Guidance for Industry
Process Validation: General
Principles and Practices
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)
January 2011
Current Good Manufacturing Practices (CGMP)
Revision 1
Guidance for Industry
Process Validation: General
Principles and Practices
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http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
and/or
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Food and Drug Administration
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and/or
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Center for Veterinary Medicine
Food and Drug Administration
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Rockville, MD 20855
(Tel) 240-276-9300
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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)
January 2011
Current Good Manufacturing Practices (CGMP)
Revision 1
Contains Nonbinding Recommendations
TABLE OF CONTENTS
I. INTRODUCTION............................................................................................................. 1
II. BACKGROUND ............................................................................................................... 3
A. Process Validation and Drug Quality .......................................................................................... 3
B. Approach to Process Validation ................................................................................................... 4
III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS
VALIDATION................................................................................................................... 5
IV. RECOMMENDATIONS.................................................................................................. 7
A. General Considerations for Process Validation .......................................................................... 7
B. Stage 1 ― Process Design.............................................................................................................. 8
1. Building and Capturing Process Knowledge and Understanding................................................... 8
2. Establishing a Strategy for Process Control.................................................................................... 9
C. Stage 2 ― Process Qualification................................................................................................. 10
1. Design of a Facility and Qualification of Utilities and Equipment ............................................... 10
2. Process Performance Qualification............................................................................................... 11
3. PPQ Protocol................................................................................................................................. 12
4. PPQ Protocol Execution and Report ............................................................................................. 13
D. Stage 3 ― Continued Process Verification ................................................................................ 14
V. CONCURRENT RELEASE OF PPQ BATCHES ...................................................... 16
VI. DOCUMENTATION...................................................................................................... 17
VII. ANALYTICAL METHODOLOGY.............................................................................. 17
GLOSSARY................................................................................................................................. 18
REFERENCES............................................................................................................................ 19
i
Guidance for Industry1
Process Validation: General Principles and Practices
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 outlines the general principles and approaches that FDA considers appropriate
elements of process validation for the manufacture of human and animal drug and biological
products, including active pharmaceutical ingredients (APIs or drug substances), collectively
referred to in this guidance as drugs or products. This guidance incorporates principles and
approaches that all manufacturers can use to validate manufacturing processes.
This guidance aligns process validation activities with a product lifecycle concept and with
existing FDA guidance, including the FDA/International Conference on Harmonisation (ICH)
guidances for industry, Q8(R2) Pharmaceutical Development, Q9 Quality Risk Management, and
Q10 Pharmaceutical Quality System.2 Although this guidance does not repeat the concepts and
principles explained in those guidances, FDA encourages the use of modern pharmaceutical
development concepts, quality risk management, and quality systems at all stages of the
manufacturing process lifecycle.
1 This guidance has been prepared by the Division of Manufacturing and Product Quality, Center for Drug
Evaluation and Research (CDER), in cooperation with CDER’s Office of Pharmaceutical Sciences, the Center for
Biologics Evaluation and Research (CBER), the Office of Regulatory Affairs (ORA) and the Center for Veterinary
Medicine (CVM) at the Food and Drug Administration.
2 To make sure you have the most recent version of a guidance, check the CDER guidance page at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, the CBER guidance
page at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm, or
the CVM guidance page at
http://www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/default.htm
.
Contains Nonbinding Recommendations
The lifecycle concept links product and process development, qualification of the commercial
manufacturing process,3 and maintenance of the process in a state of control during routine
commercial production. This guidance supports process improvement and innovation through
sound science.
This guidance covers the following categories of drugs:
• Human drugs
• Veterinary drugs
• Biological and biotechnology products
• Finished products and active pharmaceutical ingredients (APIs or drug substances)4
• The drug constituent of a combination (drug and medical device) product
This guidance does not cover the following types of products:
• Type A medicated articles and medicated feed
• Medical devices5
• Dietary supplements
• Human tissues intended for transplantation regulated under section 361 of the Public Health
Service Act6
This guidance does not specify what information should be included as part of a regulatory submission.
Interested persons can refer to the appropriate guidance or contact the appropriate Center in determining
the type of information to include in a submission.
This guidance also does not specifically discuss the validation of automated process control systems
(i.e., computer hardware and software interfaces), which are commonly integrated into modern drug
manufacturing equipment. This guidance is relevant, however, to the validation of processes that
include automated equipment in processing.
3 In this guidance, the term commercial manufacturing process refers to the manufacturing process resulting in
commercial product (i.e., drug that is marketed, distributed, and sold or intended to be sold). For the purposes of
this guidance, the term commercial manufacturing process does not include clinical trial or treatment IND material.
4 Separate current good manufacturing practice (CGMP) regulations for drug components such as APIs (drug
substances) and intermediates have not published as of the date of this guidance, but these components are subject to
the statutory CGMP requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act)
(21 U.S.C. 351(a)(2)(B)). Process validation for APIs is discussed in the FDA/ICH guidance for industry, Q7 Good
Manufacturing Practice Guidance for Active Pharmaceutical Ingredients (ICH Q7), available on the Internet at
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. Section XII of ICH
Q7 describes in detail the principles for validating API processes.
5 Guidance on process validation for medical devices is provided in a separate document, Quality Management
Systems – Process Validation, edition 2, available at http://www.ghtf.org/sg3/sg3-final.html. See infra note 6.
6 See the FDA guidance for industry, Validation of Procedures for Processing of Human Tissues Intended for
Transplantation, available on the Internet at
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
2
Contains Nonbinding Recommendations
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
In the Federal Register of May 11, 1987 (52 FR 17638), FDA issued a notice announcing the
availability of a guidance entitled Guideline on General Principles of Process Validation (the
1987 guidance).7 Since then, we have obtained additional experience through our regulatory
oversight that allows us to update our recommendations to industry on this topic. This revised
guidance conveys FDA’s current thinking on process validation and is consistent with basic
principles first introduced in the 1987 guidance. The revised guidance also provides
recommendations that reflect some of the goals of FDA’s initiative entitled “Pharmaceutical
CGMPs for the 21st Century ― A Risk-Based Approach,” particularly with regard to the use of
technological advances in pharmaceutical manufacturing, as well as implementation of modern
risk management and quality system tools and concepts.8 This revised guidance replaces the
1987 guidance.
FDA has the authority and responsibility to inspect and evaluate process validation performed by
manufacturers. The CGMP regulations for validating pharmaceutical (drug) manufacturing
require that drug products be produced with a high degree of assurance of meeting all the
attributes they are intended to possess (21 CFR 211.100(a) and 211.110(a)).
A. Process Validation and Drug Quality
Effective process validation contributes significantly to assuring drug quality. The basic
principle of quality assurance is that a drug should be produced that is fit for its intended use.
This principle incorporates the understanding that the following conditions exist:
• Quality, safety, and efficacy are designed or built into the product.
• Quality cannot be adequately assured merely by in-process and finished-product
inspection or testing.
7 The 1987 guidance was prepared by a working group that included representation from the Center for Devices and
Radiological Health (CDRH). Since that time, CDRH elected to reference a process validation guidance prepared in
cooperation with the Global Harmonization Task Force (GHTF). The principles and recommendations in that
document, Quality Management Systems – Process Validation, edition 2 (available on the Internet at
http://www.ghtf.org/sg3/sg3-final.html) are also useful to consider for drug manufacturing processes.
8 See “Pharmaceutical cGMPS for the 21st Century — A Risk-Based Approach: Second Progress Report and
Implementation Plan,” available at
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/QuestionsandAnswersonCurrentGoodMan
ufacturingPracticescGMPforDrugs/ucm071836.htm.
3
Contains Nonbinding Recommendations
• Each step of a manufacturing process is controlled to assure that the finished product
meets all quality attributes including specifications.
B. Approach to Process Validation
For purposes of this guidance, process validation is defined as the collection and evaluation of
data, from the process design stage through commercial production, which establishes scientific
evidence that a process is capable of consistently delivering quality product. Process validation
involves a series of activities taking place over the lifecycle of the product and process. This
guidance describes process validation activities in three stages.
• Stage 1 – Process Design: The commercial manufacturing process is defined during this
stage based on knowledge gained through development and scale-up activities.
• Stage 2 – Process Qualification: During this stage, the process design is evaluated to
determine if the process is capable of reproducible commercial manufacturing.
• Stage 3 – Continued Process Verification: Ongoing assurance is gained during routine
production that the process remains in a state of control.
This guidance describes activities typical of each stage, but in practice, some activities might
occur in multiple stages.
Before any batch from the process is commercially distributed for use by consumers, a
manufacturer should have gained a high degree of assurance in the performance of the
manufacturing process such that it will consistently produce APIs and drug products meeting
those attributes relating to identity, strength, quality, purity, and potency. The assurance should
be obtained from objective information and data from laboratory-, pilot-, and/or commercial-
scale studies. Information and data should demonstrate that the commercial manufacturing
process is capable of consistently producing acceptable quality products within commercial
manufacturing conditions.
A successful validation program depends upon information and knowledge from product and
process development. This knowledge and understanding is the basis for establishing an
approach to control of the manufacturing process that results in products with the desired quality
attributes. Manufacturers should:
• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on the process and ultimately on product attributes
• Control the variation in a manner commensurate with the risk it represents to the process
and product
Each manufacturer should judge whether it has gained sufficient understanding to provide a high
degree of assurance in its manufacturing process to justify commercial distribution of the
4
Contains Nonbinding Recommendations
product. Focusing exclusively on qualification efforts without also understanding the
manufacturing process and associated variations may not lead to adequate assurance of quality.
After establishing and confirming the process, manufacturers must maintain the process in a state
of control over the life of the process, even as materials, equipment, production environment,
personnel, and manufacturing procedures change.9
Manufacturers should use ongoing programs to collect and analyze product and process data to
evaluate the state of control of the process. These programs may identify process or product
problems or opportunities for process improvements that can be evaluated and implemented
through some of the activities described in Stages 1 and 2.
Manufacturers of legacy products can take advantage of the knowledge gained from the original
process development and qualification work as well as manufacturing experience to continually
improve their processes. Implementation of the recommendations in this guidance for legacy
products and processes would likely begin with the activities described in Stage 3.
III. STATUTORY AND REGULATORY REQUIREMENTS FOR PROCESS
VALIDATION
Process validation for drugs (finished pharmaceuticals and components) is a legally enforceable
requirement under section 501(a)(2)(B) of the Act (21 U.S.C. 351(a)(2)(B)), which states the
following:
A drug . . . shall be deemed to be adulterated . . . if . . . the methods used in, or the
facilities or controls used for, its manufacture, processing, packing, or holding do not
conform to or are not operated or administered in conformity with current good
manufacturing practice to assure that such drug meets the requirements of this Act as to
safety and has the identity and strength, and meets the quality and purity characteristics,
which it purports or is represented to possess.
FDA regulations describing current good manufacturing practice (CGMP) for finished
pharmaceuticals are provided in 21 CFR parts 210 and 211.
The CGMP regulations require that manufacturing processes be designed and controlled to
assure that in-process materials and the finished product meet predetermined quality
requirements and do so consistently and reliably. Process validation is required, in both general
and specific terms, by the CGMP regulations in parts 210 and 211. The foundation for process
validation is provided in § 211.100(a), which states that “[t]here shall be written procedures for
production and process control designed to assure that the drug products have the identity,
strength, quality, and purity they purport or are represented to possess...” (emphasis added). This
regulation requires manufacturers to design a process, including operations and controls, which
results in a product meeting these attributes.
9 The statute and regulations described in section III of this guidance explain the requirement that the methods and
facilities used for the manufacturing of drugs be operated and administered under control sufficient to assure that the
identity, strength, purity, and quality of a drug are as they purport or are represented to possess.
5
Contains Nonbinding Recommendations
Other CGMP regulations define the various aspects of validation. For example, § 211.110(a),
Sampling and testing of in-process materials and drug products, requires that control procedures
“. . . be estab