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

Additional copies are available from: 

Office of Training and Communication 

Division of Drug Information, HFD-240 

Center for Drug Evaluation and Research 

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857 

(Tel) 301-827-4573 

http://www.fda.gov/cder/guidance/index.htm 

or 

Office of Communication, Training and 

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

http://www.fda.gov/cber/guidelines.htm. 

(Tel) 800-835-4709 or 301-827-1800 

or 

Communications Staff, HFV-12 

Center for Veterinary Medicine 

Food and Drug Administration 

7519 Standish Place, Rockville, MD 20855 

(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 
Contains Nonbinding Recommendations 

TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND AND PURPOSE.................................................................................. 1

A. Background ....................................................................................................................................1

B. Goal of the Guidance .....................................................................................................................2

C. Scope of the Guidance ...................................................................................................................3

D. Organization of this Guidance......................................................................................................4

III. CGMPS AND THE CONCEPTS OF MODERN QUALITY SYSTEMS................... 4

A. Quality.............................................................................................................................................4

B. Quality by Design and Product Development .............................................................................4

C. Quality Risk Management ............................................................................................................5

D. CAPA (Corrective and Preventive Action)..................................................................................5

E. Change Control..............................................................................................................................5

F. The Quality Unit ............................................................................................................................5

G. Six-system Inspection Model.........................................................................................................6

IV. THE QUALITY SYSTEMS MODEL............................................................................. 8

A. Management Responsibilities .......................................................................................................8

1. Provide Leadership..........................................................................................................................8

2. Structure the Organization ..............................................................................................................9

3. Build Your Quality System to Meet Requirements...........................................................................9

4. Establish Policies, Objectives, and Plans.....................................................................................10

5. Review the System..........................................................................................................................10

B. Resources......................................................................................................................................12

1. General Arrangements...................................................................................................................12

2. Personnel Development .................................................................................................................13

3. Facilities and Equipment ...............................................................................................................13

4. Control Outsourced Operations ....................................................................................................14

C. Manufacturing .............................................................................................................................15

1. Design, Develop, and Document Product and Processes..............................................................15

2. Examine Inputs ..............................................................................................................................16

3. Perform and Monitor Operations..................................................................................................17

4. Address Nonconformities...............................................................................................................19

D. Evaluation Activities....................................................................................................................21

1. Analyze Data for Trends...............................................................................................................21

2. Conduct Internal Audits.................................................................................................................21

3. Quality Risk Management..............................................................................................................22

4. Corrective Action...........................................................................................................................22
Contains Nonbinding Recommendations 

5. Preventive Actions .........................................................................................................................23

6. Promote Improvement....................................................................................................................23

V. CONCLUSION ............................................................................................................... 24

USEFUL REFERENCE MATERIALS.................................................................................... 25

GLOSSARY................................................................................................................................. 27

 
Contains Nonbinding Recommendations 

Guidance for Industry1

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 21st 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, 

 

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). 

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Contains Nonbinding Recommendations 

 

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 regulations2) 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: 

2

 See Reference #1. 

3

 See Reference #2. 

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Contains Nonbinding Recommendations 

 

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 highquality 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 design4

(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 

4

 See ICH Q8 Pharmaceutical Development. 

3
Contains Nonbinding Recommendations 

 

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 

5

 See ICH-Q8 Pharmaceutical Development. 

4
Contains Nonbinding Recommendations 

 

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 

6

 See ICH Q9 Quality Risk Management. 

5
Contains Nonbinding Recommendations 

 

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 unit7 (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 

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. 

6
Contains Nonbinding Recommendations 

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. 

 

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. 

7
Contains Nonbinding Recommendations 

 

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 

10 See Reference #3. 

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Contains Nonbinding Recommendations 

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.) 

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Contains Nonbinding Recommendations 

• 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 

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Contains Nonbinding Recommendations 

• 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: 

• 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. 

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Contains Nonbinding Recommendations 

21 CFR CGMP Regulations Related to Management Responsibilities 

Quality System Element Regulatory Citations 

1. Leadership — 

Establish quality function: § 211.22 (a) (see definition 

 § 210.3(b)(15)) 

2. Structure 

Notification: § 211.180(f) 

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) 

3. Build QS 

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, Objectives and Plans Procedures: §§ 211.22(c-d), 211.100(a) 

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 

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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. 

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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 nonpharmaceutical 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 — 

Qualifications: § 211.25(a) 

Staff number: § 211.25(c) 

2. Develop Personnel 

Staff training: § 211.25(a-b) 

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 

 

3. Facilities and Equipment 

Lab facilities: § 211.22(b) 

 

11 See Reference # 4. 

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Contains Nonbinding Recommendations 

4. Control Outsourced Operations Consultants: § 211.34 

Outsourcing: § 211.22(a) 

C. 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 

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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. 

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. 

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Contains Nonbinding Recommendations 

 

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 

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. 

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Contains Nonbinding Recommendations 

 

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: 

• 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) 

17 See Reference #7. 

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Contains Nonbinding Recommendations 

• 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 

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Contains Nonbinding Recommendations 

 

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. 

18 See 21 CFR Part 7. 

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Contains Nonbinding Recommendations 

21 CFR CGMP Regulations Related to Manufacturing Operations 

Quality System Element Regulatory Citation 

1. Design and Develop Product and Processes Production: § 211.100(a) 

2. Examine Inputs Materials: §§ 210.3(b), 211.80 – 211.94, 211.101, 

211.122, 211.125 

Production: §§ 211.100, 211.103, 211.110, 211.111, 

211.113 

QC criteria: §§ 211.22(a-c), 211.115(b), 211.160(a), 

211.165(d), 211.188 

3. Perform and Monitor Operations 

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 

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Contains Nonbinding Recommendations 

 

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: 

19 See Reference #8. 

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Contains Nonbinding Recommendations 

• 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. 

23
Contains Nonbinding Recommendations 

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. 

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Contains Nonbinding Recommendations 

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 

2. CPGM 7356.002 Compliance Program – Drug Manufacturing Inspections 

http://www.fda.gov/cder/dmpq/compliance_guide.htm 

3. Quality Planning and Analysis, 3rd Ed. by J.M. Juran, F.M. Gryna (McGraw-Hill, New 

York, N.Y. 1993) 

4. ANSI/ISO/ASQ Q9000-2000: Quality management systems – Fundamentals and vocabulary,

(American Society for Quality, 2000) 

5. Guideline of General Principles of Process Validation, May 1987 – 

http://www.fda.gov/cder/guidance/pv.htm 

6. FDA Compliance Policy Guide 7132c.08 Process Validation Requirements for Drug 

Products and Active Pharmaceutical Ingredients Subject to Pre-Market Approval, updated 

03-12-2004 – http://www.fda.gov/ora/compliance_ref/cpg/cpgdrg/cpg490-100.html 

7. 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. 

 

8. 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 

9. Criteria for Performance Excellence, Business (Baldrige National Quality Program, NIST 

2003) http://baldrige.nist.gov/PDF_files/2003_Business_Criteria.pdf 

10. ANSI/ISO/ASQ Q9001-2000: Quality management systems – Requirements (American 

Society for Quality, 2000) 

11. ANSI/ISO/ASQ Q9004-2000: Quality management systems – Guidelines for performance 

improvement (American Society for Quality, 2000) 

12. ANSI/ISO 17025-1999: General requirements for the competence of testing 

 and calibration laboratories (American Society for Quality, 1999) 

13. 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 

14. The Balanced Scorecard Institute: http://balancedscorecard.org 

15. Guidance for Developing Quality Systems for Environmental Program (EPA QA/G-1, Nov 

2002) http://www.epa.gov/quality/qs-docs/g1-final.pdf

16. 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) . 

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Contains Nonbinding Recommendations 

17. 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

18. Procedures For The Implementation of The Federal Managers’ Financial Integrity Act 

(FMFIA); (FDA Staff Manual Guide 2350.1) 

19. Managing the Risks from Medical Product Use: Creating a Risk Management Framework

(U.S. FDA, 1999) http://www.fda.gov/oc/tfrm/1999report.html

20. 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 

21. Report on FDA Quality System Framework for Pharmaceutical Product Regulation 

Activities; (Quality System Framework Subcommittee, December 2003) 

22. Tutorials for Continuous Quality Improvement (Clemson University, 1995) 

http://deming.eng.clemson.edu/pub/tutorials/ 

23. Variation Risk Management – Focusing Quality Improvement in Product Development and 

Products by Anna C. Thornton (John Wiley and Sons, Inc.; Hoboken, New Jersey, 2004 

24. 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 

25. Chapter 3, “Quality Management in the American Pharmaceutical Industry,” in 

Pharmaceutical Quality, Ed. by R. Prince (DHI Publishing, River Grove, IL, 2004) 

26
Contains Nonbinding Recommendations 

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 

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Contains Nonbinding Recommendations 

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, 3rd 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, 3rd edition, ASQ Quality Audit Division, J.P. Russell, Editor) 

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