QSRLDTE

Quality System Regulation for
Laboratory-Developed Tests
A Practical Guide for the Laboratory
Licensed to: Isabela Liana Tincu

This document is protected by copyright. CLSI order #Ord-1224387, Downloaded on 5/6/2024.
Quality System Regulation for Laboratory-Developed Tests
Acknowledgment
CLSI gratefully acknowledges the contributing authors of this practical guide:
Taunya Alexander, CQA Penny Keller, BS, MB(ASCP) Luann Ochs, MS

BD Diagnostics Centers for Medicare & Medicaid Clinical and Laboratory
Services Standards Institute
Karen Baggett
Janssen Diagnostics Inc. Leanne M. Kiviharju Peter J. Scott
Alere, Inc. Abbott Point of Care Inc.
Lucia M. Berte, MT(ASCP)SBB, DLM;
CQA(ASQ), CMQ/OE Fred D. Lasky, PhD Melissa Triebell, RAC
Laboratories Made Better! LASKY Consulting Parallel 6, Vision Clinical Research
Patricia Garrett, PhD Morteza Minaee, BS, MS, LPD Tonya Wilbon, BS, M(ASCP)
Pat Garrett Consulting Roche-Ventana Medical Systems FDA Center for Devices and Radiological
Health
Jacalyn James, MLT(ASCP), BS
Ortho-Clinical Diagnostics, Inc.
CLSI gratefully acknowledges the special reviewers of this practical guide:
David G. Grenache, PhD, DABCC, FACB W. Gregory Miller, PhD

University of Utah and ARUP Virginia Commonwealth University
Laboratories
James H. Nichols, PhD, DABCC, FACB
Patricia A. Maloney Vanderbilt University Medical Center
Quest Diagnostics
The Clinical and Laboratory Standards Institute consensus process, which is the mechanism for moving a document through two
or more levels of review by the health care community, is an ongoing process. Users should expect revised editions of any given
document. Because rapid changes in technology may affect the procedures, methods, and protocols in a standard or guideline,
users should replace outdated editions with the current editions of CLSI documents. Current editions are listed in the CLSI catalog
and posted on our website at ww.clsi.org.
If you or your organization is not a member and would like to become one, and to request a copy of the catalog, contact us at:
P: 610.688.0100 F: 610.688.0700 E: customerservice@clsi.org W: www.clsi.org.

Copyright ©2015 Clinical and Laboratory Standards Institute. Except as stated below,
any reproduction of content from a CLSI copyrighted standard, guideline, companion
product, or other material requires express written consent from CLSI. All rights
reserved. Interested parties may send permission requests to permissions@clsi.org.
CLSI hereby grants permission to each individual member or purchaser to make a

single reproduction of this publication for use in its laboratory procedure manual at a
single site. To request permission to use this publication in any other manner, e-mail
permissions@clsi.org.
Suggested Citation
CLSI. Quality System Regulation for Laboratory-Developed Tests: A Practical Guide for
the Laboratory. CLSI document QSRLDT. Wayne, PA: Clinical and Laboratory Standards
Institute; 2015.
ISBN 1-56238-991-2 (Print)

ISBN 1-56238-992-0 (Electronic)
ISSN 1558-6502 (Print)
ISSN 2162-2914 (Electronic)
ii
Table of Contents
Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . i
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iv
Abbreviations and Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v
Chapter 1: Management Responsibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Chapter 2: Quality Audit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Chapter 3: Personnel. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
Chapter 4: Design Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
Chapter 5: Document Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
Chapter 6: Purchasing Controls. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
Chapter 7: Identification and Traceability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
Chapter 8: Production and Process Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Chapter 9: Nonconforming Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Chapter 10: Corrective and Preventive Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Chapter 11: Labeling and Packaging Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Chapter 12: Handling, Storage, Distribution, and Installation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
Chapter 13: Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
Chapter 14: Complaint Files . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Chapter 15: Servicing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85
Chapter 16: Statistical Techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 93
Appendix A. US Food and Drug Administration Quality System Regulation—21 CFR Part 820 . . . . . . . 94
Appendix B. Crosswalk: Quality System Essentials to 21 CFR Part 820 (Quality System Regulation)
and 42 CFR Part 493 (Clinical Laboratory Improvement Amendments) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
Appendix C. Supplier Qualification Survey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116
Related CLSI Reference Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
iii
Introduction
This practical guide is intended for the laboratory that is creating laboratory-developed tests (LDTs) that
may be subject to the US Food and Drug Administration (FDA) regulations, specifically the Quality System
Regulation (QSReg), 21 CFR Part 820. LDTs are those in vitro diagnostic devices that are intended for clinical use
and are designed, manufactured, and used within a single laboratory. This practical guide is intended to clarify
how to implement the QSReg that may be required for some classifications of LDTs. On October 3, 2014, the
FDA issued draft guidance for regulating LDTs that included notification or registration of LDTs with the FDA,
reporting adverse events, and other requirements. This document only addresses the QSReg that is currently
applicable to manufacturers and is expected to become applicable for some classifications of LDTs when the
final guidance is published.
CLSI solicited the help of experts from the in vitro diagnostics industry in compiling this guide. These experts
have many years of experience in complying with FDA regulations and succeeding with FDA inspections.
The QSReg can be difficult to understand, so the experts explained each section in plain language. The
regulation is compared, where appropriate, to the Clinical Laboratory Improvement Amendments (CLIA)
regulations. Similarities and differences are identified. This guide attempts to answer the question: “What does
the QSReg require, above and beyond what we already do for CLIA?”
Because regulation language can sometimes leave room for interpretation, tips and hints are provided to give
the reader ideas about methods for complying that have proven effective. In addition, brief explanations are
provided for several terms used in this guide:
Class I, II, or III: FDA categorizes laboratory tests by novelty and risk of harm to a patient, should an
erroneous result be acted upon. Well-characterized tests with very low risk are typically class l; tests with
moderate risk are typically class II; and novel tests with high or unknown risk are typically class III. FDA
intends to regulate the higher risk tests first.
Manufacture: the process of preparing the LDT for use; eg, measuring and mixing chemicals to make a
reagent.
Manufacturer: the laboratory that is preparing and using the LDT.
Product: the components of the LDT; eg, the reagents.
Validation and verification: FDA uses these terms a bit differently from CLIA. For CLIA, manufacturers
validate the test and the laboratories verify its performance characteristics before use. For LDTs, the
laboratory is the manufacturer, and must validate (prove) that the test is fit for its purpose. The validation
may involve conducting studies with patient samples (clinical studies), and comparing the LDT results to
patient outcomes or other patient-related parameters. Each new lot of LDT reagent can then be verified to
function correctly.
Throughout this document we use icons to draw the reader’s attention to important points. The icon
indicates clarifying or additional information. The icon indicates important points that need to be
considered to meet the QSReg requirements.
This practical guide is not intended to replace the QSReg, nor does it in any way usurp the authority of FDA’s
regulations or guidance documents.
For the reader’s convenience, the text of the QSReg is included in its entirety in Appendix A. A crosswalk
between the QSReg, the CLIA regulations, and the CLSI quality system essentials is included in Appendix B.
iv
Abbreviations and Acronyms
BOM bill of materials R&D Research and Development

CAP College of American Pathologists RPM revolutions per minute
CAPA corrective and preventive action SOP standard operating procedure
CFR Code of Federal Regulations UDI unique device identifier
CLIA Clinical Laboratory Improvement UPC universal product code
Amendments
CMS Centers for Medicare & Medicaid
Services
CV/%CV coefficient of variation/percent
coefficient of variation
DHF design history file
DHR device history record
DMR device master record
FDA US Food and Drug Administration
GCP good clinical practice
HCl hydrochloric acid
HEPA high-efficiency particulate air
HR human resources
HVAC heating, ventilation, and air
conditioning
IVD in vitro diagnostic
LDT laboratory-developed test
MDR medical device reporting
NaOH sodium hydroxide
NIST National Institute of Standards
and Technology
QA quality assurance
QC quality control
QMS quality management system
QSE quality system essential
QSR quality system record
QSReg Quality System Regulation
v
This page is intentionally left blank.
vi
1 Management
Responsibility

1 Chapter 1: Management
Responsibility (§ 820.20)
A good quality system is not possible without full management support. The
FDA QSReg has specific requirements for the organization’s management, which
address both responsibilities and actions.
Requirement
§ 820.20(a): Quality policy. 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.
CLIA defines that the laboratory director is responsible for ensuring that QC and
quality assessment programs are established and maintained, to ensure the
quality of the laboratory services provided and to identify failures in quality as
they occur (42 CFR § 493.1445[e][5]).
CLIA requires policies and procedures specific to quality (42 CFR § 493.1200). CLIA
Management with
executive responsibility
means a senior employee (eg,
laboratory director) who has
the authority to establish and
make changes to the quality
policy and quality system.
also requires laboratories to have a quality policy (42 CFR § 493.1239[a]; 42 CFR
§ 493.1231 to § 493.1236). This policy is usually a few statements, for example:
“We will provide high-quality products by ensuring our laboratory-

developed tests have good design, excellent technical performance,
and actionable test results. We will strive to continuously improve
our products, maintain our quality system, and meet all applicable
regulatory requirements.”
© Clinical and Laboratory Standards Institute. All rights reserved. 1

Quality System Regulation for Laboratory-Developed Tests Chapter 1: Management Responsibility
It is important that the The quality policy should reflect the goals of the laboratory’s quality system
quality policy be visible in crisp language that is meaningful for the laboratory staff as well as the
throughout the facility and laboratory’s stakeholders and investors. When developing the policy, consider
widely communicated to all adding elements addressing:
levels of the organization. The laboratory’s commitments to its customers and patient safety
Leadership’s commitment to good professional codes and standards
The quality of the laboratory’s services
Commitment to compliance with the standards and requirements for QMS
Leadership’s commitment to compliance with applicable regulations
and/or obligatory standards
The laboratory’s standard of service
Every laboratory staff member should be able to state the quality policy when
asked. Because it does not need to be memorized, it can be printed on the back of
entry badges and/or posted in conspicuous places—anywhere that is immediately
accessible to staff members.
Requirement
§ 820.20(b): Organization. Each manufacturer shall establish and maintain an
adequate organizational structure to ensure that devices are designed and
produced in accordance with the requirements of this part.
CLIA has organizational requirements that cover the laboratory testing process,
It is important that the
but not necessarily the designer/manufacturer of tests. For example, 42 CFR
quality manager (or
§ 493.1445(e)(11) states that laboratories must “Employ a sufficient number of
those people responsible for
laboratory personnel with the appropriate education and either experience or
the release of the LDT) is
training to provide appropriate consultation, properly supervise and accurately
independent from (ie, does not
perform tests and report test results in accordance with the personnel
report to) the operation
responsibilities described in this subpart;” and, in Section (e)(15): “Specify, in
manager (the person
writing, the responsibilities and duties of each consultant and each supervisor, as
responsible for the
well as each person engaged in the performance of the preanalytic, analytic, and
manufacturing of the LDT).
postanalytic phases of testing, that identifies which examinations and procedures
each individual is authorized to perform, whether supervision is required
for specimen processing, test performance or result reporting and whether
supervisory or director review is required prior to reporting patient test results.”
The laboratory should create an organizational chart. An example of an
organizational chart is shown in Figure 1.
2 © Clinical and Laboratory Standards Institute. All rights reserved.

on Chart Laboratory
Depending on the size
of the organization, the
Director
organizational structure may
be broken down into
Technical Quality Operation subgroups to facilitate
Manager Manager Manager understanding. Each
organizational chart should
have, at minimum, one link to
Laboratory Laboratory Facility HR the next level higher
Technician Technician Technician Clerk organizational level.
Laboratory Sample
Assistant Processor
Figure 1. Example Laboratory Organizational Chart

The organizational charts should be maintained with sufficient detail to define
the structure and the interrelationships within the organization so as to facilitate
understanding and communication of roles and responsibilities. Organizational
charts should be maintained in a timely manner and changed as structure or
people change.
Requirement
§ 820.20(b)(1): Responsibility and authority. Each manufacturer shall establish
the appropriate responsibility, authority, and interrelation of all personnel
who manage, perform, and assess work affecting quality, and provide the
independence and authority necessary to perform these tasks.
The laboratory should establish position descriptions indicating clearly who is
responsible for each aspect of the LDT requirements. The organization should be
structured in a way that ensures that the people who are assessing the quality of
the LDT are independent of those who are manufacturing the LDT, and have the
decision-making authority to reject and report a product that does not meet the
quality specifications, without fear of recrimination.
The intent of this requirement is to ensure that no bias is demonstrated in
those persons who make decisions regarding the quality and release of the LDT.
Independence should be demonstrated not only by the organizational structure,
but also in the job responsibilities. This is accomplished by established position
descriptions. Position descriptions outline the job responsibilities. An example of a
position description template is shown in Figure 2.

POSITION DESCRIPTION
POSITION TITLE:
DEPARTMENT/COMPANY:
REPORTS TO (POSITION TITLE):
BASIC JOB PURPOSE: Summarize in one or two sentences the fundamental

reason this job exists.
PRINCIPAL ACCOUNTABILITIES: In order of importance, describe the 4–8 major

responsibilities of this position using condensed statements describing an end
result against which some measure of performance can be applied. Attempt to
answer the questions: What is done? How is it done? Why?
EDUCATION, KNOWLEDGE, EXPERIENCE, AND SPECIFIC SKILLS REQUIRED:

Indicate applicable know-how required to perform the job satisfactorily and how
attained through years of specific education, specialized training, and/or work
experience, or a combination. Specify whether credential is either “essential” or
“desired.”
Under a robust quality MINIMUM EDUCATION:

system, sufficient SPECIFIC EXPERIENCE:
resources should be allocated
for quality system and
operational activities. Figure 2. Example Position Description
Under the model, senior
management, or a designee, Requirement
should be responsible for § 820.20(b)(2): Resources. Each manufacturer shall provide adequate
providing adequate resources resources, including the assignment of trained personnel, for management,
for the following activities: performance of work, and assessment activities, including internal quality
Supplying and maintaining audits, to meet the requirements of this part.
the appropriate facilities The laboratory director has the responsibility to employ a sufficient number of
and equipment to laboratory personnel with the appropriate education, experience, and/or training
consistently manufacture a to provide quality test results.
quality LDT
Not only must there be a sufficient number of adequately trained personnel to
Acquiring and receiving perform tests and report results, the LDT organization must be structured in a
materials that are suitable way to design and produce quality LDTs. Internal audits are covered in Chapter 2,
for their intended purpose Quality Audit. However, the intent is to ensure that there are checks and balances
Processing the materials to within the organizational structure.
produce the finished LDT The laboratory director not only needs to ensure adequate personnel for testing,
Laboratory analysis of the but also adequate personnel for meeting all of the QSReg requirements. In
finished LDT most laboratories, this will mean that deciding to undertake production of LDTs
requires additional staff, assigned to the specific responsibilities of the QSReg. It
is suggested that one person has the role of compliance specialist, and his or her

job is to ensure that all of the personnel, activities, policies, and procedures are in Management with
compliance with the QSReg. executive
responsibility is defined as a
Requirement senior employee (eg, laboratory
§ 820.20(b)(3): Management representative. Management with executive director) with responsibility
responsibility shall appoint, and document such appointment of, a member and authority to establish a
of management who, irrespective of other responsibilities, shall have quality system and to develop
established authority over and responsibility for: and implement a quality policy
(i) Ensuring that quality system requirements are effectively established and for the laboratory. If delegated,
effectively maintained in accordance with this part; and they hold the ultimate
responsibility, and authority
(ii) Reporting on the performance of the quality system to management with rests with the person having
executive responsibility for review. profit and loss responsibility for
Under CLIA, the management representative is the laboratory director. In the FDA the business.
QSReg, this person is a named individual, a member of executive management,
who has responsibility and authority over the quality system, and reports on
that system to executive management on a regular and formal basis. Every staff
person in the laboratory who is associated with LDTs in any way must know who
the quality management representative is. This role can be filled by the laboratory
director, but for FDA purposes, does not have to be the laboratory director. This
person must be accessible to staff members, as is required by CLIA, but in this case
the accessibility is specifically for reporting quality problems. Figure 3 provides an
example of a management representative appointment letter.

MANAGEMENT REPRESENTATIVE APPOINTMENT
Effective Date: __________________
[INSERT NAME] is the Management Representative for our Quality

Management System. This is a function required by the FDA. The regulation
requires a management representative with executive responsibility
who, irrespective of other responsibilities, shall have authority over and is
responsible for the following areas:
(Excerpt from QSReg)
Ensuring that quality system requirements are effectively established

and effectively maintained in accordance with 21 CFR Part 820; and
Reporting on the performance of the quality system to management

with executive responsibility for review.
NOTE: The responsibility of a management representative can include liaison

with external parties on matters relating to the quality management system.
If you have any concerns regarding product quality or the quality system,
please raise these concerns to your management or the management
representative.
Sent From: ___________________

Management With Executive Responsibility Signature
A record of attendance Figure 3. Example Management Representative Appointment Letter

and meeting minutes is
Requirement
required for management
§ 820.20(c): Management review. Management with executive responsibility
review.
shall review the suitability and effectiveness of the quality system at defined
intervals and with sufficient frequency according to established procedures
At a minimum, the
to ensure that the quality system satisfies the requirements of this part and
management representative
the manufacturer’s established quality policy and objectives. The dates and
and a quorum of executive
results of quality system reviews shall be documented.
management should be
present. The management review is a planned meeting, occurring at defined time intervals
(eg, quarterly). In this meeting, key quality indicators (inputs and outputs) are
The decisions and actions to reviewed for each of the elements of the quality system, to ensure the continuing
be taken during the review adequacy, suitability, and effectiveness of the quality system (see Figure 4,
are documented in meeting Management Review Example Agenda). Meeting minutes are taken, attendees
minutes. Included in the sign in, and actions to be taken and conclusions are documented. The meeting
minutes is a statement of should have a standing agenda. These are higher level meetings than the quality
certification regarding the assessment meetings required by CLIA. Under CLIA, the assessment meetings
overall suitability, adequacy, include laboratory personnel, and include reviews and assessments of any issues
and effectiveness of the QMS. of the entire testing process. Under the QSReg, those meetings also should be
taking place, but a meeting specifically designed to update and show involvement
of executive management is required.

Usually, these meetings occur at least twice per year, but many organizations
prefer to hold these meetings quarterly. A specific procedure for conduct of
management review meetings must state the frequency of the meetings, the
required attendees (by position or title, not name), and the standing agenda.
The frequency of management reviews should be based upon the performance of
the assay, the frequency with which any quality issues are found, and the needs of
the organization.
Figure 4 shows a typical management review meeting standing agenda.
Part 1: Review Quality Inputs

1. Quality policy and quality objectives
2. Results of internal or external audits or inspections
3. Customer feedback, including complaint data and complaint trends
4. Process performance and conformity to the product requirements
determined during the design of the product
5. Status of corrective and preventive actions (CAPAs) (eg, investigations/
actions, CAPA status, product improvement initiatives)
6. Any risk management activities
7. Results from trending activities even beyond complaints that may
indicate changes in quality (eg, frequency of recalibration or maintenance
on instrumentation)
8. Action items from previous management review meetings
9. Changes that could affect the quality management system
10. Any new or revised regulatory requirements
11. Any additional items for discussion
Part 2: Determine Quality Outputs
12. Recommend any improvements needed to maintain the effectiveness of
the quality system and its processes.
13. Identify any improvements in products related to customer requirements.
14. Assess resource needs to ensure continuing suitability, adequacy, and
effectiveness of the quality system.
15. Restate any new action items, and identify any action items that are
related to a deficiency in the quality system, ie,
a. Maintaining the effectiveness of the quality system and its
processes
b. Product improvement initiatives related to meeting customer
requirements
c. Resource needs (human or equipment)
16. Assess any changes needed to the quality system, quality policy, or quality
objectives.
17. Assess the overall state of the quality system.
Figure 4. Example Management Review Agenda

During management The last item in Figure 4, assessing the overall state of the quality system, is
reviews, assessing the critically important. This is where executive management determines whether the
overall state of the quality quality system is suitable. The meeting minutes should reflect that this specific
system is critically important. question was asked, and provide the answer:
“Is the laboratory quality system compliant with the requirements and suitable for
the continued production and reporting of LDTs?”
Requirement
§ 820.20(d): Quality planning. Each manufacturer shall establish a quality
Under a quality systems plan which defines the quality practices, resources, and activities relevant
approach, managers use to devices that are designed and manufactured. The manufacturer shall
quality planning to identify and establish how the requirements for quality will be met.
allocate resources and define
For LDT manufacturers as well as for other products, there must be a quality plan
methods to achieve the quality
that is specifically relevant to the LDT. Much of what is required to be part of the
objectives. Quality system
plan may be found in quality system documentation, such as the quality manual,
plans should be documented
device master record(s), production procedures, etc. Therefore, the plan itself may
and communicated to
be a roadmap of the quality system. The plan in this case would need to include
personnel to ensure awareness
reference to applicable quality system documents and how those documents
of how their operational
apply to the LDT(s) that is the subject of the plan. Quality plans may be specific
activities are aligned with
to one device or be generic to all LDTs manufactured. Quality plans can also be
strategic and quality goals.
specific to processes or overall systems.
The quality plan may be stated in high-level terms in the quality manual (see
below) as, for example, “The quality plan includes all policies and procedures
associated with the quality system, and also includes all quality testing and
inspection instructions, and all verification and validation activities for each LDT
product.” Specific quality goals may be included.
Requirement
§ 820.20(e): Quality system procedures. Each manufacturer shall establish
quality system procedures and instructions. An outline of the structure of
the documentation used in the quality system shall be established where
appropriate.

Figure 5 outlines the common structure of quality system documentation.

Highest level, little detail
Quality - Includes statements of quality policies
Manual and objectives, for example: “XYZ
Laboratory will calibrate and maintain
equipment to ensure quality output.”
Procedures - Specific instructions for completion

of a given task, for example, all of the
instructions for preparing a batch of
buffer reagent for a particular LDT.
Working - More detailed instructions, such as

Instructions how to calibrate the pH meter used
in preparing the buffer reagent for a
particular LDT.
Quality - All data and information generated

Records in performing the procedures and/or
work instructions.
Lowest level, most detail

Figure 5. Example Documentation Pyramid
The documentation pyramid displays four levels of documentation, which are Think about the
called tiers. documentation pyramid
1. The first tier, and the top of the pyramid, represents the quality manual as a house; a house is only as
and policies. The quality manual and policies provide the quality system stable as the foundation.
structure and summarize the quality system. Quality records are the
foundation of a quality system.
2. The second tier represents operating procedures and includes the written
Records contain significant
guidelines that explain what is expected and required.
data that prove:
3. The third tier represents work instructions and provides detailed When and what tasks were
instruction on how to perform the applicable tasks. done, and by whom
4. The fourth, and last, tier includes quality records, which document the Measurements or readings
results achieved and provide evidence of activities performed. taken
The pyramid is used to show that even though the quality manual and policy is Conditions that were
important, it is only a small portion of the overall documentation. The bulk of any monitored
documentation system is the quality records.
Whether a product passed
or failed testing
Conditions or data that
were reviewed and
approved or failed


2 Quality
Audit

2 Chapter 2: Quality Audit (§ 820.22)
Once a laboratory has a quality system in place for its LDTs, complete with policies,
processes, and procedures, how can the laboratory ensure that the components of
the quality system are being followed? Quality auditing is a very important piece of
complying with the QSReg. It documents that procedures are being followed, and it
offers opportunities to find areas for continual improvement, which leads to better
patient care.
Requirement
§ 820.22: 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. Quality audits shall
be conducted by individuals who do not have direct responsibility for the
matters being audited. Corrective action(s), including a reaudit of deficient
matters, shall be taken when necessary. A report of the results of each quality
audit, and reaudit(s) where taken, shall be made and such reports shall be
reviewed by management having responsibility for the matters audited. The
dates and results of quality audits and reaudits shall be documented.
CLIA places the responsibility for the overall quality of the laboratory with the
laboratory director. If the laboratory has a quality system in place, then quality
audits may be routinely done already, focusing on the laboratory’s processes and
finding areas for quality improvement. CLSI document QMS15—Assessments:
Laboratory Internal Audit Program, describes best practices for laboratory quality
system audits. Finding problems with the laboratory’s processes or reported
results may indicate that the laboratory has quality system problems. This typical
type of auditing only partially meets the requirement for quality audits for LDTs.
However, the same principles should be applied to the design and manufacture
of the LDT. The laboratory’s quality system should include policies, processes,
and procedures for designing and manufacturing any LDTs, and audits should be
conducted to ensure they are being followed. The sections below describe FDA’s
additional requirements for quality audits.

Quality System Regulation for Laboratory-Developed Tests Chapter 2: Quality Audit
Quality auditing can be A quality system audit as it pertains to LDTs is a comprehensive look at the
a huge task, and should organization’s performance in meeting every requirement of the QSReg for the
not be taken lightly. LDTs (see Table 1). This means looking at the activities associated with the design
and manufacture of the LDT, from inception (approval of the initial LDT design
requirements) through development through compounding and testing, and
beyond to complaint handling, record keeping, and ongoing use of the LDT (see
Table 1). Does the LDT documentation meet every element and every applicable
requirement of the QSReg?
It is expected that each applicable element of the QSReg as it relates to the design
and manufacture of the LDT is audited at least annually. IVD manufacturers
usually accomplish this task by selecting a few QSReg elements to audit each
quarter, as shown in Table 1. In this way, all of the elements have been audited by
the end of the year. An audit plan is described in the audit procedure, indicating:
Which elements will be audited
The frequency of the audit
Who will perform the audit
Which departments will be affected
Which individuals will be involved
An annual audit plan is Audits must be conducted by someone who is not involved in the element being
part of a good QMS. audited and who is qualified to audit that requirement. To be qualified to audit,
a person will understand the QSReg requirements, and the documentation that
is generated to meet the requirement. The quality audits focus on reviewing the
documentation and ask the questions shown in Table 2.
An example of an audit plan is shown in Table 1, below. In the example, the
QSReg elements are shown in the same order as in the QSReg requirements.
Following this order is not a requirement. The elements may be audited in any
order, as long as they are each audited as indicated by the auditing procedure. It
might be helpful to group particular elements together, such as nonconforming
product and complaint files, especially if the same people will be answering the
auditor’s questions. Note that the usual auditors from the Auditing function (in
the example, Janie Allen and Rick Thomas) cannot audit the Quality Audit program,
as they cannot audit themselves. In this example, Susan Sheppard is appointed to
audit the Quality Audit program.

Table 1. Example Audit Plan

Quarter QSReg Element Auditor Department Being Audited Individuals Participating
1 Laboratory Director,
Management Responsibility Janie Allen Laboratory Management Laboratory Manager
Quality Audit Susan Sheppard Auditing function Auditors
Laboratory Manager,
Personnel Rick Thomas Laboratory Management Supervisors
Design Controls Janie Allen R&D R&D Manager
2 Documentation and
Document Controls Janie Allen Manager
Records
Purchasing Controls Janie Allen Purchasing Manager
Identification and Traceability Rick Thomas Compounding Manager
Production and Process Controls Rick Thomas Compounding Manager
3 Laboratory Director,
Nonconforming Product Janie Allen Laboratory Management
Laboratory Manager
Laboratory Director,
Corrective and Preventive Action Janie Allen Laboratory Management
Laboratory Manager
Labeling and Packaging Control Rick Thomas Compounding Manager
Handling, Storage, Distribution, Laboratory Manager,
Rick Thomas Laboratory Management
and Installation Supervisors
Documentation and
Records Rick Thomas Manager
Records
4 Documentation and
Device Master Record Janie Allen Manager
Records
Documentation and
Device History Record Janie Allen Manager
Records
Documentation and
Quality System Record Rick Thomas Manager
Records
Laboratory Director,
Complaint Files Janie Allen Laboratory Management
Laboratory Manager
Laboratory Manager,
Servicing Janie Allen Laboratory Management
Supervisors
Statistical Techniques Rick Thomas R&D Manager
To prepare for an audit, the auditors create a set of questions in alignment with
each requirement of the QSReg. During the audit, documentation and records
are gathered that prove that the requirement was met. The auditors should
look at several examples of records. The number of examples chosen should be
statistically based.
Table 2 provides an example of an appropriate set of questions for the Quality
Audit requirement.

Table 2. Example Audit Questions
Requirement Question(s) Evidence to Be Gathered

Each manufacturer shall establish Do procedures exist for conducting quality audits? Copy of auditing procedures
procedures for quality audits
and conduct such audits Are the audits conducted as stated in the Evidence that audits were conducted
procedure? per the procedure, such as audit plans,
schedules, and reports
to assure that the quality system is in Have the audit findings been properly reviewed Audit reports are signed by affected
compliance with the established by direct management and at the Management managers. Management Review meeting
quality system requirements Review meetings? agendas and minutes indicate that audit
findings were reviewed.
and to determine the effectiveness of Do the Management Review minutes indicate that Management Review meeting minutes
the quality system. executive management believes that the quality
system is effective, based on the results of the
Management Review?
Quality audits shall be conducted by Have any audits been conducted by individuals Listing of who conducted each audit, by
individuals who do not have direct having direct responsibility for the matters being QSReg element, their title, and area(s) of
responsibility for the matters being audited? responsibility
audited.
Corrective actions(s) shall be taken Have audit findings resulted in corrective actions Audit report and associated corrective
when necessary. being taken? Are there any audit findings where action reports
corrective actions should have been taken, but were
not?
A reaudit of deficient matters shall be Were all corrective actions then reaudited? Audit reports and associated corrective
taken when necessary. action reports
A report of the results of each quality Were reports generated for all quality audits and Quality audit and reaudit reports
audit, and reaudit(s) where taken, reaudits? Do they indicate all of the results of the
shall be made. audits?
and such reports shall be reviewed by Do the quality audit and reaudit reports contain Quality audit and reaudit reports
management having responsibility signatures of the managers of the areas being
for the matters audited. audited?
The dates and results of quality Do the quality audit and reaudit reports contain Quality audit and reaudit reports
audits and reaudits shall be the dates when the audits and reaudits were
documented. conducted?
None of the questions Table 2 provides a few sample questions that would be asked to determine if the
in Table 2 have anything quality auditing procedures meet the QSReg requirements (ie, specifically the
to do with the actual auditing requirement). Other questions are asked for the other quality system
laboratory processes of testing elements. The questions can be created directly from the QSReg requirements.
samples. These audits address For convenience, these are reproduced in Appendix A. It is easy to see that for an
the quality system procedures extensive requirement like Design Controls, the question list can become very
required to design and lengthy and the audit can take many days. Every effort should be made to keep
manufacture the LDT as audits timely and on schedule.
required by the QSReg. Once the audit is completed and all of the evidence is gathered, an audit report
must be written. Any areas where the evidence is lacking or is deficient should
be noted. Plans should be made to correct the deficiencies, open a corrective

action, and reaudit when necessary. (See Chapter 10, Corrective and Preventive
Action, for more information.) All audit reports should indicate the results and
dates of the audit and the area being audited, and should be signed by the
auditor. The manager of the area being audited must review the audit report,
and sign the audit report as evidence of the review. Audit reports are reported
during the Management Review meetings, and are a critical component of
determining whether the quality system is under control. All of these auditing
steps should be captured in the laboratory’s auditing procedure.


3 Personnel

3 Chapter 3: Personnel (§ 820.25)
The personnel are the most essential part of any workplace, including the
laboratory. Ensuring that there are enough properly trained people is one of the
most important functions of the laboratory director.
Requirements
§ 820.25(a): General. 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.
§ 820.25(b): Training. Each manufacturer shall establish procedures for

identifying training needs and ensure that all personnel are trained to
adequately perform their assigned responsibilities. Training shall be
documented.
§ 820.25(b)(1): As part of their training, personnel shall be made aware of

device defects which may occur from the improper performance of their
specific jobs.
A good way to ensure
that every employee has
been adequately trained is to
keep a documented training
plan, customized for each
employee or each position
within the laboratory. Check off
each training as it is completed,
including the signature of the
trainer and the date.
§ 820.25(b)(2): Personnel who perform verification and validation activities

shall be made aware of defects and errors that may be encountered as part
of their job functions.
This section of the QSReg should be easy to comply with, as it aligns with the CLIA
regulations (42 CFR § 493.1235, § 493.1445, and § 493.1451). CLIA also requires a
Training didn’t happen if
“sufficient number of laboratory personnel with the appropriate education and
it isn’t documented!
either experience or training.” CLIA requires that before testing patient specimens,
Good records are the key to
all personnel must receive the appropriate training (or retraining, if necessary), and
compliance!
be competent to perform the testing reliably and accurately.
The QSReg emphasizes that training must include awareness of device defects
that might occur due to improper performance of a job, or device defects that
an employee might encounter during routine job functions. In this case, “device
defects” would refer to problems with the LDT reagents or instruments that lead
to unsafe and ineffective devices.

Quality System Regulation for Laboratory-Developed Tests Chapter 3: Personnel
Training must demonstrate that the employee is competent in recognizing the

expected types of defects. This may be achieved during competency assessment
testing using a blinded panel of defective devices (reagents and/or instruments) as
well as acceptable devices.
CLSI document QMS03, Training and Competence Assessment, provides
guidance to assist in meeting the QSReg or CLIA requirements.
Each employee and/or position should have a job description and a
training plan.
Each employee should have a training file, including a copy of educational
diplomas or transcripts, work history, all training records (tests, etc.), and
evidence of completion of necessary training.
Training records must include the employee’s name, the trainer’s name, the
date of the training, and the subject of the training completed.
Training files should be reviewed on an annual basis to ensure that the
training plans and the training records are up-to-date—and this annual
review needs to be documented.
Separately, records of the contents of any training programs (agenda,
slides, worksheets, etc.) should be maintained.
For CLIA, new employees are required to have their competency assessed
at six months in the first year, and then annually thereafter. This frequency
is sufficient to meet QSReg requirements.

4 Design
Controls

4 Chapter 4: Design Controls
(§ 820.30)
Design controls are at the heart of the QSReg. The laboratory must ensure that the
design of the LDT is controlled (ie, changes are deliberate and documented).
Requirement
§ 820.30(a): General. (1) Each manufacturer of any class III or class II device,
and the class I devices listed in paragraph (a)(2) of this section, shall establish
and maintain procedures to control the design of the device in order to
ensure that specified design requirements are met.
(2) The following class I devices are subject to design controls:
(i) Devices automated with computer software; and
(ii) The devices listed in the following chart.
Section
868.6810
Device
Catheter, Tracheobronchial Suction
Pay particularly close
attention to this
chapter. Design control
documentation has been
requested by FDA for LDTs. The
key to success is excellent
documentation!
FDA will require

notification of LDTs
878.4460 Glove, Surgeon's within six months from
publication of their final
880.6760 Restraint, Protective
guidance. See FDA’s website for
892.5650 System, Applicator, Radionuclide, Manual
the latest information.
892.5740 Source, Radionuclide Teletherapy
An LDT is probably not one of the specific devices listed in the table. It could be All of the design control
a class I device that includes instrumentation that is automated with computer documentation is
software, and therefore falls under this regulation. maintained is the “design
More likely, an LDT will be subject to this regulation because FDA has classified history file (DHF).”
the analyte in class II or class III. These are risk-based classifications; class II is for
moderate-risk devices, and class III is for high-risk devices. The classification is
usually based upon risk to health should an erroneous result occur. The LDT could
also be classified in such a way because there is not much prior knowledge of the
particular analyte, so the level of risk is not well understood. For devices and/or

Quality System Regulation for Laboratory-Developed Tests Chapter 4: Design Controls
NOTE: New LDTs will be analytes that have already been classified, these device classifications can be found
required to be in the CFR, or on FDA’s website (http://www.fda.gov/MedicalDevices/default.htm).
developed according to For novel analytes, one can receive a classification by filing a “513(g)” request. See
established design and FDA’s website for more information.
development procedures. For Once the laboratory has determined that its LDT will be subject to the design
existing LDTs, design controls control requirements, procedures need to be put in place that will demonstrate
may be employed that specified design requirements are met. The sections below will help to define
retrospectively. this requirement, and describe what must be included in the procedures.
Requirement
§ 820.30(b): Design and development planning. Each manufacturer shall
establish and maintain plans that describe or reference the design and
development activities and define responsibility for implementation. The
Creating the right plan plans shall identify and describe the interfaces with different groups or
is critical. Read all of the activities that provide, or result in, input to the design and development
requirements of this section, process. The plans shall be reviewed, updated, and approved as design and
and then create a plan that development evolves.
addresses them.
The design and development plan maps out the entire design and development
phase of the LDT, from before production (preproduction, in FDA terminology)
through the validation phase, and finally to implementation for use in the
laboratory. It steps through each of the elements below, and includes every
activity that needs to occur to develop the LDT and get it ready to be used for
patient testing. The plan includes descriptions of all of the activities, including
In the laboratory, a
who is responsible (persons, groups, or functions) for each step along the way.
single person may be
Timeframes are given for each activity. The plan is developed with the input of
responsible for many of the
every affected group, not just that of management or a small group of planners.
areas affected by creation of
Once the plan is completed and agreement is reached, representatives from
the LDT. However, be sure that
each involved functional area sign and date the plan, indicating their approval of
there is management oversight
the plan. As the design and development process proceeds, the plan is reviewed
so that the person doing the
periodically, updated if necessary, and signed again if any changes are made.
work is not the only person
signing the documentation. A Which functional areas are involved? In a laboratory operation, a few people could
member of management who fulfill many roles, but the functional responsibilities might include:
can thoroughly understand Project manager
the work should also be signing
R&D
the plan.
Quality
Regulatory
Clinical and analytical testing
Manufacturing
Marketing (if applicable)
The person with the quality role must have oversight for design control compliance.
This person ensures that each requirement is met and that the documentation
proving the requirement is met is in place. It is required that this person be
independent from the person who has the clinical and analytical testing role.

The design and development of the LDT will usually proceed through specific It is best to use the
design elements or activities. For each design element, the plan describes the same language to
strategies and objectives for that element, as well as the detailed activities, describe the design elements
responsibilities, and deliverables. used by FDA in the QSReg. This
1. Design input—In this phase, the product characteristics are defined. All practice leads to less confusion
design inputs, also sometimes referred to as “product requirements,” are when documents are viewed
captured. See Requirement § 820.30(c), below. by FDA inspectors or reviewers.
NOTE: Take care in defining the product requirements. All product

requirements (design inputs) must be measurable and testable.
Documentation must be able to show objective evidence of successful
achievement of each product requirement.
2. Design output—In this phase, the technical aspects of the product are
determined and product development occurs. At the end of this phase,
the laboratory has a product that has minimally been shown to “work”
(meet its requirements). Design output encompasses all of the output of
documentation from testing, validation and verification, manufacturing
records, and more. The Design Output files include documentation from
the time point of deciding that a design control plan will be developed,
through to the time point when the development ends. See Requirement
§ 820.30(d), below.
3. Verification—In this phase, the product is tested in the laboratory setting
to confirm that design requirements have been met. Performance is
determined, eg, precision, linearity, accuracy, stability. See Requirement
§ 820.30(f), below.
4. Design transfer/manufacturing scale-up phase—Transfer and scale-up is
applicable if reagents are manufactured by the laboratory (eg, prepared
from chemicals), and the size of the batches for routine use will be different
from the size of the batches used to design and test the LDT. In this phase,
final manufacturing specifications are determined and the manufacturing
processes are validated. See Requirement § 820.30(h), below.
5. Design validation—In this phase, the laboratory confirms, by objective
evidence, that the design requirements for the product have been met.
Clinical studies may be needed. Software validation is also completed in
this phase. Design validation must be completed before implementation
of the assay in the laboratory. For a class III device, it is also required to
be completed before FDA device approval. It is not required for design
validation to be completed before seeking FDA clearance for a class II
device. See Requirement § 820.30(g), below.
The design and development plan includes each major activity for each of the
phases listed above, with their respective timeframes and responsible persons
listed. Using a project planning and tracking tool, such as a Gantt chart, is
especially helpful. Project milestones are noted, and time points for design review
meetings are determined.

Requirement
There are many § 820.30(c): Design input. Each manufacturer shall establish and maintain
stakeholders for an procedures to ensure that the design requirements relating to a device
LDT, and all of them have are appropriate and address the intended use of the device, including the
expectations regarding needs of the user and patient. The procedures shall include a mechanism for
the test. See Table 3. addressing incomplete, ambiguous, or conflicting requirements. The design
input requirements shall be documented and shall be reviewed and approved
by a designated individual(s). The approval, including the date and signature
of the individual(s) approving the requirements, shall be documented.
The design input phase includes the physical and performance requirements for
the LDT and addresses the physicians’, patients’, and users’ requirements for the
The laboratory needs to new test. In the case of the LDT, this includes requirements for the laboratory, the
understand the patients, the physicians, FDA regulatory requirements, and any other regulatory
medical/clinical use of the LDT requirements that might be required (eg, CLIA, state). All requirements are listed.
in order to determine its Requirements typically fall into three categories:
acceptance criteria, including 1. Functional requirements—These requirements specify what the test will
targets and limits. do, its operation, and processing. These details may include the maximum
number of reagents, how fast the results should be available, or the
allowable footprint for an analyzer.
2. Performance requirements—These requirements specify how well the
test will perform (eg, accuracy, precision, and reliability), and also include
environmental specifications and safety requirements. These requirements
can be equated to CLIA 42 CFR § 493.1253(b)(2), Establishment of
The product performance specifications.
requirements
3. Interface requirements—These requirements specify how the user will
document sets the criteria for
interact with the test, and how the test will connect with computer
the test’s attributes. It can be
systems.
revised, with justification,
review, and approval. Once determined, the requirements are turned into “acceptance criteria” and
listed in terms of a target and a limit. For example, the desired precision of an
assay might list a target of a 4% CV, and a limit of a 5% CV. This means that 4% is
most desirable, and that 5% is the maximum CV that is acceptable. Design inputs
are best created by asking the customers about their needs for the test—not by
guessing. Of course, the performance may also depend on test methods, sampling
limitations, and/or the measurement devices used to perform the assay. For the
laboratories, patients, and physicians, gathering this information can be done
via surveys or through focus group discussions. It is important to get as many
Don’t guess at these perspectives as practical. For the payers and regulators, formal discussions and
requirements! Ask the meetings may be necessary. The FDA has a process called the “Presubmission
stakeholders! For some groups, Program” that can be followed to gain its feedback. Find more information on the
this can be done via a survey, presubmission process on FDA’s website.
or with focus groups. For The final output of the design input phase is a product requirements document.
others, direct communication Version control of this document is maintained within a document management
is necessary. system. It should be maintained for the entire lifecycle of the LDT, and updated
when subsequent changes are made to the test.

Table 3 lists some examples of design input requirements, including example

acceptance criteria for each design input item. In this example, the “limit”
represents the minimally acceptable performance requirement, the required
acceptance criteria. The “target” represents the desired performance goal.
Table 3. Example Design Input Requirements for ABC Laboratory’s XYZ Analyte LDT
Design Input
Category Requirement Limit Target
Laboratory Uncomplicated testing 6 processing steps 3 processing steps
process
Hands-on time ≤ 2 hours ≤ 1 hour
Total testing time ≤ 8 hours ≤ 2 hours
Reagent handling Prepare reagents with water or by Reagents are ready to use
thawing
Reagent stability Reagents are stable for at least 8 hours Reagents are stable for 1 week
Calibration stability Calibration is stable for at least 8 hours Calibration is stable for 1 week
Number of calibrators 5 3
QC With each batch of tests Every 24 hours
Cost per test (materials) $10.00 $5.00
Patients Small amount of blood 200 µL serum sample 100 µL serum sample
Low cost Reimbursement from Medicare Reimbursement from Medicare and
major payers
Meaningful results Test results are actionable by physician Test results are actionable by
(see “Physicians” section) physician (see “Physicians” section)
Physicians Actionable results Total allowable error is ≤ 15% Total allowable error is ≤ 10%
Reasonable turnaround Results are available to physician in 48 Results are available to physician in
time hours 24 hours
FDA Test provides Test results are actionable by physician Test results are actionable by
meaningful results physician
All performance claims Total allowable error is ≤ 15% Total allowable error is ≤ 10%
are reasonable for the Total analytical imprecision is ± 5% Total analytical imprecision is ± 4%
intended use of the test
Testing range is 0–100 mg/dL Testing range is 0–130 mg/dL
Test is linear throughout the testing Test is linear throughout the testing
range range
All common interferences influence All common interferences influence
test results by < 10% test results by < 5%
Test correlation to clinical condition is Test correlation to clinical condition
> 90% is > 95%
Physical characteristics No more than 4 reagents No more than 3 reagents
Instrument footprint of 20 inches × 30 Instrument footprint of 18 inches ×
inches 24 inches

Now that the LDT’s Requirement

requirements are § 820.30(d): Design output. Each manufacturer shall establish and maintain
established, the laboratory procedures for defining and documenting design output in terms that allow
must develop the test that an adequate evaluation of conformance to design input requirements.
meets those requirements. Design output procedures shall contain or make reference to acceptance
Much easier said than done! criteria and shall ensure that those design outputs that are essential for
Once the test is complete, then the proper functioning of the device are identified. Design output shall be
the laboratory needs to prove it documented, reviewed, and approved before release. The approval, including
meets the input requirements. the date and signature of the individual(s) approving the output, shall be
documented.
The design output is the result of the design effort at the end of each design
phase, and at the end of the total design effort. During design output, the design
The design output input elements are translated into design specifications that can be tested.
phase establishes Design output includes manufacturing specifications and descriptions of
specifications for the product. materials that characterize the new test. It also includes the final technical
Testing during the design documents to be used for purchasing, inspecting, producing, testing, packaging
verification phase then and labeling, and installing and servicing the test, if applicable. Procedures to be
determines whether the test used for building and testing the final LDT comprise the device master record
meets the specifications and, (DMR). In addition, design output includes performance specifications that are
thus, the design input tested to establish the product performance claims.
requirements. At this time, product and process risk assessments are conducted. For more
information, refer to CLSI documents EP18, Risk Management Techniques to
Identify and Control Laboratory Error Sources, and EP23™, Laboratory Quality
Control Based on Risk Management. Risk management should be initiated as early
as possible in the design process to ensure that risks are mitigated/designed out
during the LDT development.
In summary, each step of the testing process and each step of the manufacturing
process must be reviewed to determine if there are any risks of harm if something
were to go wrong at each particular step. Where harm could occur, steps are put
into place to help keep that harm from occurring. Using risk management helps to
make the test more robust.
Final deliverables of design output include:
Final LDT specifications
A risk assessment
Testing protocols
All materials’ and components’ specifications
The DMR (see Chapter 13, Records)
Design output design review meeting minutes (see below)
Management signatures indicating approval of the design output

Requirement Risk management is a

§ 820.30(e): Design review. Each manufacturer shall establish and maintain science of its own, but
procedures to ensure that formal documented reviews of the design applying it correctly and acting
results are planned and conducted at appropriate stages of the device’s upon its results will lead to a
design development. The procedures shall ensure that participants at each much more robust and reliable
design review include representatives of all functions concerned with the test!
design stage being reviewed and an individual(s) who does not have direct
responsibility for the design stage being reviewed, as well as any specialists
needed. The results of a design review, including identification of the design,
the date, and the individual(s) performing the review, shall be documented in
the design history file (the DHF).
Design reviews are conducted including representatives of all of the laboratory
functions concerned with the design stage being reviewed (see Requirement
Design reviews provide
§ 820.30[b]), and specified other people, at specific points in time. Design reviews
an opportunity to
evaluate the adequacy of the requirements and the capability of the design and
reflect upon the LDT’s
manufacturing to meet their requirements, and to identify problems. These
development and determine
reviews are typically performed in meetings, but meetings are not required. When
whether it is proceeding as
preparing the design and development plan, the design phases at which design
planned. It is also an
reviews will be conducted should be designated before conducting these reviews.
opportunity to identify
For example, it would be appropriate to hold a design review after an initial
problems and ways to address
reagent formulation has been determined, and after that formulation’s bench
them.
testing has been completed, but before beginning extensive validation or clinical
testing. The design review must include someone who is independent from the
development team, but who is technically knowledgeable and can understand the
Always have a
concepts and data presented. Also, identified experts in the specific technical area
knowledgeable person
should be asked to participate.
who has not been involved in
As mentioned above, it is not required that design reviews occur in meetings, the LDT’s development to be
though this is typical. Having a webinar is a good way to conduct a design the independent reviewer.
review if the functional representatives are in different locations. Additionally,
representatives from functional areas can conduct independent reviews.
The design review consists of reviewing the design requirements (design input),
the progress to date, and all information and/or data generated that are associated
with that progress. Subsequent design reviews also start with reviewing the
design requirements, followed by review of all information and/or data generated
since the previous design review. The participants are given ample opportunity
to ask questions. Questions to answer at each design review include whether the
information and/or data generated so far indicate that the product is likely to meet
its design requirements, and whether progress on the design and development
plan should continue. In addition, the results of the design review will determine
the adequacy of the design requirements. Any risks associated with achieving
the design requirements should be discussed and documented, with mitigations
identified where possible. If mitigations are not possible, indicate the actions to
be taken. This is a perfect time to make any necessary adjustments to the design
and development plan. Review and approval of any changes must be documented,
and once the initial design review has been approved, all changes must follow a

procedure for making these changes. All changes require new signatures from all
functional representatives.
Design verification is
the phase for the If a meeting is held, all design review meeting attendees should document their
analytical testing of the LDT. presence at the meeting by signing and dating an attendance sheet. All attendees
must be documented. Phone attendees, for example, can be written in. At the
end of the design review meeting, a conclusion statement must be documented
that all functional representatives agree on the outcome of the design review, ie,
whether the information and/or data generated so far indicate that the product
is likely to meet its design requirements, and whether progress on the design and
Again, good development plan should continue.
documentation is the
key to success! Requirement
§ 820.30(f): Design verification. Each manufacturer shall establish and
maintain procedures for verifying the device design. Design verification
shall confirm that the design output meets the design input requirements.
The results of the design verification, including identification of the design,
method(s), the date, and the individual(s) performing the verification, shall be
documented in the DHF.
Here is another place where CLIA’s 42 CFR § 493.1253 requirements are similar to
the FDA requirement. Meeting this requirement requires a substantial amount
of testing followed up by data analysis and report generation. For each design
element for an LDT (from the list above or others), the laboratory should generate
evidence that its LDT meets or exceeds the design requirement.
For design verification, the laboratory must show, through studies, that each of the
design input elements’ targets or limits have been met. This is accomplished by
conducting design verification experiments. First, the laboratory must determine
what kind of testing needs to be done for each design input element.
Formal reports should be generated to show the results of testing for each of
the design input elements. These reports show the evidence that design outputs
meet each design input requirement. For example, the report for reagent handling
would include the instructions for reagent preparation, and show that the test
meets the acceptance criteria. In the case of clinical correlation, the report would
be a comprehensive clinical trial report that describes the trial protocol, sites,
the data obtained, how they were analyzed, and the subsequent results, with
conclusions that show that the design verification acceptance criteria have been
met. Formal reports always include the design being verified, the method used for
verification, the signature and date of the individual performing the verification
testing, as well as the dates of acquisition of any data that are being reported.
Be sure to keep the collected data, known as the source data, accessible but
secured. Any data files used to perform calculations must accurately reflect the
source data, and should be controlled documents. Any edits to data files should
be clearly identified and understood, including who made the edit and when, and
justification for the edit, following the change control procedure. All of the testing
protocols and the testing reports are placed in the design control section of
the DHF.

Compare the design output (test results) to the previously established design Be very careful when
verification acceptance criteria. If any of the acceptance criteria are not met (ie, writing justifications to
design output does not match design input), and a justification can be written change acceptance criteria. The
describing why it is acceptable to proceed and accept the design output, then justifications must make sense
it is possible that the design verification can still be deemed acceptable. The from a clinical perspective, and
justification must be documented and accepted with signatures and dates from not be changed just to be able
the appropriate individuals. The design verification documentation should be to match the data!
updated to reflect the new, agreed-upon acceptance criteria, ensuring that any
changes to the design verification documentation go through the change control
procedure, documenting changes in all appropriate documents. Review and
approval of any changes must be documented. If a justification cannot be made,
then the design is not acceptable. Document which element of the design is not
acceptable. Determine whether the design needs to be modified and retested until
it can be shown to meet the minimum acceptable criteria.
Requirement
§ 820.30(g): Design validation. Each manufacturer shall establish and
maintain procedures for validating the device design. Design validation shall
be performed under defined operating conditions on initial production
units, lots, or batches, or their equivalents. Design validation shall ensure
that devices conform to defined user needs and intended uses and shall
include testing of production units under actual or simulated use conditions.
Design validation shall include software validation and risk analysis, where
appropriate. The results of the design validation, including identification
of the design, method(s), the date, and the individual(s) performing the
validation, shall be documented in the DHF.
Design validation provides the final proof that the test is safe and effective for
use, conforms to user needs, and meets its intended use. Any required clinical
testing is usually conducted during the design validation phase. For this testing,
it is not adequate to perform the testing in carefully controlled situations and
with expert test system operators. This testing is intended to be conducted in a
normally operating laboratory, with laboratory staff members who will typically be
performing the testing along with their routine work. This testing usually includes
performance testing in the laboratory (eg, precision, linearity, normal range), over
many days (and many calibration cycles, if appropriate) and may include either
correlation testing to another similar test, or clinical testing where the test results
are compared to the patient’s clinical condition. The manufactured reagents,
instrumentation, and the final test system software should be used for this phase
of testing. If the analyte is novel
For most tests, the regulatory agencies will expect to see nonclinical and clinical and classified in class III,
data that are statistically robust, and, in some cases, from multiple personnel clinical trials may be required
and/or multiple test systems, as applicable. Testing should be representative of to follow the GCP regulations!
the planned use of the test. Determining all of the requirements before testing is
very important! Check with regulatory authorities and other stakeholders before
beginning. Clarifying regulatory requirements before beginning testing can be very

Ensure that all planned helpful. The testing protocols will meet the requirements for design verification, as
testing is statistically well as for design validation (see Requirement § 820.30[g], below).
robust. See QSReg Chapter 16,
Formal procedures should be written for the testing. The procedures should
Statistical Techniques, for more
confirm that the requirements have been met and, ideally, should be statistically
information.
robust. CLSI has several standards and guidelines that can help with establishing
test performance. Visit the CLSI website (www.clsi.org) to find listings of CLSI’s
guidelines. Laboratories should also check FDA’s website for analyte-specific
guidance documents. CLSI offers many general guidelines, especially in the area of
evaluation protocols (see Table 4), that can help the laboratory determine its test’s
performance. FDA and other authorities have recognized CLSI’s guidelines—if the
laboratory uses them and follows them, then testing is being performed in a way
that should be found acceptable to FDA.
In addition to performance testing (nonclinical testing), the laboratory may need to
do clinical testing. With this type of testing, the test is performed on actual patient
samples, compared to another method, or compared to patient diagnosis or
outcome. The laboratory may also need to perform software testing, if software
If clinical testing needs is part of its LDT. FDA has guidance documents for clinical studies and software
to be performed, be testing listed on its website.
sure to consult FDA’s website
Once protocols and procedures for all of the testing noted above have been
for clinical study design and
written, they need to be signed off by the appropriate responsible individuals,
testing requirements. Be sure
and maintained within a document control system. More information on
to follow GCP and HIPAA!
document control can be found in CLSI document QMS02, Quality Management
System: Development and Management of Laboratory Documents, and in Chapter
5, Document Controls.

Table 4. Some Commonly Used CLSI Guidelines for Method Evaluation

Document
Code Document Title
C24 Statistical Quality Control for Quantitative Measurement Procedures: Principles and Definitions
C37 Preparation and Validation of Commutable Frozen Human Serum Pools as Secondary Reference Materials
for Cholesterol Measurement Procedures
C50 Mass Spectrometry in the Clinical Laboratory: General Principles and Guidance
EP05 Evaluation of Precision of Quantitative Measurement Procedures
EP06 Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach
EP07 Interference Testing in Clinical Chemistry
EP09 Measurement Procedure Comparison and Bias Estimation Using Patient Samples
EP10 Preliminary Evaluation of Quantitative Clinical Laboratory Measurement Procedures
EP12 User Protocol for Evaluation of Qualitative Test Performance
EP14 Evaluation of Commutability of Processed Samples
EP15 User Verification of Precision and Estimation of Bias
EP17 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures
EP18 Risk Management Techniques to Identify and Control Laboratory Error Sources
EP21 Estimation of Total Analytical Error for Clinical Laboratory Methods
EP23 Laboratory Quality Control Based on Risk Management
EP24 Assessment of the Diagnostic Accuracy of Laboratory Tests Using Receiver Operating Characteristic Curves
EP25 Evaluation of Stability of In Vitro Diagnostic Reagents
EP27 How to Construct and Interpret an Error Grid for Quantitative Diagnostic Assays
EP28 Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory
EP29 Expression of Measurement Uncertainty in Laboratory Medicine
EP30 Characterization and Qualification of Commutable Reference Materials for Laboratory Medicine
GP40 Preparation and Testing of Reagent Water in the Clinical Laboratory
MM17 Verification and Validation of Multiplex Nucleic Acid Assays
The testing procedures should be formal protocols that define the testing to be
done and the acceptance criteria. The acceptance criteria must be determined
before doing the testing! Performing the testing is likely to take several weeks, Software can be
months, or maybe even years if the test is for a rare disease or condition. Be sure to developed by the
capture all of the data that are generated, even those with issues. laboratory or it can be
commercially available. If using
If software is a part of the LDT, software validation must be conducted; see FDA’s
commercially available
guidance documents for software validation. Risk assessments are performed
software, the laboratory must
at this stage as well, and the results of the risk assessment will help determine
validate that it meets the
the appropriate QC plan for the LDT. See CLSI document EP23, Laboratory Quality
software needs of the LDT. If
Control Based on Risk Management, for more information on risk assessment and
developed by the laboratory,
QC plans.
extensive validation of the
Design validation test results are documented in formal, signed reports (as above), functionality of the software
and included in the design control section of the DHF. Be sure the reports include must be conducted.
the identification of the design and the methods for the design validation tests.

Requirement
§ 820.30(h): Design transfer. Each manufacturer shall establish and maintain
procedures to ensure that the device design is correctly translated into
production specifications.
Work instructions (operating procedures) and batch records are created to describe
how to make the reagents and/or instrumentation for the test in production
quantities, implementation of the production process, packaging, labeling,
installation, maintenance, and all other aspects of manufacturing the test. Work
instructions specify the procedures to be followed to create the reagents and
CLSI document EP23 perform the test. Batch records are generated for each lot of every component,
can help the laboratory including reagents, instruments, labels, packaging, etc. Be sure to include spaces
determine an appropriate QC for documenting the process followed for each.
plan for its test. Until now, the LDT reagents have probably been made in test quantities—small
batches that have been created for testing a few samples at a time. The laboratory
needs to determine how large the batches will be for routine use. Then, work
instructions are written that include every single step needed to create the
reagents in that batch size. Production specifications are documented in the work
instructions and/or batch records, for example:
1. Add 50 ± 0.5 grams of sodium phosphate to 5 ± 0.1 liters of water.
2. Mix for at least 10 minutes, using a two-inch long magnetic stirbar at
20 to 40 rpm.
3. Adjust the pH to 7.3 ± 0.1 pH units using 0.1 N HCl or 0.1 N NaOH.
Keeping records of all
changes is critical. 4. Record the amount of HCl or NaOH added:
Minor changes, while seeming HCl NaOH
not to affect performance by In the short instructions shown, the production specifications are noted in blue.
themselves, can accumulate Batch records must include spaces for indicating who performed each step, the
over time and make big date, the time (for any timed procedures), any quantities measured, any tests
differences. performed, and any results obtained. In regulatory speak, “If you didn’t write it
down, you didn’t do it!”
This process is repeated for everything that needs to be made for the LDT to enable
its use in the clinical laboratory. The same is true for any instrumentation that is
being manufactured. In this case, procedures for assembly of parts are required,
and specifications may appear either in the procedures, on drawings, or in both.
All of the procedures should be approved and signed by the appropriate
individuals. These procedures are maintained within a document control
system. Here is another place where CLIA’s requirements are similar to the FDA
requirements.
Requirement
§ 820.30(i): Design changes. Each manufacturer shall establish and maintain
procedures for the identification, documentation, validation or where
appropriate verification, review, and approval of design changes before their
implementation.

Design changes include any change that is made to the reagents, instrument,
software, packaging, labeling, or any of the processes, including manufacturing,
testing, and/or QC. Design changes require validation or verification data (where
appropriate). The amount of testing needed depends upon the extent and the
impact of the change. For example, a change that causes different performance
(better or worse), will require establishing new performance claims and a new
risk assessment to document whether the new performance meets clinical need.
Performance changes may also require a new FDA filing. In addition, the laboratory
will need to determine whether the change has any unanticipated impact. For
example, consider whether changing the timing for one chemistry test impacts
any other tests that may be running on the same analyzer.
Another important point to consider is the potential impact of accumulated
change. Often, small changes by themselves do not create enough impact to retest
for performance claims. But many small changes over time accumulate to create
significant changes that require new verification or new validation data. A risk
assessment of the change, any accumulated changes, and any potential impacts
on the test itself or other tests will help the laboratory determine what testing it
needs to perform and document.
The risk assessment and data for any design changes should be reviewed and
approved (with a signature and date) by each departmental representative before
implementation.
Requirement
§ 820.30(j): Design history file. Each manufacturer shall establish and
maintain a DHF for each type of device. The DHF shall contain or reference
the records necessary to demonstrate that the design was developed in The DHF can be a large
accordance with the approved design plan and the requirements of this part. paper file or it can be
electronic. It is very important
All of the records and data generated during the design and testing of the LDT
that it be well organized so
must be maintained and accessible (in electronic or paper form). The records
that individual documents can
must be maintained in a way that ensures that they cannot be lost or have any
be retrieved as needed.
information changed in an uncontrolled manner. The DHF should be organized in
a way that is easy to follow the logic and data flow of the design process and all
of the testing. A DHF will typically have a detailed table of contents, and includes
all of the design plans, testing protocols, test reports, and any other documents
generated during the LDT’s design phase. See Table 5 and Figure 6 for an example
template and table of contents, respectively.
Documents are never changed or removed from the DHF. When revisions to the
design are made, the changes are documented in the DHF. The previous data/
information are not deleted, erased, or crossed out; they remain in the DHF as
previous data. Of course, all of the documents in the DHF should have acceptance
signatures and dates!

Table 5. Example Design and Development Plan Template

Project Name
Revision Effective Date
Plan Approvals
Role Name Signature Date
Project manager
R&D
Quality
Regulatory
Clinical and
analytical testing
Manufacturing
Marketing
(as applicable)

Table of Contents
1. Introduction
a. Purpose
b. Scope
c. Definitions, abbreviations, acronyms
d. References
2. Project Team Members/Functions
3. Design Input
a. Design input strategy
b. Listing of all actions and deliverables
c. Schedule, including design reviews to be conducted
4. Design Output
a. Design output strategy, including configuration management
5. Design Verification and Validation
a. Design verification and validation strategy
6. Design Transfer
a. Design transfer strategy
7. Other
a. Quality management strategy, actions, and deliverables
b. Regulatory strategy, actions, and deliverables
c. Risk management deliverables
8. Project plan key milestones
a. Project milestones indicated
b. Design review meetings indicated
Figure 6. Example Table of Contents for a DHF


5 Document
Controls

5 Chapter 5: Document Controls
(§ 820.40)
A good document control system provides evidence that the laboratory’s activities
are performed correctly and consistently. Maintaining proper control of those
documents is critical in a good QMS.
Requirements
§ 820.40: Document controls. Each manufacturer shall establish and maintain
procedures to control all documents that are required by this part. The
procedures shall provide for the following:
§ 820.40(a): Document approval and distribution. Each manufacturer shall

designate an individual(s) to review for adequacy and approve prior to
issuance all documents established to meet the requirements of this part.
The approval, including the date and signature of the individual(s) approving
the document, shall be documented. Documents established to meet the
requirements of this part shall be available at all locations for which they are
designated, used, or otherwise necessary, and all obsolete documents shall
be promptly removed from all points of use or otherwise prevented from
Procedures may be in
the form of manuals,
computer files, or card files.
Reference procedures may be
included in a “Reference”
section.
It is very important to
be sure to remove
retired procedures that are
unintended use. obsolete, or secure them in a
FDA’s requirement for controlling document approval and distribution is not way that prevents unintended
so different from the CLIA requirement. In 42 CFR § 493.1251, CLIA requires “a use of obsolete documents.
written procedure manual for all tests, assays, and examinations performed by Each person using a procedure
the laboratory” that must be “available to, and followed by, laboratory personnel.” must ensure that he or she is
CLIA 42 CFR § 493.1251(e) states additionally that “the laboratory must maintain using the most current revision
a copy of each procedure with the dates of initial use and discontinuance.” CLIA 42 of the procedure.
CFR § 493.1253(c) and § 493.1299(c) require the laboratory to document all quality
assessment activities.

Quality System Regulation for Laboratory-Developed Tests Chapter 5: Document Controls
Be sure to verify that Written Document Control Plan

the SOPs included in Each laboratory must have a current written document control plan that addresses
the procedure manual are these key elements for the laboratory’s SOPs:
current for each of the tests
A master list of SOPs currently used in the laboratory, including listing of
offered by the laboratory.
current revision number or date
According to 42 CFR An authorization process that is standard and consistent
§ 493.1251, all laboratory Assurance that all SOPs are procedurally accurate and relevant
procedures must indicate
A process for review of each SOP at specified time intervals
the director’s review and
approval. A coversheet may A process for approving new or modified SOPs, including approvers listed
be used for the director to by title or function, not by name (limited to laboratory management, eg,
approve a manual. Annual laboratory director)
review of procedures is not A process for removal of retired or obsolete SOPs from use, and identification
required. of them as retired or obsolete
An archival system that allows for retrieval of current revisions of SOPS, as
CLIA also requires that
well as for maintenance or reference of retired or obsolete SOPs for a period
any changes to these
of time defined by the laboratory that meets or exceeds the requirements of
documents must be
applicable regulatory bodies, such as the FDA. For FDA, all records must be
approved by the laboratory
retained for a period of time equivalent to the expected life of the product (eg,
director, including date
reagent batch), but in no case less than two years from the date of release for
of approval, before
use.
implementation.
Requirement
§ 820.40(b): Document changes. Changes to documents shall be reviewed
and approved by an individual(s) in the same function or organization that
performed the original review and approval, unless specifically designated
otherwise. Approved changes shall be communicated to the appropriate
personnel in a timely manner. Each manufacturer shall maintain records of
changes to documents. Change records shall include a description of the change,
identification of the affected documents, the signature of the approving
individual(s), the approval date, and when the change becomes effective.
This requirement is also covered by CLIA in 42 CFR § 493.1251(d), which states that the
“procedures and changes in procedures must be approved, signed, and dated by the
current laboratory director before use.” Careful documentation of changes is required.
It is a good quality practice to implement a “Document Change Control Form” that
captures:
The title and number of the procedure being changed
A description of the change
The effective date of the change
Any other related documents
Approval signatures with date

The laboratory director has the responsibility to approve, sign, and date procedures
before implementation. CLIA also requires laboratory director approval, including
signature and date, of changes in procedures before use. The laboratory
must maintain a copy of every revision, including the dates of initial use and
discontinuance. Every laboratory should prevent the unintended use of obsolete Be sure to properly
documents, and apply suitable identification to them if they are retained for any document all training of
purpose. employees on any new or
revised procedure!
After approval of changes to an SOP, be sure to train all of the users of the
modified document. The training can vary depending upon the extent of the
change, and the ease of understanding of the change. For example, for a very
simple change, it may be sufficient for the users of the SOP to read the new
version, and then document that they have “read and understood” the new
version. For more extensive changes, formal training and competency assessment
may be needed.


6 Purchasing
Controls

6 Chapter 6: Purchasing Controls
(§ 820.50)
Requirement
§ 820.50: Purchasing controls. Each manufacturer shall establish and maintain
procedures to ensure that all purchased or otherwise received product and
services conform to specified requirements.
IVD test manufacturers interpret this requirement to mean that they must have
procedures for evaluating the sources of all procured materials and services that
may have an effect on the quality of their products. Further, they must have
documents that describe acceptance criteria or specifications for all materials
and services that come into their manufacturing facility to ensure that all sources
(suppliers, contractors, consultants, etc.) provide quality products and services.
This section of the regulation focuses on those incoming items and services that
pertain to manufacturing or the quality system.
The FDA’s QSReg requirements go well beyond CLIA regulations in this area.
Under CLIA, manufacturers test the ingredients and components coming in the
door, and review services provided, to ensure they conform to specifications and
“Suppliers” are vendors
from which the
laboratory obtains chemicals or
other components of the LDT
and services pertaining to
manufacturing and the quality
system.
quality requirements. However, the FDA requirements take an additional step to Doing the up-front work
require the manufacturers to qualify the suppliers to ensure that they are likely to ensure a supplier has
to continue to provide ingredients, components, and services that meet the a solid quality system, and is
specifications and quality requirements. Laboratories developing LDTs should take likely to provide high-quality,
the steps to ensure that their suppliers (including contractors and consultants) are consistent materials and
capable of continuously providing high-quality materials and services. services, helps avoid future
problems.
Manufacturers have, as part of their quality system, a document describing a
supplier approval process, and the forms and procedures that are part of the
process.

Quality System Regulation for Laboratory-Developed Tests Chapter 6: Purchasing Controls
Requirement
§ 820.50(a): Evaluation of suppliers, contractors, and consultants. Each
manufacturer shall establish and maintain the requirements, including
quality requirements, that must be met by suppliers, contractors, and
consultants. Each manufacturer shall:
(1) Evaluate and select potential suppliers, contractors, and consultants on

the basis of their ability to meet specified requirements, including quality
requirements. The evaluation shall be documented.
(2) Define the type and extent of control to be exercised over the product,
services, suppliers, contractors, and consultants, based on the evaluation
results.
(3) Establish and maintain records of acceptable suppliers, contractors, and

consultants.
Manufacturers must assemble a set of requirements that their suppliers must
meet, and they must evaluate their suppliers against these requirements. This
means that for every supplier, a manufacturer must first evaluate the supplier
against the manufacturer’s written specifications, document the evaluation, and
define the type and extent to which the supplier and its product(s) or services will
be controlled going forward.
This process is similar to laboratories being inspected using a CAP checklist, except
that for a manufacturer, it applies to every supplier of materials or services that
may have an effect on product quality and pertain to manufacturing and the
A “critical” supplier quality system.
supplies a component The document that describes a manufacturer’s supplier approval process typically
or service that could cause a defines such elements of the process as:
device or test failure if the
Supplier classification
component or service does not
meet specifications. This Supplier approval requirements
designation is usually Supplier survey
determined by conducting a
Monitoring performance
risk assessment. Examples
include components such as Change control
antibodies, enzymes, and other Also required are documentation of all of these elements, maintenance of the
reactive components, as well as documentation, and follow-up actions of any negative findings.
any manufacturing services
such as reagent compounding
or assembly of parts. Supplier Classification
Suppliers are often classified by the risk associated with the products or services
they provide, into categories such as critical or noncritical. The requirements for
approval, audit frequency, and/or level of detail of product and service inspection
may vary accordingly.

Supplier Approval Requirements

Approval involves evaluating the information supplied via survey or audit, including
the supplier’s ability to provide materials or services that meet the manufacturer’s
specifications; resolving any questions; documenting the evaluation; and adding
the supplier to an Approved Supplier list.
Suppliers’ approval requirements are tied to their Supplier Classification category,
are customized for each supplier, and are specified in writing. A critical product or
service requires more controls and monitoring.
Supplier Survey
The supplier survey is a form that may be developed and used by the manufacturer
to collect information before an audit, or to directly qualify a supplier who may
not need to be audited if an evaluation of the information provided is sufficiently
positive (see Appendix C). The groups within the manufacturer’s organization with
responsibility for approving a supplier are typically Purchasing and Quality, with
assistance from people in the organization who have expertise about the product
or services being provided.
Monitoring Performance
The manufacturer defines a process for monitoring the performance of suppliers
through:
Evaluation of data such as on-time delivery
Nonconforming material reports generated from any material receipts that
do not meet specification
Results of quality audits
Feedback from users of the specific material or service procured
The frequency and depth of review are based on the supplier’s classification:
the more critical the supplier, the more frequent and deep the review. Favorable
supplier evaluations, or timely response to corrective actions if evaluations are
unfavorable, help to maintain supplier approval. If supplier performance shows
trends toward poor quality and/or the supplier shows unwillingness to resolve
issues, the supplier may be removed from the Approved Supplier list or put on
restricted status, requiring justification and approval by specified parties for any
future purchase.

Change Control
Often, suppliers make Manufacturers are required to define a process for evaluating the impact of
chemicals or changes to products or services, and accepting or rejecting the change. The
components for different types evaluation will often require that the manufacturer review documentation
of industries. It is very to support the change, such as process or product validation, or that the
important for suppliers to manufacturer sample and evaluate materials or output of services that have
understand that changed before accepting that changed product or service.
manufacturers of medical
Once a supplier is approved, all purchases must be recorded, and their adherence
devices have these change
to the acceptance criteria or specifications tracked.
control requirements, as other
industries may not be as strict. Requirement
§ 820.50(b): Purchasing data. Each manufacturer shall establish and maintain
data that clearly describe or reference the specified requirements, including
quality requirements, for purchased or otherwise received product and
services. Purchasing documents shall include, where possible, an agreement
that the suppliers, contractors, and consultants agree to notify the
manufacturer of changes in the product or service so that manufacturers
may determine whether the changes may affect the quality of a finished
device. Purchasing data shall be approved in accordance with § 820.40.
Purchase Specifications
It’s the manufacturer’s Purchasing requirements often take the form of purchase specifications.
responsibility to specify Manufacturers create and maintain specifications for all materials or services
exactly what is required from that may have an effect on product quality and ensure that the specifications are
the supplier, and to monitor provided to suppliers. The specifications must clearly communicate the quality
material received for requirements for products and services. Such requirements may include specific
compliance with the material formulation, performance characteristics, packaging configuration, and
specifications. required attribute data in the form of test results. Purchase specifications may
be provided to the supplier with each individual order, eg, as an attachment to
a purchase order, or supplied initially per an agreement that the supplier will
maintain the manufacturer’s specifications, as referenced in the purchase order.
Specifications are living documents and are maintained per FDA’s QSReg § 820.40
(see Chapter 5, Document Controls), using a compliant document control system.
Change Notification
Manufacturers and suppliers must agree on a process for notifying manufacturers
of changes to products or services from suppliers. This process may be achieved
through inclusion in supplier agreements or contracts, or through a statement
requiring notification on individual purchase orders. Critical components carry a
higher risk of negative impact if changed, and must be monitored closely.

7 Identification
and Traceability

7 Chapter 7: Identification and
Traceability (§ 820.60 and § 820.65)
This section of the QSReg requires documenting lot numbers of reagents used, as
well as lot numbers, and expiration dates of each of the ingredients of the LDT.
Requirement
§ 820.60: Identification. Each manufacturer shall establish and maintain
procedures for identifying product during all stages of receipt, production,
distribution, and installation to prevent mixups.
CLIA requirement 42 CFR § 493.1252(c) is analogous to the FDA requirement in that
it requires the identification of product (components, materials used, devices, etc.).
The QSReg requires this identification throughout all stages of using the product.
From the raw materials used in manufacturing the product, through the finished
product itself, all materials must be identified. One way to do this is by assigning
part numbers and lot numbers to all raw materials, intermediate products (or
“work-in-progress”), and finished product. The relationship among these various
parts are defined and documented in a bill of materials (BOM), and as products
are manufactured, an inventory system is used to track the lot numbers for each
component part or material.
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. Typically, this is done through
computerized records and forms. For example, the instructions for making an
LDT reagent should include lines or spaces to record information about each
component, including:
The manufacturer’s lot number
The manufacturer’s listed expiration date
The components included in the LDT reagent

Quality System Regulation for Laboratory-Developed Tests Chapter 7: Identification and Traceability
Throughout each step of the LDT reagent preparation and testing process, the
reagents must be clearly identified with their name, lot number, and expiration
date, and should indicate whether they are ready for use or not ready for use.
Reagents that require testing before use are clearly identified as “in-process” and
should be physically separated from reagents that are ready for use. Reagents that
are tested and found to be nonconforming should be labeled as such, with the
label clearly indicating that they are not to be used. Every effort should be made to
ensure that the laboratory staff is able to identify and use the correct reagents for
preparing or using the LDT.
Do not confuse the
Requirement
QSReg concept of
§ 820.65: Traceability. Each manufacturer of a device that is intended for
“traceability” for reagent
surgical implant into the body or to support or sustain life and whose failure
components with the
to perform when properly used in accordance with instructions for use
laboratory concept of
provided in the labeling can be reasonably expected to result in a significant
“traceability” of measurement
injury to the user shall establish and maintain procedures for identifying
results!
with a control number each unit, lot, or batch of finished devices and where
appropriate components. The procedures shall facilitate corrective action.
Such identification shall be documented in the DHR.
Reminder: FDA considers Traceability applies to the components of LDTs. The manufacturer (ie, the
the laboratory to be the laboratory, for LDTs) must ensure traceability of the LDT components at all stages
manufacturer of the LDT. of manufacturing, release, and use, from the finished product lot back to the
raw materials. This means that the laboratory can determine, for each patient
result, what reagents were used to perform that test, including all of the raw
materials and their lot numbers. Traceability is necessary to establish corrective
action should product problems be linked to a particular manufactured lot and/
or component material. The laboratory must define the level of traceability for
the different products, and define the system for documenting these traceability
activities.
For example, the laboratory might receive a complaint that a patient’s LDT result
does not match his or her clinical picture. The laboratory needs to be able to trace
back to which lots of LDT reagents, raw materials, finished device, packaging,
labeling, etc. were used on the day of the patient test, whether the QC results for
that day were in range, and whether any other complaints have been received for
that day of testing. It could be that one of the raw materials used in making the
LDT was not of the correct concentration. With proper traceability, this error can
be found, and a quality check can be put into place to prevent it from happening
again. Without such traceability, the error in the raw material would likely not be
found, and could perhaps impact the number of devices, or quantity of reagents,
to be destroyed due to nonconformance.

8 Production and
Process Controls

8 Chapter 8: Production and Process
Controls (§ 820.70)
Before beginning to manufacture an LDT, the laboratory must define all of the
manufacturing steps and the necessary controls, including:
The reagent formulation and the steps to take to prepare it
– How much can each component vary, while still allowing the reagent
to work? Upper and lower specification limits are established for each
component, eg, buffer pH = 6.2, ± 0.1 unit.
The equipment to be used
– The equipment must be controlled so that it delivers the same
performance each time it is used. Again, limits of variability are
established, eg, the pipettor must be accurate within 0.01 mL.
The environmental conditions
– Often, the room temperature and/or humidity can impact the
manufacturing of the LDT. Are these parameters understood?
Any other requirements to ensure that the LDT conforms to specifications
The production and
process controls should
tie to the design and
development phase in which
many of the controls were
originally established to ensure
that the LDT conforms to its
design specifications.
The requirements in
§ 820.70(a) are intended
to ensure that product
conforms to established
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. Following the procedures ensures that the LDT is controlled and conforms
to its design specifications and is consistent, reliable, and repeatable, and that a
nonconforming product (LDT) is not produced.
Production and process
Once each step of the manufacturing process is understood and the specifications controls will always be
are defined, the allowed amount of variation of each specification is documented required for manufacturing an
through a procedure called “process validation.” Process validation is conducted LDT; the extent of those
to ensure that product can be made to meet specifications using the process, and controls may vary depending
that the process is controlled. on complexity and criticality of
When the process validation is complete, the laboratory is ready to begin the LDT.
manufacturing its LDT, always ensuring that the manufacturing process is
controlled to stay within each limit established during validation testing. Each
time the product is made using the validated processes and equipment, it should
perform to the acceptance criteria that have been established for the product.

Quality System Regulation for Laboratory-Developed Tests Chapter 8: Production and Process Controls
Requirement
§ 820.70(a): General. 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 controls necessary to ensure conformance to specifications.
Where process controls are needed they shall include:
(1) Documented instructions, standard operating procedures (SOPs), and

methods that define and control the manner of production;
(2) Monitoring and control of process parameters and component and device
characteristics during production;
(3) Compliance with specified reference standards or codes;
(4) The approval of processes and process equipment; and
(5) Criteria for workmanship which shall be expressed in documented

standards or by means of identified and approved representative samples.
The QSReg has more specific requirements than CLIA regulations for production
and process controls. 21 CFR Part 820 is specifically written for facilities that
design, manufacture, package, label, store, install, and service finished devices
intended for human use. The CLIA regulations partially fulfill those requirements
when they include procedures pertaining to LDT design and manufacture.
Laboratories creating LDTs will do some, if not all, of these activities. The QSReg
requires manufacturers to control and monitor the production processes to ensure
that the finished LDT meets specifications.
The following sections describe each of the items above, one at a time.
Requirement
§ 820.70(a)(1): Documented instructions, standard operating procedures (SOPs),
and methods that define and control the manner of production
Every step in the process of preparing (manufacturing) an LDT requires
documented procedures. The steps should be done the same way every time,
using equipment and methods that are controlled and repeatable.
Requirement
§ 820.70(a)(2): Monitoring and control of process parameters and component
and device characteristics during production
Once each process variable is understood, and its limits determined through
the validation testing described above, each variable must then be controlled to
ensure it stays within the acceptable limits. For example, if the room temperature
must be between 72 and 78°F, then the temperature must be recorded during the
time of the LDT manufacturing, and the documentation retained with the LDT
batch records (see Chapter 13, Records).

Requirement
§ 820.70(a)(3): Compliance with specified reference standards or codes
Determine if there are any applicable reference standards or codes for this LDT.
This will likely not be the case. For some industries, the regulatory authorities
have recognized consensus standards or construction codes. At the time of this
publication, CLSI is unaware of any such standards or codes for IVD devices. If
they exist in the future, compliance must be established and documentation
maintained.
Requirement
§ 820.70(a)(4): The approval of processes and process equipment
Successful validation allows the processes and the equipment to be officially
“approved” for use for manufacturing the LDT. Documentation should be put in
place with the validation results indicating the approval of specific processes and
pieces of equipment.
Requirement
§ 820.70(a)(5): Criteria for workmanship which shall be expressed in
documented standards or by means of identified and approved representative
samples
Determine if the current lot of product meets all of its acceptance criteria for
manufacturing. Typically, fulfilling this requirement is documented by checking/
testing important criteria (eg, accuracy, precision, reportable range, analytical
sensitivity and specificity). This activity may best be performed by testing the
initial product produced, or its equivalent.
In summary, process controls may include, but not be limited to:
Monitoring and controlling environmental conditions in the production
area
Monitoring and controlling all of the equipment used
Monitoring and controlling the time it takes to prepare reagents
Monitoring and controlling the room temperature during reagent
preparation, or other temperatures such as those during heating and The process controls
cooling steps should reflect the
Monitoring and controlling the atmospheric pressure, if necessary quality conditions that are
necessary to safely and
NOTE: Historically, the FDA has evaluated manufacturers’ compliance with
effectively manufacture the
regulations governing the design and production of devices. The more recent focus
LDTs.
on quality goes beyond this model by treating compliance only as a baseline. The
FDA and stakeholders focus instead on quality practices that, when present in day-
to-day device design and production, correlate to higher-quality outcomes. The
FDA is working with stakeholders to promote manufacturers’ implementation of
quality practices.1
All of the requirements for controlling the production process must be defined
in operating procedures or work instructions. Process validation is typically

Verification was added performed within the ranges of the process controls to demonstrate that the
to the requirements to process consistently results in acceptable product across the full range of process
give manufacturers the parameters. Processes must be monitored during manufacturing to ensure they
flexibility to verify changes (eg, were maintained within the defined conditions and the final LDT must be verified
change of reagent lot or to meet specifications. One method of monitoring production processes is
manufacturer of a component) through the use of statistical process control. This method allows processes to be
because FDA believes that monitored for new or unusual causes of variation.
validation is not always The acceptance criteria for the final LDT must be defined and documented.
necessary. A few examples of
processes that must be Requirement
validated include changes to § 820.70(b): Production and process changes. Each manufacturer shall
intended use, such as sample establish and maintain procedures for changes to a specification, method,
matrix, target population, or process, or procedure. Such changes shall be verified or where appropriate
purpose of the test. validated according to § 820.75, before implementation and these activities
shall be documented. Changes shall be approved in accordance with
§ 820.40.
Under § 820.70(d), LDT There must be established procedures for changing a specification, method,
manufacturers must process, or procedure for production. All changes must be assessed for their
not permit unclean or impact on the process and the product, and must be verified or validated
inappropriately clothed before implementation. Production processes cannot be modified without the
employees, or employees with appropriate testing and approvals. Appropriate personnel must be notified of
certain medical conditions, to approved changes before implementation.
work where these conditions
could have an adverse effect on Requirement
product quality. The procedure § 820.70(c): Environmental control. Where environmental conditions could
must also address acceptable reasonably be expected to have an adverse effect on product quality, the
clothing, hygiene, and personal manufacturer shall establish and maintain procedures to adequately control
practices, if contact between these environmental conditions. Environmental control system(s) shall
personnel and product or be periodically inspected to verify that the system, including necessary
environment could reasonably equipment, is adequate and functioning properly. These activities shall be
have an effect. documented and reviewed.
Environmental conditions for production processes may include, but not be
limited to:
Water quality
Training for those Filtration

working temporarily Temperature (room and refrigerator)
under the special Humidity
environmental conditions
Unidirectional flow
should be performed by
someone trained (or supervised Room pressurization
by someone trained) to work in Bioburden and particulate levels
such an environment.
The appropriate limits for these conditions must be defined if there is a potential
detrimental impact on the quality of the product when these conditions are not
maintained. The conditions must be monitored and the environmental control

systems, such as HVAC systems and HEPA filters, must be periodically inspected to Contamination controls
ensure proper function. This inspection is often defined and managed within the can include a broad
company’s preventive maintenance program. range of activities. Byproducts,
chemical odors, or discharges
Requirement
are some examples of
§ 820.70(d): Personnel. Each manufacturer shall establish and maintain
conditions that could affect the
requirements for the health, cleanliness, personal practices, and clothing of
product and must be
personnel if contact between such personnel and product or environment
adequately controlled.
could reasonably be expected to have an adverse effect on product quality.
The manufacturer shall ensure that maintenance and other personnel who
are required to work temporarily under special environmental conditions are
appropriately trained or supervised by a trained individual.
Establishing the
Device manufacturers, including laboratories making LDTs, are required to
adequacy of the
establish procedures that ensure both the safety of manufacturing personnel as
equipment used in the
well as the quality of product being manufactured. When the effect of contact
production of the LDT helps to
between personnel and the environment, production materials, or finished
reassure the reliability of the
goods could be harmful to personnel or detrimental to product quality, measures
process.
for protection must be taken. These requirements typically include personal
protective equipment, such as laboratory gowns, gloves, safety glasses, or a
respirator. They may also include instructions for a unidirectional movement of
personnel in the work environment or definitions of activities that must occur FDA expects that the
in a specialized environment such as a biosafety cabinet or chemical fume hood. maintenance is carried
Training might also be required to ensure employees are aware of areas that have out on a schedule that ensures
restricted access. that the equipment functions
properly. The schedule should
The QSReg also recognizes that there may be times when nonroutine personnel
be maintained and readily
are required to have access to the manufacturing areas, such as maintenance
available.
personnel or service providers. In these cases, the regulation requires that the
personnel who are required to work temporarily under special environmental
conditions either be trained on the requirements for that area or be supervised by
a trained individual while they are present in the area. Inherent limitations and
Requirement allowable tolerances
§ 820.70(e): Contamination control. Each manufacturer shall establish and must be visibly posted on or
maintain procedures to prevent contamination of equipment or product by near equipment, or made
substances that could reasonably be expected to have an adverse effect on readily available to personnel to
product quality. ensure they are used by those
personnel who need them.
CLIA regulations partially fulfill requirements in the QSReg to construct, arrange,
and maintain the laboratory to minimize contamination of specimens, equipment,
instruments, reagents, and supplies (42 CFR § 493.1101). The procedures should
ensure that protection of contamination of the LDT is documented and checked
periodically.
Requirement
§ 820.70(f): Buildings shall be of suitable design and contain sufficient
space to perform necessary operations, prevent mixups, and assure orderly
handling.

The product design QSReg and CLIA regulations (42 CFR § 493.1101, Standard: Facilities) both have
documents should requirements for facility design and layout. Both regulations require facilities to
identify any manufacturing be designed to accommodate the operations performed in the facility, to facilitate
material that could have an process flow, and to prevent contamination or mixups. Laboratories should ensure
effect on the product quality. that these procedures address adequate facility design and layout to perform
operations for the manufacturing of the LDT as well as the testing of the LDT.
Requirements
§ 820.70(g): Equipment. Each manufacturer shall ensure that all equipment
used in the manufacturing process meets specified requirements and
is appropriately designed, constructed, placed, and installed to facilitate
maintenance, adjustment, cleaning, and use.
§ 820.70(g)(1): Maintenance schedule. Each manufacturer shall establish and

maintain schedules for the adjustment, cleaning, and other maintenance
of equipment to ensure that manufacturing specifications are met.
Maintenance activities, including the date and individual(s) performing the
maintenance activities, shall be documented.
§ 820.70(g)(2): Inspection. Each manufacturer shall conduct periodic

inspections in accordance with established procedures to ensure adherence
to applicable equipment maintenance schedules. The inspections, including
the date and individual(s) conducting the inspections, shall be documented.
§ 820.70(g)(3): Adjustment. Each manufacturer shall ensure that any inherent

limitations or allowable tolerances are visibly posted on or near equipment
requiring periodic adjustments or are readily available to personnel
performing these adjustments.
CLIA requirements for equipment are described in 42 CFR § 493.1252–1255.
Both CLIA and the QSReg require equipment to be calibrated, maintained, and
periodically inspected to ensure proper performance. CLIA does not specify
requirements regarding adjustments to equipment. The QSReg requires that
information on the limitations or tolerances for a piece of equipment be posted or
readily available to ensure that equipment is not operated outside of its limits. In
addition, information regarding periodic adjustments, if required for equipment,
must be available to ensure that the operator is able to perform these adjustments
as required. Laboratories should ensure that these procedures address equipment
used in the manufacturing of the LDT and not just the testing of the LDT. In
addition, laboratories should ensure that these procedures address adequate
facility design and layout to perform the operations for the manufacturing of the
LDT, as well as the testing of the LDT.

Requirement Black box testing is a

§ 820.70(h): Manufacturing material. Where a manufacturing material method of testing
could reasonably be expected to have an adverse effect on product quality, software that tests the
the manufacturer shall establish and maintain procedures for the use and functionality of an application
removal of such manufacturing material to ensure that it is removed or as opposed to its internal
limited to an amount that does not adversely affect the device’s quality. The structures or workings.
removal or reduction of such manufacturing material shall be documented.
Manufacturing materials are controlled by material specifications. Material
specifications typically define the approved supplier and part number; the
documentation, such as a certificate of analysis, that must accompany the
material; and the inspection and testing requirements. Upon receipt, materials
are inspected or tested according to the specifications. Materials that meet all
requirements will be released for use. Materials that fail to meet specifications
Software used in the
are usually addressed according to the company’s procedures for nonconforming
production and as part
materials. The disposition of all materials, both acceptable and unacceptable, must
of the laboratory’s quality
be documented.
system, whether it is designing,
manufacturing, distributing, or
Requirement tracing, must be validated.
§ 820.70(i): Automated processes. When computers or automated data
processing systems are used as part of production or the quality system,
the manufacturer shall validate computer software for its intended use
according to an established protocol. All software changes shall be validated
before approval and issuance. These validation activities and results shall be
documented.
The QSReg specifies the requirement to validate automated systems/computer
systems used in either the production process or to support the quality system,
such as an electronic document management system. All validations require a
protocol and for validation to be completed and approved before implementation.
Laboratories should ensure that their procedures address validation of software
used in the manufacturing of the LDT, and not just the test results obtained from
the use of the LDT.
Where source code and design specifications cannot be obtained, “black box
testing” must be performed to confirm that the software meets the user’s needs
and its intended use.
FDA has emphasized that manufacturers are responsible for the adequacy of
the software and the activities used to produce the product. When off-the-shelf
software is used, manufacturers must ensure that it will perform as intended in
its chosen application.
Reference for Chapter 8

1 US Food and Drug Administration. Medical devices: case for quality.
http://www.fda.gov/medicaldevices/deviceregulationandguidance/
medicaldevicequalityandcompliance/ucm378185.htm.
Accessed January 6, 2015.


9 Nonconforming
Product

9 Chapter 9: Nonconforming Product
(§ 820.90)
Requirement
§ 820.90(a): Control of 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. The evaluation of nonconformance shall include a determination of
the need for an investigation and notification of the persons or organizations
responsible for the nonconformance. The evaluation and any investigation
shall be documented.
CLIA requirements 42 CFR § 493.1252(d) and § 493.1282 are analogous to some of
the nonconforming product requirements of the QSReg. Laboratories should apply
similar principles and practices to controlling nonconformances throughout the
manufacturing processes of the LDT.
The QSReg indicates specific requirements for addressing product problems
or nonconforming product before and after product has been released for
Nonconforming means
the nonfulfillment of a
specified requirement. An
important element in
addressing nonconformities is
to give all appropriate
personnel the responsibility to
identify nonconforming items,
activities, and processes, and
encourage them to suggest
improvements.
Any product returned

distribution. Nonconforming product, in the case of the LDT, is a reagent, reagent (eg, a component of the
system, instrument, manufacturing material, or test system that is not meeting its LDT, such as equipment or
specifications. This lack of conformance to the specifications can lead to erroneous reagent) should be treated as
results or other problems, including adverse events. nonconforming product until it
Under the QSReg, the LDT laboratory is required to establish and maintain has satisfied a documented
procedures and processes to ensure that any product that does not conform to acceptance procedure. If the
specified requirements is identified and controlled to prevent its unintended use. returned product may have
The requirements apply to raw materials and other products used in making or been contaminated with
running the LDT, work in progress (eg, partially finished reagents, components), biological material, before it is
and finished product (the LDT reagent, test, instrument, system, or labeling). handled, it should be
decontaminated according to
appropriate, approved
procedures.

Quality System Regulation for Laboratory-Developed Tests Chapter 9: Nonconforming Product
The procedure should Procedures must be created by the laboratory that describe the following methods
define the responsibility for the nonconforming products:
for review and the authority for Identification
the disposition, including the
review and disposition process. Documentation
It is important to document Evaluation
the disposition of Segregation
nonconforming product,
Control
including the justification for
use and the signature of the Investigation, when necessary
individual(s) authorizing use. Disposition
Examples of disposition of
Procedures also need to establish who has responsibility and authority for dealing
nonconforming product are:
with nonconforming product. In industry, this is usually a “Material Review Board.”
Rework/retest
In the laboratory, it could be the laboratory director, the quality officer, or a
Accept (use as is) specifically designated committee of individuals.
Reject/return to vendor Nonconforming product is addressed by:
Scrap Segregating it from conforming product
Conducting investigations, when necessary
Taking action to correct the nonconformity and eliminating its cause
Authorizing its use, release, or other disposition through controlled
processes executed by the designated authority, following established
procedures
Retesting and reevaluation after rework
Documenting all activities that ensure the nonconforming product was
not inadvertently used
Notifying all responsible individuals
Nonconforming products may be used, accepted, or released by exception after
correction of the nonconformance, followed by retesting and reevaluation of
the product against its established requirements. In such cases, an evaluation is
made and documented to ensure that safety and regulatory requirements are not
compromised and that the product does not adversely affect the finished LDT.
If nonconforming product is detected after use has started, an evaluation is
made to determine the appropriate corrections and corrective actions based
on the effects or potential effects of the nonconformity on product safety and
performance. Records are maintained of nonconformities and actions taken to
address them.

Requirement FDA determined that

§ 820.90(b)(1): Nonconformity review and disposition. Each manufacturer proper disposition of
shall establish and maintain procedures that define the responsibility for nonconforming product is
review and the authority for the disposition of nonconforming product. The essential for ensuring the
procedures shall set forth the review and disposition process. Disposition of safety and effectiveness of
nonconforming product shall be documented. Documentation shall include products. Although it may be
the justification for use of nonconforming product and the signature of the appropriate at times to use
individual(s) authorizing the use. nonconforming product, the
All pertinent laboratory staff must be involved in the problem assessment disposition process must be
process through discussions or active participation. Nonconformance reports are adequately controlled.
used to document the nature of the nonconformity, investigations conducted, Therefore, the disposition and
and any subsequent actions taken. The laboratory director or quality officer is justification should be based
responsible for evaluating the nonconformance and ensuring that any decisions on scientific evidence (which
are appropriate and fully documented. should be available upon
request).
Nonconforming product is not accepted by concession unless regulatory
requirements are met and the identity of the person(s) authorizing the concession
is recorded and maintained, together with the rationale for the acceptance.
The laboratory should ensure that any nonconforming product is segregated
from other product in a controlled area until disposition is made, to prevent
Reworked product
unauthorized use of the nonconforming product.
should be evaluated
The disposition of each nonconformance must be reviewed by the laboratory against the established product
director or the quality officer. requirements. Any adverse
effect of the rework upon the
Requirement
product should be determined.
§ 820.90(b)(2): Nonconformity review and disposition. Each manufacturer
shall establish and maintain procedures for rework, to include retesting and
reevaluation of the nonconforming product after rework, to ensure that the
product meets its current approved specifications. Rework and reevaluation
activities, including a determination of any adverse effect from the rework
upon the product, shall be documented in the DHR.
Generally, when nonconforming product has been identified by the laboratory, it is
past the point of rework to meet current approved specifications. However, when
nonconforming product is reworked, it is subject to retesting and reevaluation to
demonstrate conformity to the specified requirements. Rework is only completed
in accordance with an approved work instruction (procedure) that has undergone
the same authorization and approval procedure as the original work instruction.
Before authorization and approval of the rework instruction, a determination of
any adverse effect of the rework is made and documented. Records of rework are
maintained in the device history record (DHR).


10 Corrective and
Preventive Action

10 Chapter 10: Corrective and
Preventive Action (§ 820.100)
For corrective and preventive actions (CAPAs), CLIA certification regulatory

requirements 42 CFR § 493.1200(b), § 493.1239, and § 493.1282 partially fulfill
some of the QSReg requirements, but the QSReg contains more detail. In
addition, other CLIA certification requirements (42 CFR § 493.1240, § 493.1249,
§ 493.1256[c], § 493.1289, and §493.1299) are considered analogous to the
QSReg requirements because they focus on methods of CAPA for the process
of testing patient samples. Laboratories should ensure that procedures for
monitoring and assessing their processes and for correcting any problems include
procedures for the design and manufacture of the LDT. FDA expects to see specific
documentation and activities during review of the laboratory’s CAPA procedures.
Key terms that the laboratory should be familiar with include:
Cause – the basic issue that precipitates a problem
Correction – action taken to eliminate a nonconformity
Corrective action – action taken to eliminate the cause(s) of an existing
Not all quality issues are
equal! In the Preamble
to the Quality System
Regulation, FDA’s response to
comment group 159 indicates:
“FDA cannot dictate in a

regulation the degree of action
that should be taken because
each circumstance will be
different, but FDA does expect
the manufacturer to develop
procedures for assessing the
risk, the actions that need to
be taken for different levels
nonconformity of risk, and how to correct
or prevent the problem from
Preventive action – action taken to eliminate the cause(s) of a potential
recurring, depending on that risk
nonconformity, before it occurs
assessment.”
Objective evidence – information that can be verified, based on facts and
obtained by observation, measurement, or testing
For example, suppose a
Validation – confirmation by examination and objective evidence that the
laboratory worker
requirements for a specific intended use can be consistently met
receives a cut from a sharp
Verification – confirmation by examination and objective evidence that edge on an instrument. Putting
specified requirements are met a piece of tape over the sharp
edge is an immediate
correction. Replacing the part
or changing the instrument to
one with no sharp edges is a
corrective action.

Quality System Regulation for Laboratory-Developed Tests Chapter 10: Corrective and Preventive Action
Assess to determine the Requirement

significance or impact. § 820.100(a): Corrective and preventive action. Each manufacturer shall
Ensure that the overall patient establish and maintain procedures for implementing corrective and
safety goals are taken into preventive action.
account. Clearly written and unambiguous procedures are expected. These procedures
should describe the corrective action processes, responsibilities, and subsequent
documentation requirements. These procedures should also address
nonconforming product and processes related to LDTs, and document how risk
Sources for triggers to
management activities will be incorporated and used.
initiate a CAPA are:
Acceptance activities Requirement
(incoming, in-process, final The procedures shall include requirements for:
test)
§ 820.100(a)(1): Analyzing processes, work operations, concessions, quality
Nonconforming product,
audit reports, quality records, service records, complaints, returned product,
process, or system
and other sources of quality data to identify existing and potential causes of
Process controls nonconforming product, or other quality problems. Appropriate statistical
Environmental monitoring methodology shall be employed where necessary to detect recurring quality
problems.
Calibration/ maintenance
To start this process, information is required:
Internal audits
Documentation of the incident
Third party audits
Understanding of what LDT is involved, including the specific items
Supplier evaluations
involved (specific reagents, instruments, etc.)
Management review
Understanding of where the incident occurred (laboratory, satellite
results
laboratory, clinic, etc.)
Complaints/MDRs/
Understanding of the circumstance, problem, or failure
vigilance reporting
Understanding of the risk of harm associated with this nonconformity
Servicing
Understanding of when the situation occurred
Product returns
Understanding of why the situation presents a problem (specification,
Recalls
policy, procedure failure, other)
Risk management activities
Understanding of who is/was affected (eg, results reported to which
providers, and on which patient[s])
Information from all involved processes needs to be reviewed; sometimes, the
combination of data from multiple processes will lead to either confirming
an issue or identifying issues that would not have been observed in isolation.
Including all processes also ensures that all sources of information are
appropriately evaluated.

Figure 7 provides an example of an outline approach to identify the problem.
What Problem(s)
Product involved
When Date and time
Where Physical location
Process location
Goals Safety
Environmental
Production
Maintenance
Frequency
Figure 7. Example Outline to Identify Problem(s)
Optional, additional tools to use as needed include a timeline, diagrams, and a

process map. Description of
nonconformity
It is important to write an effective description, accurately describing the
should be:
nonconformance with all available details.
Specific
For any testing, there should be a valid statistical method for any sample sizes
Observable
selected that is based on the associated risk involved; valid statistical analysis
should be employed. Simply put, what statistical method was used to choose this Measurable
sample size? For example, if the past 30 days of QC data were reviewed, how was Manageable
this number of days chosen? Be sure that the choice is based on a valid statistical
methodology, and is statistically relevant. Be sure to get the advice of a statistician.
Requirement
§ 820.100(a)(2): Investigating the cause of nonconformities relating to
product, processes, and the quality system
This requirement means that the laboratory needs to determine what happened
to cause the problem. This conclusion should not be based on opinion. Instead,
it needs to be developed using facts, data, observations, and careful evaluation.
An investigation is expected to be performed to determine the cause(s) of the
problem and explain how the cause was determined.
NOTE: In general, stating that the operator/technician needs to be trained is not
an acceptable answer by itself, if this reason is judged to be the cause. What policy
or procedure was not followed? Is the procedure clear and unambiguous? Why
was this person not properly trained? What broke down? Can the training process
be improved?

It is important to use the appropriate analysis technique to determine the cause(s)

of the nonconformity. One approach is:
There are numerous 1. Ask what kind of problem needs to be solved.
types of investigation 2. Then, use the following table to decide:
techniques that can be used.
Examples include: Number of Effects and Number of
Five “whys” Suspected Causes Proposed Method of Analysis
Pareto charting (often Single effect and single cause Five “whys”
referred to as the “80/20 Single effect and multiple causes Pareto charting
rule”) Single effect and multiple complex causes Fishbone diagram
Fishbone diagram
The tool of choice should be at least partially based on the complexity of the
situation and the level of risk of the nonconformity.
It is highly recommended to use team approaches in cause analyses and
investigation activities wherever possible. This approach helps to ensure that:
Outsider points of view are considered.
Someone who will ask critical questions is included.
Stakeholder buy-in is obtained.
The five “whys” method is very simple:
Ask: “Why did this event occur?” Obtain the answer, and then, regarding the
answer, ask again, “Why did this event occur?” Obtain the answer. Repeat this
questioning until the root cause is obtained. See Table 6 for an example.
Table 6. Example Five Whys Analysis

Nonconformance: Laboratory technician cut her finger on the sharp edge of a
laboratory instrument.
1 Why did the technician cut her finger? She brushed her finger along a sharp
edge of the instrument.
2 Why did she brush her finger along a Two reasons:
sharp edge of the instrument?
There is an exposed sharp edge on
the instrument.
The work area is too crowded and
the technician must reach through a
narrow opening.
3 Why is there an exposed sharp edge The instrument needs to be
on the instrument? redesigned by the manufacturer.
4 Why is the work area too crowded? There are other instruments nearby
that are too close.
5 Why are there other instruments The laboratory work area needs to be
nearby that are too close? reconfigured.

Conclusion:
There are two causes for this nonconformance:
1. The instrument needs to be redesigned to eliminate the sharp edge.
2. The work area needs to be reconfigured to ensure adequate space for
working.
Actions:
1. Until a replacement instrument can be obtained, place a piece of thick tape
over the sharp edge of the instrument.
2. Reconfigure the workspace to allow adequate space for working.
Figure 8 is an illustration of a fishbone diagram.
Human Machine Measurement
Problem
Method Materials Environmental
Figure 8. Example Fishbone (or Ishikawa) Diagram
Figure 9 is an illustration of a Pareto chart.
40 100.0
35 90.0
80.0
30
70.0
25
Number
Percent
60.0
20 50.0
15 40.0
30.0
10
20.0
5 10.0
0 0.0
d
rd
rd
ge
nt
e
io
co
co
ge
an
at
rd
sit
re
re
d
co
ea
fr
ui
or
ce
re
ng
dr
to
eq
ed
an
ot
ni
ele
ou
tr
i
al
rn
en
tra
es
ab
QC
iti
nt
be
gt
isl
in
No
ai
um
in
M
t
m
no
iss
tn
No
M
rd
Lo
co
Re
Number of Occurrences Cumulative Percentage
Figure 9. Example Pareto Chart of Quality Audit Findings

The risk of each CAPA Requirement

will determine to what § 820.100(a)(3): Identifying the action(s) needed to correct and prevent
level the information should be recurrence of non-conforming product and other quality problems
disseminated. Once the cause(s) is determined, an assessment of what needs to be done should
occur. What process, procedure, or other actions need to be taken to immediately
Types of metrics that can be correct the nonconformance and prevent recurrence? Also, consider whether or
used for management review not the correction could cause other unintended adverse consequences. What was
include: done to immediately contain the issue, eg, notify supervisor, notify the clinical care
CAPA aging (number of provider? What else needs to be done to be sure the problem won’t happen again?
calendar days that a CAPA What changes to processes or products must be implemented?
has been opened)
NOTE: There are three types of actions taken:
CAPA effectiveness (the
1. Correction – the immediate action to take care of the immediate problem
number of effective CAPAs
(nonconformity).
divided by the number
of effectiveness checks 2. Corrective action – correcting the cause of the nonconformity so that it
completed) doesn’t happen again.
Overdue CAPAs (number of 3. Preventive action – proactively preventing a potential nonconformity,
CAPAs with tasks past their before it occurs. Preventive action cannot occur once the problem occurs;
due dates) at that time, it becomes “corrective action.”
Preventive action shift Additionally, one must consider whether “systemic action” is needed. Is the same
(ratio of preventive to nonconformity likely to occur elsewhere? If yes, then preventive action is taken for
corrective actions) each of the places where the nonconformity may occur.
CAPA leverage (number of EXAMPLE: When applying the definitions to the example of the laboratory worker
preventive actions derived receiving a cut from a sharp edge on an instrument:
from a corrective action) Correction is putting a piece of tape over the sharp edge.
Corrective action is:
1. Replacing the part or changing the instrument to one with no sharp edges
2. Inspecting all other instruments (for systemic issues) for sharp edges and
replacing the part or instrument
Preventive action is performing regular inspections/maintenance to address any
sharp edges before a laboratory worker is injured.
Requirement
§ 820.100(a)(4): Verifying or validating the corrective and preventive action to
ensure that such action is effective and does not adversely affect the finished
device
Now that the solutions (corrections and corrective actions) are determined, they
should be tested (verified and/or validated) according to defined procedures. This
step ensures that the solutions truly did address the original concern, and that the
corrections are effective.

Requirement
§ 820.100(a)(5): Implementing and recording changes in methods and
procedures needed to correct and prevent identified quality problems
The verified or validated change is now put into place. Ask questions to determine
how this implementation will be accomplished. For example:
Do procedures need to be written or revised?
Who will need to be trained?
Are additional system modifications required?
How will this change be sustained?
Should related areas be evaluated for similar concerns and action taken in
these areas to prevent similar occurrences from happening in these areas
or others?
Effectiveness checks verify an outcome, not an action. The laboratory is not

simply verifying or validating that something was done, but that it made a
difference!
Changes made should be according to change control procedures and should

consider risk.
Requirement
§ 820.100(a)(6): Ensuring that information related to quality problems or
nonconforming product is disseminated to those directly responsible for
assuring the quality of such product or the prevention of such problems
Throughout this entire process, determine who needs to know about the problem
and the subsequent remediation. It is not only necessary to remedy the current
situation, but also to prevent recurrence by making sure that the appropriate
personnel are knowledgeable of what happened, how it was fixed, and how it will
be corrected so that it does not occur again.
NOTE: Consideration should be given as to whether training is required and, if
required, identifying who will need to be trained and how this training will be
maintained (over time and if additional personnel become involved). In general,
training is expected and all training must be properly documented, maintained,
available for review, and completed before personnel are authorized to perform
activities reflecting the change.
Requirement
§ 820.100(a)(7): Submitting relevant information on identified quality
problems, as well as corrective and preventive actions, for management
review.
It is expected that incidences, corrections, and CAPA activities are reviewed as
part of the management review process discussed in Chapter 1, Management
Responsibility. Laboratories should document what information will be submitted
to management for review and how.

Requirement
§ 820.100(b): All activities required under this section, and their results, shall
be documented.
All activities must be documented. It is expected that quality documentation
should stand by itself and present the entire story; additional explanation should
not be routinely required.
In summary:
Define, document, and do.
Be uniform and consistent in all CAPA activities.
A good CAPA system is a “closed loop,” ie:
– All required steps are completed.
– Effective actions are taken.
– Management focus is documented.
– Input is provided back to design control requirements in the quality
system, for consideration in future development activities.

11 Labeling and
Packaging Controls

11 Chapter 11: Labeling and Packaging
Controls (§ 820.120 and § 820.130)
Proper labeling and packaging are important for identifying and protecting LDT
reagents and equipment. It is very important to have procedures in place that
ensure that these activities are done correctly, to ensure the integrity of the LDT.
Requirement
§ 820.120: Device labeling. Each manufacturer shall establish and maintain
procedures to control labeling activities.
(a) Label integrity. Labels shall be printed and applied so as to remain legible
and affixed during the customary conditions of processing, storage, handling,
distribution, and where appropriate use.
(b) Labeling inspection. Labeling shall not be released for storage or use until
a designated individual(s) has examined the labeling for accuracy including,
where applicable, the correct unique device identifier (UDI), or universal
product code (UPC), expiration date, control number, storage instructions,
handling instructions, and any additional processing instructions. The
mixups.
The LDT components
need proper labeling to
ensure proper use and prevent
LDTs take a considerable

amount of research
time to develop and validate.
Be sure that the LDT
release, including the date and signature of the individual(s) performing the components are stored
examination, shall be documented in the DHR. appropriately to ensure
(c) Labeling storage. Each manufacturer shall store labeling in a manner that long-term stability.
provides proper identification and is designed to prevent mixups.
(d) Labeling operations. Each manufacturer shall control labeling and

packaging operations to prevent labeling mixups. The label and labeling used
for each production unit, lot, or batch shall be documented in the DHR.
(e) Control number. Where a control number is required by § 820.65,

that control number shall be on or shall accompany the device through
distribution.
42 CFR § 493.1252(c) and (d) partially fulfill the QSReg requirements in § 820.120 as
long as the laboratory ensures the procedures include their procedures for design
and manufacturing of the LDT.

Quality System Regulation for Laboratory-Developed Tests Chapter 11: Labeling and Packaging Controls
See CLSI document The QSRs for device labeling are intended for product labeling controls from
EP25, Evaluation of the production process through distribution of product for use. Label integrity,
Stability of In Vitro Diagnostic inspection, storage, and control apply to the immediate reagent containers
Reagents, for more information through to the outer kit boxes, where applicable. Although a laboratory does not
on testing the stability of distribute its testing reagents, the labeling of reagents that remain in-house must
products. be appropriately controlled.
Labels should be designed, selected, and tested for their ability to remain fixed and
legible on the container throughout customary conditions, including processing,
distribution, and use. Each batch of new labels printed in-house, or purchased
from an external source, should be inspected to ensure it meets predefined label
specifications.
The labeling of reagents
Labels should be stored in well-marked storage locations. When labels are needed
prepared in-house must
for labeling the prepared reagents, they are removed from storage, a label is
adhere to product labeling
attached to the design history record (DHR), and the appropriate number is
controls. This labeling is in
accounted for. All leftover labels are returned to storage, after proper inspection
addition to the labeling
to ensure accuracy. If labels are printed “on demand” (ie, at the point when the
employed by the laboratory
reagent is manufactured), an additional label is printed and attached to the DHR.
when reagents are in use for
The device master record (DMR) (from which the DHR or batch record is created)
testing (eg, receive date, open
typically includes a graphic of the label for comparison to the physical label being
date, expiration date).
attached. This feature facilitates review of the DHR to verify that the correct label
is used.
Only one type of label should be removed from storage at a time, to prevent
mixups. Complete the labeling of the bottles, vials, etc., and then return any
remaining labels to storage, following inspection procedures. Then, take out the
next label needed. Using one type of labeling at a time helps to prevent using the
Handwritten labels also
wrong labels for a reagent.
need to be inspected for
accuracy. A master copy should Requirement
be maintained in the DMR, and § 820.130: Device packaging. Each manufacturer shall ensure that device
used to verify handwritten packaging and shipping containers are designed and constructed to protect
labels. A copy of the the device from alteration or damage during the customary conditions of
handwritten label should be processing, storage, handling, and distribution.
placed in the DMR with the
As with device labeling, the QSReg for device packaging is also applicable for
other batch records.
LDTs. Although a laboratory does not distribute its testing reagents, the reagents
must be packaged and stored appropriately in order to maintain the quality of
the product during routine processing, handling, storage, distribution, and use,
throughout the shelf life of the LDT components. This practice is analogous to
CLIA’s 42 CFR § 493.1242(a)(4) requirements to ensure preservation of the LDT.

Packaging design typically takes into account the needs of the customer,
environment, and storage and shipping conditions. Requirements and
specifications are developed and the proposed containers are tested to be sure
the packaging can meet the requirements, and that the products are stable and
protected within their respective containers, for the life of the LDT. Testing of
reagent containers can include:
Protection – integrity of the container/closure system that affects shelf life
of the product. These factors include exposure to light, moisture (if reagent
is intended to be dry/desiccated), microbial contamination, temperature,
and pressure.
Compatibility – tests for extraction and leaching of compounds from the
container by the reagent it contains.
Once the testing confirms that the design of the proposed container is acceptable,
the specifications are finalized for sourcing the container from the supplier, and
documented in the design history file and the DMR.


12 Handling, Storage,
Distribution, and
Installation

12 Chapter 12: Handling, Storage,
Distribution, and Installation
(§ 820.140, § 820.150, § 820.160,
§ 820.170)
Now that the LDT has been developed, validated, and tested thoroughly, the
laboratory must understand how to properly handle, store, transport, and install
the LDT components, so that stability is ensured and the LDT is ready to use when
needed.
Requirement
§ 820.140: Handling. Each manufacturer shall establish and maintain
procedures to ensure that mixups, damage, deterioration, contamination, or
other adverse effects to product do not occur during handling.
Manufacturers of IVD reagents and instruments are required to have physical,
spatial, labeling, or other means to designate:
Acceptable products that are ready to use
Unacceptable products that may not be used
In-process products that are not yet ready for use
These requirements are analogous to CLIA 42 CFR § 493.1232, § 493.1252(b),
Storing reagents in
different stages of
preparation on different
shelves in a refrigerator may
not be sufficient. Be sure to
store reagents in such a way
that mixups are unlikely to
occur.
and § 493.1252(c). The laboratory must ensure that procedures for these CLIA
requirements address the LDT device, and not just the specimens.
If the laboratory decides to use spatially separate locations to isolate each group
of product, each location must be very well labeled, and each LDT reagent or piece
of equipment within a location must be well labeled. The procedures, as well as
the logistics, should ensure that product mixups are unlikely to occur and that the
LDT reagents and equipment are being stored in a suitable manner and protected
against deterioration.

Quality System Regulation for Laboratory-Developed Tests Chapter 12: Handling, Storage, Distribution, and Installation
CLSI document EP25, Requirement

Evaluation of Stability of § 820.150: Storage.
In Vitro Diagnostic Reagents,
(a) Each manufacturer shall establish and maintain procedures for the
provides guidance on
control of storage areas and stock rooms for product to prevent mixups,
conducting stability testing.
damage, deterioration, contamination, or other adverse effects pending
use or distribution and to ensure that no obsolete, rejected, or deteriorated
product is used or distributed. When the quality of product deteriorates over
time, it shall be stored in a manner to facilitate proper stock rotation, and its
condition shall be assessed as appropriate.
(b) Each manufacturer shall establish and maintain procedures that describe
the methods for authorizing receipt from and dispatch to storage areas and
stock rooms.
It is very important that the storage of the LDT reagents and equipment is
controlled and ensures that only authorized product is used or distributed. During
the development of the LDT, the type of storage containers and area that are
suitable for the LDT must be determined, as well as the storage conditions to
prevent mixups, deterioration, or damage to the LDT. Performing proper stability
testing will help determine the proper temperature and humidity ranges for
appropriate storage of any reagents or equipment, as well as the expiration dating.
Once the proper storage conditions are known, procedures must be created and
followed to ensure that rejected or deteriorated LDT components are not used or
distributed. These procedures should ensure:
Proper storage temperature and humidity ranges are maintained.
Reagents have an expiration date indicated.
Only approved, within-expiration-date reagents are used.
Only authorized persons can remove the LDT from and dispatch it to the
storage locations.
Inventory is assessed to ensure LDT specifications are continuously met
over time.

Requirement
§ 820.160: Distribution.
(a) Each manufacturer shall establish and maintain procedures for control
and distribution of finished devices to ensure that only those devices
approved for release are distributed and that purchase orders are reviewed to
ensure that ambiguities and errors are resolved before devices are released
for distribution. Where a device’s fitness for use or quality deteriorates over
time, the procedures shall ensure that expired devices or devices deteriorated
beyond acceptable fitness for use are not distributed.
(b) Each manufacturer shall maintain distribution records which include or

refer to the location of:
(1) The name and address of the initial consignee;
(2) The identification and quantity of devices shipped;
(3) The date shipped; and
(4) Any control number(s) used.

Although LDTs are only used within the laboratory that prepares them, and not
shipped to external locations, each LDT must have assigned lot numbers for any
reagents and any other consumables. The lot numbers provide a mechanism to
track each reagent throughout its history, from manufacturing through use and
reporting of results. A procedure is needed to create and assign the lot numbers.
In addition, the LDT components must be used only within the expiration dating
that has been determined from the stability testing, and only LDT components
that have been tested and approved for use may be used for patient testing. CLIA
requires the recording of the lot numbers of products that are used for testing.
For LDTs, keep records that track storage locations, dates of storage, and use dates
for each LDT, as well as to whom the results of the LDT were provided and the
quantity used.

Requirement
§ 820.170: Installation.
(a) Each manufacturer of a device requiring installation shall establish and

maintain adequate installation and inspection instructions, and where
appropriate test procedures. Instructions and procedures shall include
directions for ensuring proper installation so that the device will perform as
intended after installation. The manufacturer shall distribute the instructions
and procedures with the device or otherwise make them available to the
person(s) installing the device.
(b) The person installing the device shall ensure that the installation,
inspection, and any required testing are performed in accordance with
the manufacturer’s instructions and procedures and shall document the
inspection and any test results to demonstrate proper installation.
The laboratory is the manufacturer of the LDT. If the LDT requires any type of
installation, whether it is installing equipment or installing (loading) reagents
onto an analyzer, detailed procedures describing those activities are necessary.
In addition, these procedures should describe the quality testing that ensures
that the installation was completed properly and according to the installation
procedures. The laboratory should maintain records to demonstrate proper
installation and that the installed LDT meets specifications.
The laboratory should The laboratory should have procedures in place that cover every aspect of the
follow its established handling, storing, distribution, and installation of the LDT, throughout all stages
procedures for the installation of manufacture and the life of the LDT. Properly following the procedures, and
of equipment and documenting the activities, will help to ensure that mixups or the use of expired or
instrumentation, and the deteriorated product does not occur. The laboratory must ensure that only those
loading of reagents. LDTs that are approved for use are being used for patient testing.

13 Records

13 Chapter 13: Records
General requirements (§ 820.180), Device
master record (§ 820.181), Device history record
(§ 820.184), and Quality system record
(§ 820.186)
Records are an important component of any QMS. Records provide the evidence
that a particular process was completed, and the results of that process. FDA has
several requirements for different types of records.
Requirement
§ 820.180: General requirements. All records required by this part shall be
maintained at the manufacturing establishment or other location that is
reasonably accessible to responsible officials of the manufacturer and to
employees of FDA designated to perform inspections. Such records,
including those not stored at the inspected establishment, shall be made
readily available for review and copying by FDA employee(s). Such records
shall be legible and shall be stored to minimize deterioration and to prevent
loss. Those records stored in automated data processing systems shall be
backed up.
(a) Confidentiality. Records deemed confidential by the manufacturer may

be marked to aid FDA in determining whether information may be disclosed
under the public information regulation in part 20 of this chapter.
(b) Record retention period. All records required by this part shall be retained
for a period of time equivalent to the design and expected life of the device,
but in no case less than 2 years from the date of release for commercial
distribution by the manufacturer.
(c) Exceptions. This section does not apply to the reports required by
§ 820.20(c) Management review, § 820.22 Quality audits, and supplier
audit reports used to meet the requirements of § 820.50(a) Evaluation
of suppliers, contractors, and consultants, but does apply to procedures
established under these provisions. Upon request of a designated employee
of FDA, an employee in management with executive responsibility shall
certify in writing that the management reviews and quality audits required
under this part, and supplier audits where applicable, have been performed
and documented, the dates on which they were performed, and that any
required corrective action has been undertaken.

Quality System Regulation for Laboratory-Developed Tests Chapter 13: Records
For LDTs, the laboratory should keep certain records that are different kinds of
records from what CLIA requires. The sections below describe the types of records
that FDA expects the laboratory to maintain for the LDTs.
Each of these records must be stored in a way that maintains the records so that
they remain legible, will not be lost, and are accessible if FDA requests to see the
documents. They may be maintained within the laboratory facility, or externally,
as long as they are accessible.
Records need to be retained for the lifetime of the device, or at least two years
after the date of manufacture, whichever is longer.
Requirement
§ 820.181: Device master record. Each manufacturer shall maintain device
master records (DMRs). Each manufacturer shall ensure that each DMR is
prepared and approved in accordance with § 820.40.
Device master record (DMR) is the term used to describe all of the routine
procedures required to manufacture devices that will consistently meet the
specific device’s requirements. The documentation referenced in the DMR is
subject to document control procedures referenced in § 820.40 of the QSReg.
These include the requirements for establishing, maintaining, approving,
distributing, changing, and controlling documents. CLIA has similar requirements
in 42 CFR § 493.1251 regarding laboratory procedure manuals. The DMR
specifically includes those procedures that are necessary for designing and
manufacturing a device.
Requirement
§ 820.181: Device master record. The DMR for each type of device shall
include, or refer to the location of, the following information:
(a) Device specifications including appropriate drawings, composition,

formulation, component specifications, and software specifications;
(b) Production process specifications including the appropriate equipment

specifications, production methods, production procedures, and production
environment specifications;
(c) Quality assurance procedures and specifications including acceptance

criteria and the quality assurance equipment to be used;
(d) Packaging and labeling specifications, including methods and processes

used; and
(e) Installation, maintenance, and servicing procedures and methods.

The DMR contains specifications for the device, accessories, labeling, and
packaging, and contains a full description of how to procure the components
and manufacture the device. Also included are specifications for facilities,

environment, and production equipment. In addition to the device specifications, a

DMR contains documents that cover typical manufacturing activities such as:
Procurement or purchasing
Assembly or manufacturing
Labeling
Test and inspection The DMR is the road
map to the
Packaging
manufacturing and testing
Installation, where applicable process for the device.
Servicing, where applicable
Sterilization, where applicable
DMRs must:
Be technically correct.
Contain the current approved device and process designs.
Be under change control.
Contain the release or effective date of the DMR.
Identify approval status.
Be written with adequate information.
Be directed toward the intended user.
The DMR can be an index of documents, not a physical file or binder with the actual
documents. The advantage of this approach is that the documents do not need to
be copied and maintained in special files. The DMR can identify the document by a
controlled identifier, eg, document number, drawing number. Physical DMRs may be
more practical for small, noncomplex devices or small companies.
Example: DMR Document Content
Device Specifications
Intended use(s)
Performance characteristics and theory of operation
Physical characteristics
Environmental limitations and product stability
Component, subassembly, and assembly drawings and specifications
Bills of material or a list of ingredients
Formulations/compositions
Wiring and piping diagrams
Software specifications
User safety characteristics

Not all types of Example: DMR Document Content (continued)

documents specified Manufacturing Process Specifications
are relevant for each type of
Process flow charts
device.
Process/assembly line diagrams
Equipment, tools, molds
Manufacturing environmental specifications, if device specific
Setup procedures
Operator instructions
Equipment maintenance procedures
Quality Assurance Procedures and Specifications
Cleaning procedures, if device specific
Safety procedures
Procurement procedures
Supplier assessment procedure
Label review procedure
Calibration/preventive maintenance procedure
Control plans, instructions, and acceptance criteria for incoming,
in-process, and finished device inspection and testing
Packaging and Labeling Specifications
Package drawings and specifications
Filling/packaging procedures
Label/labeling drawings
Instruction manuals/instructions for use
Installation, Maintenance, and Servicing Specifications, where applicable
Installation specifications and instructions
Maintenance instructions
Servicing specifications and manuals

Requirement
§ 820.184: Device history record. Each manufacturer shall maintain device
history records (DHRs). Each manufacturer shall establish and maintain
procedures to ensure that DHRs for each batch, lot, or unit are maintained
to demonstrate that the device is manufactured in accordance with the
DMR and the requirements of this part. The DHR shall include, or refer to the
location of, the following information:
(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
A “lot” or “batch” is a
unit; and
quantity of an LDT
(f) Any unique device identifier (UDI) or universal product code (UPC), and reagent that is manufactured
control number(s) used. under the same conditions (eg,
temperature, humidity), and
While the DMR contains all of the information and procedures required to make,
contains the same
label, quality test, package, install, and maintain an LDT, the DHR is different in that
components. For instruments,
it contains all of the records that document these procedures were completed for
it is usually a single instrument.
a specific lot or batch of the LDT. The DHR is specific to a lot or batch; the DMR is
overarching for all lots or batches (device/product specific).
The DHR contains the relevant information identifying a specific product lot
or batch that was manufactured, including the dates when the manufacturing
occurred. The DHR must indicate the quantity of product or units that were
manufactured for a specific batch or lot and the quantity of product that was
released for distribution and any identification or control number.
The DHRs must demonstrate that the lot was manufactured and tested according
to all required procedures as identified in the DMR. The records must also
demonstrate that the lot or batch met all required acceptance criteria.
Primary identification labels and labeling for each lot, batch, or production
unit are required to be in the DHR. Manufacturers will typically include either
original or copies of product labels including instructions for use, vial or container
labels, instrument labels, and any other identification labels or labeling in the
manufacturing batch records. In addition, each lot or batch is required to be
uniquely identified and this identification (and control number used) must be
included within the DHR.

Example: DHR Contents

Records indicating lot or batch numbers
Copies of all labels and user instructions
Records from all manufacturing processes, including:
– Dates of manufacture
– Persons performing each step
– Supplier, quantity, and expiration date of each component used
– Quantity manufactured
– Quantity released for use
Records from every procedure followed (eg, forms, checklists)
Records from quality testing
Records indicating acceptance of quality testing results
Installation records
Maintenance records
Requirement
§ 820.186: Quality system record. Each manufacturer shall maintain a
quality system record (QSR). The QSR shall include, or refer to the location
of, procedures and the documentation of activities required by this part
that are not specific to a particular type of device(s), including, but not
limited to, the records required by § 820.20 [Management responsibility].
Each manufacturer shall ensure that the QSR is prepared and approved in
accordance with § 820.40 [Document controls].
Maintaining and completing each of the elements of a good quality system
generates many types of records. The sections above describe product-specific
records that must be maintained, and apply to LDTs. Other product-specific
records are generated during the design control phases of product development.
In addition, records are generated for all of the other quality system elements. As a
general rule, any documents (policies, procedures, and records) that are generated
need to be retained in a way that allows them to be accessible for later inspection
and use. The rule is: If you didn’t document what you did, then you didn’t do
anything. Evidence of action is key, and is maintained through the keeping of good
records.
FDA will often agree to allow laboratories and manufacturers to not provide
detailed copies of management review records or quality audit records. If an
inspector asks to see these records, they may typically be provided with only the
agendas (or auditing schedule, in the case of quality audits), the list of attendees,
and the date of occurrence of the management review or the quality audit. The
purpose for this is so that the organization can be honest with itself regarding its
quality findings, and implement appropriate decisions and, if warranted, corrective
actions (which are subject to inspection), without fear of reprisal from FDA.

14 Complaint
Files

14 Chapter 14: Complaint Files
(§ 820.198)
All laboratories receive complaints and conduct investigations of those complaints

where appropriate. The QSReg requirements for handling of complaints are more
detailed than the CLIA requirements.
Requirement
§ 820.198(a): 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.
Complaint records must be kept and it is expected that the records be maintained
in a designated area; if additional information for a complaint is obtained, it
is expected to be kept with the original complaint. Written procedures should
describe the entire process from receipt of the complaint through its closure. There
does need to be a formal designation of the person(s) responsible for receiving,
reviewing, and evaluating the complaint and maintaining the files.
A complaint is any
written, electronic (eg,
e-mail), or oral communication
that alleges deficiencies related
to identity, quality, durability,
reliability, safety, effectiveness,
or performance of a device
after it is released for
distribution.
Requirement
§ 820.198(a): Complaint files. Such procedures shall ensure that: When the regulation
includes the word
(1) All complaints are processed in a uniform and timely manner; “shall,” it means that this item
must be done; it is not
(2) Oral complaints are documented upon receipt; and
optional.
(3) Complaints are evaluated to determine whether the complaint represents
an event which is required to be reported to FDA under part 803 of this
chapter [21 CFR], Medical Device Reporting.
Complaints may be received in writing, by e-mail, by phone call, during
a conversation, or by other means. It is expected that every complaint is
documented using a structured format (form) so that all relevant information is
consistently obtained. When information received is not sufficient to determine
whether the information is a complaint or not, or whether there is a need to
conduct an investigation or not, it is expected that attempts are made to obtain
this additional information. When information is obtained that the reported

Quality System Regulation for Laboratory-Developed Tests Chapter 14: Complaint Files
incident resulted in a death or serious injury, or if the incident were to recur it

could result in a death or serious injury (adverse event), FDA expects to be notified
as required by 21 CFR § 803, Medical Device Reporting.
Requirement
§ 820.198(b): Complaint files. Each manufacturer shall review and evaluate
all complaints to determine whether an investigation is necessary. When no
investigation is made, the manufacturer shall maintain a record that includes
Investigations should be the reason no investigation was made and the name of the individual
conducted in a timely responsible for the decision not to investigate.
manner.
For all complaints reported to the laboratory, it is expected that the complaint will
be investigated to understand the reason for the complaint, any incident that has
occurred, and the cause(s) for the problem. This investigation should be completed
unless the incident is basically identical to one that has been recently investigated
and has been successfully resolved. Even in this case, it is expected that the
situation be evaluated and a determination made that there are no additional
factors involved and that this is not part of a trend that should be investigated
further, or a failure of a previous “fix” for the same complaint. A reference to the
original investigation conducted should be made.
When an investigation is not performed, the documentation of the complaint
should include an explanation of why the investigation is not necessary, along
with identification of the person who made the decision.
Requirement
§ 820.198(c): Complaint files. Any complaint involving the possible failure
of a device, labeling, or packaging to meet any of its specifications shall be
reviewed, evaluated, and investigated, unless such investigation has already
been performed for a similar complaint and another investigation is not
necessary.
It is expected that all complaints received be investigated and this investigation
be documented and kept on file. As mentioned above, there are some cases where
an additional investigation is not necessary. Duplicative investigations are not
necessary, but reference to an original investigation conducted should be made.
Care should be taken not to assume the answer as to why something happened
without actually performing an investigation.
The date the complaint
was received is the date Requirement
the first person was made § 820.198(d): Complaint files. Any complaint that represents an event which
aware of the complaint (even if must be reported to FDA under part 803 of this chapter [21 CFR] shall be
this is not the formally promptly reviewed, evaluated, and investigated by a designated individual(s)
designated complaint handling and shall be maintained in a separate portion of the complaint files or
unit). otherwise clearly identified.

Laboratories that design and manufacture LDTs that are regulated by FDA also Capture, classify, and
need to be familiar with 21 CFR § 803, Medical Device Reporting. FDA has strict document events with
timelines for reporting an adverse event. When the regulation states 30 days, a sufficient detail, and report
report submitted at 31 days is judged as late and considered not compliant. device-related problem and
solution information
Requirement
appropriately. Descriptions
§ 820.198(d): Complaint files. In addition to the information required by
should be factual and as
§ 820.198(e), records of investigation under this paragraph shall include a
complete as possible. Do not
determination of:
use language such as “the
(1) Whether the device failed to meet specifications; results were ‘crazy.’”
(2) Whether the device was being used for treatment or diagnosis; and
(3) The relationship, if any, of the device to the reported incident or adverse
event.
Table 7 provides questions that the laboratory may pose to help understand each
element of this requirement
Table 7. Elements of 21 CFR § 820.198(d)

FDA Requirement Clarifying Question
(1) Whether the device failed to Did the product work as expected?
meet specifications;
(2) Whether the device was being How was the product being used at the time?
used for treatment or diagnosis; Was it being evaluated, or in actual use with a
patient?
(3) The relationship, if any, of the Did the use of the product directly cause harm
device to the reported incident or or indirectly cause harm? A product did not
adverse event. have to malfunction to cause an adverse event.
Incidences caused by inadequate instructions
for use or user error may be reportable to FDA.
Requirement
§ 820.198(e): Complaint files. When an investigation is made under this
section, a record of the investigation shall be maintained by the formally
designated unit identified in paragraph (a) of this section.
Documentation of the incident is expected using a standard format/form.
Requirement
§ 820.198(e): Complaint files. The record of investigation shall include:
(1) The name of the device;

Include the name of the device. For an LDT, it would be the laboratory’s or facility’s
name for the test, and/or the generic name of the test.

Requirement
(2) The date the complaint was received;

This date is used to determine reporting requirements for an adverse event. It is
also commonly used to determine the timeliness of reviewing, evaluating, and
closing a complaint.
Requirement
(3) Any unique device identifier (UDI) or universal product code (UPC), and
any other device identification(s) and control number(s) used;
The laboratory should be assigning a serial number or a lot number for the
LDT; a designation that is unique to that batch of reagents and/or instrument.
These numbers can be assigned using any logical method, with appropriate
documentation maintained.
A thorough investigation of an LDT must include traceability for the date/time
of testing for the LDT components (eg, lot number of reagents, control materials
used, instruments, and equipment).
Requirement
(4) The name, address, and phone number of the complainant;

Identification of the individual reporting the incident is documented, in case
additional investigation or information is required.
Requirement
(5) The nature and details of the complaint;

A designated individual should document what happened, where it happened,
and what the circumstances of the incident were. In addition, the documentation
should include whether there are any mitigating or complicating factors or
conditions.
Requirement
(6) The dates and results of the investigation;

After completing the investigation, document what was done to investigate the
incident, what was found to be the cause of the incident, and what was reported.

Requirement
(7) Any corrective action taken; and

Document actions implemented to prevent recurrence of the same or a similar
type of incident. For example, record whether procedures were rewritten,
additional training was given, etc.
Requirement
(8) Any reply to the complainant.

Document if the complainant was contacted in any manner after the report of the
initial incident. It is expected that any written correspondence be maintained and
any verbal conversation be documented and included as part of the complaint file.
Requirement
§ 820.198(e): Complaint files.
(f) When the manufacturer’s formally designated complaint unit is located

at a site separate from the manufacturing establishment, the investigated
complaint(s) and the record(s) of investigation shall be reasonably accessible
to the manufacturing establishment.
(g) If a manufacturer’s formally designated complaint unit is located outside

of the United States, records required by this section shall be reasonably
accessible in the United States at either:
(1) A location in the United States where the manufacturer’s records are
regularly kept; or
(2) The location of the initial distributor.

Although these sections are probably not applicable for LDTs, the point remains
that complaint files need to be rapidly available for review at the testing site,
regardless of the location of the files.


15 Servicing

15 Chapter 15: Servicing (§ 820.200)
Requirement
§ 820.200(a): Servicing. 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.
CLIA requirements provide definition of maintenance and verification of
performance through “function checks” as described in 42 CFR § 493.1254.
42 CFR § 493.1254: Standard: Maintenance and function checks:
(a) Unmodified manufacturer’s equipment, instruments, or test systems. The
laboratory must perform and document the following:
(1) Maintenance as defined by the manufacturer and with at least the
frequency specified by the manufacturer.
(2) Function checks as defined by the manufacturer and with at least the
frequency specified by the manufacturer. Function checks must be within
the manufacturer’s established limits before patient testing is conducted.
(b) Equipment, instruments, or test systems developed in-house, commercially
available and modified by the laboratory, or maintenance and function
check protocols are not provided by the manufacturer. The laboratory must
do the following:
(1) (i) Establish a maintenance protocol that ensures equipment, instrument,
and test system performance that is necessary for accurate and reliable
test results and test result reporting.
(ii) Perform and document the maintenance activities specified in
paragraph (b)(1)(i) of this section.

Quality System Regulation for Laboratory-Developed Tests Chapter 15: Servicing
(2) (i) Define a function check protocol that ensures equipment, instrument,
and test system performance that is necessary for accurate and reliable
test results and test result reporting.
(ii) Perform and document the function checks, including background or
baseline checks, specified in paragraph (b)(2)(i) of this section. Function
checks must be within the laboratory’s established limits before patient
testing is conducted.
Likewise, these requirements also apply to any “service” activity undertaken
by the laboratory for an LDT (eg, maintenance, repair). Servicing procedures
should include instructions for service personnel for adjustments and/or
acceptable parts replacement and should ensure that the servicing meets the
specified requirements. The procedures should also include function checks to
be completed before returning the equipment for laboratory analysis of patient
samples.
Requirement
§ 820.200(b): Servicing. Each manufacturer shall analyze service reports with
appropriate statistical methodology in accordance with § 820.100 (Corrective
and preventive action).
CLIA requirements generally cover this expectation through monitoring of the
quality system, which includes corrective and preventive actions (CAPAs). CLIA, in
42 CFR § 493.1200(b), requires that a laboratory’s quality system include a quality
assessment component that ensures continuous improvement of the laboratory’s
performance and services through ongoing monitoring that identifies, evaluates,
and resolves problems. Laboratories are also required to perform instrument
maintenance, instrument calibration as applicable, instrument-to-instrument QC,
assay QC, etc., to ensure both instrument and test reagents are performing to
performance specifications. All of these activities must be documented.
Requirement
§ 820.200(c): Servicing. Each manufacturer who receives a service report that
represents an event which must be reported to FDA under part 803 of this
chapter shall automatically consider the report a complaint and shall process
it in accordance with the requirements of § 820.198 (Complaint files).
CLIA standards include the expectation for investigation of complaints, and
include expectations for reporting of “immediate jeopardy” instances to CMS,
when there is a potential for patient harm. For FDA, additional requirements apply
for reporting adverse events, as defined in 21 CFR part 803.
As a “user facility,” the laboratory already has the responsibility to report events
that result in death or serious injury, as defined in 21 CFR § 803 Medical Device
Reporting, Subpart C—User Facility Reporting Requirements (commonly known
as MDR reporting). In such cases where the user facility is also the device
“manufacturer” (eg, LDT), then the user facility name and address are reported
on FDA Form 3500A as the Manufacturer, for individual adverse event reports.
Likewise, the user facility name and address are reported as the Manufacturer in
annual reports on FDA Form 3419, or the electronic equivalent.

NOTE: It is important that the laboratory understands that all servicing (eg,
maintenance, repair) undertaken by the laboratory in response to a problem
situation identified by a person outside or within the laboratory are “complaints”
by definition, and must be processed as such. When performing corrective
actions, laboratories should include (and document) analysis of the service reports
(ie, maintenance, QC). If the problem is associated with an adverse event, or a
potential adverse event (ie, potential harm to a patient should the error condition
remain or recur), the information, including the servicing, must be filed in an MDR
report to FDA.
Requirement
§ 820.200(d): Servicing. Service reports shall be documented and shall
include:
(1) The name of the device serviced;
(2) Any unique device identifier (UDI) or universal product code (UPC), and
any other device identification(s) and control number(s) used;
(3) The date of service;
(4) The individual(s) servicing the device;
(5) The service performed; and
(6) The test and inspection data.

CLIA requirements generally cover such types of records within record retention
standards, but do not typically define the expected content of such records. The
procedure should indicate the specific information to be included as part of the
service record report.
NOTE: CLIA requires service records to be maintained for all analytical systems.
Laboratory-generated service record content must comply with 21 CFR
§ 820.200(d), as indicated above, and be retained according to the CLIA standard.


16 Statistical
Techniques

16 Chapter 16: Statistical Techniques
(§ 820.250)
Ideally, LDTs should be validated and verified using statistically valid testing.
Fortunately, FDA and CLSI offer guidance for achieving statistically robust study
designs.
Requirement
§ 820.250: Statistical techniques.
(a) 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.
(b) Sampling plans, when used, shall be written and based on a valid
statistical rationale. Each manufacturer shall establish and maintain
procedures to ensure that sampling methods are adequate for their intended
use and to ensure that when changes occur the sampling plans are reviewed.
These activities shall be documented.
“Sampling plans” refers
to the procedure for
selecting valid samples to
measure, whether for clinical,
analytical, or process testing.
These plans may include, for
example:
Number of samples
measured
Sampling frequency (for
processes)
Number of replicates and
other parameters that are
These requirements for valid statistical procedures and techniques as well as valid
relevant to the particular
sampling plans apply wherever statistics are used. Two main areas are:
testing
Establishing, validating, and verifying the LDT’s clinical and analytical
performance
Establishing, validating, and verifying the capability of the manufacturing
process to consistently make the LDT reagents and/or instrumentation
(as applicable). For more information on validating and verifying LDT
production processes, see Chapter 8, Production and Process Controls.

Quality System Regulation for Laboratory-Developed Tests Chapter 16: Statistical Techniques
FDA expects robust CLIA requires laboratories to establish product claims for LDTs (42 CFR § 493.1253).
statistical calculations These claims include, as applicable:
and documented evidence of Accuracy
statistical validity for all
Precision
sampling plans and all
calculations. Analytical sensitivity
Analytical specificity to include interfering substances
Reportable range of test results for the test system
Reference intervals (normal values)
Any other performance characteristic required for test performance
CLIA does not offer any recommendations or requirements regarding how the
testing is to be done, or how robust it needs to be. FDA expects robust statistical
calculations and documented evidence of statistical validity for all sampling plans
and all calculations.
Fortunately, for the laboratory that does not have statistical support, FDA has
recognized many of CLSI’s documents for establishing performance claims. See
Table 8 for the appropriate CLSI documents to use for the claims listed above.
Table 8. CLSI Documents for Establishing Performance Claims

Performance Claim CLSI Document
Accuracy EP09—Measurement Procedure Comparison and Bias
Estimation Using Patient Samples
EP21—Estimation of Total Analytical Error for Clinical
Laboratory Methods
EP24—Assessment of the Diagnostic Accuracy of Laboratory
Tests Using Receiver Operating Characteristic Curves
Precision EP05—Evaluation of Precision of Quantitative Measurement
Procedures
Analytical sensitivity EP17—Evaluation of Detection Capability for Clinical
Laboratory Measurement Procedures
Analytical specificity EP07—Interference Testing in Clinical Chemistry
Reportable range EP06—Evaluation of the Linearity of Quantitative
Measurement Procedures: A Statistical Approach
EP17—Evaluation of Detection Capability for Clinical
Laboratory Measurement Procedures
Reference intervals EP28—Defining, Establishing, and Verifying Reference
(normal values) Intervals in the Clinical Laboratory
Interferences EP07—Interference Testing in Clinical Chemistry
Matrix effects EP14—Evaluation of Commutablity of Processed Samples
EP23—Laboratory Quality Control Based on Risk
QC
Management

Table 8. (Continued)
Performance Claim CLSI Document
Stability EP25—Evaluation of Stability of In Vitro Diagnostic Reagents
Commutability of EP30—Characterization and Qualification of Commutable
reference materials
Reference Materials for Laboratory Medicine
used as calibrators
Each of these documents provides recommendations regarding the types and

numbers of samples that should be tested to establish the claims.
FDA Guidance Document
In its guidance document titled “Statistical Guidance on Reporting Results from
Studies Evaluating Diagnostic Tests” (March 13, 2007, http://www.fda.gov/
MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm071148.
htm), FDA notes in the first paragraph of the introduction that each new diagnostic
test’s outcome (test results) should be compared against “an appropriate and
relevant diagnostic benchmark using subjects/patients from the intended use The FDA guidance
population; that is, those subjects/patients for whom the test is intended to be document cited in this
used.” paragraph is not part of the
There are two very important concepts integrated into this statement: QSReg requirements, but its
recommendations are good to
1. Performance testing should be performed using samples that are as close
follow.
as possible to the actual samples that will be used when the assay is
performed on human samples. Often, assay developers use “surrogate”
samples to test the performance of a new assay. These could be QC
materials; proficiency samples; pooled serum (or other sample type); frozen,
banked samples; or other types. When developing an assay using these
types of samples, it is best to conduct the final performance testing with
actual fresh human samples, where possible, because these can often
perform quite differently than surrogate samples.
2. The second important concept in the statement above is concerning the
selection of “an appropriate and relevant diagnostic benchmark.” The
results of a new assay must be compared against an existing accepted
method. This accepted method can be a reference standard (the best
available method for establishing the presence or absence of the target
condition), or another method that is not a reference standard. If no
accepted method exists for the new assay, then the laboratory may have
to compare its results against patient diagnosis by other means. If this is
the case, it is very important to discuss the comparison method with FDA
before beginning testing. See FDA’s guidance, for more information.

Another topic in the guidance document is the selection of the appropriate study
population. FDA recommends that “the set of subjects and specimens to be tested
include:
Subjects/specimens across the entire range of disease states
Subjects/specimens with relevant confounding medical conditions
Subjects/specimens across different demographic groups”
Not including all of these sample types can lead to inaccurate estimates of
diagnostic accuracy. The laboratory’s studies need to reflect real-world use of its
assay.
The FDA guidance document offers many other tips, including how to report
study results, a section on statistically inappropriate practices, and example
performance calculations in several appendixes. The reader is highly encouraged to
read and understand this guidance document.
Other Statistical Considerations
Justification of sample sizes—Establishing the performance of an assay or
a process must be done in a way that leaves little doubt as to the validity
of the results. Statistical practices must consider alpha and beta error rates,
as well as any established target performance criteria, and be sufficiently
powered for the data to be acceptable. If these terms or calculations
are unclear, a statistical text or expert should be consulted. This sample
size justification must be written and provided during the FDA approval
process, and must be statistically based.
Outliers—Sometimes FDA allows the removal of outlier data if an
appropriate reason can be established to do so, with justification. All data
must be reported, including any outliers. FDA can be expected to still
scrutinize those results, and question whether their removal is appropriate.
Outliers should not be removed from precision data. If assignable causes
for outliers in a precision study, it is better to repeat the entire study than
to remove any outliers.
Use of expert statisticians—Establishing the performance of an LDT
is critically important to understanding its efficacy for use on patient
samples. Confirming that the processes for making the LDT are consistent
is critically important to ensuring that the LDT will work the same way,
every time. Be sure to engage statistical experts to help with establishing
study protocols, performing data analysis, and making conclusions on
study results. Performing testing with too few samples, or the wrong
samples, can lead to misleading study results, potentially improper use
with patient samples, and perhaps even wrong assay results when used
in the routine laboratory setting, which can lead to patient harm. Ensuring
robust, proper studies up front can avoid such a disaster.
Process validation—For process validation, a statistically valid sampling
plan must be used to verify the capability of the reagent (or instrument, as
applicable) manufacturing process to consistently make the product.

Resources
Centers for Medicare & Medicaid Services. CLIA overview: laboratory-developed tests (LDTs) frequently asked questions.
http://www.cms.gov/Regulations-and-Guidance/Legislation/CLIA/Downloads/LDT-and-CLIA_FAQs.pdf.
Centers for Medicare & Medicaid Services, US Department of Health and Human Services. Part 493—Laboratory
Requirements: Clinical Laboratory Improvement Amendments of 1988 (Codified at 42 CFR §493). US Government Printing
Office; published annually.
http://www.gpo.gov/fdsys/pkg/CFR-2003-title42-vol3/xml/CFR-2003-title42-vol3-part493.xml.
US Food and Drug Administration. Device advice: comprehensive regulatory assistance.

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/. Accessed January 6, 2015.
US Food and Drug Administration. Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical
Laboratories: FDA Notification and Medical Device Reporting for Laboratory-developed Tests (LDTs).
http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM416684.pdf.
Accessed January 6, 2015.*
US Food and Drug Administration. Draft Guidance for Industry, Food and Drug Administration Staff, and Clinical
Laboratories: Framework for Regulatory Oversight of Laboratory-developed Tests (LDTs).
http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm416685.pdf.
Accessed January 6, 2015.*
US Food and Drug Administration. Laboratory developed tests.

http://www.fda.gov/medicaldevices/productsandmedicalprocedures/invitrodiagnostics/ucm407296.htm.
US Food and Drug Administration, US Department of Health and Human Services. Part 820—Quality System Regulation
(Codified at 21 CFR §820). US Government Printing Office; published annually.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=820. Accessed January 6, 2015.
* As of October 2014, this FDA draft guidance document contains nonbinding recommendations and is not for implementation.

Appendix A. US Food and Drug Administration

Quality System Regulation—21 CFR Part 820
Code of Federal Regulations

Title 21, Volume 8
Revised as of April 1, 2014
TITLE 21—FOOD AND DRUGS

CHAPTER I—FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCHAPTER H—MEDICAL DEVICES
PART 820—QUALITY SYSTEM REGULATION

Subpart A—General Provisions
§ 820.1: Scope.
(a) Applicability. (1) Current good manufacturing practice (CGMP) requirements are set forth in this quality system
regulation. The requirements in this part govern the methods used in, and the facilities and controls used for, the
design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for
human use. The requirements in this part are intended to ensure that finished devices will be safe and effective
and otherwise in compliance with the Federal Food, Drug, and Cosmetic Act (the act). This part establishes basic
requirements applicable to manufacturers of finished medical devices. If a manufacturer engages in only some
operations subject to the requirements in this part, and not in others, that manufacturer need only comply with
those requirements applicable to the operations in which it is engaged. With respect to class I devices, design controls
apply only to those devices listed in § 820.30(a)(2). This regulation does not apply to manufacturers of components or
parts of finished devices, but such manufacturers are encouraged to use appropriate provisions of this regulation as
guidance. Manufacturers of human blood and blood components are not subject to this part, but are subject to part
606 of this chapter. Manufacturers of human cells, tissues, and cellular and tissue-based products (HCT/Ps), as defined
in § 1271.3(d) of this chapter, that are medical devices (subject to premarket review or notification, or exempt from
notification, under an application submitted under the device provisions of the act or under a biological product license
application under section 351 of the Public Health Service Act) are subject to this part and are also subject to the
donor-eligibility procedures set forth in part 1271 subpart C of this chapter and applicable current good tissue practice
procedures in part 1271 subpart D of this chapter. In the event of a conflict between applicable regulations in part
1271 and in other parts of this chapter, the regulation specifically applicable to the device in question shall supersede
the more general.

Appendix A. (Continued)
(2) The provisions of this part shall be applicable to any finished device as defined in this part, intended for human
use, that is manufactured, imported, or offered for import in any State or Territory of the United States, the District of
Columbia, or the Commonwealth of Puerto Rico.
(3) In this regulation the term “where appropriate” is used several times. When a requirement is qualified by “where
appropriate,” it is deemed to be “appropriate” unless the manufacturer can document justification otherwise. A
requirement is “appropriate” if nonimplementation could reasonably be expected to result in the product not meeting
its specified requirements or the manufacturer not being able to carry out any necessary corrective action.
(b) The quality system regulation in this part supplements regulations in other parts of this chapter except where
explicitly stated otherwise. In the event of a conflict between applicable regulations in this part and in other parts
of this chapter, the regulations specifically applicable to the device in question shall supersede any other generally
applicable requirements.
(c) Authority. Part 820 is established and issued under authority of sections 501, 502, 510, 513, 514, 515, 518, 519, 520,
522, 701, 704, 801, 803 of the act (21 U.S.C. 351, 352, 360, 360c, 360d, 360e, 360h, 360i, 360j, 360l, 371, 374, 381, 383).
The failure to comply with any applicable provision in this part renders a device adulterated under section 501(h) of the
act. Such a device, as well as any person responsible for the failure to comply, is subject to regulatory action.
(d) Foreign manufacturers. If a manufacturer who offers devices for import into the United States refuses to permit
or allow the completion of a Food and Drug Administration (FDA) inspection of the foreign facility for the purpose
of determining compliance with this part, it shall appear for purposes of section 801(a) of the act, that the methods
used in, and the facilities and controls used for, the design, manufacture, packaging, labeling, storage, installation, or
servicing of any devices produced at such facility that are offered for import into the United States do not conform
to the requirements of section 520(f) of the act and this part and that the devices manufactured at that facility are
adulterated under section 501(h) of the act.
(e) Exemptions or variances. (1) Any person who wishes to petition for an exemption or variance from any device
quality system requirement is subject to the requirements of section 520(f)(2) of the act. Petitions for an exemption
or variance shall be submitted according to the procedures set forth in § 10.30 of this chapter, the FDA’s administrative
procedures. Guidance is available from the Food and Drug Administration, Center for Devices and Radiological Health,
Division of Small Manufacturers, International and Consumer Assistance, 10903 New Hampshire Ave., Bldg. 66, rm.
4613, Silver Spring, MD 20993-0002, 1-800-638-2041 or 301-796-7100, FAX: 301-847-8149.
(2) FDA may initiate and grant a variance from any device quality system requirement when the agency determines
that such variance is in the best interest of the public health. Such variance will remain in effect only so long as there
remains a public health need for the device and the device would not likely be made sufficiently available without the
variance.
[61 FR 52654, Oct. 7, 1996, as amended at 65 FR 17136, Mar. 31, 2000; 65 FR 66636, Nov. 7, 2000; 69 FR 29829, May 25,
2005; 72 FR 17399, Apr. 9, 2007; 75 FR 20915, Apr. 22, 2010]
§ 820.3: Definitions.
(a) Act means the Federal Food, Drug, and Cosmetic Act, as amended (secs. 201–903, 52 Stat. 1040 et seq., as amended
(21 U.S.C. 321–394)). All definitions in section 201 of the act shall apply to the regulations in this part.
(b) Complaint means any written, electronic, or oral communication that alleges deficiencies related to the identity,
quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution.
(c) Component means any raw material, substance, piece, part, software, firmware, labeling, or assembly which is
intended to be included as part of the finished, packaged, and labeled device.

(d) Control number means any distinctive symbols, such as a distinctive combination of letters or numbers, or both,
from which the history of the manufacturing, packaging, labeling, and distribution of a unit, lot, or batch of finished
devices can be determined.
(e) Design history file (DHF) means a compilation of records which describes the design history of a finished device.
(f) Design input means the physical and performance requirements of a device that are used as a basis for device
design.
(g) Design output means the results of a design effort at each design phase and at the end of the total design effort.
The finished design output is the basis for the device master record. The total finished design output consists of the
device, its packaging and labeling, and the device master record.
(h) Design review means a documented, comprehensive, systematic examination of a design to evaluate the adequacy
of the design requirements, to evaluate the capability of the design to meet these requirements, and to identify
problems.
(i) Device history record (DHR) means a compilation of records containing the production history of a finished device.
(j) Device master record (DMR) means a compilation of records containing the procedures and specifications for a
finished device.
(k) Establish means define, document (in writing or electronically), and implement.
(l) Finished device means 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.
(m) Lot or batch means one or more components or finished devices that consist of a single type, model, class, size,
composition, or software version that are manufactured under essentially the same conditions and that are intended
to have uniform characteristics and quality within specified limits.
(n) Management with executive responsibility means those senior employees of a manufacturer who have the authority
to establish or make changes to the manufacturer’s quality policy and quality system.
(o) Manufacturer means any person who designs, manufactures, fabricates, assembles, or processes a finished device.
Manufacturer includes but is not limited to those who perform the functions of contract sterilization, installation,
relabeling, remanufacturing, repacking, or specification development, and initial distributors of foreign entities
performing these functions.
(p) Manufacturing material means any material or substance used in or used to facilitate the manufacturing process, a
concomitant constituent, or a byproduct constituent produced during the manufacturing process, which is present in
or on the finished device as a residue or impurity not by design or intent of the manufacturer.
(q) Nonconformity means the nonfulfillment of a specified requirement.
(r) Product means components, manufacturing materials, in-process devices, finished devices, and returned devices.
(s) Quality means the totality of features and characteristics that bear on the ability of a device to satisfy fitness-for-
use, including safety and performance.
(t) Quality audit means a systematic, independent examination of a manufacturer’s quality system that is performed
at defined intervals and at sufficient frequency to determine whether both quality system activities and the results of
such activities comply with quality system procedures, that these procedures are implemented effectively, and that
these procedures are suitable to achieve quality system objectives.
(u) Quality policy means the overall intentions and direction of an organization with respect to quality, as established
by management with executive responsibility.

(v) Quality system means the organizational structure, responsibilities, procedures, processes, and resources for
implementing quality management.
(w) Remanufacturer means any person who processes, conditions, renovates, repackages, restores, or does any
other act to a finished device that significantly changes the finished device’s performance or safety specifications, or
intended use.
(x) Rework means action taken on a nonconforming product so that it will fulfill the specified DMR requirements
before it is released for distribution.
(y) Specification means any requirement with which a product, process, service, or other activity must conform.
(z) Validation means confirmation by examination and provision of objective evidence that the particular requirements
for a specific intended use can be consistently fulfilled.
(1) Process validation means establishing by objective evidence that a process consistently produces a result or product
meeting its predetermined specifications.
(2) Design validation means establishing by objective evidence that device specifications conform with user needs and
intended use(s).
(aa) Verification means confirmation by examination and provision of objective evidence that specified requirements
have been fulfilled.
(bb) Human cell, tissue, or cellular or tissue-based product (HCT/P) regulated as a device means an HCT/P as defined in
§ 1271.3(d) of this chapter that does not meet the criteria in § 1271.10(a) and that is also regulated as a device.
(cc) Unique device identifier (UDI) means an identifier that adequately identifies a device through its distribution and
use by meeting the requirements of § 830.20 of this chapter. A unique device identifier is composed of:
(1) A device identifier—a mandatory, fixed portion of a UDI that identifies the specific version or model of a device and
the labeler of that device; and
(2) A production identifier—a conditional, variable portion of a UDI that identifies one or more of the following when
included on the label of the device:
(i) The lot or batch within which a device was manufactured;
(ii) The serial number of a specific device;
(iii) The expiration date of a specific device;
(iv) The date a specific device was manufactured.
(v) For an HCT/P regulated as a device, the distinct identification code required by § 1271.290(c) of this chapter.
(dd) Universal product code (UPC) means the product identifier used to identify an item sold at retail in the United
States.
[61 FR 52654, Oct. 7, 1996, as amended at 78 FR 55822, Sept. 24, 2013]
§ 820.5: 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.

Subpart B—Quality System Requirements
§ 820.20: Management responsibility.
(a) Quality policy. 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.
(b) Organization. Each manufacturer shall establish and maintain an adequate organizational structure to ensure that
devices are designed and produced in accordance with the requirements of this part.
(1) Responsibility and authority. Each manufacturer shall establish the appropriate responsibility, authority, and
interrelation of all personnel who manage, perform, and assess work affecting quality, and provide the independence
and authority necessary to perform these tasks.
(2) Resources. Each manufacturer shall provide adequate resources, including the assignment of trained personnel,
for management, performance of work, and assessment activities, including internal quality audits, to meet the
requirements of this part.
(3) Management representative. Management with executive responsibility shall appoint, and document such
appointment of, a member of management who, irrespective of other responsibilities, shall have established authority
over and responsibility for:
(i) Ensuring that quality system requirements are effectively established and effectively maintained in accordance with
this part; and
(ii) Reporting on the performance of the quality system to management with executive responsibility for review.
(c) Management review. Management with executive responsibility shall review the suitability and effectiveness of
the quality system at defined intervals and with sufficient frequency according to established procedures to ensure
that the quality system satisfies the requirements of this part and the manufacturer’s established quality policy and
objectives. The dates and results of quality system reviews shall be documented.
(d) Quality planning. Each manufacturer shall 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.
(e) Quality system procedures. Each manufacturer shall establish quality system procedures and instructions. An outline
of the structure of the documentation used in the quality system shall be established where appropriate.
§ 820.22: 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. Quality audits shall be conducted by individuals who do not have direct responsibility for the matters
being audited. Corrective action(s), including a reaudit of deficient matters, shall be taken when necessary. A report
of the results of each quality audit, and reaudit(s) where taken, shall be made and such reports shall be reviewed by
management having responsibility for the matters audited. The dates and results of quality audits and reaudits shall be
documented.
§ 820.25: Personnel.
(a) General. 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.

(b) Training. Each manufacturer shall establish procedures for identifying training needs and ensure that all personnel
are trained to adequately perform their assigned responsibilities. Training shall be documented.
(1) As part of their training, personnel shall be made aware of device defects which may occur from the improper
performance of their specific jobs.
(2) Personnel who perform verification and validation activities shall be made aware of defects and errors that may be
encountered as part of their job functions.
Subpart C—Design Controls

§ 820.30: Design controls.
(a) General. (1) Each manufacturer of any class III or class II device, and the class I devices listed in paragraph (a)(2) of this
section, shall establish and maintain procedures to control the design of the device in order to ensure that specified
design requirements are met.
(2) The following class I devices are subject to design controls:
(i) Devices automated with computer software; and
(ii) The devices listed in the following chart.
Section Device
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
(b) Design and development planning. Each manufacturer shall establish and maintain plans that describe or
reference the design and development activities and define responsibility for implementation. The plans shall identify
and describe the interfaces with different groups or activities that provide, or result in, input to the design and
development process. The plans shall be reviewed, updated, and approved as design and development evolves.
(c) Design input. Each manufacturer shall establish and maintain procedures to ensure that the design requirements
relating to a device are appropriate and address the intended use of the device, including the needs of the user and
patient. The procedures shall include a mechanism for addressing incomplete, ambiguous, or conflicting requirements.
The design input requirements shall be documented and shall be reviewed and approved by a designated individual(s).
The approval, including the date and signature of the individual(s) approving the requirements, shall be documented.
(d) Design output. Each manufacturer shall establish and maintain procedures for defining and documenting design
output in terms that allow an adequate evaluation of conformance to design input requirements. Design output
procedures shall contain or make reference to acceptance criteria and shall ensure that those design outputs that are
essential for the proper functioning of the device are identified. Design output shall be documented, reviewed, and
approved before release. The approval, including the date and signature of the individual(s) approving the output, shall
be documented.

(e) Design review. Each manufacturer shall establish and maintain procedures to ensure that formal documented
reviews of the design results are planned and conducted at appropriate stages of the device’s design development. The
procedures shall ensure that participants at each design review include representatives of all functions concerned with
the design stage being reviewed and an individual(s) who does not have direct responsibility for the design stage being
reviewed, as well as any specialists needed. The results of a design review, including identification of the design, the
date, and the individual(s) performing the review, shall be documented in the design history file (the DHF).
(f) Design verification. Each manufacturer shall establish and maintain procedures for verifying the device design.
Design verification shall confirm that the design output meets the design input requirements. The results of the design
verification, including identification of the design, method(s), the date, and the individual(s) performing the verification,
shall be documented in the DHF.
(g) Design validation. Each manufacturer shall establish and maintain procedures for validating the device design.
Design validation shall be performed under defined operating conditions on initial production units, lots, or batches,
or their equivalents. Design validation shall ensure that devices conform to defined user needs and intended uses
and shall include testing of production units under actual or simulated use conditions. Design validation shall include
software validation and risk analysis, where appropriate. The results of the design validation, including identification of
the design, method(s), the date, and the individual(s) performing the validation, shall be documented in the DHF.
(h) Design transfer. Each manufacturer shall establish and maintain procedures to ensure that the device design is
correctly translated into production specifications.
(i) Design changes. Each manufacturer shall establish and maintain procedures for the identification, documentation,
validation or where appropriate verification, review, and approval of design changes before their implementation.
(j) Design history file. Each manufacturer shall establish and maintain a DHF for each type of device. The DHF shall
contain or reference the records necessary to demonstrate that the design was developed in accordance with the
approved design plan and the requirements of this part.
Subpart D—Document Controls

§ 820.40: Document controls.
Each manufacturer shall establish and maintain procedures to control all documents that are required by this part. The
procedures shall provide for the following:
(a) Document approval and distribution. Each manufacturer shall designate an individual(s) to review for adequacy and
approve prior to issuance all documents established to meet the requirements of this part. The approval, including
the date and signature of the individual(s) approving the document, shall be documented. Documents established to
meet the requirements of this part shall be available at all locations for which they are designated, used, or otherwise
necessary, and all obsolete documents shall be promptly removed from all points of use or otherwise prevented from
unintended use.
(b) Document changes. Changes to documents shall be reviewed and approved by an individual(s) in the same function
or organization that performed the original review and approval, unless specifically designated otherwise. Approved
changes shall be communicated to the appropriate personnel in a timely manner. Each manufacturer shall maintain
records of changes to documents. Change records shall include a description of the change, identification of the
affected documents, the signature of the approving individual(s), the approval date, and when the change becomes
effective.

Subpart E—Purchasing Controls
§ 820.50: Purchasing controls.
Each manufacturer shall establish and maintain procedures to ensure that all purchased or otherwise received product
and services conform to specified requirements.
(a) Evaluation of suppliers, contractors, and consultants. Each manufacturer shall establish and maintain the
requirements, including quality requirements, that must be met by suppliers, contractors, and consultants. Each
manufacturer shall:
(1) Evaluate and select potential suppliers, contractors, and consultants on the basis of their ability to meet specified
requirements, including quality requirements. The evaluation shall be documented.
(2) Define the type and extent of control to be exercised over the product, services, suppliers, contractors, and
consultants, based on the evaluation results.
(3) Establish and maintain records of acceptable suppliers, contractors, and consultants.
(b) Purchasing data. Each manufacturer shall establish and maintain data that clearly describe or reference the specified
requirements, including quality requirements, for purchased or otherwise received product and services. Purchasing
documents shall include, where possible, an agreement that the suppliers, contractors, and consultants agree to notify
the manufacturer of changes in the product or service so that manufacturers may determine whether the changes
may affect the quality of a finished device. Purchasing data shall be approved in accordance with § 820.40.
Subpart F—Identification and Traceability

§ 820.60 Identification.
Each manufacturer shall establish and maintain procedures for identifying product during all stages of receipt,
production, distribution, and installation to prevent mixups.
§ 820.65: Traceability.
Each manufacturer of a device that is intended for surgical implant into the body or to support or sustain life and
whose failure to perform when properly used in accordance with instructions for use provided in the labeling can be
reasonably expected to result in a significant injury to the user shall establish and maintain procedures for identifying
with a control number each unit, lot, or batch of finished devices and where appropriate components. The procedures
shall facilitate corrective action. Such identification shall be documented in the DHR.
Subpart G—Production and Process Controls

§ 820.70: Production and process controls.
(a) General. 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. Where process controls are needed they shall
include:
(1) Documented instructions, standard operating procedures (SOPs), and methods that define and control the manner
of production;
(2) Monitoring and control of process parameters and component and device characteristics during production;

(3) Compliance with specified reference standards or codes;
(4) The approval of processes and process equipment; and
(5) Criteria for workmanship which shall be expressed in documented standards or by means of identified and
approved representative samples.
(b) Production and process changes. Each manufacturer shall establish and maintain procedures for changes to a
specification, method, process, or procedure. Such changes shall be verified or where appropriate validated according
to § 820.75, before implementation and these activities shall be documented. Changes shall be approved in accordance
with § 820.40.
(c) Environmental control. Where environmental conditions could reasonably be expected to have an adverse effect on
product quality, the manufacturer shall establish and maintain procedures to adequately control these environmental
conditions. Environmental control system(s) shall be periodically inspected to verify that the system, including
necessary equipment, is adequate and functioning properly. These activities shall be documented and reviewed.
(d) Personnel. Each manufacturer shall establish and maintain requirements for the health, cleanliness, personal
practices, and clothing of personnel if contact between such personnel and product or environment could reasonably
be expected to have an adverse effect on product quality. The manufacturer shall ensure that maintenance and other
personnel who are required to work temporarily under special environmental conditions are appropriately trained or
supervised by a trained individual.
(e) Contamination control. Each manufacturer shall establish and maintain procedures to prevent contamination of
equipment or product by substances that could reasonably be expected to have an adverse effect on product quality.
(f) Buildings. Buildings shall be of suitable design and contain sufficient space to perform necessary operations, prevent
mixups, and assure orderly handling.
(g) Equipment. Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified
requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment,
cleaning, and use.
(1) Maintenance schedule. Each manufacturer shall establish and maintain schedules for the adjustment, cleaning,
and other maintenance of equipment to ensure that manufacturing specifications are met. Maintenance activities,
including the date and individual(s) performing the maintenance activities, shall be documented.
(2) Inspection. Each manufacturer shall conduct periodic inspections in accordance with established procedures
to ensure adherence to applicable equipment maintenance schedules. The inspections, including the date and
individual(s) conducting the inspections, shall be documented.
(3) Adjustment. Each manufacturer shall ensure that any inherent limitations or allowable tolerances are visibly
posted on or near equipment requiring periodic adjustments or are readily available to personnel performing these
adjustments.
(h) Manufacturing material. Where a manufacturing material could reasonably be expected to have an adverse
effect on product quality, the manufacturer shall establish and maintain procedures for the use and removal of such
manufacturing material to ensure that it is removed or limited to an amount that does not adversely affect the device’s
quality. The removal or reduction of such manufacturing material shall be documented.
(i) Automated processes. When computers or automated data processing systems are used as part of production or the
quality system, the manufacturer shall validate computer software for its intended use according to an established
protocol. All software changes shall be validated before approval and issuance. These validation activities and results
shall be documented.

§ 820.72 Inspection, measuring, and test equipment.
(a) Control of inspection, measuring, and test equipment. Each manufacturer shall ensure that all inspection, measuring,
and test equipment, including mechanical, automated, or electronic inspection and test equipment, is suitable for
its intended purposes and is capable of producing valid results. Each manufacturer shall establish and maintain
procedures to ensure that equipment is routinely calibrated, inspected, checked, and maintained. The procedures shall
include provisions for handling, preservation, and storage of equipment, so that its accuracy and fitness for use are
maintained. These activities shall be documented.
(b) Calibration. Calibration procedures shall include specific directions and limits for accuracy and precision. When
accuracy and precision limits are not met, there shall be provisions for remedial action to reestablish the limits and to
evaluate whether there was any adverse effect on the device’s quality. These activities shall be documented.
(1) Calibration standards. Calibration standards used for inspection, measuring, and test equipment shall be traceable
to national or international standards. If national or international standards are not practical or available, the
manufacturer shall use an independent reproducible standard. If no applicable standard exists, the manufacturer shall
establish and maintain an in-house standard.
(2) Calibration records. The equipment identification, calibration dates, the individual performing each calibration, and
the next calibration date shall be documented. These records shall be displayed on or near each piece of equipment or
shall be readily available to the personnel using such equipment and to the individuals responsible for calibrating the
equipment.
§ 820.75 Process validation.
(a) Where the results of a process cannot be fully verified by subsequent inspection and test, the process shall be
validated with a high degree of assurance and approved according to established procedures. The validation activities
and results, including the date and signature of the individual(s) approving the validation and where appropriate the
major equipment validated, shall be documented.
(b) Each manufacturer shall establish and maintain procedures for monitoring and control of process parameters for
validated processes to ensure that the specified requirements continue to be met.
(1) Each manufacturer shall ensure that validated processes are performed by qualified individual(s).
(2) For validated processes, the monitoring and control methods and data, the date performed, and, where appropriate,
the individual(s) performing the process or the major equipment used shall be documented.
(c) When changes or process deviations occur, the manufacturer shall review and evaluate the process and perform
revalidation where appropriate. These activities shall be documented.
Subpart H—Acceptance Activities

§ 820.80 Receiving, in-process, and finished device acceptance.
(a) General. Each manufacturer shall establish and maintain procedures for acceptance activities. Acceptance activities
include inspections, tests, or other verification activities.
(b) Receiving acceptance activities. Each manufacturer shall establish and maintain procedures for acceptance of
incoming product. Incoming product shall be inspected, tested, or otherwise verified as conforming to specified
requirements. Acceptance or rejection shall be documented.
(c) In-process acceptance activities. Each manufacturer shall establish and maintain acceptance procedures, where
appropriate, to ensure that specified requirements for in-process product are met. Such procedures shall ensure

that in-process product is controlled until the required inspection and tests or other verification activities have been
completed, or necessary approvals are received, and are documented.
(d) Final acceptance activities. Each manufacturer shall establish and maintain procedures for finished device
acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria. Finished
devices shall be held in quarantine or otherwise adequately controlled until released. Finished devices shall not be
released for distribution until:
(1) The activities required in the DMR are completed;
(2) the associated data and documentation is reviewed;
(3) the release is authorized by the signature of a designated individual(s); and
(4) the authorization is dated.
(e) Acceptance records. Each manufacturer shall document acceptance activities required by this part. These records
shall include:
(1) The acceptance activities performed;
(2) the dates acceptance activities are performed;
(3) the results;
(4) the signature of the individual(s) conducting the acceptance activities; and
(5) where appropriate the equipment used. These records shall be part of the DHR.
§ 820.86: Acceptance status.
Each manufacturer shall identify by suitable means the acceptance status of product, to indicate the conformance
or nonconformance of product with acceptance criteria. The identification of acceptance status shall be maintained
throughout manufacturing, packaging, labeling, installation, and servicing of the product to ensure that only product
which has passed the required acceptance activities is distributed, used, or installed.
Subpart I—Nonconforming Product

§ 820.90: Nonconforming product.
(a) Control of 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. The evaluation of nonconformance shall include
a determination of the need for an investigation and notification of the persons or organizations responsible for the
nonconformance. The evaluation and any investigation shall be documented.
(b) Nonconformity review and disposition. (1) Each manufacturer shall establish and maintain procedures that define
the responsibility for review and the authority for the disposition of nonconforming product. The procedures shall set
forth the review and disposition process. Disposition of nonconforming product shall be documented. Documentation
shall include the justification for use of nonconforming product and the signature of the individual(s) authorizing the
use.
(2) Each manufacturer shall establish and maintain procedures for rework, to include retesting and reevaluation of the
nonconforming product after rework, to ensure that the product meets its current approved specifications. Rework
and reevaluation activities, including a determination of any adverse effect from the rework upon the product, shall be
documented in the DHR.

Subpart J—Corrective and Preventive Action
§ 820.100: Corrective and preventive action.
(a) 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, and other sources of quality data to identify existing and potential causes of nonconforming
product, or other quality problems. Appropriate statistical methodology shall be employed where necessary to detect
recurring quality problems;
(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;
(4) Verifying or validating the corrective and preventive action to ensure that such action is effective and does not
adversely affect the finished device;
(5) Implementing and recording changes in methods and procedures needed to correct and prevent identified quality
problems;
(6) Ensuring that information related to quality problems or nonconforming product is disseminated to those directly
responsible for assuring the quality of such product or the prevention of such problems; and
(7) Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for
management review.
(b) All activities required under this section, and their results, shall be documented.
Subpart K—Labeling and Packaging Control

§ 820.120: Device labeling.
Each manufacturer shall establish and maintain procedures to control labeling activities.
(a) Label integrity. Labels shall be printed and applied so as to remain legible and affixed during the customary
conditions of processing, storage, handling, distribution, and where appropriate use.
(b) Labeling inspection. Labeling shall not be released for storage or use until a designated individual(s) has examined
the labeling for accuracy including, where applicable, the correct unique device identifier (UDI) or universal product
code (UPC), expiration date, control number, storage instructions, handling instructions, and any additional processing
instructions. The release, including the date and signature of the individual(s) performing the examination, shall be
documented in the DHR.
(c) Labeling storage. Each manufacturer shall store labeling in a manner that provides proper identification and is
designed to prevent mixups.
(d) Labeling operations. Each manufacturer shall control labeling and packaging operations to prevent labeling mixups.
The label and labeling used for each production unit, lot, or batch shall be documented in the DHR.
(e) Control number. Where a control number is required by § 820.65, that control number shall be on or shall accompany
the device through distribution.

§ 820.130: 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.
Subpart L—Handling, Storage, Distribution, and Installation

§ 820.140: Handling.
Each manufacturer shall establish and maintain procedures to ensure that mixups, damage, deterioration,
contamination, or other adverse effects to product do not occur during handling.
§ 820.150: Storage.
(a) Each manufacturer shall establish and maintain procedures for the control of storage areas and stock rooms for
product to prevent mixups, damage, deterioration, contamination, or other adverse effects pending use or distribution
and to ensure that no obsolete, rejected, or deteriorated product is used or distributed. When the quality of product
deteriorates over time, it shall be stored in a manner to facilitate proper stock rotation, and its condition shall be
assessed as appropriate.
(b) Each manufacturer shall establish and maintain procedures that describe the methods for authorizing receipt from
and dispatch to storage areas and stock rooms.
§ 820.160: Distribution.
(a) Each manufacturer shall establish and maintain procedures for control and distribution of finished devices to
ensure that only those devices approved for release are distributed and that purchase orders are reviewed to ensure
that ambiguities and errors are resolved before devices are released for distribution. Where a device’s fitness for use
or quality deteriorates over time, the procedures shall ensure that expired devices or devices deteriorated beyond
acceptable fitness for use are not distributed.
(b) Each manufacturer shall maintain distribution records which include or refer to the location of:
(1) The name and address of the initial consignee;
(2) The identification and quantity of devices shipped;
(3) The date shipped; and
(4) Any control number(s) used.
§ 820.170: Installation.
(a) Each manufacturer of a device requiring installation shall establish and maintain adequate installation and
inspection instructions, and where appropriate test procedures. Instructions and procedures shall include directions
for ensuring proper installation so that the device will perform as intended after installation. The manufacturer shall
distribute the instructions and procedures with the device or otherwise make them available to the person(s) installing
the device.
(b) The person installing the device shall ensure that the installation, inspection, and any required testing are
performed in accordance with the manufacturer’s instructions and procedures and shall document the inspection and
any test results to demonstrate proper installation.

Subpart M—Records
§ 820.180: General requirements.
All records required by this part shall be maintained at the manufacturing establishment or other location that is
reasonably accessible to responsible officials of the manufacturer and to employees of FDA designated to perform
inspections. Such records, including those not stored at the inspected establishment, shall be made readily available for
review and copying by FDA employee(s). Such records shall be legible and shall be stored to minimize deterioration and
to prevent loss. Those records stored in automated data processing systems shall be backed up.
(a) Confidentiality. Records deemed confidential by the manufacturer may be marked to aid FDA in determining
whether information may be disclosed under the public information regulation in part 20 of this chapter.
(b) Record retention period. All records required by this part shall be retained for a period of time equivalent to the
design and expected life of the device, but in no case less than 2 years from the date of release for commercial
distribution by the manufacturer.
(c) Exceptions. This section does not apply to the reports required by § 820.20(c) Management review, § 820.22
Quality audits, and supplier audit reports used to meet the requirements of § 820.50(a) Evaluation of suppliers,
contractors, and consultants, but does apply to procedures established under these provisions. Upon request of a
designated employee of FDA, an employee in management with executive responsibility shall certify in writing that
the management reviews and quality audits required under this part, and supplier audits where applicable, have been
performed and documented, the dates on which they were performed, and that any required corrective action has
been undertaken.
§ 820.181: Device master record.
Each manufacturer shall maintain device master records (DMRs). Each manufacturer shall ensure that each DMR is
prepared and approved in accordance with § 820.40. The DMR for each type of device shall include, or refer to the
(a) Device specifications including appropriate drawings, composition, formulation, component specifications, and
software specifications;
(b) Production process specifications including the appropriate equipment specifications, production methods,
production procedures, and production environment specifications;
(c) Quality assurance procedures and specifications including acceptance criteria and the quality assurance equipment
to be used;
(d) Packaging and labeling specifications, including methods and processes used; and
(e) Installation, maintenance, and servicing procedures and methods.
§ 820.184: Device history record.
Each manufacturer shall maintain device history records (DHRs). Each manufacturer shall establish and maintain
procedures to ensure that DHRs for each batch, lot, or unit are maintained to demonstrate that the device is
manufactured in accordance with the DMR and the requirements of this part. The DHR shall include, or refer to the
(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 unique device identifier (UDI) or universal product code (UPC), and any other device identification(s) and control
number(s) used.
§ 820.186: Quality system record.
Each manufacturer shall maintain a quality system record (QSR). The QSR shall include, or refer to the location of,
procedures and the documentation of activities required by this part that are not specific to a particular type of
device(s), including, but not limited to, the records required by § 820.20. Each manufacturer shall ensure that the QSR is
prepared and approved in accordance with § 820.40.
§ 820.198: Complaint files.
(a) Each manufacturer shall maintain complaint files. Each manufacturer shall establish and maintain procedures for
receiving, reviewing, and evaluating complaints by a formally designated unit. Such procedures shall ensure that:
(1) All complaints are processed in a uniform and timely manner;
(2) Oral complaints are documented upon receipt; and
(3) Complaints are evaluated to determine whether the complaint represents an event which is required to be reported
to FDA under part 803 of this chapter, Medical Device Reporting.
(b) Each manufacturer shall review and evaluate all complaints to determine whether an investigation is necessary.
When no investigation is made, the manufacturer shall maintain a record that includes the reason no investigation
was made and the name of the individual responsible for the decision not to investigate.
(c) Any complaint involving the possible failure of a device, labeling, or packaging to meet any of its specifications shall
be reviewed, evaluated, and investigated, unless such investigation has already been performed for a similar complaint
and another investigation is not necessary.
(d) Any complaint that represents an event which must be reported to FDA under part 803 of this chapter shall be
promptly reviewed, evaluated, and investigated by a designated individual(s) and shall be maintained in a separate
portion of the complaint files or otherwise clearly identified. In addition to the information required by § 820.198(e),
records of investigation under this paragraph shall include a determination of:
(1) Whether the device failed to meet specifications;
(2) Whether the device was being used for treatment or diagnosis; and
(3) The relationship, if any, of the device to the reported incident or adverse event.
(e) When an investigation is made under this section, a record of the investigation shall be maintained by the formally
designated unit identified in paragraph (a) of this section. The record of investigation shall include:
(1) The name of the device;
(2) The date the complaint was received;
(3) Any unique device identifier (UDI) or universal product code (UPC), and any other device identification(s) and control
number(s) used;
(4) The name, address, and phone number of the complainant;
(5) The nature and details of the complaint;
(6) The dates and results of the investigation;

(7) Any corrective action taken; and
(8) Any reply to the complainant.
(f) When the manufacturer’s formally designated complaint unit is located at a site separate from the manufacturing
establishment, the investigated complaint(s) and the record(s) of investigation shall be reasonably accessible to the
manufacturing establishment.
(g) If a manufacturer’s formally designated complaint unit is located outside of the United States, records required by
this section shall be reasonably accessible in the United States at either:
(1) A location in the United States where the manufacturer’s records are regularly kept; or
(2) The location of the initial distributor.
[61 FR 52654, Oct. 7, 1996, as amended at 69 FR 11313, Mar. 10, 2004; 71 FR 16228, Mar. 31, 2006; 78 FR 55822, Sept.
24, 2013]
Subpart N—Servicing
§ 820.200: Servicing.
(a) 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.
(b) Each manufacturer shall analyze service reports with appropriate statistical methodology in accordance with
§ 820.100.
(c) Each manufacturer who receives a service report that represents an event which must be reported to FDA under
part 803 of this chapter shall automatically consider the report a complaint and shall process it in accordance with the
requirements of § 820.198.
(d) Service reports shall be documented and shall include:
(1) The name of the device serviced;
(2) Any unique device identifier (UDI) or universal product code (UPC), and any other device identification(s) and control
number(s) used;
(3) The date of service;
(4) The individual(s) servicing the device;
(5) The service performed; and
(6) The test and inspection data.
[61 FR 52654, Oct. 7, 1996, as amended at 69 FR 11313, Mar. 10, 2004; 78 FR 55822, Sept. 24, 2013]

Subpart O—Statistical Techniques
§ 820.250: Statistical techniques.
(a) 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.
(b) Sampling plans, when used, shall be written and based on a valid statistical rationale. Each manufacturer shall
establish and maintain procedures to ensure that sampling methods are adequate for their intended use and to ensure
that when changes occur the sampling plans are reviewed. These activities shall be documented.

Appendix B. Crosswalk: Quality System Essentials

to 21 CFR Part 820 (Quality System Regulation)
and 42 CFR Part 493 (Clinical Laboratory
Improvement Amendments)
QSEs 21 CFR Part 820 (QSReg) 42 CFR Part 493 (CLIA)

The sections cited in this column include
The sections cited in this column include Subparts E, H, J, K, M, and Q as applicable to
Parts 820.5 through 820.250. high-complexity testing only.
QSE Organization 493.1101 Facilities (c)
493.1103 Requirements for transfusion
820.5 Quality system services
493.1200–1227 Quality System for
Nonwaived Testing
820.20 Management responsibility (a) No requirement
Quality policy
493.1445 Laboratory director
responsibilities
493.1451 Technical supervisor
responsibilities
820.20 Management 493.1457 Clinical consultant responsibilities

responsibility (b) Organization 493.1462 General supervisor qualifications
(1) Responsibility and authority on or before February 28, 1992
493.1471 Cytology general supervisor
responsibilities
493.1485 Cytotechnologist responsibilities
493.1495 Testing personnel responsibilities
820.20 Management 493.1200 Introduction (c) Components of
responsibility (b) Organization the laboratory’s quality system
(2) Resources
820.20 Management No requirement
responsibility (b) Organization
(3) Management representative

Appendix B. (Continued)
QSE Organization 492.1200 Introduction (b) Quality
(Continued) assessment component
493.1230 General laboratory systems
493.1239 General laboratory system quality
820.20 Management responsibility (c) assessment (b) Review of the effectiveness
Management review of corrective actions
493.1240 Preanalytic systems
493.1250 Analytic systems
493.1290 Postanalytic systems
820.20 Management responsibility (d)
No requirement
Quality planning
820.20 Management responsibility (e) 493.1200 Introduction (a) Written quality
Quality system procedures system policies and procedures
QSE Customer Focus No requirement No requirement
QSE Facilities and Safety 493.1101 Facilities (d) Safety procedures

820.70 Production and process controls (c) 493.1252 Test systems, equipment,
Environmental control instruments, reagents, materials, and
supplies (b)(1–4) Essential conditions
820.70 Production and process controls (e)
493.1101 Facilities (a)(2) Contamination
Contamination control
820.70 Production and process controls (f) 493.1101 Facilities (a)(1) Space, ventilation,
Buildings and utilities
QSE Personnel 493.1235 Personnel competency

820.25 Personnel
assessment policies
820.70 Production and process controls (d) 493.1351–1495 Personnel responsibilities
Personnel for nonwaived testing
QSE Purchasing and 493.1252 Test systems, equipment,

Inventory 820.50 Purchasing controls instruments, reagents, materials, and supplies
(a) [first sentence only]
493.1252 Test systems, equipment,
820.150 Storage instruments, reagents, materials, and supplies
(b) Proper storage of reagents and specimens

QSE Equipment 493.1101 Facilities (b) Appropriate and
820.70 Production and process controls (g) sufficient equipment and instruments
Equipment
493.1254 Maintenance and function checks
820.70 Production and process controls (i)

No requirement
Automated processes
820.72 Inspection, measuring, and test
493.1254 Maintenance and function checks
equipment
QSE Process Management 493.1241 Test request

493.1242 Specimen submission, handling,
and referral
instruments, reagents, materials, and
820.30 Design controls supplies (a) and (c–e)
493.1253 Establishment and verification of
performance specifications (b–c)
493.1290 Postanalytic systems
493.1291 Test report
820.60 Identification instruments, reagents, materials, and
supplies
493.1232 Specimen identification and
820.65 Traceability
integrity
493.1253 Establishment and verification
of performance specifications (b)(3)
Determination of calibration and control
procedures
820.70 Production and process controls (a)
General 493.1256 Control procedures
493.1261–1278 Test system control
procedures
493.1281 Comparison of test results
820.70 Production and process controls (b) 493.1251 Procedure manual (d) Changes in
Production and process changes procedures
820.70 Production and process controls (h)
No requirement
Manufacturing material

QSE Process Management See 493.1253 Establishment and verification
(Continued) 820.75 Process validation of performance specifications
493.1256 Control procedures
820.80 Receiving, in-process, and finished
and referral (a)(7) Specimen acceptability
device acceptance
and rejection
820.86 Acceptance testing No requirement
493.1251 Procedure manual (b)(1)
820.120 Device labeling Requirements for labeling [patient
specimens]
820.130 Device packaging No requirement
820.140 Handling
and referral
820.160 Distribution See QSE Information Management,
820.170 Installation 493.1291
No requirement [This is service of device for

820.200 Servicing
customer.]
493.1256 Control procedures (d)(10)(i)
820.250 Statistical techniques Control materials providing quantitative
results
QSE Documents and Records 820.40 Document controls

820.70 Production and process controls (a) 493.1251 Procedure manual
(1) Documented instructions, SOPs
493.1101 Facilities (e) Storage of records
493.1105 Retention requirements
820.180 General requirements [Records]
493.1291 Test report (j) Reports and records
maintained by the laboratory
820.181 Device master record No requirement
820.184 Device history record 493.1283 Test records
QSE Information 493.1231 Confidentiality of patient

820.186 Quality system record
Management information
No requirement 493.1291 Test report (a–i)

QSE Nonconforming Event 493.1239 General laboratory systems
Management 820.90 Nonconforming product quality assessment (b) Review of the
effectiveness of corrective actions
493.1282 Corrective action
820.100 Corrective and preventive action 493.1291 Test report (k) Errors in reported
patient information
820.198 Complaint files 493.1233 Complaint investigations
No requirement 493.1234 Communications [breakdowns]
QSE Assessments 820.22 Quality audit No requirement

493.551 General requirements for
laboratories [Accreditation]
493.801–865 Participation in Proficiency
Testing for Laboratories Performing
Nonwaived Testing
493.1236 Evaluation of proficiency testing
performance
493.1239 General laboratory quality
No requirement systems assessment
493.1249 Preanalytic systems quality
assessment
493.1289 Analytic systems quality
assessment
493.1299 Postanalytic systems quality
assessment
493.1773 Basic (external) inspection
requirements
QSE Continual Improvement 493.1200 Introduction (b) Quality

In 820.100, above assessment component that ensures
continuous improvement

Appendix C. Supplier Qualification Survey
Company Name:
Company Address:
City: State:
Zip Code: Website:
Telephone: Fax:
Principal Product or Service:
Contacts:
Responsible for Quality: (Name and Title)
E-mail: Telephone:
Responsible for Procurement/Supply Chain: (Name and Title)
E-mail: Telephone:
Sales Contact: (Name and Title)
E-mail: Telephone:
Facility Information:
Years in Business: Previous Name (if applicable):
Division or Subdivision of:
Number of Employees: Number of Employees in Quality:

Appendix C. (Continued)
1.0 Management Responsibility
Requirement Yes No N/A Remarks
1.1 Is there an established company quality
policy?
1.2 Is the quality policy communicated to all
organizational levels?
1.3 Does your quality manager report to top
management or to a level that has direct
access to top management?
1.4 Is there a management review of the
system? If yes, how frequently is it
performed?
2.0 Quality Assurance

2.1 Do you have a quality manual outlining
quality system policies and procedures? If
yes, please provide a copy of your manual.
2.2 Are internal audits performed regularly
to ensure that controls are effective for
managing products or processes?
2.3 Do you currently use a third party to audit
your quality system? If yes, please attach a
copy of your certification of compliance.
2.4 Does your company have a continuous
improvement program in place? Describe
the program.
3.0 Document Control

3.1 Are current issues of documents, drawings,
and procedures available in all locations
where the work is performed?
3.2 Is there a method for confirming that
users have the most current version of a
document, drawing, or procedure?
3.3 Is there a formal documented procedure
to update, revise, correct, and distribute
documents?
3.4 Is the responsibility for maintaining the
master list and updates clearly defined?

4.0 Purchasing Control
4.1 Do you have an Approved Supplier List?
4.2 Do you have a documented supplier
control procedure?
4.3 Are vendors monitored to assure
acceptable quality?
4.4 Do you have a corrective action process for
your suppliers?
5.0 Design Control

5.1 Are documented procedures established
and maintained to control and verify the
design of products to ensure that specified
requirements are met?
5.2 Are there documented specifications for
each product?
5.3 Is design verification performed and
documented to ensure that design output
meets the requirement of design input?
5.4 Is design validation performed to ensure
that product conforms to defined user
needs and/or requirements?
6.0 Production and Process Control

6.1 Are there written procedures or work
instructions that are sufficient to control
the quality-related parts of a process?
6.2 Do you carry out and document in-process
and final inspection of products?
6.3 Are statistical process control methods
used to control manufacturing processes?
6.4 Are process records retained?
6.5 When material is reworked, is stocked
warehouse inventory considered relative to
the rework?
6.6 Are the results of incoming inspection used
for the assessment of the suppliers?
6.7 Is the labeling of the finished parts
checked?

7.0 Measuring and Testing Equipment
7.1 Is quality measurement equipment
routinely calibrated, inspected, checked,
and maintained to an established
procedure?
If “Yes” to 7.1, please answer questions
7.1.1 to 7.1.5.
7.1.1 Are your measurement standards
certified and traceable to current NIST
standards?
7.1.2 Is it guaranteed that all relevant
inspection tools are registered, labeled,
controlled, and maintained?
7.1.3 Are the results of controlling and
maintaining the tools documented?
7.1.4 Are your shipping methods of calibrated
equipment adequate enough to maintain
the calibration status?
7.1.5 If equipment is discovered to be out of
calibration, is there a method for qualified
people to evaluate the impact to product
quality? And, are the results of the
decision and actions documented?
8.0 Identification and Traceability

8.1 Is there a method to identify a product
to its specifications during all stages of
production?
8.2 Is there a procedure for establishing lot or
batch identification?
8.3 Are records retained for product
identification traceability in case of product
recall or a need for corrective action?

9.0 Control of Nonconforming Product
9.1 Is there a documented procedure for
handling nonconforming material and
products?
9.2 Does the documented procedure
adequately define the roles and
responsibilities for the review and
disposition of nonconforming materials
and products?
9.3 Are the roles and responsibilities
to investigate the root cause of
nonconformance defined and carried out?
9.4 Are sufficient controls in place to ensure
that reworked or reprocessed materials
and products are retested and reinspected
to guarantee quality?
9.5 Is it guaranteed that blocked products are
not used?
10.0 Corrective and Preventive Action

10.1 Is there a documented procedure to
ensure that the roles and responsibilities
for carrying out corrective action
are defined to resolve causes of
nonconforming materials or products?
10.2 Is there clear evidence of responsibility for
initiating corrective action?
10.3 Are there controls in place to ensure that
corrective actions are effective?
10.4 Are preventive measures such as process
analysis used to identify and eliminate
potential causes of defects?
10.5 Are there records to show evidence of
corrective action investigations, analysis,
and actions?

11.0 Personnel
11.1 Are the personnel performing work
competent on the basis of education,
training, skills, and experience?
11.2 Do you have a procedure to identify the
training and qualification necessary to
perform all jobs?
11.3 Do you maintain records for training that
has been conducted to meet the specified
requirements?
11.4 Are retraining requirements documented
and implemented?
Report completed by and certified by:
Supplier Name: Supplier Signature:

(printed)
Title: Date:
Signature Signature
(QA) (Materials Management)
Date: Date:
Critical Supplier: Yes No

Related CLSI Reference Materials†
C24 Statistical Quality Control for Quantitative Measurement Procedures: Principles and
Definitions. 3rd ed., 2006. This guideline provides definitions of analytical intervals, planning of quality
control procedures, and guidance for quality control applications.
C37 Preparation and Validation of Commutable Frozen Human Serum Pools as Secondary Reference
Materials for Cholesterol Measurement Procedures. 1999. This guideline details procedures for the
manufacture and evaluation of human serum pools for cholesterol measurement.
C50 Mass Spectrometry in the Clinical Laboratory: General Principles and Guidance. 2007. This
guideline provides a general understanding of mass spectrometry and the principles that dictate its
application in the clinical laboratory. It includes guidance, references, and quality assurance markers that
will assist with the implementation and correct operation of a mass spectrometry (MS) system for its
many applications. Information on maintaining optimum performance, approaches to ensuring accurate
and precise mass measurement, verification of methods, quality control of assays within and between
instruments, instrument troubleshooting, sample preparation, interpretation of results, and limitations
of the technology is included.
EP05 Evaluation of Precision of Quantitative Measurement Procedures. 3rd ed., 2014. This document
provides guidance for evaluating the precision performance of quantitative measurement procedures. It
is intended for manufacturers of quantitative measurement procedures and for laboratories that develop
or modify such procedures.
EP06 Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach.

2003. This document provides guidance for characterizing the linearity of a method during a method
evaluation; for checking linearity as a part of routine quality assurance; and for determining and stating a
manufacturer’s claim for linear range.
EP07 Interference Testing in Clinical Chemistry. 2nd ed., 2005. This document provides background
information, guidance, and experimental procedures for investigating, identifying, and characterizing the
effects of interfering substances on clinical chemistry test results.
EP09 Measurement Procedure Comparison and Bias Estimation Using Patient Samples. 3rd ed., 2013.
This document addresses the design of measurement procedure comparison experiments using patient
samples and subsequent data analysis techniques used to determine the bias between two in vitro
diagnostic measurement procedures.
† CLSI documents are continually reviewed and revised through the CLSI consensus process; therefore, readers should refer to the most
current editions.

Related CLSI Reference Materials (Continued)

EP10 Preliminary Evaluation of Quantitative Clinical Laboratory Measurement Procedures. 3rd ed.,
2014. This guideline provides experimental design and data analysis for preliminary evaluation of the
performance of a measurement procedure or device.
EP12 User Protocol for Evaluation of Qualitative Test Performance. 2nd ed., 2008. This document
provides a consistent approach for protocol design and data analysis when evaluating qualitative
diagnostic tests. Guidance is provided for both precision and method-comparison studies.
EP14 Evaluation of Commutability of Processed Samples. 3rd ed., 2014. This document provides
guidance for evaluating the commutability of processed samples by determining if they behave
differently than unprocessed patient samples when two quantitative measurement procedures are
compared.
EP15 User Verification of Precision and Estimation of Bias. 3rd ed., 2014. This document describes the
estimation of imprecision and of bias for clinical laboratory quantitative measurement procedures using
a protocol that can be completed within as few as five days.
EP17 Evaluation of Detection Capability for Clinical Laboratory Measurement Procedures. 2nd ed.,
2012. This document provides guidance for evaluation and documentation of the detection capability
of clinical laboratory measurement procedures (ie, limits of blank, detection, and quantitation), for
verification of manufacturers’ detection capability claims, and for the proper use and interpretation of
different detection capability estimates.
EP18 Risk Management Techniques to Identify and Control Laboratory Error Sources. 2nd ed., 2009.
This guideline describes risk management techniques that will aid in identifying, understanding, and
managing sources of failure (potential failure modes) and help to ensure correct results. Although
intended primarily for in vitro diagnostics, this document will also serve as a reference for clinical
laboratory managers and supervisors who wish to learn about risk management techniques and
processes.
EP21 Estimation of Total Analytical Error for Clinical Laboratory Methods. 2003. This document
provides manufacturers and end users with a means to estimate total analytical error for an assay. A data
collection protocol and an analysis method which can be used to judge the clinical acceptability of new
methods using patient specimens are included. These tools can also monitor an assay’s total analytical
error by using quality control samples.
EP23™ Laboratory Quality Control Based on Risk Management. 2011. This document provides guidance
based on risk management for laboratories to develop quality control plans tailored to the particular
combination of measuring system, laboratory setting, and clinical application of the test.


EP24 Assessment of the Diagnostic Accuracy of Laboratory Tests Using Receiver Operating
Characteristic Curves. 2nd ed., 2011. This document provides a protocol for evaluating the accuracy of
a test to discriminate between two subclasses of subjects when there is some clinically relevant reason
to separate them. In addition to the use of receiver operating characteristic curves and the comparison
of two curves, the document emphasizes the importance of defining the question, selecting the sample
group, and determining the “true” clinical state.
EP25 Evaluation of Stability of In Vitro Diagnostic Reagents. 2009. This document provides guidance
for establishing shelf-life and in-use stability claims for in vitro diagnostic reagents such as reagent kits,
calibrators, and control products.
EP27 How to Construct and Interpret an Error Grid for Quantitative Diagnostic Assays. 2012. This
guideline describes what an error grid is, why it is useful, and how to construct one and interpret the
information. Guidance is provided for manufacturers and for the clinical laboratory.
EP28 Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory. 3rd ed.,
2010. This document contains guidelines for determining reference values and reference intervals for
quantitative clinical laboratory tests.
EP29 Expression of Measurement Uncertainty in Laboratory Medicine. 2012. This guideline describes
a practical approach to assist clinical laboratories in developing and calculating useful estimates of
measurement uncertainty, and illustrates their application in maintaining and improving the quality of
measured values used in patient care.
EP30 Characterization and Qualification of Commutable Reference Materials for Laboratory

Medicine. 2010. This document provides information to help material manufacturers in the production
and characterization of commutable reference materials, as well as to assist assay manufacturers and
laboratorians in the appropriate use of these materials for calibration and trueness assessment of in vitro
diagnostic medical devices.
GP40 Preparation and Testing of Reagent Water in the Clinical Laboratory. 4th ed., 2012. This
document provides guidelines on water purified for clinical laboratory use; methods for monitoring water
quality and testing for specific contaminants; and water system design considerations.
MM17 Verification and Validation of Multiplex Nucleic Acid Assays. 2008. This guideline provides
recommendations for analytic verification and validation of multiplex assays, as well as a review of
different types of biologic and synthetic reference materials.


QMS02 Quality Management System: Development and Management of Laboratory Documents. 6th
ed., 2013. This document provides guidance on the processes needed for document management,
including creating, controlling, changing, and retiring a laboratory’s policy, process, procedure, and form
documents in both paper and electronic environments.
QMS03 Training and Competence Assessment. 3rd ed., 2009. This document provides background
information and recommended processes for the development of training and competence assessment
programs that meet quality and regulatory objectives.
QMS15 Assessments: Laboratory Internal Audit Program. 2013. This document provides guidance for
how a laboratory can establish an internal audit program to enhance the quality of its services through
continual improvement. Whereas an audit program defines the “who,” “what,” “when,” “where,” and
“how” of meeting requirements for internal auditing, the audit process describes the details of how to
conduct individual laboratory internal audits.

NOTES

950 West Valley Road, Suite 2500, Wayne, PA 19087 USA
P: 610.688.0100 Toll Free (US): 877.447.1888 F: 610.688.0700 PRINT ISBN 1-56238-991-2
E: customerservice@clsi.org www.clsi.org ELECTRONIC ISBN 1-56238-992-0


QSRLDTE

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

QSRLDTE

Uploaded by

Copyright:

Available Formats

Quality System Regulation for

Licensed to: Isabela Liana Tincu

Taunya Alexander, CQA Penny Keller, BS, MB(ASCP) Luann Ochs, MS

CLSI gratefully acknowledges the special reviewers of this practical guide:

David G. Grenache, PhD, DABCC, FACB W. Gregory Miller, PhD

P: 610.688.0100 F: 610.688.0700 E: customerservice@clsi.org W: www.clsi.org.

Licensed to: Isabela Liana Tincu

CLSI hereby grants permission to each individual member or purchaser to make a

ISBN 1-56238-991-2 (Print)

Abbreviations and Acronyms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Chapter 1: Management Responsibility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Chapter 2: Quality Audit . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Chapter 4: Design Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

Chapter 5: Document Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Chapter 6: Purchasing Controls. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Chapter 7: Identification and Traceability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

Chapter 8: Production and Process Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Chapter 9: Nonconforming Product . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

Chapter 10: Corrective and Preventive Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

Chapter 11: Labeling and Packaging Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Chapter 12: Handling, Storage, Distribution, and Installation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69

Chapter 13: Records . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73

Chapter 14: Complaint Files . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79

Chapter 15: Servicing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85

Chapter 16: Statistical Techniques. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

Appendix C. Supplier Qualification Survey . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116

Related CLSI Reference Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Manufacturer: the laboratory that is preparing and using the LDT.

Product: the components of the LDT; eg, the reagents.

Abbreviations and Acronyms

BOM bill of materials R&D Research and Development

This page is intentionally left blank.

Licensed to: Isabela Liana Tincu

“We will provide high-quality products by ensuring our laboratory-

© Clinical and Laboratory Standards Institute. All rights reserved. 1

2 © Clinical and Laboratory Standards Institute. All rights reserved.

Figure 1. Example Laboratory Organizational Chart

© Clinical and Laboratory Standards Institute. All rights reserved. 3

REPORTS TO (POSITION TITLE):

BASIC JOB PURPOSE: Summarize in one or two sentences the fundamental

PRINCIPAL ACCOUNTABILITIES: In order of importance, describe the 4–8 major

EDUCATION, KNOWLEDGE, EXPERIENCE, AND SPECIFIC SKILLS REQUIRED:

Under a robust quality MINIMUM EDUCATION:

4 © Clinical and Laboratory Standards Institute. All rights reserved.

© Clinical and Laboratory Standards Institute. All rights reserved. 5

MANAGEMENT REPRESENTATIVE APPOINTMENT

Eﬀective Date: __________________

[INSERT NAME] is the Management Representative for our Quality

(Excerpt from QSReg)

Ensuring that quality system requirements are eﬀectively established

Reporting on the performance of the quality system to management

NOTE: The responsibility of a management representative can include liaison

Sent From: ___________________

A record of attendance Figure 3. Example Management Representative Appointment Letter

6 © Clinical and Laboratory Standards Institute. All rights reserved.

Part 1: Review Quality Inputs

Figure 4. Example Management Review Agenda

© Clinical and Laboratory Standards Institute. All rights reserved. 7

8 © Clinical and Laboratory Standards Institute. All rights reserved.

Figure 5 outlines the common structure of quality system documentation.

Procedures - Specific instructions for completion

Working - More detailed instructions, such as

Quality - All data and information generated

Lowest level, most detail