USFDA Guidance on

Quality Systems Approach to

Pharmaceutical CGMP Regulations

Presented by:
G. Hari Hara Rao,
Regd no: 219206,
M.Pharm I Sem,

1
 TABLE OF CONTENTS

1. Introduction
2. Background and Purpose
3
CGMPs and the concepts of modern Quality systems

4. The Quality Systems Model

5. Conclusion
6. References

2
 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
(21 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.
3
 Background and Purpose:

3.For example, the CGMP regulations stress

quality control. More recently developed quality
1.In August 2002, the FDA announced the
systems stress quality management, quality
Pharmaceutical CGMPs for the 21st Century
2.The CGMP regulations and other quality assurance, and the use of risk management
Initiative. In that announcement, the FDA
management systems differ somewhat in tools, in addition to quality control. The QS
explained the Agency’s intent to integrate
organization and in certain constituent working group decided that it would be very
quality systems and risk management
elements; however, they are very similar and useful to examine exactly how the CGMP
approaches into its existing programs with
share underlying principles. regulations and the elements of a modern,
the goal of encouraging industry to adopt
comprehensive quality system fit together
modern and innovative manufacturing
in today's manufacturing world. This
technologies
guidance is the result of that examination.

4
1.This guidance describes a comprehensive 2.A quality system addresses the public and
quality systems model, which, if private sectors’ mutual goal of providing a
implemented, will allow manufacturers to high-quality drug product to patients and
support and sustain robust, modern quality prescribers. A well-built quality system
systems that are consistent with CGMP should reduce the number of (or prevent)
regulations.
recalls, returned or salvaged products, and
defective products entering the marketplace.
Goals of
the
guidance
3.In addition, an effective quality system, by 4.A quality system can provide the
lowering the risk of manufacturing problems, necessary framework for implementing
may result in shorter and fewer FDA quality by design4 (building in quality from
inspections the development phase and throughout a
product’s life cycle), continual improvement,
and risk management in the drug
manufacturing process.
5
 Scope of the guidance:

This guidance applies to manufacturers

of drug products (finished
The document explains how
pharmaceuticals), including products It may also be useful to manufacturers of
implementing comprehensive quality
regulated by the Center for Biologics components (including active
systems can help manufacturers achieve
Evaluation and Research (CBER), the pharmaceutical ingredients) used in the
compliance with 21 CFR parts 210 and
Center for Drug Evaluation and Research manufacture of these products.
211.
(CDER), and the Center for Veterinary
Medicine (CVM).

6
Organization of the guidance:

Management
Responsibilities

Resources

Manufacturing
Operations

Evaluation Activities

7
CGMPs and the concepts of modern quality
systems:
1.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.
2.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.

3.Quality Risk Management: Quality risk management can in 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.

8
 4.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.

Root cause analysis with

corrective action to help
Preventive action to avert
Remedial corrections of an understand the cause of the
recurrence of a similar
identified problem deviation and potentially
potential problem
prevent recurrence of a
similar problem

9
5.Change Control: Change control is another well-known
CGMP concept that focuses on managing change to
prevent unintended consequences.

6.The Quality Unit: 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.

10
The Quality Unit:

1.Assessing the
2.Evaluating the
suitability of
performance of the
Quality incoming
components,
manufacturing 3.Determining the
process to ensure acceptability of
control containers,
closures, labeling,
adherence to each batch for
functions: in-process
proper
specifications and
release.
materials, and the
limits.
finished products.

11
The Quality Unit:

Review of associated
records

Review and approval

Auditing and
of all procedures
performing/evaluating
related to production
trend analyses.
and maintenance

Quality
Assurance
Functions:

12
 • Ensuring that controls are implemented
Other CGMP and completed satisfactorily during
assigned manufacturing operations.
• Ensuring that developed procedures and
responsibilities specifications are appropriate and
of the QU are followed, including those used by a firm
consistent with under contract to the manufacturer.
• Approving or rejecting incoming materials,
modern quality in-process materials, and drug products.
system • Reviewing production records and
investigating any unexplained
approaches: discrepancies

13
 Six-system Inspection Model:
The quality system
The FDA's Drug
provides the One of the important
Manufacturing
foundation for the themes of the systems
Inspection
manufacturing based inspection
Compliance Program,
systems that are Those familiar with the compliance program is
which contains
The diagram below linked and function six-system inspection that you have the
instructions to FDA
shows the relationship within it. The quality approach will see ability to assess
personnel for
among the six system model organizational whether each of the
conducting
systems: the quality described in this differences in this systems is in a state
inspections, is a
system and the five guidance does not guidance; however, of control. The quality
systems-based
manufacturing consider the five the inter-relationship system model
approach to inspection
systems. manufacturing should be readily presented in this
and is very consistent
systems as discrete apparent. guidance will also
with the robust quality
entities, but instead serve to help firms
system model
integrates them into achieve this state of
presented in this
appropriate sections control.
guidance.
of the model.
14
Six-system Inspection Model:

15
The Quality systems models:

This section describes model for

use in pharmaceutical
manufacturing that can help
manufacturers comply with the
CGMP regulations.

This section describes a robust

quality systems model that, if
properly implemented, can provide
the controls to consistently produce
a product of acceptable quality.

• Management Responsibilities
The model is described according • Resources
to four major factors: • Manufacturing Operations
• Evaluation Activities

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 • Provide Leadership.
• Structure the Organization.
Management • Build Your Quality System
to Meet Requirements
Responsibilities: • Establish Policies,
Objectives, and Plans
• Review the System.

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Provide Leadership:
• Actively participating in system design, implementation, and monitoring,
including system review
• Advocating continual improvement of operations of the quality system
• Committing necessary resources
• 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.

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 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.

Structure Of Senior managers have the

responsibility to ensure that the
The organization’s structure is
documented.
Organization:
All managers have the
responsibility to communicate
employee roles, responsibilities,
and authorities within the system
and ensure that interactions
19
are
defined and understood.
 • The scope of the quality system,
Implementing a robust For example, according to including any outsourcing.
Build Your quality system can help the model, when • The quality standard that will be
ensure compliance with documenting the followed.
System To • The manufacturer’s policies to
Meet CGMP regulations related implementation of a implement the quality systems
to drug safety, identity, quality system, the criteria and the supporting
Requirements strength, quality, and following should be objectives.
purity. addressed: • The procedures needed to
establish and maintain the
quality system

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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.
• Managers operating within a quality
system should define the quality
objectives identified for implementing the
quality policy.
• 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.

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Review The System:

Under a quality systems approach, a review should consider

at least the following:

Any changes
in business
The status of practices or
The Any follow-up Product
The results of Customer The analysis actions to environment
appropriatene actions from characteristics
audits and feedback, of data prevent a that may affect
ss of the previous meeting the
other including trending potential the quality
quality policy management customer’s
assessments complaints. results problem or a system (such
and objectives reviews needs
recurrence as the volume
or type of
operations)

22
 General
Agreements

Personnel
Development
Resources:
Facilities And
Equipment

Control
Outsourced
Operations. 23
 General Agreements:

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

For laboratory
To supply and
analysis of the
maintain the
To acquire and For processing the finished drug
appropriate facilities
receive materials that materials to produce product, including
and equipment to
are suitable for their the finished drug collection, storage,
consistently
intended purpose. product. and examination of
manufacture a
in-process, stability,
quality product. 24
and reserve samples
 Personnel Development:
Managers should encourage communication by creating an environment that values employee
suggestions and acts on suggestions for improvement.

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.

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

Under the CGMP regulations,

equipment must be qualified,
calibrated, cleaned, and
maintained to prevent
contamination and mix-ups.

26
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.
• 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.
27
 Manufacturing:

Design, Develop, and Document Product

And Process.
Examine Outputs.
Perform and Monitor Operations.
Address nonconformities.
Quality risk management.
Corrective action.
Preventive actions.
Promote improvement.
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 1. Design, Develop,
Documentation
And Document
includes:
Product And Process:
Resources and facilities used
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. Procedures to carry out the process

Identification of the process owner who will maintain and update

the process as needed

In addition, quality and manufacturing processes and procedures

— and changes to them — must be defined, approved, and Identification and control of important variables
controlled.

Quality control measures, necessary data collection, monitoring,

and appropriate controls for the product and process

Any validation activities, including operating ranges and

It is important to establish responsibility for designing or changing acceptance criteria
products. Documenting processes, associated controls, and
changes to these processes will help ensure that sources of
variability are identified.
Effects on related process, functions, or personnel
29
2.Examine Outputs:

Materials can include items

such as components (e.g.,
In a modern quality In addition, it is
ingredients, process water,
systems model, the term Systems that produce recommended that
and gas), containers, and The CGMP regulations
input includes any material these in-house materials changes to materials (e.g.,
closures. A robust quality require either testing or use
that goes into a final should be designed, specification, supplier, or
system will ensure that all of a certificate of analysis
product, no matter whether maintained, qualified, and materials handling) be
inputs to the manufacturing (COA) plus an identity
the material is purchased validated where appropriate implemented through a
process are reliable analysis for the release of
by the manufacturer or to ensure that the materials change control system
because quality controls materials for
produced by the meet their acceptance (certain changes require
will have been established manufacturing.
manufacturer for the criteria. review and approval by the
for the receipt, production,
purpose of processing. QU.
storage, and use of all
inputs.

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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 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.

31
 Both the CGMP regulations and quality systems models call for
the monitoring of critical processes that may be responsible for
causing variability during production. For example:

Under a quality system, trends

Procedures must be in should be continually identified
Process steps must be place to prevent and evaluated. One way of
verified by a second objectionable accomplishing this is the use of Process capability
person. Process steps can microorganisms in finished statistical process control. The assessment can serve as a
also be performed using a products not required to be information from trend analyses basis for determining the
can be used to continually
validated computer system. sterile and to prevent monitor quality, identify potential need for changes that can
Batch production records microbial contamination of variances before they become result in process
must be prepared finished products purported problems, bolster data already improvements and
contemporaneously with to be sterile. Sterilization collected for the annual review, efficiency
each phase of production. processes must be and facilitate improvement
validated for sterile drugs. throughout the product life
cycle.
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 4. Additional Nonconformities:
In a quality system, it
A key component in is important to develop
any quality system is and document
handling procedures that define
nonconformities and/or who is responsible for
deviations. The halting and resuming Remedial action can include any of the following:
investigation, operations, recording
conclusion, and follow- non-conformities,
up must be investigating
documented. discrepancies, and
taking remedial action.

With proper
authorization, allow
Use the product for
the product to
another application
Correct the non- proceed with
where the deficiency Reject the product
conformity justification of the
does not affect the
conclusions
product’s quality
regarding the
problem’s impact 33
 Analyze Data
For Trends.

Conduct
Internal Audits.

Quality Risk
Management.
Evaluation
Activities:
Corrective
Actions.

Preventive
Actions.

Promote
Improvement 34
 1.Analyze Data For
Trends:
Quality systems call for continually
monitoring trends and improving
systems. This can be achieved by
monitoring data and information, Quality systems procedures involve collecting
identifying and resolving problems, data from monitoring, measurement,
and anticipating and preventing complaint handling, or other activities, and
problems. tracking this data over time, as appropriate.

35
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.
• 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
• 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.

36
Quality Risk Effective decision-making in a quality systems environment is
Management: 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.

In a manufacturing quality systems environment, risk management

is used as a tool in the development of product specifications and
critical process parameters.
37
 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.

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.

38
 Corrective
Actions:
• Nonconformance reports and
It is essential to determine rejections
what actions will reduce • Returns
the likelihood of a problem • Complaints
recurring. Examples of • Internal and external audits
sources that can be used • Data and risk assessment
to gather such information related to operations and quality
system processes
include the following: • Management review decisions
39
 1.Succession planning,
training, capturing institutional
knowledge, and planning for
personnel, policy, and
process changes are
preventive actions that will
Preventive Actions: help ensure that potential
problems and root causes are
identified, possible
consequences assessed, and
appropriate actions
considered.

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

40
Promote Improvement:
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.
41
 1.The central goal of a quality system
is the consistent production of safe and
effective products and ensuring that
these activities are sustainable.

2.A robust quality system will promote

process consistency by integrating
Conclusion: effective knowledge-building
mechanisms into daily operational
decisions.

3. 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, 42
and available for the consumer.
 • Science-based approaches
• Decisions based on an understanding of the
intended use of a product
• Proper identification and control of areas of
Specifically, potential process weakness
successful • Responsive deviation and investigation systems
quality systems that lead to timely remediation
share the • Sound methods for assessing and reducing risk
following • Well-defined processes and products, starting
characteristics: from development and extending throughout the
product life cycle.
• Systems for careful analysis of product quality
• Supportive management (philosophically and
financially)

43
Useful Reference
Materials

44
 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
45
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)
46
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) .

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) 47
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)
48
49