Within the pharmaceutical industry, measurement

is a major activity.
Measurements are taken of: time; linear
dimensions; mass or weight; temperature; volume
or capacity; velocity or speed; pressure; heat;
electrical values, such as current, voltage and
resistance; and many other things.
Consequently, there is a high level of
instrumentation used in the pharmaceutical
industries.
An instrument is defined as the device used to
measure a parameter (Temperature,
pressureetc.).
In all cases, the accuracy of the instruments is a
critical factor in ensuring that manufacturing
continues to take place in a controlled manner
and hence the validated status of all processes
is maintained.
The process of ensuring that instrumentation
maintains its accuracy is known as calibration.

The definition of calibration is as follows:
The set of operations which establish, under
specified conditions, the relationship between
values indicated by a measuring instrument or
measuring system, or values represented by a
material measure, and the corresponding known
values of a reference standard (EU Guide to
GMP).
To review the degree of error between a
reading taken from an operational instrument
and the same reading taken from a standard
instrument.
To alter the operational instrument in order to
reduce the degree of error to zero or an
acceptable level.
Calibration should be considered as one part of
the ongoing validation of a facility.
It will cover both the production departments
and the laboratories.
All companies should have a formal programme for the calibration of its
instruments. In summary, the programme has a number of stages, all of which
need to be addressed, those stages are:
All the pieces of equipment that can be defined as instruments are
identified
BQC013
A full list of these instruments is produced
For each one, the appropriate category is identified (critical, major or
reference)
For each one, tolerance and acceptance limits are determined
Written procedures are developed and authorized. These will vary
depending on the category of instrumentation.
The programme is defined in terms of schedule and frequency
Responsibilities are assigned for the various calibrations
Contracts are set up for any calibrations that
need to be outsourced.
Resources, including manpower and
equipment, are provided.
Calibration is carried out and records kept.
Calibration equipment is maintained in an
appropriate manner.
All companies prepare their documentation in a manner specific to their own
policies and procedures. However, there will be a number of generic documents
required for the calibration programme. These will include:
Master list or inventory of all instrumentation within the company; specifications
relating to the performance of each instrument.
Standard operating procedures for the calibration of each type of instrument.
A planning programme listing the individual calibrations to be carried out
(preferably as part of the formal planned preventative maintenance programme of
the company).
Records of calibrations that have been carried out internally within the company;
calibration certificates issued internally or by external bodies carrying out
calibration on behalf of the company; and training plans and records for the
calibration technicians.
All calibration records and certificates constitute GMP records and hence should be
completed, stored and archived in accordance with documentation procedures.
The purpose of this document is to catalogue all
instruments on a calibration regime and to trigger
the execution of the calibrations at predetermined
times. It should contain a:
record for each instrument requiring periodic
calibration.
Each record should include:
the last due date, the last calibration date, the
expiry date, the (next) due date, and the calibration
period.
Wherever possible, due dates should be planned to
coincide with manufacturing plant planned
shutdown dates or preventive maintenance dates.
The specification for calibration of an individual instrument is
very important and requires appropriate authorization and
control. In particular, there are a number of key factors:
The category of the instrument
critical instrument will be treated significantly differently from a
major or a reference instrument.
Accuracy and range: these should be set to meet the minimum
needs of the parameter being measured.
Calibration period: this should be arrived at to give a reasonable
balance between over frequent calibration and as-found failures.
It may include consideration of, for example: the durability and
stability of the instrument; the required accuracy; the nature of the
environment and usage; and the degree of criticality of the
measured parameter.
The calibration standard operating procedure, which states how to
calibrate an instrument. It should contain all the instructions
necessary to ensure that a competent craftsperson following the
instructions will correctly calibrate the instrument.
Each calibration SOP should have a unique identity and the
appropriate one for each instrument should be included on the
instrument calibration index.
The calibration SOP should be signed by the appropriate functions
within the company to indicate acceptance of the calibration
instructions, the category rating, the accuracy and range. These
would include the instrument specialist, a product or process
specialist and a representative of quality assurance.
Any changes to the format of the calibration SOP should be
authorized by the same signatories. The revisions should be
recorded on a revision-tracking sheet, which should list all the
material changes from the previous version and a rationale for
each.
This is a record of every calibration report
produced and should indicate the date it was
created, the due date, calibrated by whom and
passed failed results
Calibrations certificates (report) should only be issued (or adopted if
externally generated) for calibrations that meet the accuracy requirements
laid down in the appropriate specification.
Calibration certificates (report) should have a unique certificate number,
and give a clear indication of the tag number and plant number or
manufacturers serial number of the instrument.
Certificates should be traceable to a national standard, by detailing the
identity of the test equipment used; or derived from acceptable values of
natural physical constants, such as those provided for in British Standard
BS EN 300121. They should contain the date that calibration was carried
out, together with the next due date and date of expiry of the calibration.
There should also be an indication of the person who carried out the
calibration and that persons signature to indicate responsibility for the
accuracy of the information on the certificate.
Externally produced calibration certificates may not have all the above
information. To be adopted they must have the missing information
added by hand to complete the minimum requirements. This should be
added by a member of the companys internal instrument group and
signed and dated.
An instrument Calibration label is the unique
identifier that applies to each instrument
location within the manufacturing plant.
Each instrument should be labeled with such a
label carrying a summary of the calibration
history of that instrument.
The tag should carry such information as the
identification number of the instrument; the
date of the previous calibration; the due date
for the next calibration; and the signature of the
calibration technician.
The calibration should be carried out following the
instructions in the appropriate calibration SOPs and the
required responses on the worksheet completed.
First of all, the as-found condition is determined. This is
defined as the accuracy of the instrument over the required
range before any calibrating adjustment or repairs are made.
If this is outside the limits specified on the calibration
certificate, it may indicate that faulty product has been
produced since the instrument was last known to have been
correct. To address this possibility, a deviation should be
raised in accordance with procedure. It may also be
necessary to place on hold any product batches that may
consequentially have suspect quality, depending on the
nature of the instrument in question.
The instrument is then calibrated and a final as-
left condition determined. This is defined as the
accuracy of the instrument over the required range
after calibration.
If the as-left condition meets the accuracy
requirements, the calibration certificate is
completed, and a calibration sticker indicating the
calibration date affixed in a prominent position.
If the as-left condition does not meet the accuracy
requirements, the technician raises a deviation. The
deviation shall address the controls to be used to
ensure that the instrument is not used for drug
products and the actions to repair or replace it.
The technician shall therefore, in conjunction with
departmental personnel, establish if it is necessary
to put the associated manufacturing plant on
hold to prevent inadvertent usage on drug
products.
When the calibration is carried out and the Report
is completed, the master list is updated to show
the completion date and the instrument calibration
Master list is updated to the new calibration date.
All instruments covered by the calibration
programme should be calibrated prior to the
expiry date. If a critical instrument were used on
drug products when its calibration has expired, a
deviation would need to be raised, which would
address the risk to product quality of the batches
made during the time that the calibration of the
instrument has expired. If such an instrument
cannot be immediately calibrated or replaced by
one that is calibrated, the piece of manufacturing
plant to which it relates should be put on hold to
prevent inadvertent usage on drug products unless
an approved deviation allows continued use.
Recalibration may be carried out as part of
preventive maintenance procedures, in which case
a calibration SOPs and Master list would not be
needed. However, a calibration certificate should
still be generated.
External parties (individuals or organizations)
may be used for calibrating or repairing
instruments. Where they are used, they should be
monitored by internal personnel in order to ensure
that the companys procedure for the control of
external parties is being met.
Absolute standards and international standards: These
are the ultimate standards against which all reference
equipment is calibrated.
Primary standard: This is the main reference equipment
used to calibrate the rest of the instrumentation.
It is either maintained at the appropriate national testing
laboratory or kept at the company, and is used as the
reference standard against which the company secondary
standards are calibrated. It is generally four times more
accurate than the secondary standard.

Secondary standard: This is the calibration
standard maintained within the company,
which is used to carry out routine calibrations.
It is generally four times more accurate than
the measuring standard.

Measuring standard: This is the instrument
used for routine measurement and control
within the company.

The types of equipment found in a
calibration laboratory will vary with
the type of operations that the
company is carrying out and the
types of instrumentation that is
installed around the premises.
It is important that calibration equipment is
stored and handled in an appropriate manner.
As a minimum, the temperature and the
humidity of the calibration laboratory should
be controlled.

The influence of other environmental
conditions such as vibrations should also be
considered.

The frequency of calibration of individual instruments will
vary depending on circumstances, such as: the pattern of
usage; the sensitivity of the process being controlled and/or
monitored; the recommendations within the manufacturers
operation and maintenance manual; and the history of
previous calibration performance. For example, an
instrument that has been shown to maintain its previous
calibration state over a period of more than six months
would not necessarily need to be calibrated on a quarterly
basis.
However, the key point to be considered in determining
frequency of calibration is the process that is being
controlled and/or monitored and, in particular, the
importance of the level of accuracy obtained. There are three
categories of instrumentation as follows:
Critical instruments: These are instruments
whose performance will affect both the process
and the product. An example of such an
instrument would be a temperature control on
an autoclave. These instruments would
generally be calibrated at least six monthly.
Major instruments: These are instruments
whose performance will affect either the
process or the product. An example of such an
instrument would be a balance in the
dispensary. These instruments (and, in the
context of calibration, a balance may be
considered as an instrument) would generally
be calibrated at least annually.
Reference instruments: These are instruments
that are installed as reference points only and
whose performance does not affect either the
process or the product. An example of such an
instrument would be a thermometer in an
ambient condition warehouse where
temperature is monitored but not controlled.
These instruments would generally be
calibrated on installation but not afterwards.
When a new instrument is purchased, there are a number of
steps that should be taken.
Firstly, the instrument should be identified and the
instrument group informed so that they can issue a tag
number.
Secondly, it must be categorized as either critical, major or
reference. This categorization and the rationale behind it is
recorded and authorized, ensuring that the decision is
consistent with company policy.
All critical instruments should be purchased with current
calibration certificates that cover appropriate accuracy and
range, and state a specific expiry date. These certificates
must be traceable to national standards. If certificates cannot
be supplied with the instrument, there will be a need to
carry out initial calibration.
On an annual basis, it is a good idea to review the calibration
programme to ensure that it is still appropriate and effective.
There are two key elements that should be reviewed.
Firstly, the frequency of calibration of individual instruments
needs to be determined. As mentioned above, the history of
previous calibrations should be taken into account when
determining the most appropriate frequency of calibration. There
may be some instruments for which a recategorization is
appropriate.
Secondly, this would be the time to review standard operating
procedures to determine whether they need to be amended. For
example, the procedure is generally written such that the
instrument is tested across the whole of its operational range.
However, if an instrument is normally used to measure around
one focal point in the range, it may be more appropriate to
concentrate the taking of readings around this point.
It is necessary to have in place a training programme that covers
not only the people carrying out the calibration, but also the
people reviewing the data to ensure that there is full
understanding. Like any other part of the training programme,
there should be a written training plan and full records of all the
training that has already been completed.
In this way, the company is able to monitor the skills pool
available and the ongoing plans to maintain that pool.
Training should be carried out when a person commences a role
and also on a regular basis thereafter.
Refresher training on at least an annual basis is recommended in
order to check that standard operating procedures are carried out
in the correct manner and that no bad habits have been learned
over time.
When a new piece of instrumentation is purchased and installed,
it is important to ensure that all relevant personnel are trained in
the new methodology relating to calibration.