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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5428_Библиотеки_им_академика_М_И_Перельмана
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Calibration of equipments either daily or before use such as balances and pH meters;
however less frequent but more intense calibration would be done by the metrology
department.
Maintaining accurate records for calibration of each instrument/equipment which is
used in GMP-related activities and these records include calibration, repair and
maintenance data.
Acquiring any instrument in consultation with metrology department. No instrument
should be purchased which is not suitable for the activities being or to be performed.
Difference between calibration and validation
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Calibration Validation
It is measurement of critical
value of equipments function
falling with in the optimum
range of its working
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 attributes
It is applicable mainly for
measuring and test equipment
It is applicable mainly for procedure, process or
method.
Principal is comparison of it’s
critical value with known
national/international standard
having fixed value.
Principal is comparison of it’s derived value with
established range.
Example of equipment
requiring calibration are Q.C
instruments, pressure,
temp./vacuum gauges,
weighing balance etc.
Example of process/procedure /method requiring
validation are batch manufacturing process. Aseptic fill
procedure, cleaning procedure, Analytical method.
Terminology and definition
Accuracy is the closeness of the agreement between the observed or measured value
and the accepted reference value.
Calibration is the comparison of a measurement system or device of unknown
accuracy to another measurement system or device with a known accuracy to detect,
correlate, report, or eliminate by adjustment any variation from the required
performance limits of the unverified measurement system or device.
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Calibration Control Program is a system that provides control of all devices that have
been accepted into calibration and/or service program as measurement standards, or
M&TE, and includes the approval, maintenance, inspection, handling, transportation,
use, calibration, service, repair and cleaning of these devices.
Calibration interval is the time gap between two consecutive calibration programs.
Calibration Standard Operating Procedure (SOP) is the written down procedure for
performing the calibration and/or service of M&TE to obtain predefined accuracy and
performance requirements.
Calibration Status is identification of all M&TE as to the type of calibration and
maintenance required, and if calibrated, the calibration validity. This validity provides
the information whether the calibration period is over or not.
Family refers to the group of similar instruments/equipment built to perform the same
type of measurement or functions exclusive of manufacturer and model. Grouping the
equipment/ instruments into a family does not indicate that they will have same range
of accuracy and capabilities.
Good Manufacturing Practices (GMP) refers to the regulations regarding
manufacturing practices initially set by the United States Food and Drug
Administration (USFDA).
Instruments are used to confirm the measurement related to product or validation by
M&TE to generate the reportable data.
Measurement Standards is a device, solution, material, or radioisotope sealed source
that is used as a reference for measurement and traceable to NIST or other recognized
sources, or derived from accepted values of natural physical constants. The
designations of measurement standards include reference, certified, and transfer
standards.
Measurement Traceability means the ability to relate individual measurement results
to NIST standards through comparison.
Measuring and Test Equipment are the devices and instruments used to test, measure,
calibrate, evaluate, inspect, or otherwise examine the materials, supplies, equipment,
and systems to determine compliance with specifications established in technical
documents.
Metrologist refers to the person who develops or evaluates the calibration systems that
measure characteristics of the objects, substances, or phenomena such as length, mass,
time, temperature, electric current, luminous intensity, and derived units of physical or
chemical measure. Metrologists identify magnitude of error sources contributing to
uncertainty of results to determine the reliability of the measurement process in
quantitative terms. They redesign or adjust measurement capability to reduce the
errors. Calibration methods and techniques are developed based on the principle of
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measurement science, technical analysis of measurement problems, and accuracy, and
precision requirements. Metrologists direct engineering, quality, and laboratory
professionals in design, manufacture, evaluation, and calibration of measurement
standards, instruments, and test system to ensure selection of approved
instrumentations.
Metrology is the reference standard laboratory that possesses and uses M&TE of
required order of accuracy, and including reference, certified and transfer standards to
provide measurement support to all applicable in-house precision equipment.
Precision is the quality or state of being precise. Used or intended for precise
measurement. Made for the least variation from a set of standards.
Scheduling System is an established document to assure that M&TE is calibrated at
planned intervals, and that cannot be properly labeled will not miss these intervals.
Service Inspection refers to the inspection of test equipment, or other calibration
equipment or system that is intended to detect malfunctions and assure reliable
operation during the calibration I service interval, and to prevent deterioration due to
age or usage. Service inspection includes:
Visual checks for damage, wear, and surface quality. Operational test for secondary
functional characteristics such as distortion, ripple, regulation, and sensitivity.
Preventive Maintenance (PM) such as cleaning, lubricating, filter replacement, and
painting.
All services rendered must be documented.
Guidelines
Calibration intervals
At intervals established with the objective of achieving and maintaining a desired level of
accuracy and quality, M&TE should be calibrated. All M&TE will be calibrated at the
manufacturer’s recommended calibration interval to assure that M&TE is operating within
its accuracy specifications. Calibration data will be recorded and then analyzed to determine
the optimum calibration interval. All instruments shall be calibrated at least annually to
assure compliance with GMPs. The movement and analysis of calibration data will be a
continuous process, and if the data shows that the accuracy of an instrument has degraded
much faster than the expected, the calibration interval must be adjusted to reflect this
change.
Interval Application
Either to single item or group of items intervals may be applied. The items are reasonably
similar with respect to family and responsibility.
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Interval Types
For each piece of equipment calibration intervals must be determined. The intervals may be
fixed or variable.
Interval Units
Calibration intervals determined for each piece of equipment should be based on calendar,
cumulative, utilization time, or any other suitable criteria.
Interval Assignments
To attain a desired probability calibration intervals will be assigned. M&TE will be within
the documented accuracy specifications at the time of recalibration. On the basis of
equipment manufacturer’s recommendation, engineering judgment, or other appropriate
source initial intervals for new equipment will be done. Calibration intervals will be
described in the individual calibration SOPs, recorded and tracked in the computerized
calibration database.
Interval Adjustments
On the basis of calibration data or other information, calibration intervals may be adjusted.
The information may support a change. Any adjustment to calibration interval should be
documented by the corporate metrology and approved by QA.
Standard Grace Period
When M&TE requires a scheduled calibration, it should have a standard grace period. Yearly
calibration should be performed every 365 days ± 10 days. The half-yearly calibration
should be done every 182 days ± 5 days, and quarterly calibration should be done every 91
days ± 5 days.
Temporary Interval Extensions
Because of critical tests, production schedule, and other reasons the calibration intervals may
be extended temporarily.
Limitation of Extension
Only one extension is allowed per calibration interval and the duration of extension must be
treated as a documented policy.
Product Acceptance
Each batch/ product must be quarantined till the calibration results come.
Extension Approval
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Before approval of temporary extension of calibration interval, written permission must be
obtained from the QA department.
Measurement Traceability
The assigned values of measurement equipment to values in terms of the NIST or equivalent
body should be directly or indirectly traceable and the calibration system should have
provision for the same.
Traceability of documents
Calibration Contractor who performs the calibration work should be identifiable.
Certification Data includes the values determined by the measurement process should be
made available whenever required.
Date of calibration and reference traceability should be made available.
Additional Traceability of documents (as necessary)
The calibration standards such as natural physical constants, derived standards, or internal
standards, if used, are not traceable to national standards and hence, require complete
documentation describing their validity.
Adequacy of Calibration Equipment
The items must be calibrated by using calibration systems having adequate accuracy,
stability, and range of verifications with specified uncertainty limits. All calibration shall be
performed with test standards having a minimum of four times accuracy of the device under
test, wherever possible and shall be traceable to NIST or equivalent standards. All the test
standards shall be arranged serially and stored in a controlled environment of the metrology
laboratory so that their stability and repeatability do not change. From the calibration
laboratory the instruments shall be removed by metrology personnel only for field
calibration, repair, etc.
Control of Contractor
When an outside contract maintenance and calibration service agency is engaged by
the metrology department for M&TE works, it remains the responsibility of both
metrology and QA departments to see that the contractor’s calibration system comply
with the requirement of the company.
The metrology department shall provide preapproval of a vendor to QA department
and subsequently the QA department shall conduct audit of the agency to assure the
compliance with the GMPs. To ensure the GMP compliance, it is required to have an
agreement with the outside agency.
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Use approved procedure outlined by the metrology department for maintaining and
calibrating the client’s M&TE.
Provide a complete system calibration and to give certified report of calibration,
supported with all necessary documents.
Allow periodic audits of the facilities and records by their client and/or the client’s
authorized representative.
Records
Records for all M&TE works included in the calibration controlling program shall be
maintained. For each instrument, a file of calibration history shall be prepared and
maintained. These records shall be maintained and kept by the metrology department.
Content
The record shall contain the following information
Name of the instrument
Identification: to each item of M&TE shall be assigned a non-repetitive identification
number.
Location: for calibration each equipment records shall be provided to locate it.
Calibration control and history: A record of information for M&TE requiring calibration
of equipment shall be maintained with respect to all information related to control, audit and
history of calibration system followed. The system shall include following information: date
of calibration and date due for recalibration, signatures of all authorized personnel, and
records of out-of-tolerance condition, location, identification of standards, and identification
of procedures used.
Logbook: The metrology department shall maintain records for all M&TE logbooks for at
least 5 years containing information about calibration, repair, maintenance, and cleaning. For
compliance with GMP, these records should be retained for additional 15 years or until the
date of expiration of the products being produced has been reached, whichever is greater.
Scheduling System
To optimize the management of equipment inventory, a computerized system shall be used
for scheduling of M&TE calibration. The computerized scheduling system will also provide
information about
Notification of pending calibration,
Procedure for extension of interval,
Identification of service equipment that has exceeded the calibration due date,
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When the new equipment would be received and entering into the calibration program
before use.
Labeling Practice
All calibrated equipments shall be labeled as, CALIBRATED, CALIBRATION NOT
REQUIRED, LIMITED CALIBRATION, etc.
Calibration Procedure
For calibration of measurement equipment, SOPs shall be prepared and followed. The
primary content of SOPs would be
Title
Purpose
Required Documentation and materials
Safety
Procedure
Acceptance criteria
Calibration Quality
The calibration control system shall be so designed that it can achieve and maintain the
calibration of high degree of quality consistently.
Levels of Calibration Quality
The quality level of the equipments can be calibrated by grouping the equipments with
similar characteristics or individually. The quality level of M&TE may be defined as
acceptable quality level, average intolerance, failure rate, etc.
Deviation from Quality Level
If the observed quality level consistently deviates from the specified (expected) range,
suitable measure is to be taken to reduce the difference between the expected and observed
values. The actions to be taken are revision of procedure, change of procedure, removal of
equipment previously used, instrument repair/ replacement, up gradation of equipment.
Environmental controls of Metrology laboratory
The environmental factors are temperature, relative humidity, air pressure differentials,
vibration, electromagnetic interference, voltage regulation of electricity, etc. To ensure
consistent calibration accuracy, acceptable ambient operating conditions are to be
established.
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Metrology Ambient Operating Condition Limit
As required by the metrology the ambient conditions of the environment such as
temperature, relative humidity, general cleanliness are to checked and recorded daily at
particular time intervals. A chart recorder or electronic records of temperature and humidity
should be kept on file at least for a period of 20years. Temperature can be recorded
continuously by using a NIST or equivalent traceable circular chart recorder. The ambient
temperature in the metrology laboratory must be 22 o C±2 o C, relative humidity would be
40% ±20% with not more than a 5% change in the reading during one hour.
Cleanliness
In calibration areas proper degree of cleanliness is to be maintained. This cleanliness is to be
consistent with Good Housekeeping Practices.
Loss of Environmental Controls
When the environmental control is lost and ambient operating conditions will exceed the
acceptance limits, all calibrations within the affected areas shall be stopped till either the
control is returned and an appropriate stabilization is achieved, or the evaluation on the
effects indicate that the calibration areas are not affected by this loss of control.
Field calibrations
Calibration activities shall be performed under normal laboratory conditions. Temperature
and humidity shall be monitored and recorded in the metrology logbooks during calibration
process.
Selection and Training of personnel
The selection and training of competent personnel is an important activity in an established
and maintained calibration controlled program. The personnel having required education,
experience, and training should perform the calibration activities.
Technical/ Academic Requirements
A Metrologist should have following technical/ academic qualification.
High school diploma or equivalent,
Diploma in Instrumentation from a recognized technical institution or equivalent,
Journeyman instrument mechanic trade certificate or equivalent experience directly
related to the trade is preferred but not essential,
Certified Engineering Technologist (CET) designation is preferred but not essential.
Education/ Training
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Personnel working in calibration of measurement instrumentation and devices should have
technical education and training in the area of working which includes calibration aspects of
GLP and GMP, documentation, calibration procedures, calibration adjustments, and use of
measurement equipment and standards.
Qualification Documentations
All certificates, diploma, and other documents related to qualification of a Metrologist
should be kept in file to be produced on request for inspection. This file would be separate
from personal file which is a confidential document file.
Calibration Control Program Maintenance
Computer shall be used to maintain the calibration control program. The database software
and developmental tools should be upgraded to ensure compatibility with system and
environment. This software can be linked with equipment Preventive Maintenance (PM),
spare parts inventory tracking and reordering, and work order generation function as these
are developed. However, the software should be validated.
Calibration Data Trending and Analysis
Commercial software can be used to develop and analyze instrumentation calibration data.
This analysis can determine the optimum calibration interval, which should be within one
year.
Automation Calibration Testing
To automate calibration routines and acquisition of calibration data, the software may either
be developed or purchased from a vendor in combination with M&TE.
ICH Guidelines for Calibration
Calibration of an instrument is the process of determining its accuracy . The process
involves obtaining a reading from the instrument and measuring its variation from the
reading obtained from a standard instrument. Calibration adjusts the precision and accuracy
of an instrument. It is also important for adjustment of process of qualification and
validation too. There are two main objectives of calibration:
Accuracy, and
Traceability
Equipment may be defined as a physical entity which is used to carry out a general or
specific activity in a plant. Equipment may be a single piece such as Tablet press, HPLC,
FTIR, Weighing balance, etc. or it may be an integrated system such as Air handling unit,
water demineralization plant, etc.
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As regards ICH guidelines for calibration of equipment, there should be local identification
by a unique identification number and this must be recorded in the master GMP
instrument/equipment list. The numbering system depends on the particular manufacturing
plant only. The procedure for each instrument must be documented and preserved in the
history file. The document must be approved by the head of the Quality Control department
of the company. The document must contain the procedure for generation, verification and
standardization of accuracy and reliability. For approval of procedure, it must mention the
steps and forms required for calibration. Stickers may be used for calibration and for other
purposes. The document must contain
The procedure for tracking of scheduled calibration activities,
Procedure for notification to the users in due dates, about calibration and out of
tolerance findings,
Review of all systems,
Calibration records,
The procedure to be followed by the QC department,
The document must include the procedure for reporting any GMP critical instrument. We
shall here cite an example of calibration procedure for an instrument such as UV-Visible
Spectrophotometer.
Ultraviolet and visible absorption spectrophotometry is the measurement of absorption of
monochromatic radiation by solutions of chemical substances, in the range of 185 nm to 380
nm, and 380 nm to 780 nm of the spectrum respectively.
The magnitude of absorption of a solution is expressed in terms of the absorption, A, defined
as the logarithm to base 10 of the reciprocal of the transmittance, T, for monochromatic
radiation. For ease in calculation, the specific absorbance of a 1%w/v solution in a 1 cm cell
is measured at a defined wavelength at 24 o – 26 o C, unless otherwise mentioned. It is
expressed as:
img
Where, c is the concentration of the absorbing substance, and l is the thickness of the
absorbing layer in cm.
Apparatus
A spectrophotometer suitable for measuring in the ultraviolet and visible ranges of spectrum
consists of an optical system capable of producing monochromatic light in the range of 200
nm to 800 nm and a devise suitable for measuring the absorbance
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. The two empty cells are
used; one for the solution under examination and other one should be the reference liquid
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