errors or deficiencies in device design. Over 90 percent of all software related device failures were due to design-related errors, generally, the failure to validate software prior to routine production. Management Review Harmonization with ISO 13485 Quality System Regulations (21 CFR 820) Published 1996 , Effective 1997

Flexibility of the Quality System Regulation The regulation is a framework that specifies the requirements that each manufacturer must incorporate into their quality management system. The regulation does not prescribe how to implement the requirements. Within the regulation framework, each manufacturer must develop a quality management system that is appropriate to their devices and business: Risk class of the device Type of device Sterile> Process Controls (e.g. controlled environments, sterilization validation) Software> Design Control (e.g. software development and validation) Complexity of the device Complexity of the manufacturing process Size of the organization

CDRH Inspections

Warning Letters Are Public Info http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/

Quality System Regulation - Content

Quality System Regulation -Content Acceptance Activities Management Responsibility Non-Conforming Product Quality Audit Corrective and Preventive Action Personnel Labeling and Package Control Design Controls Handling, Storage, Distribution and Installation Document Controls Records Purchasing Controls Servicing Identification and Traceability Statistical Techniques Production and Process

Quality System Regulation

Quality System Regulation Definitions of “System”: “A set of connected things or parts forming a complex whole.” “A group of related parts that work together as part of an interconnecting network” The individual requirements of the regulation do not standalone. They are interdependent, providing inputs and outputs to other requirements or subsystems. As we discuss each section of the regulation, we will point out how that section links with other requirements of the regulation.