GUIDELINE ON GENERAL PRINCIPLES
OF PROCESS VALIDATION
MAY, 1987
Prepared by: Center for Drug Evaluation and Research,
Center for Biologics Evaluation and Research, and
Center for Devices and Radiological Health
Food and Drug Administration
Maintained by: Division of Manufacturing and Product Quality (HFD-320)
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857
Reprinted February, 1993
by
The Division of Field Investigations
Office of Regional Operations
Office of Regulatory Affairs
U.S.Food and Drug Administration
Note: This printed form of the Guideline was prepared by Dr. Arthur Shaw,
Food and Drug Administration, for a Course offered by the Center for
Professional Advancement in March of 1994. There have been no changes in the
text from the original printed version of the Guideline.However the text has
been reformatted to reduce the number of pages. The Table of Contents reflects
the new pagination. The old pagination is noted in the Guideline.
TABLE OF CONTENTS
I. PURPOSE
II. SCOPE
III. INTRODUCTION
IV. GENERAL CONCEPTS
V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS
VI. GMP REGULATION FOR MEDICAL DEVICES
VII. PRELIMINARY CONSIDERATIONS
VIII. ELEMENTS OF PROCESS VALIDATION
A. Prospective Validation
1. Equipment and Process
a. Equipment : Installation Qualification
b. Process: Performance Qualification
c. Product: Performance Qualification
2. System to Assure Timely Revalidation
3. Documentation
B. Retrospective Process Validation
IX. ACCEPTABILITY OF PRODUCT TESTING
Guideline on General Principles of Process Validation
I. PURPOSE
This guideline outlines general principles that FDA considers to be
acceptable elements of process validation for the preparation of human and
animal drug products and medical devices.
II. SCOPE
This guideline is issued under Section 10.90 (21 CFR 10.90) and is applicable
to the manufacture of pharmaceuticals and medical devices. It states principles
and practices of general applicability that are not legal requirements but are
acceptable to the FDA. A person may rely upon this guideline with the assurance
of its acceptability to FDA, or may follow different procedures. When different
procedures are used, a person may, but is not required to, discuss the matter in
advance with FDA to prevent the expenditure of money and effort on activities
that may later be determined to be unacceptable. In short, this guideline lists
principles and practices which are acceptable to the FDA for the process
validation of drug products and medical devices; it does not list the principles
and practices that must, in all instances, be used to comply with law.
This guideline may be amended from time to time. Interested persons are
invited to submit comments on this document and any subsequent revisions.
Written comments should be submitted to the Dockets Management Branch (HFA-305),
Food and Drug Administration, Room 4-62, 5600 Fishers Lane, Rockville, Maryland
20857. Received comments may be seen in that office between 9 a.m. and 4 p.m.,
Monday through Friday.
III. INTRODUCTION
Process validation is a requirement of the Current Good Manufacturing
Practices Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211,
and of the Good Manufacturing Practice Regulations for Medical Devices, 21 CFR
Part 820, and therefore, is applicable to the manufacture of pharmaceuticals and
medical devices. Several firms have asked FDA for specific guidance on what FDA
expects firms to do to assure compliance with the requirements for process
validation. This guideline discusses process validation elements and concepts
that are considered by FDA as acceptable parts of a validation program.The
constituents of validation
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presented in this document are not intended to be all-inclusive. FDA
recognizes that, because of the great variety of medical products (drug products
and medical devices), processes and manufacturing facilities, it is not possible
to state in one document all of the specific validation elements that are
applicable. Several broad concepts, however, have general applicability which
manufacturers can use successfully as a guide in validating a manufacturing
process. Although the particular requirements of process validation will vary
according to such factors as the nature of the medical product (e.g., sterile vs
non-sterile) and the complexity of the process, the broad concepts stated in
this document have general applicability and provide an acceptable framework for
building a comprehensive approach to process validation.
Definitions
Installation qualification - Establishing confidence that process equipment
and ancillary systems are capable of consistently operating within established
limits and tolerances.
Process performance qualification - Establishing confidence that the process
is effective and reproducible.
Product performance qualification - Establishing confidence through
appropriate testing that the finished product produced by a specified process
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 - Establishing documented evidence which provides a high degree of
assurance that a specific process will consistently produce a product meeting
its pre-determined specifications and quality attributes.
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.
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Worst case - A set of conditions encompassing upper and lower processing
limits and circumstances, including those within standard operating procedures,
which pose the greatest chance of process or product failure when compared to
ideal conditions. Such conditions do not necessarily induce product or process
failure.
IV. GENERAL CONCEPTS
Assurance of product quality is derived from careful attention to a number of
factors including selection of quality parts and materials, adequate product and
process design, control of the process, and in-process and end-product testing.
Due to the complexity of today's medical products, routine end-product testing
alone often is not sufficient to assure product quality for several reasons.
Some end-product tests have limited sensitivity.(1) In some cases, destructive
testing would be required to show that the manufacturing process was adequate,
and in other situations end-product testing does not reveal all variations that
may occur in the product that may impact on safety and effectiveness.(2)
The basic principles of quality assurance have as their goal the production
of articles that are fit for their intended use. These principles may be stated
as follows:
(1) quality, safety, and effectiveness must be designed and built into the
product;
(2) quality cannot be inspected or tested into the finished product; and
(3) each step of the manufacturing process must be controlled to maximize the
probability that the finished product meets all quality and design
specifications.
Process validation is a key element in assuring that these quality assurance
goals are met
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It is through careful design and validation of both the process and process
controls that a manufacturer can establish a high degree of confidence that all
manufactured units from successive lots will be acceptable. Successfully
validating a process may reduce the dependence upon intensive in-process and
finished product testing. It should be noted that in most all cases, end-product
testing plays a major role in assuring that quality assurance goals are met;
i.e., validation and end-product testing are not mutually exclusive.
The FDA defines process validation as follows:
Process validation is establishing documented evidence which provides a
high degree of assurance that a specific process will consistently produce a
product meeting its pre-determined specifications and quality
characteristics.
It is important that the manufacturer prepare a written validation protocol
which specifies the procedures (and tests) to be conducted and the data to be
collected. The purpose for which data are collected must be clear, the data must
reflect facts and be collected carefully and accurately. The protocol should
specify a sufficient number of replicate process runs to demonstrate
reproducibility and provide an accurate measure of variability among successive
runs. The test conditions for these runs should encompass upper and lower
processing limits and circumstances, including those within standard operating
procedures, which pose the greatest chance of process or product failure
compared to ideal conditions; such conditions have become widely known as "worst
case" conditions. (They are sometimes called "most appropriate challenge"
conditions.) Validation documentation should include evidence of the suitability
of materials and the performance and reliability of equipment and systems.
Key process variables should be monitored and documented. Analysis of the
data collected from monitoring will establish the variability of process
parameters for individual runs and will establish whether or not the equipment
and process controls are adequate to assure that product specifications are
met.
Finished product and in-process test data can be of value in process
validation, particularly in those situations where quality attributes and
variabilities can be readily measured. Where finished (or in-process) testing
cannot adequately measure certain attributes, process validation should be
derived primarily from qualification of each system used in production and from
consideration of the interaction of the various systems.
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V. CGMP REGULATIONS FOR FINISHED PHARMACEUTICALS
Process validation is required, in both general and specific terms, by the
Current Good Manufacturing Practice Regulations for Finished Pharmaceuticals, 21
CFR Parts 210 and 211. Examples of such requirements are listed below for
informational purposes, and are not all-inclusive.
A requirement for process validation is set forth in general terms in Section
211.100 -- Written procedures; deviations -- which states, in part:
"There 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."
Several sections of the CGMP regulations state validation requirements in
more specific terms. Excerpts from some of these sections are:
Section 211.110, Sampling and testing of in-process materials and drug
products.
(a) "....control procedures shall be established to monitor the output and
VALIDATE the performance of those manufacturing processes that may be
responsible for causing variability in the characteristics of in-process
material and the drug product." (emphasis added)
Section 211.113, Control of Microbiological Contamination.
(b) "Appropriate written procedures, designed to prevent microbiological
contamination of drug products purporting to be sterile, shall be established
and followed. Such procedures shall include VALIDATION of any
sterilization process." (emphasis added)
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VI. GMP REGULATION FOR MEDICAL DEVICES
Process validation is required by the medical device GMP Regulations, 21 CFR
Part 820. Section 820.5 requires every finished device manufacturer to:
"...prepare and implement a quality assurance program that is appropriate to
the specific device manufactured..."
Section 820.3(n) defines quality assurance as:
"...all activities necessary to verify confidence in the quality of the
process used to manufacture a finished device."
When applicable to a specific process, process validation is an essential
element in establishing confidence that a process will consistently produce a
product meeting the designed quality characteristics.
A generally stated requirement for process validation is contained in section
820.100:
"Written manufacturing specifications and processing procedures shall be
established, implemented, and controlled to assure that the device conforms to
its original design or any approved changes in that design."
Validation is an essential element in the establishment and implementation of
a process procedure, as well as in determining what process controls are
required in order to assure conformance to specifications.
Section 820.100(a) (1) states:
"...control measures shall be established to assure that the design basis for
the device, components and packaging is correctly translated into approved
specifications."
Validation is an essential control for assuring that the specifications for
the device and manufacturing process are adequate to produce a device that will
conform to the approved design characteristics
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VII. PRELIMINARY CONSIDERATIONS
A manufacturer should evaluate all factors that affect product quality when
designing and undertaking a process validation study. These factors may vary
considerably among different products and manufacturing technologies and could
include, for example, component specifications, air and water handling systems,
environmental controls, equipment functions, and process control operations. No
single approach to process validation will be appropriate and complete in all
cases; however, the following quality activities should be undertaken in most
situations.
During the research and development (R& D) phase, the desired product
should be carefully defined in terms of its characteristics, such as physical,
chemical, electrical and performance characteristics.(3) It is important to
translate the product characteristics into specifications as a basis for
description and control of the product.
Documentation of changes made during development provide traceability which
can later be used to pinpoint solutions to future problems.
The product's end use should be a determining factor in the development of
product (and component) characteristics and specifications. All pertinent
aspects of the product which impact on safety and effectiveness should be
considered. These aspects include performance, reliability and stability.
Acceptable ranges or limits should be established for each characteristic to set
up allowable variations.(4) These ranges should be expressed in readily
measurable terms.
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The validity of acceptance specifications should be verified through testing
and challenge of the product on a sound scientific basis during the initial
development and production phase.
Once a specification is demonstrated as acceptable it is important that any
changes to the specification be made in accordance with documented change
control procedures.
VIII. ELEMENTS OF PROCESS VALIDATION
A. Prospective Validation
Prospective validation includes those considerations that should be made
before an entirely new product is introduced by a firm or when there is a change
in the manufacturing process which may affect the product's characteristics,
such as uniformity and identity. The following are considered as key elements of
prospective validation.
1. Equipment and Process
The equipment and process(es) should be designed and/or selected so that
product specifications are consistently achieved. This should be done with the
participation of all appropriate groups that are concerned with assuring a
quality product, e.g., engineering design, production operations, and quality
assurance personnel.
a. Equipment : Installation Qualification
Installation qualification studies establish confidence that the process
equipment and ancillary systems are capable of consistently operating within
established limits and tolerances. After process equipment is designed or
selected, it should be evaluated and tested to verify that it is capable of
operating satisfactorily within the operating limits required by the process.(5)
This phase of validation includes examination of equipment design; determination
of calibration, maintenance, and
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adjustment requirements; and identifying critical equipment features that
could affect the process and product. Information obtained from these studies
should be used to establish written procedures covering equipment calibration,
maintenance, monitoring, and control.
In assessing the suitability of a given piece of equipment, it is usually
insufficient to rely solely upon the representations of the equipment supplier,
or upon experience in producing some other product.(6) Sound theoretical and
practical engineering principles and considerations are a first step in the
assessment.
It is important that equipment qualification simulate actual production
conditions, including those which are "worst case" situations.
Tests and challenges should be repeated a sufficient number of times to
assure reliable and meaningful results. All acceptance criteria must be met
during the test or challenge. If any test or challenge shows that the equipment
does not perform within its specifications, an evaluation should be performed to
identify the cause of the failure. Corrections should be made and additional
test runs performed, as needed, to verify that the equipment performs within
specifications. The observed variability of the equipment between and within
runs can be used as a basis for determining the total number of trials selected
for the subsequent performance qualification studies of the process.(7)
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Once the equipment configuration and performance characteristics are
established and qualified, they should be documented. The installation
qualification should include a review of pertinent maintenance procedures,
repair parts lists, and calibration methods for each piece of equipment. The
objective is to assure that all repairs can be performed in such a way that will
not affect the characteristics of material processed after the repair. In
addition, special post-repair cleaning and calibration requirements should be
developed to prevent inadvertent manufacture a of non-conforming product.
Planning during the qualification phase can prevent confusion during emergency
repairs which could lead to use of the wrong replacement part.
b. Process: Performance Qualification
The purpose of performance qualification is to provide rigorous testing to
demonstrate the effectiveness and reproducibility of the process. In entering
the performance qualification phase of validation, it is understood that the
process specifications have been established and essentially proven acceptable
through laboratory or other trial methods and that the equipment has been judged
acceptable on the basis of suitable installation studies.
Each process should be defined and described with sufficient specificity so
that employees understand what is required. Parts of the process which may vary
so as to affect important product quality should be challenged.(8) In
challenging a process to assess its adequacy, it is important that challenge
conditions simulate those that will be encountered during actual production,
including "worst case" conditions. The challenges should be repeated enough
times to assure that the results are meaningful and consistent.
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Each specific manufacturing process should be appropriately qualified and
validated. There is an inherent danger in relying on what are perceived to be
similarities between products, processes, and equipment without appropriate
challenge.(9)
c. Product: Performance Qualification
For purposes of this guideline, product performance qualification activities
apply only to medical devices. These steps should be viewed as pre-production
quality assurance activities.
Before reaching the conclusion that a process has been successfully
validated, it is necessary to demonstrate that the specified process has not
adversely affected the finished product. Where possible, product performance
qualification testing should include performance testing under conditions that
simulate actual use. Product performance qualification testing should be
conducted using product manufactured from the same type of production equipment,
methods and procedures that will be used for routine production. Otherwise, the
qualified product may not be representative of production units and cannot be
used as evidence that the manufacturing process will produce a product that
meets the pre-determined specifications and quality attributes.(10)
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After actual production units have successfully passed product performance
qualification, a formal technical review should be conducted and should
include:
o Comparison of the approved product specifications and the actual qualified
product.
o Determination of the validity of test methods used to determine compliance
with the approved specifications.
o Determination of the adequacy of the specification change control
program.
2. System to Assure Timely Revalidation
There should be a quality assurance system in place which requires
revalidation whenever there are changes in packaging, formulation, equipment, or
processes which could impact on product effectiveness or product
characteristics, and whenever there are changes in product characteristics.
Furthermore, when a change is made in raw material supplier, the manufacturer
should consider subtle, potentially adverse differences in the raw material
characteristics. A determination of adverse differences in raw material
indicates a need to revalidate the process.
One way of detecting the kind of changes that should initiate revalidation is
the use of tests and methods of analysis which are capable of measuring
characteristics which may vary. Such tests and methods usually yield specific
results which go beyond the mere pass/fail basis, thereby detecting variations
within product and process specifications and allowing determination of whether
a process is slipping out of control.
The quality assurance procedures should establish the circumstances under
which revalidation is required. These may be based upon equipment, process, and
product performance observed during the initial validation challenge studies. It
is desirable to designate individuals who have the responsibility to review
product, process, equipment and personnel changes to determine if and when
evalidation is warranted.
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The extent of revalidation will depend upon the nature of the changes and how
they impact upon different aspects of production that had previously been
validated. It may not be necessary to revalidate a process from scratch merely
because a given circumstance has changed. However, it is important to carefully
assess the nature of the change to determine potential ripple effects and what
needs to be considered as part of revalidation.
3. Documentation
It is essential that the validation program is documented and that the
documentation is properly maintained. Approval and release of the process for
use in routine manufacturing should be based upon a review of all the validation
documentation, including data from the equipment qualification, process
performance qualification, and product/package testing to ensure compatibility
with the process.
For routine production, it is important to adequately record process details
(e.g., time, temperature, equipment used) and to record any changes which have
occurred. A maintenance log can be useful in performing failure investigations
concerning a specific manufacturing lot. Validation data (along with specific
test data) may also determine expected variance in product or equipment
characteristics.
B. Retrospective Process Validation
In some cases a product may have been on the market without sufficient
premarket process validation. In these cases, it may be possible to validate, in
some measure, the adequacy of the process by examination of accumulated test
data on the product and records of the manufacturing procedures used.
Retrospective validation can also be useful to augment initial premarket
prospective validation for new products or changed processes. In such cases,
preliminary prospective validation should have been sufficient to warrant
product marketing. As additional data is gathered on production lots, such data
can be used to build confidence in the adequacy of the process. Conversely, such
data may indicate a declining confidence in the process and a commensurate need
for corrective changes.
Test data may be useful only if the methods and results are adequately
specific. As with prospective validation, it may be insufficient to assess the
process solely on the basis of lot by lot conformance to specifications if test
results are merely expressed in terms of pass/fail. Specific results, on the
other hand, can be statistically analyzed and a determination can be made of
what variance in data can be expected. It is important to maintain records which
describe the operating characteristics of the process, e.g., time, temperature,
humidity, and equipment settings.(11) Whenever test data are used to demonstrate
conformance to specifications, it is important that the test methodology be
qualified to assure that test results are objective and accurate.
IX. ACCEPTABILITY OF PRODUCT TESTING
In some cases, a drug product or medical device may be manufactured
individually or on a one-time basis. The concept of prospective or retrospective
validation as it relates to those situations may have limited applicability, and
data obtained during the manufacturing and assembly process may be used in
conjunction with product testing to demonstrate that the instant run yielded a
finished product meeting all of its specifications and quality characteristics.
Such evaluation of data and product testing would be expected to be much more
extensive than the usual situation where more reliance would be placed on
prospective validation.
(1) For example, USP XXI states: "No sampling plan for applying sterility
tests to a specified proportion of discrete units selected from a sterilization
load is capable of demonstrating with complete assurance that all of the
untested units are in fact sterile."
(2) As an example, in one instance a visual inspection failed to detect a
defective structural weld which resulted in the failure of an infant warmer. The
defect could only have been detected by using destructive testing or expensive
test equipment.
(3) For example, in the case of a compressed tablet, physical characteristics
would include size, weight, hardness, and freedom from defects, such as capping
and splitting. Chemical characteristics would include quantitative
formulation/potency; performance characteristics may include bioavailability
(reflected by disintegration and dissolution). In the case of blood tubing,
physical attributes would include internal and external diameters, length and
color. Chemical characteristics would include raw material formulation.
Mechanical properties would include hardness and tensile strength; performance
characteristics would include biocompatibility and durability.
(4) For example, in order to assure that an oral, ophthalmic, or parenteral
solution has an acceptable pH, a specification may be established by which a lot
is released only if it has been shown to have a pH within a narrow established
range. For a device, a specification for the electrical resistance of a
pacemaker lead would be established so that the lead would be acceptable only if
the resistance was within a specified range.
(5) Examples of equipment performance characteristics which may be measured
include temperature and pressure of injection molding machines, uniformity of
speed for mixers, temperature, speed and pressure for packaging machines, and
temperature and pressure of sterilization chambers.
(6) The importance of assessing equipment suitability based upon how it will
be used to attain desired product attributes is illustrated in the case of
deionizers used to produce Purified Water, USP. In one case, a firm used such
water to make a topical drug product solution which, in view of its intended
use, should have been free from objectionable microorganisms. However, the
product was found to be contaminated with a pathogenic microorganism. The
apparent cause of the problem was failure to assess the performance of the
deionizer from a microbiological standpoint. It is fairly well recognized that
the deionizers are prone to build-up of microorganisms -- especially if the flow
rates are low and the deionizers are not recharged and sanitized at suitable
intervals. Therefore, these factors should have been considered. In this case,
however, the firm relied upon the representations of the equipment itself,
namely the "recharge" (i.e., conductivity) indicator, to signal the time for
regeneration and cleaning. Considering the desired product characteristics, the
firm should have determined the need for such procedures based upon pre-use
testing, taking into account such factors as the length of time the equipment
could produce deionized water of acceptable quality, flow rate, temperature, raw
water quality, frequency of use, and surface area of deionizing resins.
(7) For example, the AAMI Guideline for Industrial Ethylene Oxide
Sterilization of Medical Devices approved 2 December 1981, states: "The
performance qualification should include a minimum of 3 successful, planned
qualification runs, in which all of the acceptance criteria are
met.....(5.3.1.2.)
(8) For example, in electroplating the metal case of an implantable
pacemaker, the significant process steps to define, describe, and challenge
include establishment and control of current density and temperature values for
assuring adequate composition of electrolyte and for assuring cleanliness of the
metal to be plated. In the production of parenteral solutions by aseptic
filling, the significant aseptic filling process steps to define and challenge
should include the sterilization and depyrogenation of containers/closures,
sterilization of solutions, filling equipment and product contact surfaces, and
the filling and closing of containers.
(9) For example, in the production of a compressed tablet, a firm may switch
from one type of granulation blender to another with the erroneous assumption
that both types have similar performance characteristics, and, therefore,
granulation mixing times and procedures need not be altered. However, if the
blenders are substantially different, use of the new blender with procedures
used for the previous blender may result in a granulation with poor content
uniformity. This, in turn, may lead to tablets having significantly differing
potencies. This situation may be averted if the quality assurance system detects
the equipment change' in the first place, challenges the blender performance,
precipitates a revalidation of the process, and initiates appropriate changes.
In this example, revalidation comprises installation qualification of the new
equipment and performance qualification of the process intended for use in the
new blender.
(10) For example, a manufacturer of heart valves received complaints that the
valve-support structure was fracturing under use. Investigation by the
manufacturer revealed that all material and dimensional specifications had been
met but the production machining process created microscopic scratches on the
valve supporting wireform. These scratches caused metal fatigue and subsequent
fracture. Comprehensive fatigue testing of production units under simulated use
conditions could have detected the process deficiency.
In another example, a manufacturer recalled insulin syringes because of
complaints that the needles were clogged. Investigation revealed that the
needles were clogged by silicone oil which was employed as a lubricant during
manufacturing. Investigation further revealed that the method used to extract
the silicone oil was only partially effective. Although visual inspection of the
syringes seemed to support that the cleaning method was effective, actual use
proved otherwise.
(11) For example, sterilizer time and temperature data collected on recording
equipment found to be accurate and precise could establish that process
parameters had been reliably delivered to previously processed loads. A
retrospective qualification of the equipment could be performed to demonstrate
that the recorded data represented conditions that were uniform throughout the
chamber and that product load configurations, personnel practices, initial
temperature, and other variables had been adequately controlled during the
earlier runs.
July 1, 1996 http://www.fda.gov/cder/pv.htm
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