Lecture 4 - Quality System Regulation (QSR)

CORRECTIVE & PREVENTATIVE ACTION (CAPA) SUBSYSTEMS

820.100 CAPA 820.90 Nonconforming Product 820.198 Complaints 820.200 Servicing 820.250 Statistical Technique

MANAGEMENT SUBSYSTEMS

820.20 Management Responsibility 820.22 Quality Audits 820.25 Personnel

Device History File (DHF)

820.3(e) a compilation of records which describes the design history of a finished device. Each manufacturer shall establish and maintain a *__* for each type of device. This includes past versions of all the records in your Device Master Record. Assumes a fully change-controlled, systemic approach to documentation. The *___*shall maintain records to demonstrate development was in accordance with design plan and requirements of 820.30. Explains how you developed the recipe for making your device. Forms the Device Master Record.

DESIGN AND DEVELOPMENT SUBSYSTEMS

820.30 Design Controls 820.70(b) Production and Process Changes 820.181 Device Master Record 820.250 Statistical Techniques

Device Master Record (DMR)

A compilation of records containing the procedures and specifications for a finished device. It is a comprehensive record of all of the procedures and instructions required to manufacture each type of product. A *__* contains or refers to the location of documents for manufacturing and processing activities, such as procurement, processing, labeling, test and inspection, and packaging. The *__* also contains information on the design, formulation, specifications, complete manufacturing procedures, quality assurance requirements, acceptance criteria, packaging, and labeling of a finished product. All the documentation for design and manufacturing of your current product. Assumes all processes and decisions are fully documented.

HOW A DEVICE BECOMES ADULTERATED - 21 U.S.C. § 351

A device shall be deemed adulterated if the methods used in, or the facilities or controls used or controls used for, its manufacture, packing, storage or installation are not in conformity with applicable requirements under section 360j(f)(1) Section 360j(f)(1) provides that FDA may ― prescribe regulations requiring that the methods used in, and the facilities and controls used for, the manufacture, pre-production design validation (including a process to assess the performance of a device but not including an evaluation of the safety or effectiveness of a device), packing, storage, and installation of a device conform to current good manufacturing practice, as prescribed in such regulations, to assure that the device will be safe or effective otherwise in compliance with this Act.

DESIGN REVIEW

A documented, comprehensive, systematic examination to: • Evaluate adequacy of the design requirements. • Evaluate capability of the design to meet requirements. • Identify problems. • Ensure that formal reviews of design results are planned and conducted at appropriate stages. • Ensure participants include representatives of all functions concerned with design stage being reviewed. • Document results in the Design History File (DHF). • Occur throughout the design process.

QUALITY MANAGEMENT SYSTEM

A manufacturer must develop a Quality Management System (QMS) commensurate (in proportion) with: • risk presented by the device • complexity of device and manufacturing processes • size and complexity of organization There is a great deal of variability between companies in QMS sophistication and complexity.

HYPOTHETICAL CASE

You work for a Company (FFGC) that makes latex examination gloves (non-sterile). FFGC designed the gloves. The company sources its raw materials from various companies and then prepares the polymer mixture and forms the gloves. Your gloves have received 510(k) clearance and are currently on the market in the US. The latex supplier, the Lucky Latex Company (LLC), notifies you that in July 2016, it changed the composition of the latex that FFGC purchases for its gloves. Does FFGC need to take any actions? Yes. You are out of compliance with the FDA. You will need to file a threshold 510 (k) and will also need to focus on period of time you were not in compliance. You need to figure up how to remedy the issue and consult with the FDA to see if there will be any ramifications due to lapse. Update DMR/DHR/DHF, CAPA, Risk assessment, look at complaint file, create new labeling since composition changed, change purchase control, make sure progress verification and validation are still checked, look at impact on on shelf life etc., audit the supplier,

QSR 820.3 Definition of Establish

Means define, document (in writing or electronically), and implement.

COMPLAINT FILES (820.198)

All manufacturers - including QSR - exempt ones - must • Maintain complaint files. • Designate a formal complaint handling unit. • Establish and maintain procedures for receiving, reviewing, and evaluating complaints.

QSR 820.3 Definition of Finished Device

Any device or accessory to any device that is suitable for use or capable of functioning, whether or not it is packaged, labeled, or sterilized. It is not always obvious what is a "finished device."

QSR 820.3 Definition of Manufacturer

Any person who designs, manufactures, fabricates, assembles, or processes a finished device. This includes but is not limited to those who perform the functions of contract sterilization, installation, relabeling, re-manufacturing, repacking, or specification development, and initial distributors of foreign entities performing these functions. Note the breadth of the definition: a company can be a "defined term" without making anything.

Purchasing Controls (820.50) Supplier

Anyone that is independent from the manufacturer's quality management system and not a part of their Quality Audit (internal or external). • Some *___* are more critical than others; there can be different procedures for different classes.

CORRECTIVE AND PREVENTATIVE ACTION (CAPA) (820.100)

Collect and analyze data to identify nonconforming product and other quality problems • Investigate cause. • Identify and implement corrective and preventive action. Verify and validate actions and effectiveness • Communicate information on the quality problems and the necessary actions to appropriate staff. • Forward information to management review. • Companies often fall short in the verification phase. • *___* need to be closed in a timely manner; FDA has cited many companies for languishing *___*

DESIGN OUTPUT

Define and document design output in terms that allow evaluation to design input. Reference acceptance criteria. These need to be clear and precise. Identify design outputs essential for the proper functioning of device. Document, review, and approve design outputs before release. Results of design effort at each phase and the end of the total design effort. Finished design *__* is basis for the Device Master Record.

DESIGN AND DEVELOPMENT PLANNING

Describe design and development activities. Define responsibility for implementation. Identify and describe interfaces between different groups or activities. Review, update, and approve plans as design and development evolves. To be done at the start of design controls - in the transition between research and development. Useful to address potential risks - including the degree of hazard - associated with the device.

DESIGN CHANGES

Designs are not static. Controlling and documenting design changes can be crucial in demonstrating that a product change does not require a new 510(k). Identify, document, validate or verify, review, and approve design changes before implementation.

Document Controls (802.40)

Each manufacturer shall establish and maintain procedures to control all documents that are required by this part. • Review and approval of all documents prior to issuance. • Review and approval of all changes to documents. • Who has the authority to change documents? • Maintain records of changes. • Delete obsolete versions of documents so they cannot be used. • Don't want multiple versions of a document circulating.

Device History Record (DHR)

Each manufacturer shall maintain *___*. Each manufacturer shall establish and maintain procedures to ensure that *___*for each batch, lot, or unit are maintained to demonstrate that the device is manufactured in accordance with the device master record and the requirements of this part. The *___* shall include, or refer to the location of, the following information: All your production batch records. Assumes that nothing happens in manufacturing without appropriate work orders, and that all actions and decisions are documented *___* is the evidence that a particular unit, batch or lot of devices was made according to the recipe. (a) The dates of manufacture; (b) The quantity manufactured; (c) The quantity released for distribution; (d) The acceptance records which demonstrate the device is manufactured in accordance with the DMR; (e) The primary identification label and labeling used for each production unit; and (f) Any device identification(s) and control number(s) used.

DESIGN INPUT

Ensure requirements are appropriate and address intended use of device. Address incomplete, ambiguous, or conflicting requirements. Document, review, and approve input requirements. Design Inputs initially developed and approved during the early stage of design controls

MANAGEMENT SUBSYSTEMS 820.22 Quality Audits

Establish procedures for quality audits. Conduct audits to assure compliance by individuals not having direct responsibility for areas audited. Perform corrective action(s), including re-audit of deficiencies. Generate a written report of audit results for management review. Practical Issue: What happens to address audit findings. Legal Issue: FDA's access to audit reports.

MANAGEMENT SUBSYSTEMS 820.25 Personnel

Hire sufficient personnel with necessary education, background, training, and experience. Establish procedures for identifying training needs and to ensure personnel are adequately trained. Document training. Make personnel aware of device defects that could occur from improper job performance. Make personnel aware of defects and errors that could be encountered as part of their job. NB: Training is key; many failures relate to inadequate training.

DESIGN VALIDATION

Means establishing by objective evidence that device specifications conform with user needs and intended use(s). Validate the device design. Perform under defined operating conditions on initial production units or equivalent. Ensure devices conform to defined user needs and intended uses. Test of production units under actual or simulated use conditions. Perform software validation and risk analysis, where appropriate. Document results in the DHF.

MANAGEMENT SUBSYSTEMS 820.20 Management Responsibility

Quality Policy • Must be established by management with executive responsibility. • Must be understood, implemented, and maintained at all levels of the organization. Must establish and maintain an adequate organizational structure, including: • Appropriate responsibility, authority, and interrelation of personnel. • Adequate resources. • Appointed management representative. Management Review Management with executive responsibility shall review the suitability and effectiveness of the quality system • At defined intervals. • With sufficient frequency - at least annually. • According to established procedures. Management Representative • Member of management. • Responsible for ensuring establishment of quality system and reporting on quality system performance to management with executive responsibility. As functional matter, role of management is critical.

QSR - SCOPE

Regulations apply to finished devices, § 820.1(a)(1). The regulations do not apply to manufacturers of components or parts of finished devices, but such manufacturers are encouraged to use applicable Part 820 provisions as guidance. Applicable to servicing done by manufacturers but not to work done by third-party service organizations. QSR uses broad terms such as "where appropriate," "adequate," and "suitable." • This naturally leads to questions of interpretation. Manufacturers of Class II and III devices must comply with QSRs. Some Class I devices also subject to QSRs. • 868.6810 Catheter, Tracheobronchial Suction • 878.4460 Glove, Surgeon's • 880.6760 Restraint, Protective • 892.5650 System, Applicator, Radionuclide, Manual • 892.5740 Source, Radionuclide Teletherapy Other Class I devices exempted by regulation from QSRs except for provisions relating to complaints.

Design and Development Subsystem: DESIGN CONTROLS (820.30)

Since 1984, the FDA has identified lack of design controls as one of the major causes of device recalls. The SMDA provided the FDA with the authority to add preproduction design controls to the device GMP regulation. The design control requirements are not intended to apply to development of concepts and feasibility studies. FDA will evaluate the process, the methods, and the procedures that a manufacturer has established to implement the requirements for design controls. Design controls are a significant amount of work Applicable to all class II and III and the following class I devices • Devices automated with computer software • Tracheobronchial suction catheters • Surgeon's gloves • Protective restraints • System, radionuclide applicator, manual • Source, radionuclide teletherapy

BASIC TENETS

Some basic principles employed in the QSR and FDA's interpretation may seem counter-intuitive: • Good science ≠ FDA science. • "Quality Product" does not mean it was designed and manufactured in compliance with FDA's "Quality System" requirements. • If it was not documented, it was not done (even if it actually was done). • A device can be "adulterated" even though it works perfectly and is not unsafe.

DESIGN TRANSFER

Sometimes a device is transferred from one facility to another. Ensure the device design is correctly translated into production specifications.

DESIGN VERIFICATION

Verify the device design. Confirm that design output meets design input requirements. • Design Output = Design Input. Document results in the DHF. May occur more than once throughout the design process.

Purchasing Controls (820.50) Internal Supplier

• An internal supplier: • Part of the manufacturer's organization. • Operates under a separate quality management system. • Not part of the manufacturer's internal audit scope (quality audit). • Internal suppliers are to be controlled in a similar way as external suppliers. • Both internal and external suppliers are required to be controlled under 21 CFR 820.50.

KEY CAPA ELEMENTS

• Correction • Corrective action • Preventative action • A good CAPA process will have all three elements. NB: A good CAPA process will open a window into a company's problems.

KEY CAPA ELEMENTS - Corrective Action

• Elimination of the causes of an existing nonconformity. • Identify and eliminate the causes of existing nonconforming product and other quality problems.

KEY CAPA ELEMENTS - Preventative Action

• Identify and eliminate the causes of potential nonconforming product and other quality problems.

PURCHASING CONTROLS (802.50)

• Many companies encounter QSR issues because of products from suppliers. • Establish and maintain procedures to ensure that all purchased or otherwise received product and services conform to specified requirements. • Evaluate suppliers, contractors, and consultants. • How to handle suppliers that have quality issues. • Establish and maintain purchasing data/documents that describe or reference specified requirements (including notification of change agreements). • Approve purchasing data/documents.

QSR (Quality System Regulation)

• One of the "general controls." •Provides framework of basic requirements for manufacturers to follow. • One of the most important areas of enforcement activity. • Very broad regulations which need to be implemented through very precise policies and enforcement action. • QSR non-compliance can occur even if product quality is high. • There can be a tension between QSR compliance and a company achieving its sales objectives. • Achieving complete compliance is exceedingly difficult. • Effective June 1, 1997, replacing the 1978 GMP for medical devices. • Preamble to the 1997 regulation - important background. • Requirements are not prescriptive.

Potential Consequences for Failure to Comply with QSR

• Recall • Warning letter • Import Detentions • Seizure of product • Refusal to approve product/withdrawal of product approval • Consent decree/disgorgement of profits • Injunction • Application Integrity Policy • Criminal investigation, indictment and prosecution • Product liability implications • Reputation • Customer satisfaction

KEY CAPA ELEMENTS - Correction

• Repair, rework, or make adjustments that relates to the disposition of an existing nonconformity. • Identify and correct existing nonconforming product or other quality problems.