Guidance for Industry
Quality Systems Approach to Pharmaceutical Current
Good Manufacturing Practice Regulations
This draft guidance, when
finalized, will represent 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.
This draft guidance is intended to help manufacturers that
are 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FDA's guidance documents, including this draft guidance, do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.
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 existing programs with
the goal of encouraging the adoption of 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 technologies
and in our understanding of quality systems. Many pharmaceutical manufacturers
are implementing comprehensive, modern quality systems and risk management
approaches. The Agency also saw a need to address the harmonization of the
CGMPs and other non-U.S. pharmaceutical regulatory systems as well as FDA’s own
medical device quality systems regulations.
The CGMP initiative steering committee created a Quality
System Guidance Development working group (QS working group) to compare the current CGMP regulations, which call for
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) and various quality system models, such as the
Drug Manufacturing Inspections Program (i.e., systems-based inspectional
program), 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 regulations do provide great flexibility, the CGMP regulations do
not consider all of the elements that today constitute most quality management
systems. The CGMP regulations and other 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.
This guidance describes a comprehensive quality systems
model, which, if implemented, will allow manufacturers to operate robust, modern
quality systems that are fully compliant with CGMP regulations. The guidance
demonstrates how and where the requirements of the CGMP regulations fit within
this comprehensive model. 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 prevent or reduce the number of recalls,
returned or salvaged products, and defective products entering the
marketplace.
·
It is important that we harmonize the CGMPs 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. 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, can handle many types of
changes to facilities, equipment, and processes without the need for a
regulatory submission. Manufacturers with appropriate process knowledge and a
robust quality system should be able to implement many types of improvements
without the need for a prior regulatory filing. 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 (building in
quality from the development phase and throughout a product’s life-cycle),
continuous 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.
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 used in the manufacture of these products.
This document is not intended to create new
expectations for pharmaceutical manufacturing that go beyond the requirements
laid out 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. In the end, the Agency expects compliance with the CGMP regulations, and
FDA’s inspection program remains geared to compliance with those regulations.
To provide a reference familiar to industry, the quality
systems model described in 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, we note that correlation. 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.
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.
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 draft
guidance document, the phrase achieving quality means achieving these
characteristics for the product.
Quality by design means designing and developing
manufacturing processes during the product development stage to
consistently ensure a predefined quality at the end of the manufacturing
process. A quality
system provides a sound framework for the transfer of process knowledge from
development to the commercial manufacturing processes and for postdevelopment
changes and optimization
The concept risk
management is a major focus of the Pharmaceutical CGMPs for the 21st
Century Initiative. Risk management can guide the setting of specifications
and process parameters. Risk assessment is also used in determining the need
for discrepancy investigations and corrective action. As risk assessment
is used more formally by manufacturers, it can be implemented within the
quality system framework.
CAPA is a well-known CGMP regulatory concept that
focuses on investigating and correcting discrepancies and attempting to prevent
recurrence. Quality system models discuss CAPA as three concepts, all of which
are used in this guidance.
- Remedial corrections
- Root cause analysis with corrective action to prevent
recurrence
- Preventive action to prevent initial occurrence
Change control is
another well-known CGMP regulatory concept that focuses on managing change to
prevent unintended consequences. The major implementation of change control in
the CGMP regulations is through the assigned responsibilities of the quality
control unit. Certain manufacturing changes (e.g., changes that alter
specifications, a critical product attribute or bioavailability) require
regulatory filings and prior regulatory approval (601.12 and 314.70).
A quality system also
contains change control activities, including quality planning and control of
revisions to specifications, process parameters, and procedures. In this
guidance, change is discussed in terms of creating a regulatory
environment that encourages change towards continuous improvement. This means a
manufacturer is empowered to make changes based on the variability of materials
used in manufacturing and optimization of the process from learning over time.
Many of the modern quality systems ideas described in this
section 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 consists of testing
of selected in-process materials and finished products to evaluate the
performance of the manufacturing process, and to ensure adherence to
proper specifications and limits.
- QA primarily includes the
review and approval of all procedures related to production, maintenance,
and review of associated records, and auditing, and performing trend
analyses.
This guidance uses the term quality unit
(QU) to reflect modern practice while remaining consistent with the CGMP
definition in 21 CFR 210.3(b)(15). The concept quality unit is also consistent
with modern quality systems in ensuring that the various operations associated
with all systems are appropriately conducted, approved, and monitored. The CGMP
regulations specifically assign the quality unit the authority to create,
monitor, and implement the quality system. However, the quality unit is not
meant to take on the responsibilities of other units of a manufacturer’s
organization, such as the responsibilities handled by manufacturing personnel,
engineers, and development scientists.
Other CGMP assigned responsibilities of the quality unit are
consistent with a modern quality system approaches (see § 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 in-process materials and drug products — although such
activities do not substitute for, or preclude, the daily responsibility of
manufacturing personnel to build quality into the product
- Reviewing
production records and investigating any unexplained discrepancies
Under a robust quality system,
the manufacturing units and the quality unit can remain independent, but still
be included in the total concept of producing quality products. In very small
operations, a single individual can function as the quality unit. That person
is still accountable for implementing all the controls and reviewing results of
manufacture to ensure that product quality standards have been met.
The FDA's Drug Manufacturing Inspection Compliance Program,
which constitutes instructions to FDA personnel for conducting inspections, is
a systems-based approach for inspections and is very consistent with the robust
quality systems model presented in this guidance.
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 systems model described in this
guidance does not treat 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 to
be able 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 the desired state of control.
FIG. 1 - SIX-SYSTEM
INSPECTION APPROACH
The goal of this section is
to describe a model for use in pharmaceutical manufacturing that can help
achieve compliance with CGMP regulations. It should be noted that implementing
an effective quality system in a manufacturing organization will require
significant costs in time and resources. However, the long-term benefits of
implementing a quality system will outweigh the costs.
This section describes a robust quality systems model,
which, if implemented, can provide the controls
needed 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 organized into
four major sections:
- Management Responsibilities
- Resources
- Manufacturing Operations
- Evaluation Activities
Under each of these sections, 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.
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 systems structure appropriate for
the specific organization. Management has ultimate responsibility to provide
the leadership needed for the successful functioning of the quality system.
This section describes management's role in developing, implementing, and
managing a robust quality system. There is little 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 demonstrates commitment to developing and
maintaining their quality system. Leadership
is demonstrated by aligning quality system plans with the manufacturer’s
strategic plans to ensure that the quality system supports the manufacturer’s
mission and strategies. Senior managers set implementation priorities and
develop action plans. Managers 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 and the quality
system
·
Committing necessary resources
In a robust quality
systems environment, managers should demonstrate strong and visible support for
the quality system and ensure its global implementation throughout the
organization (e.g., across multiple sites).
Managers should also
encourage internal communication on quality issues at all levels in the
organization. Communication should be ongoing among research and
development, regulatory affairs, manufacturing, and quality unit 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 determine the structure of 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.
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 effect solutions. Usually, a senior
manager administers the quality system and can, thus, ensure that the
organization receives prompt feedback on quality issues.
Implementing a robust quality system can help ensure
compliance with regulations related to safety, identity, strength, quality, and
purity as long as the quality system addresses the minimum requirements of CGMP
regulations as well as the needs of the manufacturer. Under the quality
systems model, the Agency recommends that senior managers ensure that the
quality system they design and implement provides clear organizational guidance
and facilitates systematic evaluation of issues. For example, according to the
model, when documenting a quality system, the following should be included.
·
The scope of the quality system, including any outsourcing (see
IV.B.4.)
·
The standard of quality that will be used
·
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
submit change requests to directives. It is also recommended that, when operating
under a quality system, manufacturers develop and document record control
procedures to complete, secure, protect, and archive records, including data,
which act as evidence of operational and quality system activities. This
approach is consistent with the CGMP regulations, which require manufacturers
to develop and document 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
Under a
modern quality system, policies, objectives, and plans provide the means by
which senior managers articulate their vision of quality to all levels of the
organization.
It is
expected that under a quality system senior management would incorporate a
strong commitment to quality into the organizational mission. Senior managers
are expected to 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 (as applicable), and revised as needed.
Managers
operating within a quality system are expected to define the quality objectives
needed to implement the quality policy. Senior management is expected to
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 system, managers would be expected to use quality planning to identify
resources and define methods to achieve the quality objectives. It is
recommended that quality plans be documented and communicated to personnel to
ensure awareness of how their operational activities are aligned with strategic
and quality goals.
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 are expected to conduct reviews of the whole quality system according
to a planned schedule. Such a review typically includes both an assessment of
the product as well as customer needs (in this section, customer is
defined as the recipient of the product and the product is the goods or
services being provided). Under a quality system, the 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 meet 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 is typically included as a standing agenda item in general
management meetings.
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 are expected to 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 ensure that they are complying with all
regulations.
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, Objectives and Plans
|
Procedures: § 211.22(c-d), 211.100(a)
|
5. System Review
|
Record review: § 211.180(e),
211.192, 211.198(b)(2)
|
Appropriate allocation of resources is key to creating a robust
quality system and to complying with the CGMP regulations. This section
discusses the role of resources in developing, implementing, and managing a
robust quality system that fully complies with the CGMP regulations.
1. General Arrangements
Under a robust quality system, there should be
sufficient allocation of resources for quality system and operational
activities. Under the model, senior management, or a designee, is 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. Develop Personnel
Under a
quality system, senior management is expected to support a problem-solving and
communicative organizational culture. Managers are expected to encourage
communication by creating an environment that values employee suggestions and
acts on suggestions for improvement. Management is also expected to develop
cross-cutting groups to share ideas to improve procedures and processes.
In the
quality system, it is recommended that personnel be qualified to do the
operations that are assigned to them in accordance with the nature of, and
potential risk to quality presented by, their operational activities. Under a
quality system, managers are expected to define appropriate qualifications for
each position to help ensure individuals are assigned appropriate
responsibilities. Personnel should also understand the impact of their
activities on the product and the customer (this quality systems parameter is
also found in the CGMP regulations, which identify specific qualifications
(i.e., education, training, and experience or any combination thereof; see §§
211.25(a) & (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 would 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 is expected to 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 supervisory managers ensure that skills
gained from training be incorporated into 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 specific
facility and equipment requirements.
According to
CGMP regulations, the QCU has the responsibility of reviewing and approving all
initial design criteria and procedures pertaining to facilities and equipment
and any subsequent changes (see § 211.22(c)). FDA can, as resources permit,
provide a preoperational review of manufacturing facilities.[11]
According to
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 generic quality system models. The CGMP regulations
place as much emphasis on process equipment as on testing equipment (§ 211.42(b)), while most quality systems focus
only on testing equipment.
When
outsourcing, a second party is hired 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 regulation training. Quality systems call for
contracts (quality agreements) that clearly describe the materials or service,
quality specifications responsibilities, and communication mechanisms.
Under a
quality system, the manufacturer ensures that the contract firm is qualified. The
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 contracting manufacturer’s officers are
familiar with the specifics requirements of the contract. However, under the
CGMP requirements, the QCU is responsible for approving or rejecting products
or services provided under contract (see § 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 Operations
|
Consultants:
§ 211.34
|
Outsourcing: §
211.22(a)
|
There is significant overlap
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.
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. Quality and manufacturing processes and procedures — and changes to
them — should be defined, approved, and controlled (CGMP also requires this;
see § 211.100). It is important to establish responsibility for designing or
changing products. Documenting associated processes will ensure that critical
variables are identified.
This documentation includes:
·
Resources and facilities needed
·
Procedures to carry out the process
·
Identification of the process owner who will maintain and update
the process as needed
·
Identification and control of
critical 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. Management, 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, risk factors, and manufacturing processes as well as
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. Therefore, the
Agency recommends that manufacturers always refer to the packaging and labeling
control regulations at 21 CFR 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.
In modern
quality systems environments, when new or reengineered processes are developed,
it is expected that they will be designed in a controlled manner. A design
plan would include authorities and responsibilities; design and development
stages; and appropriate review, verification, and validation. If different
groups are involved in design and development, the model recommends that
responsibilities of the different groups be documented to avoid omission of key
duties and ensure that the groups communicate effectively. Plans should be
updated when needed during the design process. Prior to implementation of
processes (or shipment of a product), a robust quality system will ensure that
the process and product will perform as intended. Change controls should be
maintained throughout the design process.
In modern
quality systems models, the term input refers to 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 quality systems model calls for the verification
of the components and services provided by suppliers and contractors; however,
the model offers a method for implementing verification that is different from
those in the CGMP regulations.
The CGMP regulations require either testing or use of
a certificate of analysis (COA) plus an identity analysis (see §§ 211.22 and 211.84). In the preamble to the CGMP
regulations (see comment 239 in the preamble), these requirements were
explicitly interpreted. 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 must be done to establish reliability and to
determine a schedule for periodic rechecking. As an essential element of
purchasing controls, it is recommended that data for acceptance and rejection
of materials be analyzed for information on supplier performance.
The quality systems approach also calls for the
auditing of suppliers on a periodic basis. During the audit, the 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. The FDA recommends that a combination approach be
used (i.e., verifying the suppliers' COA through analysis and audits of the
supplier). If full analytical testing is not done, the audit should cover the
supplier’s analysis. (A specific identity test is still required in §
211.84(d)(1).)
Under a quality systems approach, there should
be procedures to verify that materials are from approved 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 the materials meet their acceptance criteria.
In addition,
we recommend 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 quality control unit (see §
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 prevented.
The core purpose of implementing a quality systems
approach is to enable a manufacturer to more efficiently and effectively
perform and monitor operations. 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 (CGMP also requires this; see § 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. Areas of
process weakness should be identified, and factors that are influential on
critical quality attributes 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 section
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. In a quality system, process
validation provides initial proof, through commercial batch manufacture, 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 continuous improvement. Modern
equipment with the potential for continuous 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, the entire life-cycle should be addressed by
the establishment of continuous improvement mechanisms in the quality system. Thus, in accordance with the quality systems approach,
process validation is not a one time event, but an activity that continues.
As experience
is gained in commercial production, opportunities for process improvements may
become evident. (CGMP regulations at § 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 insights into the
product’s state of control. Change control systems should provide for 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 (see § 211.110) and quality systems models call for the
monitoring of critical process parameters during production.
·
Process steps should be verified using a validated computer
system or a second person. Batch production records should be prepared
contemporaneously with each phase of production. Although time limits can be
established when they are important to the quality of the finished product
(CGMP addresses this; see § 211.111), this does not preclude the ability to
establish production controls based on in-process parameters that can be based
on desired process endpoints measured using real time testing or monitoring
apparatus (e.g., blend until mixed vs. blend for 10 minutes).
·
Procedures should be in place to prevent objectionable
microorganisms in finished product that is not required to be sterile and to
prevent microbial contamination of finished products purported to be sterile
(CGMP also requires this; see § 211.113) Sterilization processes should be
validated (CGMP also requires this; see § 211.113(b)) for sterile drugs.
Pharmaceutical
products must meet their specifications and manufacturing processes must
consistently meet their parameters. 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). Knowledge continues to accumulate from
development through the entire commercial life of the 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 the need for change towards continuous
improvement. When implementing data collection procedures, consider the
following:
·
Are 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 V.E.1.)?
·
What records are needed?
A modern quality system approach indicates that change
control is warranted when data analysis or other information reveals an area
needing improvement. Changes to an established process should be controlled
and documented to ensure that desired attributes for the finished product will
be met (CGMP also requires this; see § 211.100(a)).
Change control with regard to pharmaceuticals is
addressed in more detail in the CGMPs. When developing a process change, it is
important to keep the process design and scientific knowledge of the product in
mind. When major design issues are encountered through process
experience, a firm may need 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, determining its effect should be based on monitoring and
evaluating those specific elements that may be affected based on understanding
of the process. This allows the steps taken to implement a change and the
effects of the change on the process to be considered systematically.
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, will help a manufacturer manage change and implement continuous
improvement in manufacturing.
Under a
quality system, 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.
Invalidation of test results should be scientifically and statistically sound
and justified.
The Agency
recommends that, upon the completion of manufacturing and to maintain quality,
the manufacturer should consider 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.).
A key component in any quality system is handling
nonconformities and/or deviations. The investigation, conclusion, and follow-up
should be documented (CGMP also requires this; see 21 CFR 211.192). To ensure
that a product conforms to requirements and expectations, it is important to
measure process and the product attributes (e.g., specified control
parameters strength) as planned. Discrepancies may be detected during any
stage of the process by an employee or during quality control activities. Not
all discrepancies will result in product defects; however, it is important to
document and handle them 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 critical to develop and document procedures to define
responsibilities for halting and resuming operations, recording the
nonconformity, investigating the discrepancy, and taking remedial action. The
corrected product or process should also be re-examined for conformance and
assessed for the significance of the nonconformity (CGMP also requires this;
see § 211.115). If the nonconformity is significant, based on consequences to
process efficiency, product quality, safety, and availability, it is important
to evaluate how to prevent recurrence.
Under a
quality system, if a product or process does not meet requirements and has not
been released for use, it is essential to identify or segregate it so that it
is not distributed to the customer by accident. Remedial action may include
correcting the nonconformity; or, with proper authorization, allowing the
product to proceed with proper authorization and the problem documented, or
using the product for another application; or rejecting the product. If an
individual product that does not meet requirements has been released, the
product can be recalled.
[19] Customer complaints
should be handled as discrepancies and be investigated (CGMP addresses this;
see § 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 Product and Processes
|
Production: § 211.100(a)
|
2. Examine Inputs
|
Materials: §§ 210.3(b), 211.80 – 211.94, 211.101, 211.122, 211.125
|
3. Perform and Monitor Operations
|
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)
|
QC checkpoints: §§ 211.22 (a),
211.84(a), 211.87, 211.110(c)
|
4. Address Nonconformities
|
Discrepancy investigation: §§ 211.22(a), 211.115, 211.192, 211.198
Recalls: 21 CFR Part 7
|
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.
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
annual review required in the CGMP regulations (§ 211.180(e)) call for review
of representative batches on an annual basis; quality systems calls for
trending on a regular basis. 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. These
trending analyses can help focus internal audits (see IV.D.2.).
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 entire system
at least annually. Quality systems recommend that procedures 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 not routinely review
or copy reports and records that result from internal audits per Compliance
Policy Guide 130.300.)
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, 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 the consequences of action
or inaction — otherwise known as risk assessment. It is important to
engage appropriate parties in assessing the consequences. Such parties include
customers, appropriate manufacturing personnel, and other stakeholders. Assessing
consequences includes using the manufacturer’s risk assessment model to address
risks, developing a strategy by deciding which options to implement, taking
actions to implement the strategy, and evaluating the results. Since risk
assessment is a reiterative process, the assessment 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 assessment is used as a tool in
the development of product specifications and critical process parameters. Used
in conjunction with process understanding, risk assessment helps manage and
control change.
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 maintain records of corrective actions taken
(CGMP also requires this; see § 211.192).
It is
essential to determine what actions are needed to prevent problem recurrence
using information from sources such as:
·
Nonconformance reports and rejections
·
Complaints
·
Internal and external audits
·
Data and risk analyses related to operations and quality system
processes
·
Management review decisions
Being
proactive is an essential tool in quality systems management. Tasks can
include succession planning, training, capturing institutional knowledge, and
planning for personnel, policy, and process changes.
A preventive
action procedure will help ensure that potential problems and root causes are
identified, possible consequences assessed, and actions considered. The
selected preventative 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 using information from reviews of
data and risk analyses associated with operational and quality system
processes, and by keeping abreast of changes in scientific and regulatory
requirements.
The
effectiveness and efficiency of the 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 (section
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 ensure that 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
|
Annual Review: § 211.180(e)
|
3. Risk Assessment
|
—
|
4. Corrective Action
|
Discrepancy investigation: § 211.22(a), 211.192
|
5. Preventive Action
|
—
|
6. Promote Improvement
|
—
|
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
to ensure consistent production of safe and effective products and 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
have 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 risk
·
Well-defined processes and
products, starting from development and extending throughout the product life
cycle
·
Systems for careful analyses 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.