**Guidance for Industry**

**Quality Systems Approach to Pharmaceutical CGMP Regulations**

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**Center for Biologics Evaluation and Research (CBER)**

**Center for Veterinary Medicine (CVM)**

**Office of Regulatory Affairs (ORA)**

**September 2006**

**Pharmaceutical CGMPs**

**Guidance for Industry**

**Quality Systems Approach to Pharmaceutical CGMP Regulations**

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*or*

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*(Tel) 301-827-3800\
http://www.fda.gov/cvm/guidance/published.html*

**U.S. Department of Health and Human Services**

**Food and Drug Administration**

**Center for Drug Evaluation and Research (CDER)**

**Center for Biologics Evaluation and Research (CBER)**

**Center for Veterinary Medicine (CVM)**

**Office of Regulatory Affairs (ORA)**

**September 2006**

**Pharmaceutical CGMP Regulations**

**TABLE OF CONTENTS**

#  {#section .TOC-1 .unnumbered}

# [I. Introduction 1](#i.-introduction)[II. background and purpose 1](#ii.-background-and-purpose) {#i.-introduction-1ii.-background-and-purpose-1 .TOC-1}

## [A. Background 1](#a.-background) {#a.-background-1 .TOC-2}

## [B. Goal of the Guidance 2](#b.-goal-of-the-guidance) {#b.-goal-of-the-guidance-2 .TOC-2}

## [C. Scope of the Guidance 3](#c.-scope-of-the-guidance) {#c.-scope-of-the-guidance-3 .TOC-2}

## [D. Organization of this Guidance 4](#d.-organization-of-this-guidance) {#d.-organization-of-this-guidance-4 .TOC-2}

# [III. CGMPS and the concepts of modern Quality systems 4](#iii.-cgmps-and-the-concepts-of-modern-quality-systems) {#iii.-cgmps-and-the-concepts-of-modern-quality-systems-4 .TOC-1}

## [A. Quality 4](#a.-quality) {#a.-quality-4 .TOC-2}

## [B. Quality by Design and Product Development 4](#b.-quality-by-design-and-product-development) {#b.-quality-by-design-and-product-development-4 .TOC-2}

## [C. Quality Risk Management 5](#c.-quality-risk-management) {#c.-quality-risk-management-5 .TOC-2}

## [D. CAPA (Corrective and Preventive Action) 5](#d.-capa-corrective-and-preventive-action) {#d.-capa-corrective-and-preventive-action-5 .TOC-2}

## [E. Change Control 5](#e.-change-control) {#e.-change-control-5 .TOC-2}

## [F. The Quality Unit 5](#f.-the-quality-unit) {#f.-the-quality-unit-5 .TOC-2}

## [G. Six-system Inspection Model 6](#g.-six-system-inspection-model) {#g.-six-system-inspection-model-6 .TOC-2}

# [IV. The QUALITY SystemS MODEL 8](#iv.-the-quality-systems-model) {#iv.-the-quality-systems-model-8 .TOC-1}

## [A. Management Responsibilities 8](#__RefHeading___Toc147046897) {#a.-management-responsibilities-8 .TOC-2}

### [1. Provide Leadership 8](#provide-leadership) {#provide-leadership-8 .TOC-3}

### [2. Structure the Organization 9](#structure-the-organization) {#structure-the-organization-9 .TOC-3}

### [3. Build Your Quality System to Meet Requirements 9](#build-your-quality-system-to-meet-requirements) {#build-your-quality-system-to-meet-requirements-9 .TOC-3}

### [4. Establish Policies, Objectives, and Plans 10](#establish-policies-objectives-and-plans) {#establish-policies-objectives-and-plans-10 .TOC-3}

### [5. Review the System 10](#review-the-system) {#review-the-system-10 .TOC-3}

## [B. Resources 12](#b.-resources) {#b.-resources-12 .TOC-2}

### [1. General Arrangements 12](#general-arrangements) {#general-arrangements-12 .TOC-3}

### [2. Personnel Development 13](#personnel-development) {#personnel-development-13 .TOC-3}

### [3. Facilities and Equipment 13](#facilities-and-equipment) {#facilities-and-equipment-13 .TOC-3}

### [4. Control Outsourced Operations 14](#control-outsourced-operations) {#control-outsourced-operations-14 .TOC-3}

## [C. Manufacturing 15](#manufacturing) {#c.-manufacturing-15 .TOC-2}

### [1. Design, Develop, and Document Product and Processes 15](#design-develop-and-document-product-and-processes) {#design-develop-and-document-product-and-processes-15 .TOC-3}

### [2. Examine Inputs 16](#examine-inputs) {#examine-inputs-16 .TOC-3}

### [3. Perform and Monitor Operations 17](#perform-and-monitor-operations) {#perform-and-monitor-operations-17 .TOC-3}

### [4. Address Nonconformities 19](#address-nonconformities) {#address-nonconformities-19 .TOC-3}

## [D. Evaluation Activities 21](#d.-evaluation-activities) {#d.-evaluation-activities-21 .TOC-2}

### [1. Analyze Data for Trends 21](#analyze-data-for-trends) {#analyze-data-for-trends-21 .TOC-3}

### [2. Conduct Internal Audits 21](#conduct-internal-audits) {#conduct-internal-audits-21 .TOC-3}

### [3. Quality Risk Management 22](#quality-risk-management) {#quality-risk-management-22 .TOC-3}

### [4. Corrective Action 22](#corrective-action) {#corrective-action-22 .TOC-3}

### [5. Preventive Actions 23](#preventive-actions) {#preventive-actions-23 .TOC-3}

### [6. Promote Improvement 23](#promote-improvement) {#promote-improvement-23 .TOC-3}

# [V. Conclusion 24](#v.-conclusion) {#v.-conclusion-24 .TOC-1}

# [Useful REFERENCE materials 25](#useful-reference-materials) {#useful-reference-materials-25 .TOC-1}

# [GLOSSARY 27](#glossary) {#glossary-27 .TOC-1}

#####   {#section-1 .TOC-5}

**Guidance for Industry**[^1]

**Quality Systems Approach to Pharmaceutical Current Good Manufacturing
Practice Regulations**

# 

This guidance represents the Food and Drug Administration\'s (FDA\'s)
current thinking on this topic. It does not create or confer any rights
for or on any person and does not operate to bind FDA or the public. You
can use an alternative approach if the approach satisfies the
requirements of the applicable statutes and regulations. If you want to
discuss an alternative approach, contact the FDA staff responsible for
implementing this guidance. If you cannot identify the appropriate FDA
staff, call the appropriate number listed on the title page of this
guidance.

# 

# I. Introduction

This guidance is intended to help manufacturers implementing modern
quality systems and risk management approaches to meet the requirements
of the Agency\'s current good manufacturing practice (CGMP) regulations
(2l CFR parts 210 and 211). The guidance describes a *comprehensive
quality systems (QS) model,* highlighting the model\'s consistency with
the CGMP regulatory requirements for manufacturing human and veterinary
drugs, including biological drug products. The guidance also explains
how manufacturers implementing such quality systems can be in full
compliance with parts 210 and 211. This guidance is not intended to
place new expectations on manufacturers, nor to replace the CGMP
requirements. Readers are advised to always refer to parts 210 and 211
to ensure full compliance with the regulations.

FDA\'s guidance documents, including this guidance, do not establish
legally enforceable responsibilities. Instead, guidances describe the
Agency\'s current thinking on a topic and should be viewed only as
recommendations, unless specific regulatory or statutory requirements
are cited. The use of the word *should* in Agency guidances means that
something is suggested or recommended, but not required.

# II. background and purpose

## A. Background

## 

In August 2002, the FDA announced the Pharmaceutical CGMPs for the
21^st^ Century Initiative. In that announcement, the FDA explained the
Agency's intent to integrate *quality systems* and *risk management*
approaches into its existing programs with the goal of encouraging
industry to adopt modern and innovative manufacturing technologies. The
CGMP initiative was spurred by the fact that since 1978, when the last
major revision of the CGMP regulations was published, there have been
many advances in manufacturing science and in our understanding of
quality systems. In addition, many pharmaceutical manufacturers are
already implementing comprehensive, modern quality systems and risk
management approaches. This guidance is intended to help manufacturers
implementing modern quality systems and risk management approaches to
meet the requirements of the Agency\'s CGMP regulations. The Agency also
saw a need to harmonize the CGMPs with other non-U.S. pharmaceutical
regulatory systems and with FDA's own medical device quality systems
regulations. This guidance supports these goals. It also supports the
objectives of the Critical Path Initiative, which intends to make the
development of innovative medical products more efficient so that safe
and effective therapies can reach patients sooner.

The CGMPs for the 21st Century Initiative steering committee created a
Quality System Guidance Development working group (QS working group) to
compare the current CGMP regulations, which call for some specific
quality management elements, to other existing quality management
systems. The QS working group mapped the relationship between CGMP
regulations (parts 210 and 211 and the 1978 Preamble to the CGMP
regulations[^2]) and various quality system models, such as the Drug
Manufacturing Inspections Program (i.e., systems-based inspectional
program),[^3] the Environmental Protection Agency\'s Guidance for
Developing Quality Systems for Environmental Programs, ISO Quality
Standards, other quality publications, and experience from regulatory
cases. The QS working group determined that, although the CGMP
regulations do provide great flexibility, they do not incorporate
explicitly all of the elements that today constitute most quality
management systems.

The CGMP regulations and other quality management systems differ
somewhat in organization and in certain constituent elements; however,
they are very similar and share underlying principles. For example, the
CGMP regulations stress quality control. More recently developed quality
systems stress quality management, quality assurance, and the use of
risk management tools, in addition to quality control. The QS working
group decided that it would be very useful to examine exactly how the
CGMP regulations and the elements of a modern, comprehensive quality
system fit together in today\'s manufacturing world. This guidance is
the result of that examination.

## B. Goal of the Guidance

This guidance describes a comprehensive quality systems model, which, if
implemented, will allow manufacturers to support and sustain robust,
modern quality systems that are consistent with CGMP regulations. The
guidance demonstrates how and where the elements of this comprehensive
model can fit within the requirements of the CGMP regulations. The
inherent flexibility of the CGMP regulations should enable manufacturers
to implement a quality system in a form that is appropriate for their
specific operations.

The overarching philosophy articulated in both the CGMP regulations
*and* in robust modern quality systems is:

> ***Quality should be built into the product, and***
>
> ***testing alone cannot be relied on to ensure product quality*.**

This guidance is intended to serve as a bridge between the 1978
regulations and our current understanding of quality systems. In
addition to being part of the FDA\'s CGMP initiative, this guidance is
being issued for a number of reasons:

-   A quality system addresses the public and private sectors' mutual
    goal of providing a high-quality drug product to patients and
    prescribers. A well-built quality system should reduce the number of
    (or prevent) recalls, returned or salvaged products, and defective
    products entering the marketplace.

-   It is important that the CGMP regulations are harmonized to the
    extent possible with other widely used quality management systems,
    including ISO 9000, non-U.S. pharmaceutical quality management
    requirements, and FDA's own medical device quality system
    regulations. This guidance serves as a first step to highlight
    common elements between the CGMP regulations and Quality Management
    Systems. With the globalization of pharmaceutical manufacturing and
    the increasing prevalence of drug- and biologic-device combination
    products, the convergence of quality management principles across
    different regions and among various product types is very desirable.

-   The FDA has concluded that modern quality systems, when coupled with
    manufacturing process and product knowledge and the use of effective
    risk management practices, can handle many types of changes to
    facilities, equipment, and processes without the need for prior
    approval regulatory submissions. Manufacturers with a robust quality
    system and appropriate process knowledge can implement many types of
    improvements. In addition, an effective quality system, by lowering
    the risk of manufacturing problems, may result in shorter and fewer
    FDA inspections.

-   A quality system can provide the necessary framework for
    implementing *quality by design*[^4] (building in quality from the
    development phase and throughout a product's life cycle), continual
    improvement, and risk management in the drug manufacturing process.
    A quality system adopted by a manufacturer can be tailored to fit
    the specific environment, taking into account factors such as scope
    of operations, complexity of processes, and appropriate use of
    finite resources.

## C. Scope of the Guidance

This guidance applies to manufacturers of drug products (finished
pharmaceuticals), including products regulated by the Center for
Biologics Evaluation and Research (CBER), the Center for Drug Evaluation
and Research (CDER), and the Center for Veterinary Medicine (CVM). It
may also be useful to manufacturers of components (including active
pharmaceutical ingredients) used in the manufacture of these products.

This document is ***not*** intended to create new requirements for
pharmaceutical manufacturing that go beyond those established in the
current regulations, nor is the guidance intended to be a guide for the
conduct of FDA inspections. Rather, the document explains how
implementing comprehensive quality systems can help manufacturers
achieve compliance with 21 CFR parts 210 and 211. Although the QS
working group found that many of the quality system elements correlate
with specific CGMP requirements, some do not. The Agency expects
compliance with CGMP regulations, and FDA's inspection program will
remain focused on compliance with those regulations.

## D. Organization of this Guidance

To provide a reference familiar to industry, the quality systems model
described in section IV of this guidance is organized --- in its major
sections --- according to the structure of international quality
standards. Major sections of the model include the following:

-   Management Responsibilities

-   Resources

-   Manufacturing Operations

-   Evaluation Activities

Under each of these sections the key elements found in modern quality
systems are discussed. When an element correlates with a CGMP regulatory
requirement, that correlation is noted. In some cases, a specific CGMP
regulation is discussed in more detail as it relates to a quality system
element. At the end of each section, a table is included listing the
quality system elements of that section and the specific CGMP
regulations with which they correlate. A glossary is included at the end
of the document.

# **III. CGMPS and the concepts of modern Quality systems** 

## 

Several key concepts are critical for any discussion of modern quality
systems. The following concepts are used throughout this guidance as
they relate to the manufacture of pharmaceutical products.

## A. Quality

Every pharmaceutical product has established identity, strength, purity,
and other quality characteristics designed to ensure the required levels
of safety and effectiveness. For the purposes of this guidance document,
the phrase *achieving quality* means achieving these characteristics for
a product.

## 

## B. Quality by Design and Product Development

*Quality by design* means designing and developing a product and
associated manufacturing processes that will be used during product
development to ensure that the product consistently attains a predefined
quality at the end of the manufacturing process.[^5] Quality by design,
in conjunction with a quality system, provides a sound framework for the
transfer of product knowledge and process understanding from drug
development to the commercial manufacturing processes and for
post-development changes and optimization. The CGMP regulations, when
viewed in their entirety, incorporate the concept of quality by design.
This guidance describes how these elements fit together.

## C. Quality Risk Management 

*Quality risk management* is a valuable component of an effective
quality systems framework.[^6] Quality risk management can, for example,
help guide the setting of specifications and process parameters for drug
manufacturing, assess and mitigate the risk of changing a process or
specification, and determine the extent of discrepancy investigations
and corrective actions.

## D. CAPA (Corrective and Preventive Action)

## 

*CAPA* is a well-known CGMP regulatory concept that focuses on
investigating, understanding, and correcting discrepancies while
attempting to prevent their recurrence. Quality system models discuss
CAPA as three separate concepts, all of which are used in this guidance.

-   Remedial corrections of an identified problem

-   Root cause analysis with corrective action to help understand the
    cause of the deviation and potentially prevent recurrence of a
    similar problem

-   Preventive action to avert recurrence of a similar potential problem

## 

## E. Change Control

*Change control* is another well-known CGMP concept that focuses on
managing change to prevent unintended consequences. The CGMP regulations
provide for change control primarily through the assigned
responsibilities of the quality control unit. Certain major
manufacturing changes (e.g., changes that alter specifications, a
critical product attribute or bioavailability) require regulatory
filings and prior regulatory approval (21 CFR 314.70, 514.8, and
601.12).

Effective change control activities (e.g., quality planning and control
of revisions to specifications, process parameters, procedures) are key
components of any quality system. In this guidance, *change* is
discussed in terms of creating a regulatory environment that encourages
change towards continual improvement. This means a manufacturer is
empowered to make changes subject to the regulations based on the
variability of materials used in manufacturing and process improvements
resulting from knowledge gained during a product's lifecycle.

## F. The Quality Unit 

Many of the modern quality system concepts described here correlate very
closely with the CGMP regulations (refer to the charts later in the
document). Current industry practice generally divides the
responsibilities of the quality control unit (QCU), as defined in the
CGMP regulations, between quality control (QC) and quality assurance
(QA) functions.

-   QC usually involves (1) assessing the suitability of incoming
    components, containers, closures, labeling, in-process materials,
    and the finished products; (2) evaluating the performance of the
    manufacturing process to ensure adherence to proper specifications
    and limits; and (3) determining the acceptability of each batch for
    release.

-   QA primarily involves (1) review and approval of all procedures
    related to production and maintenance, (2) review of associated
    records, and (3) auditing and performing/evaluating trend analyses.

This guidance uses the term *quality unit*[^7] (QU) to reflect modern
practice while remaining consistent with the CGMP definition in §
210.3(b)(15). The concept of a *quality unit* is also consistent with
modern quality systems in ensuring that the various operations
associated with all systems are appropriately planned, approved,
conducted, and monitored.

The CGMP regulations specifically assign the QU the authority to create,
monitor, and implement a quality system. Such activities do not
substitute for, or preclude, the daily responsibility of manufacturing
personnel to build quality into the product. The QU should not take on
the responsibilities of other units of a manufacturer's organization,
such as the responsibilities handled by manufacturing personnel,
engineers, and development scientists.[^8] Manufacturing personnel and
the QU are both critical in fulfilling the manufacturer's responsibility
to produce quality products.

Other CGMP assigned responsibilities of the QU are consistent with
modern quality system approaches (§ 211.22):

-   Ensuring that controls are implemented and completed satisfactorily
    during manufacturing operations

-   Ensuring that developed procedures and specifications are
    appropriate and followed, including those used by a firm under
    contract to the manufacturer

-   Approving or rejecting incoming materials, in-process materials, and
    drug products

-   Reviewing production records and investigating any unexplained
    discrepancies

Under a quality system, it is normally expected that the product and
process development units, the manufacturing units, and the QU will
remain independent. In very limited circumstances, a single individual
can perform both production and quality functions. That person is still
accountable for implementing all the controls and reviewing the results
of manufacture to ensure that product quality standards have been met.
Under such circumstances, it is recommended that another qualified
individual, not involved in the production operation, conduct an
additional, periodic review of QU activities.

## G. Six-system Inspection Model 

The FDA\'s Drug Manufacturing Inspection Compliance Program, which
contains instructions to FDA personnel for conducting inspections, is a
systems-based approach to inspection and is very consistent with the
robust quality system model presented in this guidance.[^9] The diagram
below shows the relationship among the six systems: the quality system
and the five manufacturing systems. The quality system provides the
foundation for the manufacturing systems that are linked and function
within it. The quality system model described in this guidance does not
consider the five manufacturing systems as discrete entities, but
instead integrates them into appropriate sections of the model. Those
familiar with the six-system inspection approach will see organizational
differences in this guidance; however, the inter-relationship should be
readily apparent. One of the important themes of the systems based
inspection compliance program is that you have the ability to assess
whether each of the systems is in a state of control. The quality system
model presented in this guidance will also serve to help firms achieve
this state of control.

# IV. The QUALITY SystemS MODEL

The goal of this section is to describe a model for use in
pharmaceutical manufacturing that can help manufacturers comply with the
CGMP regulations. It should be noted that implementing an effective
quality system in a manufacturing organization will require a
significant investment of time and resources. However, we believe the
long-term benefits of implementing a quality system will outweigh the
costs.[^10]

This section describes a robust quality systems model that, if properly
implemented, can provide the controls to consistently produce a product
of acceptable quality. Where applicable, the relationship between
elements of this model and CGMP regulations is noted. At the end of each
section, a table shows how the specific CGMP regulations correlate to
the elements in the quality systems model. As already explained, many of
the quality systems elements correlate closely with the CGMP
regulations. It is important to emphasize that this guidance is not
recommending new regulatory requirements. The guidance is intended to
provide recommendations to manufacturers who are implementing, or plan
to implement, a quality systems model to help them comply with CGMP
regulations. FDA regulatory and inspectional coverage will remain
focused on the specific CGMP regulations.

The model is described according to four major factors:

-   Management Responsibilities

-   Resources

-   Manufacturing Operations

-   Evaluation Activities

In each of the sections that follow, the specific elements of a robust
modern quality systems model are described. When elements of the quality
systems model correlate with specific CGMP regulations, this correlation
is noted.

## A. Management Responsibilities 

Modern robust quality systems models call for management to play a key
role in the design, implementation, and management of the quality
system. For example, management is responsible for establishing the
quality system structure appropriate for the specific organization.
Management has ultimate responsibility to provide the leadership needed
for the successful functioning of a quality system. This section
describes management\'s role in developing, implementing, and managing a
robust quality system. There is some overlap with the CGMP regulations
in this section (see the table at the end of the section).

### 1. Provide Leadership 

### 

In a robust, modern quality system, senior management should demonstrate
commitment to developing and maintaining their quality system. Quality
system plans should be aligned with a manufacturer's strategic plans to
ensure that the system is part of the manufacturer's mission and quality
strategies. For example, quality systems departments normally have equal
standing with other departments within an organization. Quality systems
staff are effectively integrated into manufacturing activities and are
involved in activities such as nonconformance investigations. Senior
managers set implementation priorities and develop action plans. All
levels of management can provide support of the quality system by:

-   Actively participating in system design, implementation, and
    monitoring, including system review (see IV.A.5.)

-   Advocating continual improvement of operations of the quality system

-   Committing necessary resources

    In a robust quality systems environment, all managers should
    demonstrate strong and visible support for the quality system and
    ensure its implementation throughout the organization (e.g., across
    multiple sites).

    All managers should encourage internal communication on quality
    issues at all levels in the organization. Communication should be
    ongoing among research and development, regulatory affairs,
    manufacturing, and QU personnel on issues that affect quality, with
    management included whenever appropriate.

### 

### 2. Structure the Organization

When designing a robust quality system, management has the
responsibility to *structure* the organization and ensure that assigned
authorities and responsibilities support the production, quality, and
management activities needed to produce quality products. Senior
managers have the responsibility to ensure that the organization's
structure is documented.

All managers have the responsibility to communicate employee roles,
responsibilities, and authorities within the system and ensure that
interactions are defined and understood.

An organization also has the responsibility to give the individual who
is appointed to manage the quality system the authority to detect
problems and implement solutions. Usually, a senior manager administers
the quality system and can, thus, ensure that the organization receives
prompt feedback on quality issues.

### 3. Build Your Quality System to Meet Requirements 

Implementing a robust quality system can help ensure compliance with
CGMP regulations related to drug safety, identity, strength, quality,
and purity. Under the quality systems model, the Agency recommends that
senior managers ensure that the quality system that is designed and
implemented provides clear organizational guidance and facilitates
systematic evaluation of issues. For example, according to the model,
when documenting the implementation of a quality system, the following
should be addressed:

-   The scope of the quality system, including any outsourcing (see
    IV.B.4.)

-   The quality standard that will be followed

-   The manufacturer's policies to implement the quality systems
    criteria and the supporting objectives (see IV.A.4.)

-   The procedures needed to establish and maintain the quality system

    It is recommended under a modern quality systems approach that a
    formal process be established to change procedures in a controlled
    manner*.* It is also recommended that, when operating under a
    quality system, manufacturers develop and document control
    procedures to complete, secure, protect, and archive records,
    including data, which provide evidence of operational and quality
    system activities. This approach is consistent with the CGMP
    regulations, which require manufacturers to establish and follow
    scientifically sound and appropriate written controls for
    specifications, plans, and procedures that direct operational and
    quality system activities and to ensure that these directives are
    accurate, appropriately reviewed and approved, and available for use
    (see the CGMPs at § 211.22 (c) and (d)).

### 4. Establish Policies, Objectives, and Plans

Policies, objectives, and plans under a modern quality system provide
the means by which senior managers articulate their vision of and
commitment to quality to all levels of the organization.

Under a quality system, senior management should incorporate a strong
commitment to quality into the organizational mission. Senior managers
should develop an organizational quality policy that aligns with this
mission; commit to meeting requirements and improving the quality
system; and propose objectives to fulfill the quality policy. Under a
quality system, to make the policy relevant, it must be communicated to,
and understood by, personnel and contractors (if applicable) and
revised, as needed.

Managers operating within a quality system should define the quality
objectives identified for implementing the quality policy. Senior
management should ensure that the quality objectives are created at the
top level of the organization (and other levels as needed) through a
formal quality planning process. Objectives are typically aligned with
the manufacturer's strategic plans. A quality system seeks to ensure
that managers support the objectives with necessary resources and have
measurable goals that are monitored regularly.

Under a quality systems approach, managers would use quality planning to
identify and allocate resources and define methods to achieve the
quality objectives. Quality system plans should be documented and
communicated to personnel to ensure awareness of how their operational
activities are aligned with strategic and quality goals.

### 

### 5. Review the System 

System review is a key component in any robust quality system to ensure
its continuing suitability, adequacy, and effectiveness. Under a quality
system, senior managers should conduct reviews of the quality system's
performance according to a planned schedule. Such a review typically
includes assessments of the process, product, and customer needs (in
this section, *customer* is defined as the recipient of the product and
the product is the goods or services provided). Under a quality systems
approach, a review should consider at least the following:

-   The appropriateness of the quality policy and objectives

-   The results of audits and other assessments

-   Customer feedback, including complaints

-   The analysis of data trending results

-   The status of actions to prevent a potential problem or a recurrence

-   Any follow-up actions from previous management reviews

-   Any changes in business practices or environment that may affect the
    quality system (such as the volume or type of operations)

-   Product characteristics meeting the customer's needs

    When developing and implementing new quality systems, reviews should
    take place more frequently than when the system has matured. Outside
    of scheduled reviews, the quality system should typically be
    included as a standing agenda item in general management meetings.
    In addition, a periodic review performed by a qualified source,
    external to the organization, may also be useful in assessing the
    suitability and effectiveness of the system.

    Review outcomes typically include:

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```
-   Improvements to the quality system and related quality processes

-   Improvements to manufacturing processes and products

-   Realignment of resources

    Under a quality system, the results of a management review would
    typically be recorded. Planned actions should be implemented using
    effective corrective and preventive action and change control
    procedures.

    The following table shows how the CGMP regulations correlate to
    specific elements in the quality systems model for this section.
    Manufacturers should always refer to the specific regulations to
    make sure they are in compliance.

+-----------------------------+----------------------------------------+
| **21 CFR CGMP Regulations   |                                        |
| Related to Management       |                                        |
| Responsibilities**          |                                        |
+-----------------------------+----------------------------------------+
| **Quality System Element**  | **Regulatory Citations**               |
+-----------------------------+----------------------------------------+
| 1\. Leadership              | ---                                    |
+-----------------------------+----------------------------------------+
| 2\. Structure               | Establish quality function: § 211.22   |
|                             | (a) (see definition                    |
|                             |                                        |
|                             | § 210.3(b)(15))                        |
+-----------------------------+----------------------------------------+
|                             | Notification: § 211.180(f)             |
+-----------------------------+----------------------------------------+
| 3\. Build QS                | QU procedures: § 211.22(d)             |
+-----------------------------+----------------------------------------+
|                             | QU procedures, specifications: §       |
|                             | 211.22(c), with reinforcement in: §§   |
|                             | 211.100(a), 211.160(a)                 |
+-----------------------------+----------------------------------------+
|                             | QU control steps: § 211.22(a), with    |
|                             | reinforcement in §§ 211.42(c),         |
|                             | 211.84(a), 211.87, 211.101(c)(1),      |
|                             | 211.110(c), 211.115(b), 211.142,       |
|                             | 211.165(d), 211.192                    |
+-----------------------------+----------------------------------------+
|                             | QU quality assurance;                  |
|                             | review/investigate: §§ 211.22(a),      |
|                             | 211.100(a-b) 211.180(f), 211.192,      |
|                             | 211.198(a)                             |
+-----------------------------+----------------------------------------+
|                             | Record control: §§ 211.180(a-d),       |
|                             | 211.180(c), 211.180(d), 211.180(e),    |
|                             | 211.186, 211.192, 211.194, 211.198(b)  |
+-----------------------------+----------------------------------------+
| 4\. Establish Policies,     | Procedures: §§ 211.22(c-d), 211.100(a) |
| Objectives and Plans        |                                        |
+-----------------------------+----------------------------------------+
| 5\. System Review           | Record review: §§ 211.100, 211.180(e), |
|                             | 211.192, 211.198(b)(2)                 |
+-----------------------------+----------------------------------------+

## B. Resources

## 

Appropriate allocation of resources is key to creating a robust quality
system and complying with the CGMP regulations. This section discusses
the role of resources in developing, implementing, and managing a robust
quality system that complies with the CGMP regulations.

### 1. General Arrangements 

Under a robust quality system, sufficient resources should be allocated
for quality system and operational activities. Under the model, senior
management, or a designee, should be responsible for providing adequate
resources for the following:

-   To supply and maintain the appropriate facilities and equipment to
    consistently manufacture a quality product

-   To acquire and receive materials that are suitable for their
    intended purpose

-   For processing the materials to produce the finished drug product

-   For laboratory analysis of the finished drug product, including
    collection, storage, and examination of in-process, stability, and
    reserve samples

### 2. Personnel Development 

Under a quality system, senior management should support a
problem-solving and communicative organizational culture. Managers
should encourage communication by creating an environment that values
employee suggestions and acts on suggestions for improvement. Management
should also develop cross-functional groups to share ideas to improve
procedures and processes.

In a quality system, personnel should be qualified to do the operations
that are assigned to them in accordance with the nature of, and
potential risk of, their operational activities. Under a quality system,
managers should define appropriate qualifications for each position to
help ensure that individuals are assigned appropriate responsibilities.
Personnel should also understand the effect of their activities on the
product and the customer. Although QU personnel should not take on the
responsibilities of other units of the organization, these personnel
should be selected based on their scientific and technical
understanding, product knowledge, process knowledge and/or risk
assessment abilities to appropriately execute certain quality functions
(this quality systems feature is also found in the CGMP regulations,
which identify specific qualifications, such as education, training, and
experience or any combination thereof (see § 211.25(a) and (b)).

Under a quality system, continued training is critical to ensure that
the employees remain proficient in their operational functions and in
their understanding of CGMP regulations. Typical quality systems
training should address the policies, processes, procedures, and written
instructions related to operational activities, the product/service, the
quality system, and the desired work culture (e.g., team building,
communication, change, behavior). Under a quality system (and the CGMP
regulations), training should focus on both the employees' specific job
functions and the related CGMP regulatory requirements.

Under a quality system, managers are expected to establish training
programs that include the following:

-   Evaluation of training needs

-   Provision of training to satisfy these needs

-   Evaluation of effectiveness of training

-   Documentation of training and/or re-training

    When operating in a robust quality system environment, it is
    important that managers verify that skills gained from training are
    implemented in day-to-day performance.

### 3. Facilities and Equipment 

### 

Under a quality system, the technical experts (e.g., engineers,
development scientists), who have an understanding of pharmaceutical
science, risk factors, and manufacturing processes related to the
product, are responsible for defining specific facility and equipment
requirements.

Under the CGMP regulations, the quality unit (QU) has the responsibility
of reviewing and approving all initial design criteria and procedures
pertaining to facilities and equipment and any subsequent changes (§
211.22(c)).

Under the CGMP regulations, equipment must be qualified, calibrated,
cleaned, and maintained to prevent contamination and mix-ups (§§ 211.63,
211.67, 211.68). *Note that the CGMP regulations require a higher
standard for calibration and maintenance than most non-pharmaceutical
quality system models.* The CGMP regulations place as much emphasis on
process equipment as on testing equipment (§§ 211.160, 211.63, 211.67,
and 211.68) while most quality systems focus only on testing
equipment.[^11]

### 4. Control Outsourced Operations 

Outsourcing involves hiring a second party under a contract to perform
the operational processes that are part of a manufacturer's inherent
responsibilities. For example, a manufacturer may hire another firm to
package and label or perform CGMP regulatory training. Quality systems
call for contracts (quality agreements) that clearly describe the
materials or service, quality specification responsibilities, and
communication mechanisms.

Under a quality system, the manufacturer should ensure that a contract
firm is qualified before signing a contract with that firm. The contract
firm's personnel should be adequately trained and monitored for
performance according to their quality system, and the contract firm\'s
and contracting manufacturer's quality standards should not conflict. It
is critical in a quality system to ensure that the management of the
contractor be familiar with the specific requirements of the contract.
However, under the CGMP requirements, the manufacturer's QU is
responsible for approving or rejecting products or services provided
under a contract (§ 211.22(a)).

As the following table illustrates, the CGMP regulations are consistent
with the elements of a quality system in many areas in this section.
However, manufacturers should always refer to the specific regulations
to ensure that they are complying with all regulations.

+--------------------------------+-------------------------------------+
| **21 CFR CGMP Regulations      |                                     |
| Related to Resources**         |                                     |
+--------------------------------+-------------------------------------+
| **Quality System Element**     | **Regulatory Citation**             |
+--------------------------------+-------------------------------------+
| 1\. General Arrangements       | ---                                 |
+--------------------------------+-------------------------------------+
| 2\. Develop Personnel          | Qualifications: § 211.25(a)         |
+--------------------------------+-------------------------------------+
|                                | Staff number: § 211.25(c)           |
+--------------------------------+-------------------------------------+
|                                | Staff training: § 211.25(a-b)       |
+--------------------------------+-------------------------------------+
| 3\. Facilities and Equipment   | Buildings and facilities: §§        |
|                                | 211.22(b), 211.28(c),               |
|                                |                                     |
|                                | 211.42 -- 211.58, 211.173           |
+--------------------------------+-------------------------------------+
|                                | Equipment: §§ 211.63 -- 211.72,     |
|                                | 211.105, 211.160(b)(4), 211.182     |
+--------------------------------+-------------------------------------+
|                                | Lab facilities: § 211.22(b)         |
+--------------------------------+-------------------------------------+
| 4\. Control Outsourced         | Consultants: § 211.34               |
| Operations                     |                                     |
+--------------------------------+-------------------------------------+
|                                | Outsourcing: § 211.22(a)            |
+--------------------------------+-------------------------------------+

## 

## 

## Manufacturing 

Significant overlap exists between the elements of a quality system and
the CGMP regulation requirements for manufacturing operations. It is
important to emphasize again that FDA's enforcement programs and
inspectional coverage remain based on the CGMP regulations. When quality
system elements in this section do not correlate to the CGMP
regulations, the guidance makes recommendations to help facilitate
compliance with the CGMP regulations. The language in this section has
been tailored to the pharmaceutical manufacturing environment.

### 1. Design, Develop, and Document Product and Processes 

In a modern quality systems manufacturing environment, the significant
characteristics of the product being manufactured should be defined from
design to delivery, and control should be exercised over all changes. In
addition, quality and manufacturing processes and procedures --- and
changes to them --- must be defined, approved, and controlled (§
211.100). It is important to establish responsibility for designing or
changing products. Documenting processes, associated controls, and
changes to these processes will help ensure that sources of variability
are identified.

Documentation includes:

-   Resources and facilities used

-   Procedures to carry out the process

-   Identification of the process owner who will maintain and update the
    process as needed

-   Identification and control of important variables

-   Quality control measures, necessary data collection, monitoring, and
    appropriate controls for the product and process

-   Any validation activities, including operating ranges and acceptance
    criteria

-   Effects on related process, functions, or personnel

    As discussed under section IV.A., above, the model calls for
    managers to ensure that product specifications and process
    parameters are determined by the appropriate technical experts
    (e.g., engineers, development scientists). In the pharmaceutical
    environment, experts would have an understanding of pharmaceutical
    science, equipment, facilities, and process types and of how
    variations in materials and processes can ultimately affect the
    finished product.

    Packaging and labeling controls, critical stages in the
    pharmaceutical manufacturing process, are not specifically addressed
    in quality systems models. However, the Agency recommends that
    manufacturers always refer to the packaging and labeling control
    regulations at § 211 Subpart G. In addition --- and this ***is***
    consistent with modern quality systems --- FDA recommends that, as
    part of the design process, before commercial production, the
    controls for all processes within the packaging and labeling system
    be planned and documented in written procedures. The procedures
    should outline quality control activities and the responsible
    positions. Specifications and controls for the packaging and
    labeling materials should also be determined before commercial
    production. Distinct labels with discriminating features for
    different products, such as a product marketed with different
    strengths, should be included to prevent mislabeling and resulting
    recalls.

### 

### 2. Examine Inputs 

In a modern quality systems model, the term *input* includes any
material that goes into a final product, no matter whether the material
is purchased by the manufacturer or produced by the manufacturer for the
purpose of processing. *Materials* can include items such as components
(e.g., ingredients, process water, and gas), containers, and closures. A
robust quality system will ensure that all inputs to the manufacturing
process are reliable because quality controls will have been established
for the receipt, production, storage, and use of all inputs.

The CGMP regulations require either testing or use of a certificate of
analysis (COA) plus an identity analysis (§ 211.84) for the release of
materials for manufacturing. In the preamble to the CGMP regulations,
these requirements were explicitly interpreted.[^12] The preamble states
that reliability can be validated by conducting tests or examinations
and comparing the results to the supplier's COA. Sufficient initial
tests should be done to establish reliability and to determine a
schedule for periodic reassessment. As an essential element of
purchasing controls, it is recommended that data trends for acceptance
and rejection of materials be analyzed for information on supplier
performance.[^13]

The quality systems approach also calls for periodic auditing of
suppliers based on risk assessment. During the audit, a manufacturer can
observe the testing or examinations conducted by the supplier to help
determine the reliability of the supplier's COA. An audit should also
include a systematic examination of the supplier's quality system to
ensure that reliability is maintained. It is recommended that a
combination approach be used (i.e., verify the suppliers\' COA through
analysis *and* audits of the supplier). Under a quality systems
approach, if full analytical testing is not done, the audit should cover
the supplier's analysis (i.e., a specific identity test is still
required under § 211.84(d)(2)).

Under a quality systems approach, procedures should be established to
verify that materials are from qualified sources (for application and
licensed products, certain sources are specified in the submissions).
Procedures should also be established to encompass the acceptance, use,
or the rejection and disposition of materials produced by the facility
(e.g., purified water). Systems that produce these in-house materials
should be designed, maintained, qualified, and validated where
appropriate to ensure that the materials meet their acceptance criteria.

In addition, it is recommended that changes to materials (e.g.,
specification, supplier, or materials handling) be implemented through a
change control system (certain changes require review and approval by
the QU (§ 211.100(a)). It is also important to have a system in place to
respond to changes in materials from suppliers so that necessary
adjustments to the process can be made and unintended consequences
avoided.

### 3. Perform and Monitor Operations 

An important purpose of implementing a quality systems approach is to
enable a manufacturer to more efficiently and effectively validate,
perform, and monitor operations (§ 211.100(a)) and ensure that the
controls are scientifically sound and appropriate. The goal of
establishing, adhering to, measuring, and documenting specifications and
process parameters is to objectively assess whether an operation is
meeting its design and product performance objectives. In a robust
quality system, production and process controls should be designed to
ensure that the finished products have the identity, strength, quality,
and purity they purport or are represented to possess (see, e.g., §
211.100(a)).

In a modern quality system, a design concept established during product
development typically matures into a commercial design after process
experimentation and progressive modification.

Risk management can help identify areas of process weakness or higher
risk and factors that can influence critical quality attributes that
should receive increased scrutiny. The FDA recommends that scale-up
studies be used to help demonstrate that a fundamentally sound design
has been fully realized. A sufficiently robust manufacturing process
should be in place prior to commercial production. With proper design
(see IV.C.1.) and reliable mechanisms to transfer process knowledge from
development to commercial production, a manufacturer should be able to
validate the manufacturing process.[^14] Conformance batches provide
initial proof that the design of the process produces the intended
product quality. Sufficient testing data will provide essential
information on performance of the new process, as well as a mechanism
for continual improvement. Modern equipment with the potential for
continual monitoring and control can further enhance this knowledge
base. Although initial commercial batches can provide evidence to
support the validity and consistency of the process,[^15] the *entire
product life cycle* should be addressed by the establishment of
continual improvement mechanisms in the quality system.[^16] Thus, in
accordance with the quality systems approach, process validation is not
a one-time event, but an activity that continues throughout a product's
life.

As experience is gained in commercial production, opportunities for
process improvements may become evident. (CGMP regulations § 211.180
require the review and evaluation of records to determine the need for
any change. These records contain data and information from production
that provide insight into the product's state of control. Change control
systems should provide a dependable mechanism for prompt implementation
of technically sound manufacturing improvements.)

Under a quality system, written procedures are followed and deviations
from them are justified and documented (CGMP requires this; see §
211.100(b)) to ensure that the manufacturer can trace the history of the
product, as appropriate, concerning personnel, materials, equipment, and
chronology and that processes for product release are complete and
recorded.

Both the CGMP regulations (§ 211.110) and quality systems models call
for the monitoring of critical processes that may be responsible for
causing variability during production. For example:

-   Process steps must be verified by a second person (§ 211.188).
    Process steps can also be performed using a validated computer
    system. Batch production records must be prepared contemporaneously
    with each phase of production (§ 211.100(b)). Although time limits
    for production can be established when they are important to the
    quality of the finished product (CGMP addresses this; see §
    211.111), the manufacturer should have the ability to establish
    production controls using in-process parameters that are based on
    desired process endpoints measured using real time testing or
    monitoring apparatus (e.g., blend until mixed vs. blend for 10
    minutes).

-   Procedures must be in place to prevent objectionable microorganisms
    in finished products not required to be sterile and to prevent
    microbial contamination of finished products purported to be
    sterile. Sterilization processes must be validated for sterile drugs
    (§ 211.113(b)).[^17]

    Manufacturing processes must consistently meet their parameters, and
    in-process materials must meet acceptance criteria or limits (§
    211.110(b) and (c)) so that, ultimately, finished pharmaceutical
    products will meet their acceptance criteria. Under a quality
    system, selected data are used to evaluate the quality of a process
    or product. In addition, data collection can provide a means to
    encourage and analyze potential suggestions for improvement. A
    quality systems approach calls for the manufacturer to develop
    procedures that monitor, measure, and analyze the operations
    (including analytical methods and/or statistical techniques).
    Monitoring of the process is important due to the limitations of
    testing. Knowledge continues to accumulate from development through
    the entire commercial life of a product. Significant unanticipated
    variables should be detected by a well-managed quality system and
    adjustments implemented. Procedures should be revisited as needed to
    refine operational design based on new knowledge. Process
    understanding increases with experience and helps identify when
    change will lead to continual improvement. When implementing data
    collection procedures, consider the following:

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-   Are data collection methods documented?

-   When in the product life cycle will the data be collected?

-   How and to whom will measurement and monitoring activities be
    assigned?

-   When should analysis and evaluation (e.g. trending) of laboratory
    data be performed? (see IV.D.1)

-   What records should be collected?

    A modern quality system approach indicates that change control is
    warranted when data analysis or other information reveals an area
    for improvement. Changes to an established process must be
    controlled and documented to ensure that desired attributes for the
    finished product will be met (§ 211.100(a)).

    Change control with regard to pharmaceuticals is addressed in more
    detail in the CGMP regulations. When developing a process change, it
    is important to keep the process design and scientific knowledge of
    the product in mind. If major design issues are encountered through
    process experience, a firm may want to revisit the adequacy of the
    design of the manufacturing facility (§ 211.42), the design of the
    manufacturing equipment (§ 211.63), the design of the production and
    control procedures (§ 211.100), or the design of laboratory controls
    (§ 211.160). When implementing a change, its effect should be
    determined by monitoring and evaluating those specific elements that
    may be affected based on an understanding of the process. This
    approach allows the steps taken to implement a change and the
    effects of the change on the process to be considered
    systematically. Application of risk analysis may facilitate
    evaluating the potential effect of the change. Evaluating the
    effects of a change can entail additional tests or examinations of
    subsequent batches (e.g., additional in-process testing or
    additional stability studies). The quality system elements
    identified in this guidance, if implemented and maintained, will
    help a manufacturer manage change and implement continual
    improvement in manufacturing.

    Under a quality systems approach, procedures should be in place to
    ensure the accuracy of test results. Test results that are out of
    specification may be due to testing problems or manufacturing
    problems and should be investigated. Any invalidation of a test
    result should be scientifically sound and justified.

    To maintain quality, the Agency recommends that prior to completion
    of manufacturing, the manufacturer should consider storage and
    shipment requirements to meet special handling needs (in the case of
    pharmaceuticals, one example might be refrigeration).

    Under a quality system, trends should be continually identified and
    evaluated. One way of accomplishing this is the use of statistical
    process control. The information from trend analyses can be used to
    continually monitor quality, identify potential variances before
    they become problems, bolster data already collected for the annual
    review, and facilitate improvement throughout the product life
    cycle. Process capability assessment can serve as a basis for
    determining the need for changes that can result in process
    improvements and efficiency (see IV.D.1.).

### 4. Address Nonconformities

A key component in any quality system is handling nonconformities and/or
deviations. The investigation, conclusion, and follow-up must be
documented (§ 211.192). To ensure that a product conforms to
requirements and expectations, it is important to measure the process
and the product attributes (e.g., specified control parameters,
strength) as planned. Discrepancies may be detected during any stage of
the process or during quality control activities. Not all discrepancies
will result in product defects; however, it is important to document and
handle discrepancies appropriately. A discrepancy investigation process
is critical when a discrepancy is found that affects product quality
(CGMP also requires this;

see § 211.192).

In a quality system, it is important to develop and document procedures
that define who is responsible for halting and resuming operations,
recording non-conformities, investigating discrepancies, and taking
remedial action. Under a quality system, if a product or process does
not meet requirements, it is essential to identify and/or segregate the
product so that it is not distributed to the customer. Remedial action
can include any of the following:

-   Correct the non-conformity

-   With proper authorization, allow the product to proceed with
    justification of the conclusions regarding the problem's impact

-   Use the product for another application where the deficiency does
    not affect the products' quality

-   Reject the product

    The corrected product or process should also be re-examined for
    conformance and assessed for the significance of the non-conformity
    (see, e.g., § 211.115). If the non-conformity is significant, based
    on consequences to process control, process efficiency, product
    quality, safety, efficacy, and product availability, it is important
    to evaluate how to prevent recurrence (see IV.D.4.). If an
    individual product that does not meet requirements has been
    released, the product can be recalled.[^18] Customer complaints must
    be reviewed and then investigated if a discrepancy is identified (§
    211.198).

    The following table shows how the CGMP regulations correlate to
    specific elements in the quality systems model. Manufacturers should
    always refer to the specific regulations to ensure that they are
    complying with all regulations.

+-------------------------------+--------------------------------------+
| **21 CFR CGMP Regulations     |                                      |
| Related to Manufacturing      |                                      |
| Operations**                  |                                      |
+-------------------------------+--------------------------------------+
| **Quality System Element**    | **Regulatory Citation**              |
+-------------------------------+--------------------------------------+
| 1\. Design and Develop        | Production: § 211.100(a)             |
| Product and Processes         |                                      |
+-------------------------------+--------------------------------------+
| 2\. Examine Inputs            | Materials: §§ 210.3(b), 211.80 --    |
|                               | 211.94, 211.101, 211.122, 211.125    |
+-------------------------------+--------------------------------------+
| 3\. Perform and Monitor       | Production: §§ 211.100, 211.103,     |
| Operations                    | 211.110, 211.111, 211.113            |
+-------------------------------+--------------------------------------+
|                               | QC criteria: §§ 211.22(a-c),         |
|                               | 211.115(b), 211.160(a), 211.165(d),  |
|                               | 211.188                              |
+-------------------------------+--------------------------------------+
|                               | QC checkpoints: §§ 211.22 (a),       |
|                               | 211.84(a), 211.87, 211.110(c)        |
+-------------------------------+--------------------------------------+
| 4\. Address Nonconformities   | Discrepancy investigation: §§        |
|                               | 211.22(a), 211.100, 211.115,         |
|                               | 211.192, 211.198                     |
|                               |                                      |
|                               | Recalls: 21 CFR Part 7               |
+-------------------------------+--------------------------------------+

## 

## D. Evaluation Activities** **

As in the previous section, the elements of a quality system correlate
closely with the requirements in the CGMP regulations. See the table at
the end of the section for the specifics.

### 1. Analyze Data for Trends 

Quality systems call for continually monitoring trends and improving
systems. This can be achieved by monitoring data and information,
identifying and resolving problems, and anticipating and preventing
problems.

Quality systems procedures involve collecting data from monitoring,
measurement, complaint handling, or other activities, and tracking this
data over time, as appropriate. Analysis of data can provide indications
that controls are losing effectiveness. The information generated will
be essential to achieving problem resolution or problem prevention (see
IV.D.3.).

Although the CGMP regulations (§ 211.180(e)) require product review on
at least an annual basis, a quality systems approach calls for trending
on a more frequent basis as determined by risk. Trending enables the
detection of potential problems as early as possible to plan corrective
and preventive actions. Another important concept of modern quality
systems is the use of trending to examine processes as a whole; this is
consistent with the annual review approach. Trending analyses can help
focus internal audits (see IV.D.2.).

### 2. Conduct Internal Audits

A quality systems approach calls for audits to be conducted at planned
intervals to evaluate effective implementation and maintenance of the
quality system and to determine if processes and products meet
established parameters and specifications. As with other procedures,
audit procedures should be developed and documented to ensure that the
planned audit schedule takes into account the relative risks of the
various quality system activities, the results of previous audits and
corrective actions, and the need to audit the complete system.
Procedures should describe how auditors are trained in objective
evidence gathering, their responsibilities, and auditing procedures.
Procedures should also define auditing activities such as the scope and
methodology of the audit, selection of auditors, and audit conduct
(audit plans, opening meetings, interviews, closing meeting and
reports). It is critical to maintain records of audit findings and
assign responsibility for follow-up to prevent problems from recurring
(see IV.D.3.).

The quality systems model calls for managers who are responsible for the
areas audited to take timely action to resolve audit findings and ensure
that follow-up actions are completed, verified, and recorded. (FDA's
policy is to refrain from both reviewing and copying reports or records
that result from internal audits per Compliance Policy Guide
130.300.[^19])

### 3. Quality Risk Management

Effective decision-making in a quality systems environment is based on
an informed understanding of quality issues. Elements of risk should be
considered relative to intended use of a product, and in the case of
pharmaceuticals, patient safety and ensuring availability of medically
necessary drug products. Management should assign priorities to
activities or actions based on an assessment of the risk including both
the probability of occurrence of harm and of the severity of that harm.
It is important to engage appropriate parties in assessing the risk.
Such parties include customers, appropriate manufacturing personnel, and
other stakeholders. Implementation of quality risk management includes
assessing the risks, selecting and implementing risk management controls
commensurate with the level of risk, and evaluating the results of the
risk management efforts. Since risk management is an iterative process,
it should be repeated if new information is developed that changes the
need for, or nature of, risk management.

In a manufacturing quality systems environment, risk management is used
as a tool in the development of product specifications and critical
process parameters. Used in conjunction with process understanding,
quality risk management helps manage and control change.

### 4. Corrective Action

Corrective action is a reactive tool for system improvement to ensure
that significant problems do not recur. Both quality systems and the
CGMP regulations emphasize corrective actions. Quality systems
approaches call for procedures to be developed and documented to ensure
that the need for action is evaluated relevant to the possible
consequences, the root cause of the problem is investigated, possible
actions are determined, a selected action is taken within a defined
timeframe, and the effectiveness of the action taken is evaluated. It is
essential to document corrective actions taken (CGMP also requires this;
see § 211.192).

It is essential to determine what actions will reduce the likelihood of
a problem recurring. Examples of sources that can be used to gather such
information include the following:

-   Nonconformance reports and rejections

-   Returns

-   Complaints

-   Internal and external audits

-   Data and risk assessment related to operations and quality system
    processes

-   Management review decisions

### 5. Preventive Actions

Being proactive is an essential tool in quality systems management.
Succession planning, training, capturing institutional knowledge, and
planning for personnel, policy, and process changes are preventive
actions that will help ensure that potential problems and root causes
are identified, possible consequences assessed, and appropriate actions
considered.

The selected preventive action should be evaluated and recorded, and the
system should be monitored for the effectiveness of the action. Problems
can be anticipated and their occurrence prevented by reviewing data and
analyzing risks associated with operational and quality system
processes, and by keeping abreast of changes in scientific developments
and regulatory requirements.

### 6. Promote Improvement

The effectiveness and efficiency of a quality system can be improved
through the quality activities described in this guidance. Management
may choose to use other improvement activities as appropriate. It is
critical that senior management be involved in the evaluation of this
improvement process (see IV.D.3.).

The following table shows how the CGMP regulations correlate to specific
elements in the quality systems model for this section. Manufacturers
should always refer to the specific regulations to make sure they are
complying with all regulations.

  -------------------------------- --------------------------------------
  **21 CFR CGMP Regulations        
  Related to Evaluation            
  Activities**                     

  **Quality System Element**       **Regulatory Citation**

  1\. Analyze Data for Trends      Annual Review: § 211.180(e)

  2\. Conduct Internal Audits      \--

  3\. Risk Assessment              

  4\. Corrective Action            Discrepancy investigation: §§
                                   211.22(a), 211.192

  5\. Preventive Action            ---

  6\. Promote Improvement          § 211.110
  -------------------------------- --------------------------------------

# V. Conclusion

# 

Implementation of a *comprehensive quality systems model* for human and
veterinary pharmaceutical products, including biological products, will
facilitate compliance with 21 CFR parts 210 and 211. The central goal of
a quality system is the consistent production of safe and effective
products and ensuring that these activities are sustainable. Quality
professionals are aware that good intentions alone will not ensure good
products. A robust quality system will promote process consistency by
integrating effective knowledge-building mechanisms into daily
operational decisions. Specifically, successful quality systems share
the following characteristics, each of which has been discussed in
detail above:

-   Science-based approaches

-   Decisions based on an understanding of the intended use of a product

-   Proper identification and control of areas of potential process
    weakness

-   Responsive deviation and investigation systems that lead to timely
    remediation

-   Sound methods for assessing and reducing risk

-   Well-defined processes and products, starting from development and
    extending throughout the product life cycle

-   Systems for careful analysis of product quality

-   Supportive management (philosophically and financially)

Both good manufacturing practice and good business practice require a
robust quality system. When fully developed and effectively managed, a
quality system will lead to consistent, predictable processes that
ensure that pharmaceuticals are safe, effective, and available for the
consumer.

# 

# Useful REFERENCE materials

1.  1978 Preamble to the Good Manufacturing Practice Final Regulations
    -- *Federal Register* Docket No. 73N-0339\]
    <http://www.fda.gov/cder/dmpq/preamble.txt>

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1.  CPGM 7356.002 Compliance Program -- Drug Manufacturing Inspections
    <http://www.fda.gov/cder/dmpq/compliance_guide.htm>

2.  *Quality Planning and Analysis, 3^rd^ Ed. by J.M. Juran, F.M. Gryna
    (*McGraw-Hill, New York, N.Y. 1993)

3.  *ANSI/ISO/ASQ Q9000-2000:* *Quality management systems --
    Fundamentals and vocabulary,* (American Society for Quality, 2000)

4.  *Guideline of General Principles of Process Validation*, May 1987 --
    <http://www.fda.gov/cder/guidance/pv.htm>

5.  FDA Compliance Policy Guide 7132c.08 *Process Validation
    Requirements for Drug Products and Active Pharmaceutical Ingredients
    Subject to Pre-Market Approva*l, updated 03-12-2004 --
    <http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg490-100.html>

6.  Guidance for Industry - *Sterile Drug Products Produced by Aseptic
    Processing Current Good Manufacturing Practice* -- September 2004.
    See also the draft guidance on investigating *Out-of-Specification
    (OOS) Test Results for Pharmaceutical Production.*

7.  FDA Compliance Policy Guide Sec. 130.300, *FDA Access to Results of
    Quality Assurance Program Audits and Inspections*, (CPG 7151.02)
    http://www.fda.gov/ora/compliance_ref/cpg/cpggenl/cpg130-300.html

8.  *Criteria for Performance Excellence, Business* (Baldrige National
    Quality Program, NIST 2003)
    <http://baldrige.nist.gov/PDF_files/2003_Business_Criteria.pdf>

9.  *ANSI/ISO/ASQ Q9001-2000:* *Quality management systems --
    Requirements* (American Society for Quality, 2000)

10. *ANSI/ISO/ASQ Q9004-2000:* *Quality management systems -- Guidelines
    for performance improvement* (American Society for Quality, 2000)

11. *ANSI/ISO(PMB to double check reference) 17025-1999: General
    requirements for the competence of testing and calibration
    laboratories* (American Society for Quality, 1999)

12. CMMI-SE/SW, V1.1: *Capability Maturity Model Integration for Systems
    Engineering and Software Engineering, Staged Representation*
    (Software Engineering Institute, Carnegie Mellon University, 2002)
    <http://www.sei.cmu.edu/pub/documents/02.reports/pdf/02tr002.pdf>

13. The Balanced Scorecard Institute:
    [http://balancedscorecard.org](http://balancedscorecard.org/)

14. Guidance for Developing Quality Systems for Environmental Program
    (EPA QA/G-1, Nov 2002)
    <http://www.epa.gov/quality/qs-docs/g1-final.pdf>

15. Guidance for Industry *Q7A Good Manufacturing Practice Guidance for
    Active Pharmaceutical Ingredients* (U.S. Department of Health and
    Human Services/ Food and Drug Administration, August 2001) .

16. Good Manufacturing Practices for Pharmaceutical Products: Main
    Principles (World Health Organization Technical Report Series, No.
    908, 2003)
    <http://www.who.int/medicines/library/qsm/trs908/trs908-4.pdf>

17. *Procedures For The Implementation of The Federal Managers'
    Financial Integrity Act (FMFIA)*; *(*FDA Staff Manual Guide 2350.1)

18. *Managing the Risks from Medical Product Use: Creating a Risk
    Management Framework* (U.S. FDA, 1999)
    <http://www.fda.gov/oc/tfrm/1999report.html>

19. *Framework for Environmental Health Risk Assessment -- Final Report,
    Vol.1* (Presidential/Congressional Commission on Risk Assessment and
    Risk Management, 1997)
    <http://www.riskworld.com/Nreports/1997/risk-rpt/pdf/EPAJAN.PDF>

20. *Report on FDA Quality System Framework for Pharmaceutical Product
    Regulation Activities;* (Quality System Framework Subcommittee,
    December 2003)

21. *Tutorials for Continuous Quality Improvement* (Clemson
    University, 1995) <http://deming.eng.clemson.edu/pub/tutorials/>

22. *Variation Risk Management -- Focusing Quality Improvement in
    Product Development and Products by Anna C. Thornton* (John Wiley
    and Sons, Inc.; Hoboken, New Jersey, 2004

23. Guidance for Industry for the *Submission of Documentation for
    Sterilization Process Validation in Applications for Human and
    Veterinary Drug Products* --
    <http://www.fda.gov/cder/guidance/cmc2.pdf>

24. Chapter 3, "Quality Management in the American Pharmaceutical
    Industry," in *Pharmaceutical Quality,* Ed. by R. Prince (DHI
    Publishing, River Grove, IL, 2004)

# GLOSSARY

# 

To gain a common understanding of a quality systems approach, the
following terms are used throughout the guidance.

**Annual Review** -- An evaluation, conducted at least annually, that
assesses the quality standards of each drug product to determine the
need for changes in drug product specifications or manufacturing or
control procedures

**CAPA** -- Corrective and preventive action: A systematic approach that
includes actions needed to correct ("correction"), prevent recurrence
("corrective action"), and eliminate the cause of potential
nonconforming product and other quality problems (preventive action)
(21CFR 820.100)

**Continual Improvement** -- Ongoing activities to evaluate and
positively change products, processes, and the quality system to
increase effectiveness

**Correction** -- Repair, rework, or adjustment relating to the
disposition of an existing discrepancy

**Corrective Action** -- Action taken to eliminate the causes of an
existing discrepancy or other undesirable situation to prevent
recurrence

**Customer** -- A person or organization (internal or external) that
receives a product or service anywhere along the product's life cycle

**Discrepancy** -- Datum or result outside of the expected range; an
unfulfilled requirement; may be called non-conformity, defect,
deviation, out-of-specification, out-of-limit, out-of-trend

**Harm --** Damage to health, including the damage that can occur from
the loss of product quality or availability

**Non-conformity --** A deficiency in a characteristic, product
specification, process parameter, record, or procedure that renders the
quality of a product unacceptable, indeterminate, or not according to
specified requirements

**Preventive Action** -- Action taken to eliminate the cause of a
potential discrepancy or other undesirable situation to prevent such an
occurrence

**Product/Service** -- The intended results of activities or processes;
products/services can be tangible or intangible

**Quality** -- A measure of a product's or service's ability to satisfy
the customer's stated or implied needs

**Quality Assurance** -- Proactive and retrospective activities that
provide confidence that requirements are fulfilled

**Quality Control** -- The steps taken during the generation of a
product or service to ensure that it meets requirements and that the
product or service is reproducible

**Quality Management** -- Accountability for the successful
implementation of the quality system

**Quality Objectives** -- Specific measurable activities or processes to
meet the intentions and directions as defined in the quality policy

**Quality Plan** -- The documented result of quality planning that is
disseminated to all relevant levels of the organization

**Quality Planning** -- A management activity that sets quality
objectives and defines the operational and/or quality system processes
and the resources needed to fulfill the objectives

**Quality Policy** -- A statement of intentions and direction issued by
the highest level of the organization related to satisfying customer
needs. It is similar to a strategic direction that communicates quality
expectations that the organization is striving to achieve.

**Quality System** -- Formalized business practices that define
management responsibilities for organizational structure, processes,
procedures, and resources needed to fulfill product/service
requirements, customer satisfaction, and continual improvement

**Quality Unit** -- A group organized within an organization to promote
quality in general practice

**Risk** -- The combination of the probability of occurrence of harm and
the severity of that harm

**Risk Assessment** -- A systematic process for organizing information
to support a risk decision that is made within a risk management
process. The process consists of the identification of hazards and the
analysis and evaluation of risks associated with exposure to those
hazards.

**Risk Management** -- The systematic application of quality management
policies, procedures, and practices to the tasks of assessing,
controlling, communicating, and reviewing risk

**Senior Management --** Top management officials in a firm who have the
authority and responsibility to mobilize resources

**Stakeholder** -- An individual or organization having an ownership or
interest in the delivery, results, and metrics of the quality system
framework or business process improvements

# 

**Verification** -- Confirmation, through the provision of objective
evidence, that specified requirements have been fulfilled. (Reference:
The ASQ Auditing Handbook, 3^rd^ edition, ASQ Quality Audit Division,
J.P. Russell, Editor)

**Validation** -- Confirmation, through the provision of objective
evidence, that the requirements for a specific intended use or
application have been fulfilled. (Reference: The ASQ Auditing Handbook,
3^rd^ edition, ASQ Quality Audit Division, J.P. Russell, Editor)

[^1]: This guidance was developed by the Office of Compliance in the
    Center for Drug Evaluation and Research (CDER) in cooperation with
    the Center for Biologics Evaluation and Research (CBER), the Center
    for Veterinary Medicine (CVM), and the Office of Regulatory Affairs
    (ORA).

[^2]: See Reference #1.

[^3]: See Reference #2.

[^4]: See ICH Q8 Pharmaceutical Development.

[^5]: See ICH-Q8 Pharmaceutical Development.

[^6]: See ICH Q9 Quality Risk Management.

[^7]: Generally, the term *quality unit* is used in this guidance.
    However, *quality control unit* is used when directly quoting parts
    210 and 211.

[^8]: See Reference #1, comment 91.

[^9]: See Reference #2; This inspectional approach is currently in use
    by CDER and by CBER for blood and blood product inspections. CBER
    and CVM are developing a similar approach for drug product
    inspections.

[^10]: See Reference #3.

[^11]: See Reference \# 4.

[^12]: See Reference #1, comment 239.

[^13]: The Agency recommends that manufacturers have a measure of the
    variability of materials that could affect their process controls.
    For example, certain changes in physical properties may affect the
    process, which may affect a finished product's dissolution
    characteristics.

[^14]: See Reference #5.

[^15]: Even with good design and development work, initial *conformance
    batches* will provide confidence that future batches will meet
    specifications only if the process is repeated within defined
    operating parameters, equipment tolerances, personnel practices,
    environmental attributes, and material quality.

[^16]: See Reference #6.

[^17]: See Reference #7.

[^18]: See 21 CFR Part 7.

[^19]: See Reference #8.