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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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which must have the same spectral characteristics. Where double-beam-recording
instruments are used, the solvent cell is placed in the reference beam.
Control of wavelengths
The wavelength scale is verified using the absorption maxima of holmium perchlorate
solution, the line of hydrogen or deuterium discharge lamp or the lines of mercury vapor.
The permitted tolerance is ±1 nm for the range 200 nm to 400 nm and ±3 nm for 400 nm to
600 nm.
Control of absorbance
The absorbance should be checked using suitable filters or a solution of potassium
dichromate UV at wavelengths indicated below:
Wavelength A (1%, 1cm) Limits
235.0 nm 124.5 122.9 – 126.2
257.0 nm 144.0 142.8 – 145.7
313.0 nm 48.6 47.0 – 50.3
350.0 nm 106.6 105.6 – 108.2
This provides the exact values with permitted limits of the specific absorbance for each
wavelength. The tolerance for the absorbance is ± 0.01. Solutions of potassium dichromate
UV should be dried at 130 o C to constant weight and then, used.
Reference solution
For the control of absorbance at wavelengths of 235 nm, 257 nm, 313 nm, and 350 nm,
dissolve 57.0 – 63.0 mg of potassium dichromate UV in 0.005M sulphuric acid solution and
dilute to 1000 ml with the same acid. For measurement of absorbance dissolve 57.0 – 63.0
mg of potassium dichromate UV in 0.005M sulphuric acid solution and dilute to 100 ml with
the same acid.
Limit of stray light
Stray light can be detected at a given wavelength with suitable filters or solution. For
example, the absorbance of a 1.2% solution of potassium chloride at about 200 nm in a 1 cm
cell should be greater than 2.0 against water used as reference liquid. Measure the
absorbance of the above solution at 198.0, 199.0, 200.0, 201.0, 202.0 nm using water as
blank.
Resolution power
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Check the absorbance of hexane using water as a blank. Record the spectrum of a 0.02%
solution of toluene in hexane in the range of 260 nm to 420 nm. Use hexane only when its
transmittance is less than 97%.
Acceptance criteria
Absorbance should be greater than 2.0.
Wavelength accuracy: at 656.1 ±0.3 nm and at 486.0±0.3 nm
Resolution: 1.0 nm or less
Baseline Flatness: ±0.002Abs
Frequency: Once in a month
WHO Guidelines for Calibration
In pharmaceutical industries applications, performance and accuracy of instrumentation
devices are governed by Current Good Manufacturing Practices (cGMPs). Verification of
proper process instrumentation operation is an important factor for finished product in
Quality Assurance (QA) programs. In GMP processes, outside of validated parameters
weighing additions, sterilization temperatures, compounding pressures, and other factors are
most likely not recoverable and costly to the business. Mistakenly released products within
an established QA program could be detrimental to patients’ health and manufacturers’
reputation, including legal implications
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. Proper operation of process systems and
laboratory equipment in the pharmaceutical environment is critical for product quality,
manufacturing cost, and research development. Processes controlled by instrumentation
outside of defined tolerances, presumably irreversible, will lead to distraction of affected
materials and rise of production costs. Incorrect data of laboratory instrumentation and
measurements could delay development and release of new products resulting in potential
losses of the market share. The Product Master File and Batch Records contain information
concerning weighing specifications, sterilization requirements, compounding parameters,
and other details of scientifically developed process tolerances. Production recipes include
sequential order of all process activities and permitted fluctuations. Examples of windows
for validated parameters critical in determination of final pharmaceutical product quality are
maximum and minimum temperatures for sterilization, weights of each chemical addition,
mixing time, and feeding rates
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. In research and development applications precision of data
is one of the requirements which is associated with current Good Laboratory Practices
(cGLPs).
img
Fig. 3.1 Validation life cycle
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These recipes include sequential order of all process activities and permitted fluctuations.
Examples of windows for validated parameters critical in determination of final
pharmaceutical product quality are maximum and minimum temperatures for sterilization,
weights of each chemical addition, mixing time, and feeding rates
20
. In research and
development applications precision of data is one of the requirements which is associated
with current Good Laboratory Practices (cGLPs). Calibration record keeping and
maintenance of standards and instruments should be good and these are necessary for
expected reliability of experimental outcomes. Introductions of new drugs to the market
could be affected by failures of upholding metrology standards in science laboratories.
Additions of chemical components, process temperatures, pressures, flows, etc. should be
measured accurately and recorded. According to the cGMP the Standard Operating
Procedures (SOPs) for validated pharmaceutical processes are must and the SOPs should
cover maximum allowed fluctuations for specified parameters. Products made outside of
critical control defined specifications require sanctions of product “on hold” for
investigation. An almost certain outcome from investigations will result in destruction or
rework of manufactured material. Variations allowed in processes need to agree with the
equipment and instrumentation capabilities. In validated processes, the tests for qualification
and procedures for instruments will give the necessary assurance of accurate process
executions. For the system qualification and validation, verification of the instrument’s
compliance to the process requirements is an important phase. Selection processes used for
calibration procedures, calibration frequencies, and certification methods for instruments,
sensors, control loops, and systems depend on applications, accuracies, and characteristics of
instruments stability. Data of pharmaceutical manufacturing processes and laboratory testing
depend on the instrumentation accuracy. Product quality compliance requires calibration
standard certification as per the National Institute of Standards and Technology (NIST).
Calibration procedures require the formats of records to establish documentation layout and
flow designed to assure traceability of collected data. Verification of performance of
instrument measuring devices consists of two parts–
Calibration certification, and
Calibration check
The calibration certification summarizes a methodical process defined by a written and
approved procedure developed for a range of measurements.
A calibration check is a simplified confirmation of the instrument, loop, or device
performance. Usually calibration checks are represented by one or two test measurements.
A successfully executed calibration procedure confirms that manufacturing processes and
laboratory experiments are not affected by the tested instrument within the last calibration
time interval. Calibration failure in the “as found” data calls for an investigation of the
product produced within the last calibration period. In the laboratory environment, all tested
lots would be affected by an instrument calibration failure. Strict procedures are required for
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notification of calibration failures. The instruments, whose tolerances are out of standard,
should be adjusted and controlled by Standard Operating Procedures (SOPs). Each SOP
should have the instructions for adjustments as per the reference in the published literature.
For investigation, some instruments may require additional testing and cannot be adjusted or
repaired individually. The tests required for investigation may be required to determine a
magnitude of losses or for application/design/ replacement of the instrument.
An appropriate and established method of calibration, and functional tests, and
instrumentation tolerances are very important for product development, quality assurance
programs, and production. This incurs some costs.
Management of calibration program
A modern pharmaceutical facility requires various instruments installed in operations,
utilities, laboratories, and development areas. All these instruments must properly work and
their accuracies should be maintained by a Calibration Program. Functions of a Calibration
Program are very much essential for Preventive Maintenance and Quality Assurance
activities
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. For review and approval of Preventive Maintenance activities pre and post
calibration data are required. For assurance of reliability of the system, there should be
appropriate method for Pre-Calibration, Preventive Maintenance work, and PostCalibration
activities because Calibration and Preventive Maintenance cannot be done independently. In
many cases, Preventive Maintenance can disturb instrumentation and during calibration
work unfortunate discoveries may interfere with the quality investigations, production loss,
and poor business reviews. Interfacing of Calibration and Preventive Maintenance work
requires maintenance, engineering, and quality reviews. For assurance of consistent
productions, experiments and repeatability, Preventive Maintenance and Calibration works
for all systems and devices require initial and periodic evaluations. The method of reviewing
of these results should be clearly mentioned in the specific procedures. For example,
preventive maintenance work related to control valves, removal, and reinstallation of
instruments necessitate coordination with calibration activities. Bearing greasing, belts
replacements, and other mechanical work may not be related to the calibration program.
Thus, an established calibration program deals with the following activities:
Documentation records of instruments to trace and apply according to the
requirements of the industry standards of metrology.
Continuous use of approved calibration SOPs. On the basis of the results of
Preventative Maintenance and Quality Assurance, reviews and recommendations
should be done for modifications of calibration SOPs. Development of new SOPs.
Notification of calibration failures to related departments. Calibration failures are to be
investigated and assistance to be provided to the affected departments by providing the
technical expertise and improvements.
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(a)
(b)
(c)
(d)
Maintenance of calibration schedules and coordination with the production and
maintenance activities. Each of the above function represents specific responsibilities
and procedures of a comprehensive calibration program
21
.
Descriptions of internal and external configuration associated with the functions are
very important for understanding the scope of calibration work.
According to GMP, each pharmaceutical company should identify the qualification and
validation work required to prove that the critical aspects of their particular operation are
controlled.
The key elements of a qualification and validation programme of a company should be
clearly defined and documented in a validation master plan. Qualification and validation
should establish and provide documentary evidence that:
The premise should support the utilities, equipment and processes those have been
designed according to the requirements for GMP (design qualification or DQ);
The premise should support the utilities and equipment those have been built and
installed in compliance with their design specifications (installation qualification or
IQ);
The premise should support the utilities and equipment that operate according to their
design specifications (operational qualification or OQ);
The specific process will consistently produce a product meeting its predetermined
specifications and quality characteristics (process validation or PV, also called
performance qualification or PQ).
The GMP shall be conducted as per the pre-defined protocols. A written report that
summarizes the recorded result and conclusions shall be prepared, documented and
maintained. Periodic validation should be conducted to ensure that they remain capable of
achieving the intended results. Critical process should be validated, prospectively or
retrospectively. When any new master formula or method of preparation is adopted, steps
should be taken to demonstrate its suitability for routine processing. Significant changes to
the manufacture, processes, including any change in equipment or materials that may
influence product quality and/or the reproducibility of the process; hence, these shall be
validated.
Any aspect of operation, including significant alterations to the premises, facilities,
equipment or processes, may affect the quality of the product, directly or indirectly, should
be qualified and validated. Qualification and validation should not be considered as
ratification exercises. An ongoing programme should follow their first implementation and
should be based on an annual review. In the relevant documentation of the company such as
the quality manual or validation master plan, it should be written that the validation program
shall be continued and maintained. The responsibility for performing the validation should
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be clearly defined. Validation studies are essential part of GMP and should be performed
according to the predefined and approved protocols. A summarized written report on the
results obtained along with the conclusions should be prepared and stored.
Processes and procedures should be established based on the results of the validation,
performed. Particular attention should be paid to the validation of analytical test methods,
automated systems, and cleaning procedures.
Validation of Equipments
Equipments must be installed, operated, and maintained as per the design specifications.
Quality Assurance is responsible for ensuring that all equipment used to test product is
validated. Quality Assurance is responsible for ensuring that the GMP aspects of the
equipment validation programme are in accordance with relevant procedures and those
critical parameters and report conclusions are supported. Equipment places itself in-between
raw material and finished product. The equipments must be installed, operated and
maintained as per the specification designed. Therefore, installation qualification (IQ),
operational qualification (OQ), performance qualification (PQ) of equipment used in
manufacture of drugs is very important activity of validation program. A manufacturer
should work in such a way that the product being manufactured and used by the end user is
safe. This can be made successful by keeping all records related to the process and testing all
the inputs throughout including equipment and intermediate/product. Some companies are
large enough to perform each validation work by separate person or department. In some
companies same person does all the functions related to validation. Fig 3.2 shows the
functions of validation work.
Fig. 3.2 Functions of validation department
The complete works to be done for validation are listed below with an assumption that the
work is being done from scratch.
Setting up a Validation Department
Writing a validation plan
Writing the policies, SOPs (Standard Operating Procedures) and administrative
procedures
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Establishing a change control board
Establishing the document reviewers and approvers
Establishing document distribution system
Identification of equipment to be validated and preparation of master list
Assigning protocols to process, equipment, facilities, computer, and cleaning
validation
Identification of critical equipment to be validated first, then most important to less
important
Assigning equipment numbers
Assigning protocol numbers
Assigning change control numbers
Changing protocols
Performing commissioning at the original equipment manufacturer (OEM)
Writing and executing qualification protocols
Deficiencies
Deviations
Addendums
Archiving
Requalification
Internal audits
FDA audits
Everything on a piece of equipment should be validated; how much and to what extent are to
be decided. If it is moveable, it must be tested. The following methods are to be used to
obtain a list of components need to be tested.
Observe the equipment when it is being operated
Prepare the list of major components from the equipment manufacturer’s installation
and operational manual and prepare a list of spare parts.
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Fig. 3.3 Equipments used in granulation section or department
Several attempts have been made throughout the pharmaceutical industries to establish a
standard for testing the equipment challenge conditions. Before determining which test
condition to be used, it is necessary to know the normal operating conditions for that
particular equipment from the equipment operator. Then, select an appropriate challenge
condition from the following list. The purpose is to gain the confidence that the equipment is
operating under a state of control.
Minimum/maximum operating ranges: This is applicable to utilities, motor speeds,
temperature, time, air pressure, vacuum, water pressure, steam pressure, flow rates, weights,
and volumes, etc.
Minimum/maximum load evaluations: This is applicable to mixers, blenders, so on. Each
company should have standards indicating whether the limits are exceeded or not, good
results will not be achieved. Challenge testing should go outside these limits.
The most appropriate challenge condition: These should be considered meticulously; if it is
not accurately described it can be interpreted differently.
Effective ranges of critical parameters: The problem lies with the word ‘critical’. If different
people are asked about the word ‘critical’, different answers would be given.
Proven acceptable range (PAR) and range of experience: This is not applicable for a new
piece of equipment. The problem with these is that the ranges may not necessarily be the
minimum and maximum ranges.
The intended range of use: It is a frequently used condition. The limitation is that the ranges
may not necessarily be the minimum and maximum ranges.
Worst case: This is the one tested the most. It is similar to minimum/maximum load
evaluations and minimum/maximum ranges. Edge of failure: This is not applicable to
equipment because something would have to be made to fail to obtain the edge of failure;
although it could be applied to a tablet. The point at which the tablet is destroyed is just
beyond the edge of failure. Therefore, a slight back-off would be its edge of failure.
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It is necessary to decide an acceptable number of times a step of process needs to be
repeated successfully to declare that the operation is validated – 10, 100, or 1000. The
number of repetition of a step of the process during qualification should be based on
statistical significance. There is a conventional perception about validation that once is a
chance, twice is nice, and third is validation. Sometimes, validation is performed for more
than three times (three trials). Three is considered a minimum because the experimental
design may state that a higher level of confidence may be required to prove the process. The
number of times or duration of trials used in validation is also intended to represent a typical
production lot size.
Validation of Granulation Equipment (V-SHELL BLENDER)
Granulation section or department contains the following equipment:
As an example of validation: validation of a V-shell blender is described here. The blender is
driven by a motor and it operates almost at a fixed speed. With the rotation of the blender,
two inclined cylinders intermesh their flows, causes a radial blending action. In some
blenders an intensifier bar is attached to the axis of the blender. Thus, when it rotates, the
solid particles are suspended so that a spray of liquid can uniformly coat the particles. To
achieve liquid-solid blending, there are three requirements:
Liquid and solids are finely divided,
The particles are suspended in space, and
These are kept in continual motion.
The blender can be used in tablet formulation to make the powder more compressible to
produce tablets that do not break during handling.
Installation Qualification (IQ)
The IQ evaluation creates confidence that the equipment is properly installed. The
installation must meet the specified guidelines set by the manufacturer including the change
in design at installation. The supporting electrical utilities must meet all electrical codes. The
elements of a V-shell blender are shown in Fig 3.4 below.
img
Fig. 3.4 IQ elements of V-shell blender
The information required for an IQ evaluation is
Equipment identification,
Required documentation,
Equipment utility requirements,
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Major component specifications,
Component material,
Lubricants, and
Equipment safety features
Equipment identification
This document includes the equipment identification numbers as shown in the table 3.4.
Table 3.4 Information related to Equipment identification
img
Required documentation
The equipment manufacturer’s operation, maintenance manual, and the drawings as shown
in Table 3.5 and 3.6 are to be retained as records. Records pertaining to the SOPs that cover
the setup, operation, and cleaning of the blender are to be kept as document.
Table 3.5 Manufacturer’s manual and drawing
img
Table 3.6 Standard Operating Procedures
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Equipment Utility Requirements
At the time of qualification testing the manufacturer’s specified volts (V), amps (A) and
compressed air requirements are to be compared to the ’as found’ conditions and the results
are to be documented and retained. The power supply at source (volts, amps) and also the
instruments used to measure the volts, amps, and compressed air are also to be recorded as
shown in the Table 3.7 and 3.8.
Table 3.7 Utilities
img
Table 3.8 Instruments used
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Major component specification
The component specification protocol verifies that the blender components purchased were
delivered and installed. The records of major components as shown in Table 3.9 are to be
maintained.
Table 3.9 Major components
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