Process Validation

Process Validation: General Principles and Practices

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.

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)

• 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 devices

• 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

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 Process Validation
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.

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.

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

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 Process Validation
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 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.

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

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 Process Validation
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.

IV. RECOMMENDATIONS

In the following sections, we describe general considerations for process validation, the
recommended stages of process validation, and specific activities for each stage in the
product lifecycle.

A. General Considerations for Process Validation

In all stages of the product lifecycle, good project management and good archiving that
capture scientific knowledge will make the process validation program more effective and
efficient. The following practices should ensure uniform collection and assessment of
information about the process and enhance the accessibility of such information later in the
product lifecycle.

• We recommend an integrated team approach11 to process validation that includes

expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy,
analytical chemistry, microbiology, statistics, manufacturing, and quality assurance). Project
plans, along with the full support of senior management, are essential elements for success.

• Throughout the product lifecycle, various studies can be initiated to discover, observe,
correlate, or confirm information about the product and process. All studies should be
planned and conducted according to sound scientific principles, appropriately documented,
and approved in accordance with the established procedure appropriate for the stage of the
lifecycle.

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 Process Validation
• The terms attribute(s) (e.g., quality, product, component) and parameter(s) (e.g., process,
operating, and equipment) are not categorized with respect to criticality in this guidance.
With a lifecycle approach to process validation that employs risk based decision making
throughout that lifecycle, the perception of criticality as a continuum rather than a binary
state is more useful. All attributes and parameters should be evaluated in terms of their roles
in the process and impact on the product or in-process material, and re-evaluated as new
information becomes available. The degree of control over those attributes or parameters
should be commensurate with their risk to the process and process output. In other words, a
higher degree of control is appropriate for attributes or parameters that pose a higher risk.
The Agency recognizes that terminology usage can vary and expects that each
manufacturer will communicate the meaning and intent of its terminology and categorization
to the Agency.

• Many products are single-source or involve complicated manufacturing processes.

Homogeneity within a batch and consistency between batches are goals of process
validation activities. Validation offers assurance that a process is reasonably protected
against sources of variability that could affect production output, cause supply problems, and
negatively affect public health.

B. Stage 1 ― Process Design

Process design is the activity of defining the commercial manufacturing process that will be
reflected in planned master production and control records. The goal of this stage is to
design a process suitable for routine commercial manufacturing that can consistently deliver
a product that meets its quality attributes.

1. Building and Capturing Process Knowledge and Understanding

Generally, early process design experiments do not need to be performed under the CGMP
conditions required for drugs intended for commercial distribution that are manufactured
during Stage 2 (process qualification) and Stage 3 (continued process verification). They
should, however, be conducted in accordance with sound scientific methods and principles,
including good documentation practices. This recommendation is consistent with ICH Q10
Pharmaceutical Quality System.

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 Process Validation

Process
validation

Process Qualification

Continued Process Verification.

Process Design

Decisions and justification of the controls should be sufficiently documented and internally
reviewed to verify and preserve their value for use or adaptation later in the lifecycle of the
process and product. Although often performed at small-scale laboratories, most viral
inactivation and impurity clearance studies cannot be considered early process design
experiments. Viral and impurity clearance studies intended to evaluate and estimate product
quality at commercial scale should have a level of quality unit oversight that will ensure that

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 Process Validation
the studies follow sound scientific methods and principles and the conclusions are supported
by the data.

Product development activities provide key inputs to the process design stage, such as the
intended dosage form, the quality attributes, and a general manufacturing pathway. Process
information available from product development activities can be leveraged in the process
design stage. The functionality and limitations of commercial manufacturing equipment
should be considered in the process design, as well as predicted contributions to variability
posed by different component lots, production operators, environmental conditions, and
measurement systems in the production setting. However, the full spectrum of input
variability typical of commercial production is not generally known at this stage. Laboratory
or pilot-scale models designed to be representative of the commercial process can be used
to estimate variability.

Designing an efficient process with an effective process control approach is dependent on

the process knowledge and understanding obtained. Design of Experiment (DOE) studies
can help develop process knowledge by revealing relationships, including multivariate
interactions, between the variable inputs (e.g., component characteristics 13 or process
parameters) and the resulting outputs (e.g., in-process material, intermediates, or the final
product). Risk analysis tools can be used to screen potential variables for DOE studies to
minimize the total number of experiments conducted while maximizing knowledge gained.
The results of DOE studies can provide justification for establishing ranges of incoming
component quality, equipment

PPQ Protocol

A written protocol that specifies the manufacturing conditions, controls, testing, and expected
outcomes is essential for this stage of process validation. We recommend that the protocol
discuss the following elements:

• The manufacturing conditions, including operating parameters, processing limits, and

component (raw material) inputs.

• The data to be collected and when and how it will be evaluated.

• Tests to be performed (in-process, release, characterization) and acceptance criteria for

each significant processing step.

• The sampling plan, including sampling points, number of samples, and the frequency of
sampling for each unit operation and attribute. The number of samples should be adequate
to provide sufficient statistical confidence of quality both within a batch and between

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 Process Validation
batches. The confidence level selected can be based on risk analysis as it relates to the
particular attribute under examination. Sampling during this stage should be more extensive
than is typical during routine production.

• Criteria and process performance indicators that allow for a science- and risk-based
decision about the ability of the process to consistently produce quality products. The criteria
should include: — A description of the statistical methods to be used in analyzing all
collected data (e.g., statistical metrics defining both intra-batch and inter-batch variability). —
Provision for addressing deviations from expected conditions and handling of nonconforming
data. Data should not be excluded from further consideration in terms of PPQ without a
documented, science-based justification.17

• Design of facilities and the qualification of utilities and equipment, personnel training and
qualification, and verification of material sources (components and container/closures), if not
previously accomplished.

• Status of the validation of analytical methods used in measuring the process, in process
materials, and the product.

• Review and approval of the protocol by appropriate departments and the quality unit.

Standard vs. non-standard methods of manufacture for EU

Control strategy: A planned set of controls, derived from current product and process
understanding that ensures process performance and product quality. The controls can
include parameters and attributes related to active substance and finished product materials
and components, facility and equipment operating conditions, in-process controls, finished
product specifications, and the associated methods and frequency of monitoring and control.
(ICH Q10)

Continuous process verification: An alternative approach to process validation in which

manufacturing process performance is continuously monitored and evaluated. (ICH Q8)
Critical process parameter (CPP): A process parameter whose variability has an impact on a
critical quality attribute and therefore should be monitored or controlled to ensure the
process produces the desired quality. (ICH Q8)

Critical quality attribute (CQA): A physical, chemical, biological or microbiological property

or characteristic that should be within an appropriate limit, range, or distribution to ensure the
desired product quality. (ICH Q8)

Design space: The multidimensional combination and interaction of input variables (e.g.,
material attributes) and process parameters that have been demonstrated to provide

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 Process Validation
assurance of quality. Working within the design space is not considered as a change.
Movement out of the design space is considered to be a change and would normally initiate
a regulatory post approval change process. Design space is proposed by the applicant and
is subject to regulatory assessment and approval. (ICH Q8)

Lifecycle: All phases in the life of a product from the initial development through marketing
until the product’s discontinuation. (ICH Q8)

Pharmaceutical quality system (PQS): Management system to direct and control a

pharmaceutical company with regard to quality. (ICH Q10)

Process validation: The documented evidence that the process, operated within
established parameters, can perform effectively and reproducibly to produce a medicinal
product meeting its predetermined specifications and quality attributes.

Annex I: Process validation scheme

process validation

Where validation data on production scale batches are not provided with the application and
traditional process validation as described in section 5.1 is proposed, the process validation
scheme described below should be submitted by the applicant. This should outline the
formal process validation studies to be conducted on production scale batches (the number
of batches used would depend on the variability of the process, the complexity of the
process / product and the experience of the manufacturer, but would usually be a minimum
of 3 consecutive batches). The information from these studies will be available for
verification post authorisation by the supervisory authority. The process validation scheme
should be submitted in the marketing authorisation dossier and should include the following
information as a minimum:

• Short description of the process with a summary of the critical processing steps or critical process
parameters to be monitored during validation;

• Finished product release specification (references to the dossier);

• Details of analytical methods (references to the dossier);

• In-process controls proposed with acceptance criteria;

• Additional testing intended to be carried out (e.g. with proposed acceptance criteria and analytical
validation as appropriate);

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 Process Validation
• Sampling plan - where, when and how the samples are taken;

• Details of methods for recording and evaluation of results;

• Proposed timeframe. Following completion of the scheme, a report containing the following
information and signed by the appropriate authorised person should be generated and made
available for inspection:

• Batch analytical data;

• Certificates of analysis;

• Batch production records;

• Report on unusual findings, modifications or changes found necessary with appropriate

rationale;

Continuous process verification

In cases where continuous process verification is proposed (as described in section 5.2) a
continuous process verification scheme should be submitted by the applicant. This should
outline the monitoring to be performed on production scale batches. The information
obtained will be available for verification post authorisation by the supervisory authority. The
continuous process verification scheme should be Submitted in the marketing authorisation
dossier and should include, as appropriate, the following information on the monitoring
proposed:

Details of on-line / in-line / at-line monitoring including parameters tested, number of

samples, size of samples and frequency of monitoring

• Details of Analytical Methods (References to the dossier);

• Acceptance criteria;

• information/ data including, as appropriate, information on statistical models or tools used

to determine whether the continuous verification data supports the ability of the process and
controls to produce reproducible product at a commercial scale;

• if a design space has been developed, how the proposed monitoring will contribute to
design space verification.

Process validation justification is crucial for ensuring that the processes involved in
manufacturing or delivering a product consistently meet predetermined specifications and
quality standards. Here's a breakdown of why process validation justification is important:

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 Process Validation
1. Regulatory Compliance: Many industries, particularly pharmaceuticals, medical devices,
and food manufacturing, are highly regulated. Regulatory bodies like the FDA (Food and
Drug Administration) or EMA (European Medicines Agency) require companies to validate
their manufacturing processes to ensure product safety and efficacy. Justifying the validation
process demonstrates compliance with these regulations.
2. Quality Assurance: Validating processes helps ensure that products meet quality
standards consistently. This is vital for maintaining customer satisfaction, brand reputation,
and minimizing the risk of recalls or product defects.
3. Risk Reduction: Validating processes identifies and mitigates potential risks associated
with manufacturing. By thoroughly understanding the process and its variability, companies
can implement measures to reduce risks of product failures, deviations, or non-compliance.
4. Cost Savings: While process validation requires an upfront investment in time and
resources, it can ultimately lead to cost savings by reducing scrap, rework, and product
failures. Validated processes are more efficient and less prone to errors, resulting in lower
production costs over time.
5. Continuous Improvement: Justifying process validation encourages a culture of
continuous improvement within an organization. By analyzing data and feedback gathered
during validation activities, companies can identify areas for optimization and refinement,
leading to further improvements in product quality and process efficiency.
6. Customer Confidence: Validated processes in still confidence in customers and
stakeholders that products are consistently manufactured to meet their expectations. This is
particularly important in industries where product quality directly impacts consumer safety
and well-being.
7. Legal Protection: In the event of product liability claims or legal disputes, having well-
documented process validation can serve as evidence that due diligence was exercised in
ensuring product quality and safety.

Appendix 7

As Per WHO Non sterile process validation

continued process verification. Documented scientific evidence that the process remains
in a state of control during commercial manufacture.

critical process parameter. A process parameter whose variability has an impact on a

critical quality attribute and therefore should be monitored and/or controlled to ensure the
process produces the desired quality.

critical quality attribute. A physical, chemical, biological or microbiological property or

characteristic of materials or products that should be within an appropriate limit, range or
distribution to ensure the desired product quality. in-line. Measurement where the sample is
not removed from the process stream: can be invasive or non-invasive. life-cycle. All phases
in the life of a product from the initial development through marketing until the product’s
discontinuation.

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 Process Validation
process qualification. Process qualification combines the actual facility, utilities, equipment
(each now qualified) and the trained personnel with the commercial manufacturing process,
control procedures and components to produce commercial batches; confirms the process
design; and demonstrates that the commercial manufacturing process performs as
expected.

process validation. The collection and evaluation of data, from the process design stage
through to commercial production, which establishes scientific evidence that a process is
capable of continuously delivering the finished pharmaceutical product, meeting its
predetermined specifications and quality attributes.

quality target product profile (QTPP). A prospectively documented summary of the quality
characteristics of a finished pharmaceutical product (FPP) that ideally will be achieved to
ensure the desired quality, taking into account safety and efficacy of the FPP. The QTPP
forms the basis of design for the development of the product and typically would include.

intended use in a clinical setting, route of administration, dosage form, delivery systems;

■ dosage strength(s).

■ container-closure system;

■ Therapeutic moiety release or delivery and attributes affecting pharmacokinetic

characteristics (e.g. dissolution, aerodynamic performance) appropriate to the FPP dosage
form being developed;

■ FPP quality criteria (e.g. sterility, purity, stability and drug release) appropriate for the
intended marketed product.

The objectives of process validation include ensuring that:

■ the process design is evaluated to show that the process is reproducible, reliable and
robust;

■ the commercial manufacturing process is defined, monitored and controlled;

■ assurance is gained on a continuous basis to show that the process remains in a state of
control.

The validation should cover all manufactured strengths of a product, and the extent of
validation at each manufacturing site should be based on risk assessment. A matrix
approach or bracketing may be acceptable and should also be based on appropriate risk
assessment. There are various approaches to process validation, which include: traditional
process validation (consisting of prospective and concurrent validation); process design

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 Process Validation
followed by process qualification and continued process verification; or a combination of
traditional process validation and the new approach described in these guidelines. Historical
data should be evaluated in cases where there have been changes to the process.
Manufacturers should plan to implement the new approach to process validation, which
covers process design, process qualification and continued process verification throughout
the product life-cycle.

Validation should be done in accordance with process validation protocols. A written protocol
is essential for this stage of process validation. The protocol should include or reference at
least the following elements:

the manufacturing conditions, including operating parameters, processing limits and

component (raw material)inputs;

■ The data to be collected and when and how they will be evaluated;

■ The type of testing or monitoring to be performed (in-process, release, characterization)

and acceptance criteria for each significant processing step;

■ The scientifically justified sampling plan, including sampling points, number of samples
and the frequency of sampling for each unit operation and attribute;

■ The number of batches for which additional monitoring is proposed;

■ Status of the validation of analytical methods used in measuring the process, in-process
materials and the product;

■ A description of the statistical models or tools used;

■ Review and approval of the protocol by appropriate departments and the quality unit;

■ A description of the process;

■ Details of the equipment and/or facilities to be used (including measuring or recording

equipment) together with its calibration status;

■ The variables to be monitored, with appropriate justification;

■ The samples to be taken

■ “who”, “where”, “when”, “how”, “how many” and “how much” (sample size);

■ The product performance characteristics or attributes to be monitored, together with the

test methods.

■ The acceptable limits;

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 Process Validation
■ Personnel responsibilities;

■ details of methods for recording and evaluating results, including statistical analysis. Data

should be collected and reviewed against predetermined acceptance criteria and fully

documented in process validation reports.

6. Continued process verification

Manufacturers should monitor the product quality of commercial batches after completion of

process design and process qualification. This will provide evidence that a state of control is

maintained throughout the product life-cycle.

The scope and extent of process verification will be influenced by a number of factors,

including.

■ Prior development and knowledge of the manufacturing of similar products and/or

processes;

■ the extent of process understanding gained from development studies and commercial

manufacturing experience;

■ the complexity of the product and/or manufacturing process;

■ the level of process automation and analytical technologies used;

■ for legacy products, with reference to the product life-cycle process, robustness and

manufacturing history since the point of commercialization, as appropriate. Manufacturers

should describe the appropriateness and feasibility of the verification strategy (in the

protocol), including the process parameters and material attributes that will be monitored, as

well as the validated analytical methods that will be employed. Manufacturers should define:

■ the type of testing or monitoring to be performed;

■ the acceptance criteria to be applied;

■ how the data will be evaluated and the actions to be taken.

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 Process Validation
Any statistical models or tools used should be described. If continuous processing is

employed, the stage at which the commercial process is considered to be validated should

be stated, based on the complexity of the process, expected variability and manufacturing

experience of the company. Periods of enhanced sampling and monitoring may help to

increase process understanding as part of continuous improvement. Information on process

trends, such as the quality of incoming materials or components, in process and finished

product results and non-conformances, should be collected and assessed to verify the

validity of the original process validation or to identify changes to the control strategy

required. The scope of continued process verification should be reviewed periodically, and

modified if appropriate, throughout the product life-cycle.

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