CALIBRATION MANAGEMENT BUSINESS PERSPECTIVE

WHAT IS CALIBRATION:


Calibration is the process of determining the absolute values corresponding to the graduations on an arbitrary scale on an instrument. It is a set of operations that establish relationship between values indicated by an instrument or system for measuring, recording and controlling and the corresponding known values of a reference standard. It is a demonstration that an instrument produces results within specified limits when compared to those produced by a reference standard or a standard which is traceable to a national or international standard. Because: All equipment degrades slowly over time. The electronic equipment is no exception. As they age they drift from their specifications. Rough handling of the equipment adversely affects calibration. Calibration is required also because different people handle equipment differently. Laboratory output is analytical data. This data is used in sentencing batches of drugs for patients use. Hence, the data generated in the laboratory should be reliable, precise and accurate. The Initial stage of pharmaceutical manufacturing starts with laboratory testing of input materials both, raw and packaging materials. Several in process control tests form an integral part of pharmaceutical manufacturing. The final product is sentenced based on the laboratory testing. Accuracy of testing and testing equipments if not established make the whole exercise of testing meaningless. Erroneous data results in wrong interpretations adverse to the business. In legal or other disputes testing and test equipment accuracy becomes very critical. Reporting unreliable and inconsistent data leads to: reanalysis, reworks, batch recalls, complaints, regulatory punitive actions, poor credibility, and financial loss.

WHY CALIBRATE:


CALIBRATION MANAGEMENT BUSINESS PERSPECTIVE



WHAT TO CALIBRATE:
 

 

Any instrument / equipment used for controlling, monitoring, measuring, testing, calibrating. All analytical instruments and equipments having an impact on product quality; gauges and recorders used in production; flow meters, measuring equipment and devices; tanks and storage vessels. Analytical balances. Spectrophotometers, chromatographs, pH meters, polarimeter, particle counter. Thermometers; other temperature measuring devices; temperature recorders; disintegration / dissolution apparatus; measuring equipment like Vernier Calipers; volumetric glass ware like burettes, pipettes, measuring cylinders.

WHO CALIBRATES:


Company staff skilled and trained; external engineers technicians skilled and trained; external laboratory or external calibration agency; government agencies.

CALIBRATION PROCESS:


Subject the equipment to comparison; confirm that it already meets the specifications; bring it up to specifications; make adjustments during calibration to fall within certain tolerances. Tolerances need to be small, acceptable deviations from the equipment's specified accuracy, as suggested by the manufacturer of the equipment or published literature.

CALIBRATION MANAGEMENT BUSINESS PERSPECTIVE



COST OF CALIBRATION:
  

Machines need to be calibrated regularly for proper functioning. A qualified and trained engineer or mechanic is required for calibration. Time taken to test and calibrate one unit could take hours depending on how complex or sophisticated it is. If a problem has been found the machine should not be used first until a replacement part has arrived. For minor cases a simple adjustment may suffice to make it work again

ININ-HOUSE CALIBRAITON LAB:



The cost of calibration includes setting up a fully equipped in-house calibration lab. Things need to be inensured are; Space requirements, availability of references standards with traceability to national standards, maintenance of standards, trained staff and their retention, documentation, and calibration process audits.

EXTERNAL CALIBRATION LAB OR AGENCY:

 

If not in-house calibration lab, an external reputed lab or agency has to be identified. inTheir accreditation, their infrastructure and capabilities, timely support, due diligence and or auditing, suitability of calibration certificates, and charges per calibration need to be looked into.

CALIBRATION MANAGEMENT BUSINESS PERSPECTIVE



FREQUENCY:


Derive own frequency of calibration based on full justifications duly recorded and approved. Criticality of equipment direct impact, indirect impact or no impact; and past history and present performance trend of the equipment need to be looked into. Use risk based approach. Frequency may change depending on operation and use of instrument / equipment.

BENEFITS OF CALIBRATION:


The benefits of calibration are: Reliable measurements; assured product quality and patient safely; financial benefits through reduced or no rework, reprocessing, retesting, and recalls; no regulatory observations and penal actions; reduced customer complaints; and motivated staff.

DEALING WITH CALIBRATION FAILURES



CALIBRATION: Definitions


Calibration is a comparison between measurements. One of known magnitude or correctness made or set with one device and another measurement made in a similar way with a second device. The device with the known or assigned correctness is called the standard. The second device is the unit under test (UUT) or the test instrument (TI).

ELEMENTARY REQUIREMENTS OF CALIBRATION:



Calibration must be traceable to a Standard (National / International / Regional); at a defined frequency as per schedule / programme; as per defined procedure specific directions and limits for accuracy and precision; recorded log books, tags, reports, certificates; and performed by suitably qualified and trained personnel. And finally, compendia / specification requirements.

COMMONLY FOUND INSPECTION OBSERVATIONS



Failure to maintain equipment at appropriate intervals to prevent malfunctions or contamination. Calibration stickers are illegible and damaged making ascertaining calibration status difficult. Calibration trending is not done for critical instruments, and the responsibilities of staff carrying out calibration are not well defined. There are no controls on vendor calibration procedures, original calibration data is not available for review; no robust calibration programme in place; no SOP for calibration; routine calibration, inspection, and checking equipment is not performed according to a written program record of training on calibration is not available. New working standard are standardized against old working standards; weights used for calibration of balances are stored in uncontrolled manner; change control SOP does not mention changes related calibration; calibration status label does not have all the required details; and instruments which are calibrated prior to use are not labelled Calibrate Prior To Use

CALIBRATION REGULATORY PERSPECTIVE



Calibration:


Calibration is required to ensure monitoring data and that the reports are accurate; to ensure continued process control; and for safety of drug product and process employed in producing drug substances and drug products.

Definition:


Schedule M or L1 or any other guidelines issued by drug regulatory agencies in India are yet to define calibrate. Regulatory officers during their inspections expect calibration compliance as they feel fine. (Mostly balances in stores are insisted to have to calibration status).

CALIBRATION OF GLASSWARE & ANALYTICAL EQUIPMENT USED FOR PHARMACOPOEIAL ANALYSIS



DOCUMENTATION REQUIRED:


SOPs
 

For operation For calibration The results of calibration carried out for each instrument shall be reported accurately, clearly and unambiguously in a prepre-designed calibration record format for every instrument. To achieve performance consistency of instrument proper maintenance of every instrument should be maintained per the predetermined maintenance schedule. This should be properly documented. Historical Data on Out Of Calibration should be documented for each instrument along with investigation report.

Calibration Record


Maintenance Record


CALIBRATION OF GLASSWARES
  

There are two grades of apparatus Class A and Class B. Glass apparatus may be employed in routine work after calibration. Class A is intended for use in work of the highest accuracy. The tolerance on capacity for volumetric flasks, pipettes and burettes as laid down in the relevant Indian Standards given an page A-8, table 2 in IP 1996. AVolumetric glassware is normally calibrated a 270C as per pharmacopoeial requirement, otherwise calibrate at room temperature by measuring temperature of water and applying the correction factor. Calibration of volumetric flasks: (Capacity 5, 10, 50, 100, 250, 1000ml)
 

Clean the volumetric flask with chromic acid solution. Clean the volumetric flask with distill water. Dry at 70C temperature. Do not use cloth or tissue paper for drying. 70 First weigh empty flask and then fill up with double distill water up to mark and again weigh it at required temperature. Ensure to consider lower miniscus all the time. Find the difference between the two weights, and convert it into volume and apply the correction factor.

CALIBRATION OF GLASSWARES Volumetric Glassware IP

Volumetric Flasks: IS 915: 1975 Nominal Capacity Tolerance + ml (Class A) Tolerance + ml (Class B) 5 0.02 0.04 10 0.02 0.04 25 0.03 0.06 20 0.04 0.08 100 0.06 0.15 250 0.1 0.2 500 0.15 0.3 1000 0.2 0.8

One Mark pipettes: IS 1117: 1975 Nominal Capacity Tolerance + ml (Class A) Tolerance + ml (Class B) 1 0.01 0.02 2 0.01 0.02 5 0.02 0.03 10 0.02 0.04 20 0.03 0.05 25 0.03 0.06 50 0.04 0.08 100 0.06 0.12

Graduated pipettes: IS 4162:1967 Nominal Capacity Subdivision ml Tolerance + ml Tolerance + ml (Class A) Tolerance + ml (Class B) 0.006 0.02 0.01 0.06 0.03 0.10 0.05 0.10 0.01 0.15 ------------1 0.01 2 0.2 5 0.05 10 0.10 25 0.02 -------------

Burettes: IS 1997:1967 Nominal Capacity Subdivision ml Tolerance + ml (Class A) Tolerance + ml (Class B) 1 0.05 0.01 0.02 25 0.05 0.01 0.06 50 0.1 0.05 0.1 100 0.1 0.01 0.2 ---------------------------------

CALIBRATION OF ANALYTICAL INSTRUMENTS / EQUIPMENT



Weighing on an Analytical Balance:



Weighing is a frequent step in analytical procedures and balance is an essential piece of laboratory equipment in most analyses. In spite of this, weighing is a common sourced of error that can be difficult to detect in the final analytical results. Unless balance is checked before each weighing operation is performed, errors can easily occur, resulting in faulty analytical data. Balance should be kept in suitable location with sufficiently low level of Vibration and Air current. The surrounding area should be clean and tidy. When the balance location is changed it must be allowed to adjust to the temperature, its new environment and be re-calibrated. reThe balance users should check the balance: Environment, calibration, and balance uncertainties. Do not assume that the balance has been left in the proper operating condition by the previous user. Turn on the balance and allow to equilibrate for at least 1 hour before proceeding with calibration. (Microbalances may require up to 24 hours to reach equilibrium). ReRe-calibrate balance, if the balance power has gone and resumed. Balance may not give correct weighing until it has been calibrated. Electronic analytical balance has an internal calibration system based on the applied load. Calibration applies for the current ambient temperature. Balance should be calibrated daily prior to first weighing of the day. The calibration should typically include 2-3 weights in the operating range. 2Calibration of the full operating range should be carried out every quarter. Weight box used for calibration should be certified and have traceability to National Standard Laboratory (NPL) or equivalent.

Balance Environment:
    

Balance Calibration:
      

CALIBRATION OF ANALYTICAL INSTRUMENTS / EQUIPMENT



Calibration parameters:
   

Accuracy: Check accuracy using different standard weights. Tolerance: 0.1 % of the actual weight. Linearity: Check 6 different weights. Plot a graph of actual weights against observed weights. It should be linear. Precision: Check 6 times weights of similar weight (100mg). Calculate % RSD for observed weight. Tolerance: NMT 0.5% Corner Load Test: Weigh 100mg in four corner and middle of the pan of the balance. Calculate % RSD for observed weight. Tolerance: NMT 0.5% Drift is one of the common errors. It is easiest to reduce or eliminate. Check for the following causes:
        

Balance Uncertainties:


Balance door is open. Temperature of the balance and material to be weighed are not the same. Sample is losing or gaining weight. Balance moved, but not allowed to equilibrate to its surroundings or re-calibrated. reAir currents are present in the laboratory. Temperature in the laboratory varies. Balance is not properly leveled. Laboratory operations cause vibration. Hysteresis of the mechanical part occurs during weighing. (Hysteresis I the balances caused by excessive stretching of the strings and it is primarily due to accidental dropping of object onto the pan).

Karl Fischer Titrator



Calibration parameter


Factor: Calculate the factor for 6 different weights of di-sodium tirtrate or known quantity of water in methanol. Calculate % diRSD for factor. Tolerance: NMT 1 %

CALIBRATION OF ANALYTICAL INSTRUMENTS / EQUIPMENT



Auto Titrator:


Burette Calibration:


Set burette 5ml and 20ml. Measure the volume of water by using measuring cylinder for 3 different setting of volumes. Tolerance: 0.05ml. Perform 6 sets of assay of known material. Calculate correlation coefficient between the weights taken and ml of the volumetric solution required for assay. Calculate % RSD for six different assays. Tolerance: NMT 1%.

Auto Titrator Calibration:



pH Meter:


#pH (as predetermined schedule). Adjust pH meter with Buffer pH 7.0 solution and pH4.0 solution and check with pH 10.0 solution. Tolerance of check solution is 0.05. Refractive Index: Check the refractive index of water, Carbon Tetrachloride and Toluene. (Use certified reference materials). They are 1.3325 (at 25C), 1.4603 and 1.4969 (both at 20C) respectively. (When the white light is 25 20 used, the refractometer is provided with a compensating system. The thermometer is graduated at intervals of 0.5 0.5C or less). Calibration of Wavelength:


Refractometer:


UVUV-VIS Spectrophotometer:
  

Check it with Homium filter or Holmium Perchlorate solution. Tolerance: UV Range: +/- 1nm; VIS Range: +/- 3nm. +/+/Check A (1%, 1cm) value of Potassium dichromate solution (60mcg/ml in 0.01 N Sulphuric Acid) at different wavelengths. Measure the absorbance and transmittance of 1.2% (w/v) Potassium Chloride solution at 200 nm. Abs: NLT 2.0; Trans: NMT 1.0% Check the absorbance of 0.02% v/v solution of Toluene in Hexane (UV grade) at maxima and minima at about 269 and 266nm. Ratio of 269/266 = NLT 1.5.

Calibration of Absorbance:


Stray Light:


Resolution Power:


Photometric Accuracy: Measure the absorbance of Potassium Nitrate solution of different concentrations (0.355%, 0.710% and 1.065%) at 302nm. Abs: 0.250, 0.500 and 0.751 respectively. Tolerance: upto + 0.010.

CALIBRATION OF ANALYTICAL INSTRUMENTS / EQUIPMENT



Fourier Transform Infra Red Spectrophotometer (FTIR):

 

Verification of wave numbers:



Check the wave numbers using polystyrene film of thickness 0.05 mm. Tolerance: 0.3 Wave number.

Spectral Resolution: Record the spectrum of polystyrene film. Check the depth from the maximum absorption at about 2851 cm-1 to the minimum 2870 cm-1. It should be NLT 18 absorption at about 1583 cm-1. It should be NLT 12% Transmittance.

High Performance Liquid Chromatograph (HPLC):



Flow Rate:


Set flow rate at 1 ml, 2ml and 2.5ml/min. Measure the volume of water by weight using measuring cylinder for three different settings of flow rate. Tolerance: 1% of the set flow rate. Peak Tailing Factor, Column Efficiency, and Capacity Factor. Set the column oven at 35C. Place NIST traceable temperature probe in the column oven. Measure temperature at 35 different temperature settings after stabilizing. Tolerance 2C. Set the column oven at 10C. Place NIST traceable temperature probe in the column oven. Measure temperature at 10 different temperature settings after stabilizing. Tolerance: 2C.

 

System Suitability:


Column Oven:


Sample compartment of Auto Sampler:



Polarimeter:


Angle of Optical Rotation:



Check the alignment of sodium lamp compartment. Ensure zero setting. Measure the angle of optical rotation (five times each) of 10%, 20%, 30%, 40%, and 50% solution previously dried sucrose at 25C. Tolerance of angle of rotation should be 25 0.50.

CALIBRATION OF ANALYTICAL INSTRUMENTS / EQUIPMENT



Standard angle of rotation of different solutions. Concentration 10 gm / 100ml 20 gm / 100ml 30 gm / 100ml 40 gm / 100ml 50 gm / 100ml Angle of Rotation 13.330 26.610 39.860 53.060 66.230

Oven / Vacuum Oven:



Temperature:
  

Set temperature at 60C. Measure the temperature of the oven at five different locations (4 corners and middle ) using liquid 60 paraffin bath and calibrated thermometer. Take average of these 5 values. Similarly set the temperature at 105C and measure the temperature as above. Tolerance: Difference between set and 105 observed temperatures should be 1 C. Temperature mapping should be performed annually to identify be performed annually to identify weak sopt and decide sensor position.

CALIBRATION OF ANALYTICAL INSTRUMENTS / EQUIPMENT



Dissolution Calibration:
  

Calibration of dissolution machine includes: Level test, Centering test, Wobble test, Paddle / Basket depth, Dissolution vessel test, Temperature control test, Rotation speed accuracy test, and Dissolution suitability test. Level test:


Check level of plate holding dissolution vessel using sprit level. Put 900ml water. Lower the shaft in dissolution vessel. Centering should be within +/- mm of vessel center axis. Check using +/centering gauge. No more than 1 mm from center axis. Use height gauge. It should be exactly 25mm (+/-mm) from bottom of vessel. (+/Inside surface should free of abnormalities. The lowest point in the vessel must be in line with vertical axis of the shaft. Set the temperature of water bath at 37C. Start heater. Allow water bath to attain the set temperature. Measure the 37 temperature using calibrated thermometer. Set the rotation speed to 50 rpm, 75rpm, 100rpm. It should be within +/- 4 % +/Prednisone is a disintegrating tablet and it is highly affected by mechanical parameters and vessels. These tablets are sensitive sensitive to centering, vibrations, shaft wobbling, shaft verticality and degassing. Salicylic acid is non-disintegrating tablet. It is affected by poorly de-aerated media, warped or dirty baskets and unclean or nondescratched vessel. These tablets are not sensitive to mechanical parameters.

Centering test:


   

Wobble test:


Paddle / Basket Depth:



Dissolution vessel test:



Temperature control test:



 

Rotation speed accuracy test:



Dissolution suitability test:

 

CALIBRATION OF ANALYTICAL INSTRUMENTS / EQUIPMENT



Sources of errors in Dissolution Calibration:



DeDe-aerated media.


Dissolved air can slow down dissolution by creating barrier either by adhering to the tablet surface or basket screen or particles can clig to bubbles on the glass surface of vessel or shaft. Reference standard used must be dried properly. Solution must be prepared on the day of use. For dissolving the standard small of alcohol can be used. Vibration can arise from bearing can get worn and cause vibration and wobble. Drive belt should be checked for wear and dirt. Vessels need to be locked in the place so they are not moving with the flow of water in bath. External sources might include bench top, sonicators, shakers, centrifuges. Tester should not be near hood. Heavy foot traffic and door slamming should be avoided. Basket and Paddle shaft must be straight and true. If paddles are partially coated with teflon, the layer can get peeled off causing flow disturbances. The baskets screen size may change over time due to usage of acidic medium. The attachments may be clip type or with O rings can contribute to variation. Vessels have problems of irregular inner surface which can affect significantly. Vessel may develop residue buildup either from oily products or sticky excipients. On prolong use vessel might develop scratches on inner surface which can affect dissolution. If surfactants are used in concentration more than 0.5% while preparing dissolution medium then more rinsing to vessel are required as it is difficult to remove residue easily. Melting Point:


Use properly dried standard:



Vibration interference:


Instrument:
  

Melting Point Apparatus:



Check the melting points of Vanilin, Acetanilide, Sulphanilamide and Caffeine using calibrated thermometer capable of determining determining temperature to level of 0.5C. They are between 81 83C, 115-116C, 164-166C and 234-237C respectively. 0.5 83 115-116 164-166 234-237

CALIBRATION OF ANALYTICAL INSTRUMENTS / EQUIPMENT



Thermometers:(IS4825:1968 and IS 6274:1971)

 

D.T. Machine Cycles per minute:



Check the number of cycles per minute three times. It should be 30 cycle/min. tolerance: 2 cycles/min Set the temperature 25C and 37C. Start the instrument. Measure the temperature of water in beaker at different time 25 37 intervals such as 15, 30, 45 and 60 minutes using calibrated thermometer. Tolerance: 2C of set temperature. Check the distance traveled during oscillation three times. Take average value. It should be 55mm. Tolerance: 5mm. Check the time for set 15, 30 and 45 minutes using calibrated clock. It should match with the time of calibrated clock. Instrument Identification for according to EN45001:
               

Thermostat Temperature:


  

Distance traveled during oscillation:



Time Display:


Historical Background:


Protocol No. Lab/Dept. Name Producer Name Catalog Name New/Old/Refurbished Arrival Date Place in the lab Calibration / Validate Company Name Instrument Name Distributor Name Serial Name Purchasing Date Installing Date Servicing Details Calibration / Validation Frequency

CALIBRATION OF ANALYTICAL INSTRUMENTS / EQUIPMENT



Traceability of Standards:


The Quality Standard regulation requires that standards used to calibrate equipment be traceable to the National Institute of Standards and Technology (NIST), or other recognized national or international standards. Traceability also can achieved through a contract calibration laboratory which in turn used NIST services. The accuracy of a measurement can only be assured if the measuring device is known to accurate both before and after the measurement is mode. Calibrated prior to use; formal testing of accuracy and precision; traceable reference standards; approved calibration methods; tolerances and full results documented rage conditions investigated; qualification of calibration laboratory; status label (identification, recalibration date); reports certified; records consolidated and archived. Internal weekly or as used checks; upscale and downscale, running logs reviewed by management; tolerances and results on the record; traceable reference standards; out of range conditions investigated; statement of adjustment or repair.

Instrument Calibration Programs:



External Calibration:


Internal Calibration Performance Checks:



MANUFACTURERS ARE RESPONSIBLE FOR ENSURING THE ESTABLISHMENT OF ROUTINE CALIBRATION ON THEIR TEST EQUIPMENT (VOLUMETRIC & MEASURING INSTRUMENT). SO IT WILL BE SUITABLE FOR ITS INTENDED USE.