analytical calibration

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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 IPVolumetric 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 pipe

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