4 PROCESS VALIDATION
INTRODUCTION
TERMS AND DEFINITIONS
WHY VALIDATE PROCESSES
WHAT PROCESSES SHOULD BE VALIDATED
TYPES OF PROCESS VALIDATION
Prospective Validation
Retrospective Validation
PROCESS VALIDATION STUDIES
Planning the Process Validation
Study
Installation and Operation Qualification
Process Performance Qualification
Product Performance Qualification
DOCUMENTATION
REVALIDATION
REFERENCES
FOOTNOTES
The Quality System (QS) regulation defines process validation
as establishing by objective evidence that a process consistently
produces a result or product meeting its predetermined specifications
[820.3(z)(1)]. The requirement for process validation appears
in section 820.75 of the Quality System (QS) regulation. The goal
of a quality system is to consistently produce products that are
fit for their intended use. Process validation is a key element
in assuring that these principles and goals are met.
The process validation requirements stated in the QS regulation
and the guidance offered here have general applicability to manufacturing
processes for medical devices. Many technologies are used in the
production of medical devices. The details of process validation
will vary according to the nature of the medical device (e.g.,
sterile or non-sterile) and the nature and complexity of the process
being validated.
Processes are developed according to the design controls in 820.30
and validated according to 820.75. The process specifications,
hereafter called parameters, are derived from the specifications
for the device, component or other entity to be produced by the
process. The parameters are documented in the device master record
per 820.30, 820.40 and 820.181. The process is developed such
that the required parameters are achieved. To ensure that the
output of the process will consistently meet the required parameters
during routine production, the process is validated.
The basic principles for validation may be stated as follows:
Terms other than those used herein may be found in the literature.
Validation: confirmation by examination and provision of
objective evidence that the particular requirement for a specific
intended use can be consistently fulfilled.
Process validation: establishing by objective evidence
that a process consistently produces a result or product meeting
its predetermined specifications.
Installation qualification: establishing documented evidence
that process equipment and ancillary systems are capable of consistently
operating within established limits and tolerances.
Process performance qualification: establishing documented
evidence that the process is effective and reproducible.
Product performance qualification: establishing documented
evidence through appropriate testing that the finished product
produced by a specified process(es) meets all release requirements
for functionality and safety.
Prospective validation: validation conducted prior to the
distribution of either a new product, or product made under a
revised manufacturing process, where the revisions may affect
the product's characteristics.
Retrospective validation: validation of a process for a
product already in distribution based upon accumulated production,
testing and control data.
Validation protocol: a written plan stating how validation
will be conducted, including test parameters, product characteristics,
production equipment, and decision points on what constitutes
acceptable test results.
There are many reasons, in addition to the regulatory requirements,
for validating processes. A manufacturer can assure through careful
design of the device and packaging, careful design and validation
of processes, and process controls, that there is a high probability
that all manufactured units will meet specifications and have
uniform quality. The dependence on intensive in-process and finished
device testing can be reduced. However, in-process and finished
product testing still play an important role in assuring that
products meet specifications. A properly validated and controlled
process will yield little scrap or rework, resulting in increased
output. Consistent conformance to specifications is likely to
result in fewer complaints and recalls. Also, when needed, the
validation files contain data to support improvements in the process
or the development of the next generation of the process.
Where process results cannot be fully verified during routine
production by inspection and test, the process must be validated
according to established procedures [820.75(a)]. When any of the
conditions listed below exist, process validation is the only
practical means for assuring that processes will consistently
produce devices that meet their predetermined specifications:
Process validation may be conducted at different points during
the life cycle of a product. The types of process validation are
defined in terms of when they occur in relation to product design,
transfer to production and release of the product for distribution.
Prospective validation is conducted before a new product is released
for distribution or, where the revisions may affect the product's
characteristics, before a product made under a revised manufacturing
process is released for distribution.
Concurrent validation is a subset of prospective validation and
is conducted with the intention of ultimately distributing product
manufactured during the validation study. Concurrent validation
is feasible when nondestructive testing is adequate to verify
that products meet predetermined specifications and quality attributes.
If concurrent validation is being conducted as the initial validation
of a new process or a process which has been modified, product
should be withheld from distribution until all data and results
of the validation study have been reviewed, and it has been determined
that the process has been adequately validated.
Concurrent validation may be conducted on a previously validated
process to confirm that the process is validated. If there have
been no changes to the process and no indications that the process
is not operating in a state of control, product could be released
for distribution before revalidation of the process is completed.
There is some risk to early release of product in that subsequent
analysis of data may show that the process is not validated.
Retrospective validation is the validation of a process based
on accumulated historical production, testing, control, and other
information for a product already in production and distribution.
This type of validation makes use of historical data and information
which may be found in batch records, production log books, lot
records, control charts, test and inspection results, customer
complaints or lack of complaints, field failure reports, service
reports, and audit reports. Historical data must contain enough
information to provide an in-depth picture of how the process
has been operating and whether the product has consistently met
its specifications. Retrospective validation may not be feasible
if all the appropriate data was not collected, or appropriate
data was not collected in a manner which allows adequate analysis.
Incomplete information mitigates against conducting a successful
retrospective validation. Some examples of incomplete information
are:
If historical data is determined to be adequate and representative,
an analysis can be conducted to determine whether the process
has been operating in a state of control and has consistently
produced product which meets its predetermined specifications
and quality attributes. The analysis must be documented.
After a validated process has been operating for some time, retrospective
validation can be successfully used to confirm continued validation
of that process if no significant changes have been made to the
process, components, or raw materials.
Statistical process control is a valuable tool for generating
the type of data needed for retrospective analysis to revalidate
a process and show that it continues to operate in a state of
control.
Careful planning of a validation study is essential to ensure
that the process is adequately validated. The plan should include
design reviews. The plan for the validation study is documented
in the validation protocol. A copy of the protocol and validation
results are placed in the Design History File (DHF) [820.30 (j)]
or quality system record file (820.186). The operational, monitoring,
and other production-related procedures are part of the device
master record (DMR) (820.181). Planning for the validation should
include the following elements as well as any other relevant issues
that must be addressed to conduct the validation study:
The validation plan should also cover the installation and operation
qualification of any equipment used in the process, process performance
qualification, and product performance qualification.
After process equipment is designed or selected, it should be
installed, reviewed, calibrated, challenged, and evaluated to
ensure that it is capable of operating within established limits
and tolerances as well as throughout all anticipated operating
ranges. Installation and operation qualification studies establish
confidence that all equipment used in the manufacturing process
meets specified requirements and is appropriately designed, constructed,
placed, and installed to facilitate maintenance, adjustment, cleaning,
and use [820.70(g)].
The installation and operation qualification phases of process
validation include:
Equipment fabricators may perform qualification runs at their
facilities and analyze the results to determine that the process
equipment is ready for delivery to the medical device manufacturer.
Device manufacturers should obtain copies of the suppliers' qualifications
studies to use as guides, to obtain basic data, and to supplement
their own qualification studies. However, it is usually insufficient
to rely solely upon the representations and studies of the equipment
supplier. The device manufacturer is ultimately responsible for
evaluating, challenging, and testing the equipment and deciding
whether the equipment is suitable for use in the manufacture of
a specific device(s). The evaluations may result in changes to
the equipment or process. Such changes must meet QS requirements
in 820.30, Design Control; 820.40, Document Controls; 820.50,
Purchasing Controls; 820.70, Process Controls; 820.72, Inspection,
Measuring, and Test Equipment; 820.75, Process Validation; 820.181,
Device Master Record.
Installation and operation qualifications should include establishing
pertinent methods, procedures, and schedules for calibration,
cleaning, and maintenance, and establishing a repair parts list
for each piece of equipment. Planning for eventual maintenance
and repairs can reduce or prevent confusion during emergency repairs
which could lead to improper repairs such as the use of the wrong
replacement part. Post-repair cleaning, calibration, and re-start
requirements should be established if necessary to prevent inadvertent
manufacture of nonconforming devices. The objective is to assure
that all repairs can be performed in a way that will not affect
the characteristics of material processed or devices manufactured
after repairs.
Process and monitoring equipment (instruments) should be calibrated
at the beginning of the validation study, and the calibration
should be checked at the end of the study to establish confidence
in the validation of the process. Equipment found out of calibration
at the end of a process validation study may indicate that the
process has not been operating in a state of control and cannot
be considered validated. More frequent calibration or more robust
equipment may be necessary, or you may wish to use stand-alone
instruments in parallel with the built-in process monitoring equipment.
It is important to document installation and operation qualification
studies. Such documentation can substitute for part of the requalification
of equipment in future process validation studies. When equipment
is moved to a new location, installation and operation should
be requalified. By comparing data from the original installation
and operation qualification and the requalification, the manufacturer
can determine whether there have been any changes in equipment
performance as a result of the move. Changes in equipment performance
should be evaluated to determine whether it is necessary to revalidate
the process.
The purpose of process performance qualification is to
rigorously test the process to determine whether it is capable
of consistently producing an output or in-process or finished
devices which meet specifications. In entering theprocess performance
qualification phase of validation, it is understood that the:
Challenges to the process should simulate conditions that will
be encountered during actual production. Challenges should include
the range of conditions allowed in written standard operating
procedures and should be repeated enough times to assure that
the results are meaningful and consistent. Challenges may need
to include forcing the preceding process to operate at its allowed
upper and lower limits.
Process and product data should be analyzed to determine what
the normal range of variation is for the process output. Knowing
what is the normal variation of the output is crucial in determining
whether a process is operating in a state of control and is capable
of consistently producing the specified output.
Process and product data should also be analyzed to identify any
variation due to controllable causes. Depending on the nature
of the process and its sensitivity, controllable causes of variation
may include:
Appropriate measures should be taken to eliminate controllable causes of variation. For example, extreme variations in temperature can be eliminated by installing heating and air conditioning. Employee training can be improved and conducted more frequently, and employees can be monitored more closely to assure that they are properly performing the process. Eliminating controllable causes of variation will reduce variation in the process output and result in a higher degree of assurance that the output will consistently meet specifications.
After routine production begins, data derived from monitoring
the process and output product can be analyzed for variation and
compared to the normal range of variation. Such analyses can detect
when the process output is shifting so that corrections can be
made before, or soon after, nonconforming product is produced.
The purpose of product performance qualification is to
demonstrate that the process has not adversely affected the finished
product and that the product meets its predetermined specifications
and quality attributes. Product performance qualification and
design validation of initial finished devices are closely related.
According to the design control requirements, design validation
shall be performed under defined operating conditions on initial
production units, lots, or batches, or their equivalents [820.30(g)].
Products used for design validation should be manufactured using
the same production equipment, methods and procedures that will
be used in routine production. Otherwise, the product used for
design validation may not be representative of production units
and cannot be used as evidence that the manufacturing process
will produce a product that meets pre-determined specifications
and quality attributes.
Design validation can be conducted using finished products made
during process validation studies and will satisfy the need for
product performance qualification. Design validation shall ensure
that devices conform to defined user needs and intended uses and
shall include testing production units under actual or simulated
use conditions [820.30(g)]. Original designs and design changes
are subject to design control requirements [820.30(i)]. The results
of design validation are subject to review under the design control
review requirements [820.30(e)].
The requirements for process validation are described in section
820.75 and include documentation requirements for the process
validation study phase as well as for routine production using
a validated process. Records of validation activities and results
must be maintained [820.75(a)]. Validation protocols and results
may be filed in the DHF [820.30(j)] or in the QS files (820.186).
Records must include the date and signature of the individual(s)
approving the validation and, where appropriate, the major equipment
validated [820.75(a)]. Procedures for monitoring and control of
process parameters must be established and maintained for validated
processes [820.75(b)]. Procedures for the operation, monitoring
and control of processes are part of the DMR (820.181).
When a validated process is used for manufacturing finished devices,
the process must be performed by a qualified individual [820.75(b)(1)].
Records must be maintained of the monitoring and control methods
and data; where appropriate, the individual(s) performing the
process; the date performed; and major equipment used. The records
should be maintained in the DHR (820.184).
As long as the process operates in a state of control and no changes
have been made to the process or output product, the process does
not have to be revalidated. Whether the process is operating in
a state of control is determined by analyzing day-to-day process
control data and any finished device testing data for conformance
with specifications and for variability.
When changes or process deviations occur, the process must be
reviewed and evaluated, and revalidation must be performed where
appropriate [820.75(c)]. Review, evaluation, and revalidation
activities must be documented.
Processes may be routinely validated on a periodic basis; however,
periodic validation may not be adequate. More important is appropriate
monitoring so that if problems develop or changes are made, the
need for immediate revalidation is considered.
1. Guideline on General Principles of Process Validation, May
1987, FDA, CDRH/CDER
2. Journal of Validation Technology, Vol. 1, No. 4, August 1995
1. For example, USP 23 states: "Absolute sterility cannot be practically demonstrated without complete destruction of every finished article." [Added note: Also, a positive test result may be caused by operator error rather than non sterility.]
2. For example, visual inspections usually are not capable of detecting defects in structural welds. Such defects may be detectable only by using destructive testing, expensive test equipment, or very slow test methods. [RETURN to text above]
Updated January 1, 1997
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