Quality System Regulation (QS Reg) for Laboratory-Developed Tests (LDTs) – CLSI

Disclaimer: This post is for academic purposes only. Please read the original document if you intend to use them for clinical purposes.

This document summarizes the main themes and important ideas presented in the provided excerpts from the Clinical and Laboratory Standards Institute (CLSI) document “Quality System Regulation for Laboratory-Developed Tests: A Practical Guide for the Laboratory.” It is intended to assist laboratories that design, manufacture, and use LDTs in understanding and implementing the US FDA’s Quality System Regulation (QSReg), 21 CFR Part 820. A significant development highlighted in the introduction is the FDA’s final rule, published on May 6, 2024, establishing LDTs as medical devices under the Federal Food, Drug, and Cosmetic Act, thereby making them subject to QSReg requirements for certain classifications.

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Main Themes and Important Ideas:

–Applicability of QSReg to LDTs:

• The guide focuses on how the QSReg, typically applicable to medical device manufacturers, now extends to laboratories developing certain LDTs. The FDA issued draft guidance in 2014 and a final rule on May 6, 2024, solidifying this regulatory oversight.
• While some LDTs offered under enforcement discretion categories may have differing levels of immediate required compliance, the expectation is that a significant portion of LDTs will fall under these regulations based on their risk classification (Class II or III analytes or automated Class I devices).
• The term “manufacturer” in this context refers to the laboratory that is preparing and using the LDT. The “product” refers to the components of the LDT, such as reagents.

–Quality Management System (QMS) and Quality Plan:

• A fundamental requirement is establishing and maintaining a QMS.
• Manufacturers (laboratories) must establish a quality plan which defines the quality practices, resources, and activities relevant to devices that are designed and manufactured. The manufacturer shall establish how the requirements for quality will be met.
• This plan can be specific to a single LDT or generic to all LDTs manufactured and may serve as a roadmap of the quality system, referencing relevant quality system documentation.

–Key QSReg subparts and their application to LDTs:

The document outlines various subparts of the QSReg and provides practical guidance for their implementation in an LDT setting. Key areas covered include:

• Management Responsibility: Ensuring management commitment and establishing a quality plan.
• Quality Audit : Conducting systematic and independent audits to assess QMS compliance and suitability. Audits must be performed by qualified individuals not involved in the audited area. An annual audit plan is part of a good QMS.
• Personnel: Providing adequate resources and trained personnel.
• Design Controls : A critical aspect for certain LDTs, encompassing planning, input, output, review, verification, validation, transfer, changes, and the Design History File (DHF). Certain LDTs under enforcement discretion do not currently need to comply with design controls. The design process includes verification (i.e. confirm that design requirements have been met) and validation (i.e. prove that the test is fit for its purpose).
• Document Controls: Establishing procedures for the approval, distribution, and control of all required documents.
• Purchasing Controls: Evaluating and selecting suppliers, defining control over them, maintaining an approved supplier list, and ensuring purchasing data clearly describes quality requirements. Suppliers should agree to notify the manufacturer of changes that may affect product quality.
• Identification and Traceability: Implementing systems to identify reagents, components, and the finished test throughout the process. For LDTs, this means that the laboratory is responsible for creating a system for identifying every lot of reagent that is made, every component and raw material that went into the reagent, the finished test, etc. Traceability for reagent components is distinct from the Traceability of measurement results in a clinical lab.
• Production and Process Controls: Defining and controlling all manufacturing steps, including reagent formulation, equipment use, and environmental conditions, to ensure the LDT conforms to specifications. The main objective of production and process controls is to ensure that manufacturing procedures have been defined for making an LDT for use in patient testing. Compliance with relevant reference standards or codes (e.g., CLSI guidance) must be established.
• Acceptance Activities and Acceptance Status: Establishing procedures for receiving, in-process, and finished device acceptance to ensure conformance to specifications.
• Non-conforming Product: Establishing procedures for identifying, documenting, evaluating, and dispositioning nonconforming products. Rework requires retesting and reevaluation.
• Corrective and Preventive Action (CAPA): Implementing procedures for identifying and addressing root causes of nonconformities and preventing their recurrence.
• Labeling and Packaging Controls: Controlling the design, selection, testing, and inspection of labels and packaging to ensure integrity and accuracy. Even though LDT reagents are not typically distributed externally, in-house labeling must be controlled.
• Handling, Storage, Distribution, and Installation: Establishing procedures for these activities to maintain the stability and quality of LDT components. For LDTs, distribution control focuses on assigning lot numbers for internal tracking. Installation procedures are necessary for equipment and reagent loading.
• Records: Maintaining various records, including the Device Master Record (DMR), Device History Record (DHR), and Quality System Record (QSR), to provide evidence of QMS implementation and product history. The DMR contains procedures and specifications, while the DHR documents the manufacturing history of a specific lot or batch. Records must be legible, stored to prevent deterioration or loss, and readily accessible.
• Complaint Files: Establishing procedures for receiving, reviewing, and investigating complaints.
• Servicing: Establishing procedures for servicing, although the direct applicability to in-house used LDTs might be limited but could relate to instrument maintenance.
• Statistical Techniques: Identifying and using valid statistical techniques for establishing, controlling, and verifying process capability and product characteristics, including written and statistically rational sampling plans.

–Importance of Documentation: Throughout the guide, there is a strong emphasis on establishing and maintaining documented procedures, records, and plans as evidence of compliance with the QSReg.

–Risk-Based Approach: The classification of LDTs into Class II (moderate risk) or Class III (high risk) based on the potential health consequences of erroneous results underscores a risk-based approach to regulation.

–Supplier Management: Manufacturers must evaluate and monitor their suppliers based on their ability to meet quality requirements. Change control processes are required for changes to supplier products or services.

–Statistical Justification: When establishing performance specifications or designing sampling plans, statistical rationale is crucial.

Conclusion:

The excerpts from the CLSI guide clearly indicate the expanding regulatory landscape for laboratories involved in developing and using LDTs. The FDA’s final rule establishing LDTs as devices necessitates a comprehensive understanding and implementation of the Quality System Regulation (21 CFR Part 820) for many laboratories. This briefing highlights the key areas of focus, including the establishment of a robust QMS, adherence to design controls (where applicable), meticulous documentation practices, effective supplier management, and the application of statistical techniques. Laboratories must familiarize themselves with the specific requirements based on the risk classification of their LDTs and proactively implement the necessary procedures to ensure compliance.

_{Citation: CLSI. Quality System Regulation for Laboratory-Developed Tests: A Practical Guide for the Laboratory. CLSI document QSRLDT. Clinical and Laboratory Standards Institute; 2024}