Quality Control

Certification of Analyst, Purpose :

Certification of Analyst, The purpose of this SOP is to determine the capability of the newly recruited analyst to perform analysis accurately within the specified parameters and to demonstrate the analyst’s ability to perform in quality control laboratory at XX Pharmaceuticals Ltd.

Certification of Analyst, Scope :

This SOP applies to assure that the analysts are familiar with all test parameters, analytical procedures, instruments operation and documentation in quality control laboratory of XX Pharmaceuticals Ltd.

Definitions/Abbreviation:

Standard Operating Procedure (SOP): Standard Operating Procedure.

Responsibilities:

The roles and responsibility is as follows:

Officer/Executive/ Sr. Executive, Quality Control

[][]To follow the instructions of this procedure correctly.
[][]To maintain the records properly as per SOP.

Manager, Quality Control

[][]Responsible for the certification of analyst and verification of results and comparison with acceptance criteria.
[][]To ensure that this procedure is kept up to date.
[][]To confirm that the SOP is technically sound and reflects the required working practices.
[][]To arrange training on the SOP to all concerned personnel and to ensure implementation of the SOP after training.

Head of Quality Assurance

[][]Approval of SOP
[][]To ensure the overall implementation of the SOP.

Procedure:

General Precaution(s):

[][]Training should be conducted until the analyst is competent enough to carry out the analysis independently.
[][]Make sure that new employee know about the laboratory safety procedure.
[][]Adequate knowledge on handling of spillages and management of chemicals & reagents in the laboratory.
[][]Hands on waste management in the laboratory.
[][]Understanding the operation, cleaning and calibration procedure of instruments used in the laboratory.

Operation:

[][]Recently approved two specific samples of raw material or finished product or packaging material shall be given to the analyst to perform test for analyst certification.
[][]The samples are to be coded as (A) or (B).
[][]These samples packed in a manner which can prevent exposure to moisture, light and heat.
[][]In-Charge, QC should ensure that the analyst is performing the specified tests following respective method of analysis and specification.
[][]The analytical findings shall be recorded in the respective worksheet and the summary of results shall be entered in the prescribed format (Annexure-I).
[][]In-Charge, QC shall review the results in comparison with the known values for the test carried out and forward to Head of QA for approval.
[][]The analyst shall be considered qualified if the results obtained by him/her within the specification limit and within acceptable limit for certification of analyst.
[][]The details like calculations, chromatograms and spectrums along with comments of Head of QA shall be filed in training file of analyst.
[][]No repeat of the test will be allowed to the analyst.
[][]The result are provided by analyst will be crosscheck to the previous result and check the similarity.
[][]Head of QA will decide for the selection of analyst for routine analysis after review of analysis report. If the analyst is failed to qualify the test analyst will undergo further training.
[][]The certification of analyst shall be applicable to him/her only for carrying out these activities for which he/she is certified.
[][]Re-certification of the analyst shall be carried out once in every three years.
[][]The acceptance criteria for the analytical results shall depend upon the nature of tests carried out and the range provided in the specifications.
[][]Following acceptance criteria may be used for evaluation comparing with approved analyst.
[][]Assay by Spectrophotometer +/- 1% of previous value
[][]Assay by HPLC +/-0.5% of previous value
[][]IR spectra should match with standard and previous spectra
[][]Water content by KF +/-1% of previous value

Annexure:

Annexure-I: Analyst Certification Report.

Water Sampling, Purpose :

Water Sampling, The purpose of this SOP is to describe the procedure for sampling and analysis of water in quality control laboratory.

Water Sampling, Scope :

This procedure is applicable for sampling and analysis in Quality Control Laboratory for purified water, water for injection, purified steam condensate, potable water, drinking water and effluent treatment plant water from different user points used in XX  Pharmaceuticals Ltd.

Definitions / Abbreviation:

[][]QC: Quality Control
[][]QA: Quality Assurance
[][]QCom: Quality Compliance
[][]COA: Certificate of Analysis
[][]WFI : Water for Injection
[][]PW: Purified water
[][]ETP: Effluent treatment plant

Responsibilities:

The roles and responsibility is as follows:

Lab Attendant, QC

[][]To collect water sample from different sampling points.

Officer / Executive, QC Officer / Executive, QC

[][]To prepare schedule sampling of water.
[][]To organize the sampling of water.
[][]Analysis of water and preparation of respective test report.
[][]Trend analysis of water.
[][]To ensure that this procedure is followed.
[][]To maintain the records properly as per SOP.

Sr. Executive, QC

[][]Reviewing of test report.

Manager, Quality Control

[][]Approval of test report.
[][]To ensure implementation of the SOP after training.

Head of Quality Assurance

[][]To ensure the overall implementation of the SOP.
[][]Approval of the SOP.

Procedure:

Precaution(s):

[][]Use gloves, mask & cap during sampling.
[][]Collect sample carefully to avoid contamination.
[][]Carefully collect water sample with high temperature and close the cap of container freely.

Sample Collection :

[][]Take required number of 500 ml to 1 Liter clean glass containers with cap for sampling.
[][]Open sampling points such as tap fixtures / hosepipe and allow water to run for not less than 1 minute.
[][]Rinse the container with respective water.
[][]Collect approximately 500 ml of water and immediately recap the sample containers after collecting samples. Keep the cap slightly loose when water temperature is above 30°C.
[][]Label the sample container providing information such as name of water, sample point no. / location, time, initial of sampler and date of sampling.
[][]Transfer the sample immediately to laboratory and analyze the sample within 24 hours of sampling. Preserve the sample in refrigerator (2°C to 8°C), if required.
[][]Entry information of sampling in sampling register after sampling.

Test Schedule :

Perform the test as per the following schedule :

Source of Water /Test frequency

Potable Water/ Once in a month
Purified Water/ Once in 14 days
ETP Water /Once in a week
Water for Injection/ Once in a week

Chemical Analysis :

[][]Perform analysis of water as per respective specification and method.
[][]Compile the raw data and prepare the certificate of analysis as per respective annexure with the test results & take approval of the COA.
[][]Share the water test reports with Engineering department and or Production department.
[][]Water test results are to be evaluated on a continuous basis and should be summarized in trend analysis report six monthly in order to identify significant trends.
[][]Inform respective department i.e. Engineering, Production and Quality Assurance Department whenever atypical data found beyond alert limit.
[][]Inform respective department i.e. Engineering, Production and Quality Assurance Department for taking actions whenever data found beyond action limit.

Annexure:

Annexure-I : Format for Certificate of Analysis for Potable water/Drinking water
Annexure-II : Format for Certificate of Analysis for Purified water/Water for injection/Purified Steam Condensate
Annexure-III : Format for Certificate of Analysis for Effluent Water
Annexure-IV : Format for Water Sampling Register
Annexure-V : Water sampling points

Calibration of Semi-micro Osmometer, Purpose:

Calibration of Semi-micro Osmometer, The purpose of this SOP is to describe the operation, calibration and cleaning of Semi-micro Osmometer (Brand: KNAUER; Model: K-7400) used in the quality control laboratory of XX Pharmaceuticals Limited.

Calibration of Semi-micro Osmometer,Scope:

This procedure is applicable for Semi-micro Osmometer, installed in the quality control laboratory general block of Labaid Pharmaceuticals Limited.

Definitions / Abbreviation:

Standard Operating Procedure (SOP): Standard Operating Procedure.
QC: Quality Control.

Responsibilities:

The roles and responsibility is as follows:

Sr. Executive/Executive, QC

[][]To ensure that this procedure is followed.
[][]To maintain the records properly as per SOP.

Manager, Quality Control

[][]To ensure that this procedure is kept up to date.
[][]To confirm that the SOP is technically sound and reflects the required working practices.
[][]To arrange training on the SOP to all concerned personnel and to ensure implementation of the SOP after training.
[][]Schedule calibration of the instrument at the defined intervals.

Head of Quality Assurance

Approval of the SOP.
To ensure the overall implementation of the SOP.

Procedure:

Precaution(s):

[][]Prior to use, user must ensure that equipment is calibrated.
[][]To ensure a fixed sample volume, always introduce the solutions with a clean and dry pipette into the measuring vessel.
[][]Handle the thermistor always very carefully. All abrasive materials should be kept away from it.
[][]Solutions containing proteins, such as sera, can only be measured once. Freezing causes denaturisation of the protein so that repetition of the measurement with the same sample would result in increased values. Thus, in the case of sera, only one measurement is possible for one sample.
[][]Only real osmolalities can be measured. It is not possible to prepare other standard solutions by dilution of a calibration solution since the activity coefficient of the solution changes with dilution.
[][]In this case Store the water which is used for the zero point calibration in glass bottles.
[][]If the same salt solution is measured several times, it must be mixed after thawing (stir briefly). During the thawing process ice floats to the top of the solution. As ice does not contain salt, the top layer of the solution is diluted while thawing.
[][]Calibration solutions can become more concentrated if the bottle is opened frequently. So, use KNAUER calibration solutions in glass ampoules.
[][]Prior to the measuring, a little bit water condensed in the cooling compartment should be removed with a dry cloth.

Operation:

[][]Preparing the Osmometer K-7400
[][]Switch ON the instrument at least 5 minutes before use.
[][]Press the vibrator key to check the stirrer. It will run for a second.
[][]Optionally a thermo printer can be connected to the RS232 socket. The result of each measurement will be printed automatically.
[][]After a calibration, an outprint of Calibration will be found automatically.
[][]In case of interrupted runs (caused by any error), the screen displays the corresponding error message.

Preparing a Measurement

[][]Place 0.15 ml sample or calibration solution into a clean, dry measurement vial.
[][]Put the vial all the way into the adapter. The meniscus of the liquid must be horizontal.
[][]Place the measuring head on the instrument in such a way that the vial extends into the cooling cavity.
[][]Thus the instrument is ready for calibrating or measuring.

Calibration:

[][]Prepare the instrument for a measurement of deionised water.
[][]Set the first field in the second row of the CALIBRATE screen to „0000“.
[][]Press the start key.
[][]After finishing the run on the screen is displayed 0000 mOsmol > -0.81°C<.
[][]To accept this value, press the START key again.
[][]Wait for the warming up to the stand-by temperature.
[][]Prepare the instrument for a measurement of a 300 mOsm/kg calibration solution.
[][]Activate the second calibration field and select “0300” and repeat steps
[][]For a 4 point calibration, repeat the procedure for calibration fields

Measuring Samples:

[][]Prepare the instrument for a measurement of a sample solution.
[][]Press the START key to start the measurement run.
[][]The instrument detects the freezing point depression and if the crystallisation occurred properly displays the corresponding osmolality on the main screen.
[][]The printer output is given automatically.
[][]If no crystallisation (temperature increase) takes place after the automatically start of the vibrator the measurement will be stopped with the error message “> ERROR < NO FREEZE”.
[][]If the crystallisation (temperature increase) takes place before the start of the vibrator the measurement also will be stopped with an error message> ERROR < FREEZE.
[][]Do not remove the measurement vessel from the adapter before the sample is molten. Otherwise the danger of damaging the measuring head is given. The sample melting can be accelerated by warming up with the fingers.

Cleaning procedure:

[][]Measuring vessel and thermistor should be cleaned occasionally with KNAUER cleaning solution supplied with the instrument. (Dilution: 1: 10 solution in purified water of 40±5°C)
[][]Clean and dry the measuring vessels with alcohol or acetone because remaining solvent vapours could cause false results.

Annexure:

Annexure-I: Operation Logbook for Semi-micro Osmometer.

Calibration of Oven , Purpose :

Calibration of Oven , The purpose of this SOP is to describe the operation, calibration and cleaning of Oven (256 L) (Brand: Memmert, Model: UNE 600) used for drying of glassware in the quality control laboratory at XX Pharmaceuticals Ltd.

Calibration of Oven , Scope :

This SOP applies for operation, cleaning and calibration of Oven (256 L) (Brand: Memmert, Model: UNE 600) in quality control laboratory of  XX Pharmaceuticals Ltd.

Definitions/Abbreviation:

Standard Operating Procedure (SOP): Standard Operating Procedure.

Responsibilities:

The roles and responsibility is as follows:

Sr. Executive/Executive, Quality Control

[][]To follow the instructions of this procedure correctly.
[][]To maintain the records properly as per SOP.

Manager, Quality Control

[][]To ensure that this procedure is kept up to date.
[][]To confirm that the SOP is technically sound and reflects the required working practices.
[][]To arrange training on the SOP to all concerned personnel and to ensure implementation of the SOP after training.
[][]Schedule calibration of the instrument at the defined intervals.

Manager, Quality Control

[][]Approval of SOP
[][]To ensure the overall implementation of the SOP.

Annexure:

N/A

Procedure:

General Precaution(s):

[][]Do not wipe with damped cloth at on position.
[][]Do not overload the chamber with glassware.
[][]Do not keep the items those may produce inflammation with air.
[][]Keep glassware to avoid the touch of inner surface of the chamber.
[][]Avoid opening the door for long period.
[][]Do not move the oven at on position. Severe vibrations may cause serious damage of the temperature probes.

Operation:

[][]Connect the instrument to the main power supply.
[][]Switch ‘ON’ the mains.
[][]Press push/turn control key to put on the main power switch in front of the instrument. The oven will start in normal mode with the display of timer, the chamber temperature, alarm temperature (red color indication).
[][]Hold down the SET key and turn the push/turn control key at the clockwise or anti clockwise for setting date, local time, operating temperature, alarm temperature. After setting, SET key will be released the display briefly flashes the set point.
[][]The display then changes to the actual current temperature and starts to the setting temperature. The temperature will be automatically increased at setting temperature and display the setting temperature digitally.
[][]Observe the display temperature until stable position.
[][]Hold down the SET key (appr. 3 seconds) to select the operation mode, if require. The current operating mode will be flashed on the display. There are three operating mode in the oven:

Normal Operation
Weekly Programmer
Ramp time Programme Operation

[][]Select the required programme and set as per operation manual.
[][]Select the fan speed to set the air changes.
[][]Turn the push/turn control at clockwise until the fan symbol flashing to move the air slider opens and closes the air valve to control the supply and discharge of air.
[][]Check the chamber temperature using by a calibrated digital thermometer, when the setting Temperature reaches.
[][]Keep the glassware’s inside the oven.
[][]The oven will automatically control the Temperature.
[][]The instrument will automatically adjust the temperature. When the temperature exceed the setting temperature, “off” light will illuminate and if the temperature decrease the “on” light will illuminate.

Cleaning Procedure :

[][]Switch off the oven and disconnect the power plug.
[][]Remove all glassware’s from the chamber of oven.
[][]Clean inside & outside of the chamber with dry cloth.
[][]Reload all items into the chamber when reach to dry the chamber surface.
[][]At the end of cleaning, connect the power plug and switch on the oven.
[][]Clean the chamber once in a month.
[][]Clean the outer surface of the oven every day.

Calibration Procedure:

[][]Switch ‘ON’ the mains of instrument.
[][]Set the desired temperature. Follow above operation procedure
[][]Allow sufficient time to equilibrate the set temperature.
[][]Check the temperature using a calibrated thermometer/data logger and record the temperature in the calibration certificate as per Annexure-V of Engineering SOP
[][]Carry out others two calibration temperatures in the same manner.
[][]Calibrate the oven once in a year ± 15 days.

Maintenance :

[][]If oven shows any mechanical, electrical or any others problem, inform to supplier or Engineering Department for corrective action.
[][]After corrective action, recalibrate the oven if it is necessary.

Atomic Absorption Spectrophotometer Calibration, Purpose :

Atomic Absorption Spectrophotometer Calibration, The purpose of this SOP is to describe the operation and cleaning procedure of Atomic Absorption Spectrophotometer Model No. – A Analyst 400 with Graphite Furness HGA 900 used for analysis of the finished product & raw materials in the Quality Control Laboratory at XX Pharmaceuticals Ltd.

Atomic Absorption Spectrophotometer Calibration, Scope :

This procedure is applicable for the Atomic Absorption Spectrophotometer, installed in the Quality Control Laboratory of XX Pharmaceuticals Limited.

Definitions / Abbreviation:

Standard Operating Procedure (SOP): A written authorized procedure, which gives instructions for performing operations.
QC: Quality Control.

Responsibilities:

The roles and responsibility is as follows:

Sr. Executive/Executive, QC

[][]To ensure that this procedure is followed.
[][]To maintain the records properly as per SOP.

Manager, Quality Control

[][]To ensure that this procedure is kept up to date.
[][]To confirm that the SOP is technically sound and reflects the required working practices.
[][]Arrange training on the SOP to all concerned personnel.
[][]To ensure implementation of the SOP after training.
[][]Schedule calibration of the instrument at the defined intervals.

Head of Quality Assurance

[][]Approval of the SOP.
[][]To ensure overall implementation of the SOP.

Procedure:

Precaution(s):

[][]Care must be taken in handling the instrument opening, putting sample, and closing especially.
[][]Ensure optimum fluid level, otherwise flame will not ignite.
[][]All the solutions must be prepared carefully.
[][]The detection chamber must be clean and free from any dust of foreign particles.
[][]The selection of correct hollow cathode lamp of a particular atom must be present on a correct position of the lamp holder.
[][]The Air conditioning system and air exhauster must be open during operation of the Instrument.

Operation

[][]Procedure for getting concentration of a particular atom in Flame Method
[][]Ensure proper cleaning of the machine before operation.
[][]Turn on the computer and printer.
[][]Turn on the switch of the instrument.
[][]Turn on the switch of air compressor.
[][]Let open the exhaust switch for a few minutes of the compressor to expel moisture from it.
[][]Close the exhaust switch to retain huge amount of compressed air in it.
[][]Set the accessories apparatus of the flame mode.
[][]Turn on the switch of the Flame mode.
[][]Turn on the operating software on the computer.
[][]Align and optimize the instrument.
[][]Turn the screw of the acetylene gas cylinder and ensure its proper flow to the ignition chamber.
[][]Method setting: A method set by following way-
[][]At first click to file manager.
[][]Then go to new and click to method.
[][]Select the element (test element) from starting condition and click OK.
[][]Click on spectrometer at define element & write the method name in method description.
[][]Then select AA/AA-BG (as per method) from signal option.
[][]Click on setting and select the time, delay time & replicates.
[][]Click on sampler and select Air from Oxidant.
[][]Click on calibration and select Linear Through zero then select results unit (ppb, ppm etc) from equation & units.
[][]Click on standard concentration & select Blank and standard (1, 2, 3 etc).
[][]Then check sequence setting: set the number of standard and samples sequentially and save it.
[][]Then check sequence setting: set the number of standard and samples sequentially and save it.

[][]After completion the program, arrange & displayed the results window, the calibration window, the manual analysis control window and the flame control window from monitor window bar.
[][]Click “ON” button on the right side of the Flame option.
[][]Then follow the instruction of the software and input information accordingly.
[][]After completion of the calibration curve input sample according to software instructions.
[][]After completing analysis print the output or it may be saved.
[][]Turn off the software.
[][]Turn off the gas flow.
[][]Turn off the main instrument and expel air from compressor.
[][]Turn off the Switch of the computer.

Cleaning

[][]Clean all parts of the machine with cotton cloth using methanol after use.
[][]Procedure for getting concentration of a particular atom in Graphite Method
[][]Ensure proper cleaning of the machine before operation.
[][]Turn on the computer and printer
[][]Turn on the switch of the instrument
[][]Turn on the switch of air compressor
[][]Let open the exhaust switch for a few minutes of the compressor to expel moisture from it
[][]Close the exhaust switch to retain huge amount of compressed air in it.

[][]Set the accessories apparatus of the Graphite mode.
[][]Check the cooling system, the water level retain between maximum and minimum level.
[][]Turn on the switch of the Graphite mode.
[][]Turn on the operating software on the computer.
[][]Align and optimize the instrument.
[][]Turn the screw of the Argon gas cylinder and ensure its proper flow to the ignition chamber.
[][]Method setting: A method set by following way-
[][]At first Click to file manager.
[][]Then go to new and click to method.
[][]Then go to new and click to method.
[][]Then select the element (test element) from starting condition and click OK.
[][]Then go to spectrometer at define element & write the method name in method description and select AA/AA-BG from signal option. (as per method)
[][]Click on setting and select the time, delay time, BOC time & replicates.
[][]Click on sampler and go to Furness program & select Temperature, Ramp time, Hold time, internal flow & gas type.
[][]Click on Autosampler and select sample volume, Diluent location, matrix modifiers volume & location.
[][]Click on calibration and select Linear Through zero from calibration equation.
[][]Then select result unit (ppm, ppb etc) from equation and unit.
[][]Click on standard concentration & select Blank and standard (1, 2, 3 etc).
[][]Click on calculate standard volume & select stock standards, location & concentrations. Select the location of blank & reagent blank. Then click to OK and save it.
[][]Then click on Displayed the sample information editor. Write sample location and sample ID then save as in sample information file.
[][]Click on Auto (Automated analysis control)
[][]Click on Open from results data set name (for Data save).

[][]Click on analyze.

[][]After completion the program, arrange & displayed the results window, the calibration window, the automated analysis control window and the Furness control window from monitor window bar.
[][]Then click on analyze all
[][]Then follow the instruction of the software and input information accordingly
[][]After completion of the calibration curve automatically input sample according to software instructions.
[][]After completing analysis print the output or it may be saved.
[][]Turn off the software.
[][]Turn off the gas flow.
[][]Turn off the main instrument and expel air from compressor.
[][]Turn off the Switch of the computer.

Cleaning

[][]Clean all parts of the machine with cotton cloth using methanol after use.
[][]Procedure for getting concentration of a particular atom in MHS Method
[][]Ensure proper cleaning of the machine before operation.
[][]Ensure proper cleaning of the machine before operation.
[][]Set the MHS part with AAS properly.
[][]Set the sample tube on the flame chamber properly.
[][]Turn on the computer and printer.
[][]Turn on the switch of the instrument.
[][]Turn on the switch of air compressor.
[][]Let open the exhaust switch for a few minutes of the compressor to expel moisture from it.
[][]Close the exhaust switch to retain huge amount of compressed air in it.
[][]Turn on the switch of apparatus of the Graphite mode.
[][]Check the cooling system, the water level retain between maximum and minimum.
[][]Turn on the switch of the Flame mode.
[][]Turn on the operating software on the computer.
[][]Align and optimize the instrument.
[][]Turn the screw of the Argon & acetylene gas cylinder and ensure its proper flow to the ignition chamber.
[][]Method setting: A method set by following way-
[][]At first Click to file manager.
[][]Then go to new and click to method.
[][]Select the element (test element) from starting condition and click OK.
[][]Then go to spectrometer at define element & write the method name in method description.
[][]Click on setting and select the time, delay time, BOC time & replicates.
[][]Then click on sampler and go to Furness program & select Temperature, Ramp time,
[][]Hold time, internal flow & gas type.
[][]Click on calibration and select Linear Through zero from calibration equation.
[][]Then select result unit (ppm, ppb etc) from equation and unit.
[][]Click on standard concentration & select Blank and standard (1, 2, 3 etc).
[][]Then check sequence setting: set the number of standard and samples sequentially and save it.
[][]After completion the program, arrange & displayed the results window, the calibration
[][]window, the manual analysis control window and the flam control window from monitor window bar
[][]Then click “ON” button on the right side of the Flam option.
[][]Then follow the instruction of the software and input information accordingly
[][]After completion of the calibration curve input sample according to software instructions.
[][]After completing analysis print the output or it may be saved.
[][]Turn off the software.
[][]Turn off the gas flow.
[][]Turn off the main instrument and expel air from compressor.
[][]Turn off the Switch of the computer.

Cleaning

Clean all parts of the machine with cotton cloth using methanol after use.

Calibration:

Calibration for Flame System:
Wavelength Accuracy Using Ni:

Test Conditions:

[][]Open the default Nickel method (File-New-Method-Ni)
[][]Open the continuous Graphics window so the system will set up for Nickel.
[][]Ensure the lamp has been on for 15 minutes before measuring g absorbance with the Nickel standard.

Test prerequisites:

[][]Burner position Optimized and Nebulizer adjusted using Copper.

Test Steps:

[][]Under the tool bar, double click on the instrument icon in the ‘Spectrometer status panel’ to open the diagnostic/spectrometer window.
[][]Select the ‘Optical Position’ button at the button of the diagnostics window.
[][]Select the ‘Optical Position’ button at the button of the diagnostics window.
[][]A graphic plot of the peaked positions for the prism and Grating will be displayed

The Prism Tolerance is ±190 motor steps
The Grating Tolerance is +380, -260 motor steps

Sensitivity and Precision Using Ni:

Apparatus:

Volumetric flask with stopper, 1000 ml
Glass pipette 3 ml
Beaker 10 to 200 ml

Reagents:

1000 ppm Ni AAS standard solution.
Nitric acid

Preparation for 3ppm Ni standard solution:

[][]Pour a small quantity of 1000 ppm Ni AAS standard solution in the beaker. Use it to rinse the 3 ml pipette and the beaker, then discard it.
[][]Pour another 5ml (minimum) 1000ppm Ni AAS standard solution into the beaker.
[][]Pipette 3 ml standard from the beaker into the 1000 ml volumetric flask.
[][]Half fill the volumetric flask with de-ionized water.
[][]Pour 10 ml (approximately) of nitric acid into the volumetric flask.
[][]Fill the volumetric flask with de-=ionized water exactly to the mark.

Note: 3ppm Ni standard should be produced before the day of test.

Test Steps:

Edit the Nickel default method and enter/verify the following parameter:
Signal type: A
Read time:10.0
Replicates: 10

[][]While in the method editor, go to the calibration/ standard concentrations page. Enter blank for calibration blank ID and Nickel standard for standard ID.
[][]In the ‘Flame Control’ window, select the ‘Flam On/off’ icon to light the flame.
[][]In the ‘Manual Analysis Control’ window, aspirate blank and select ‘Analysis Blank’. 10 Replicates will be measured and autozero will occur.
[][]Aspirate a 3ppm Ni standard and select ‘Analysis Sample’. 10 Replicates will be measured.
[][]The results will be displayed in the result window. Record the values for mean absorbance and relative standard deviation (RSD).The value should meet following requirements.

Mean Absorbance ≥ 0.200
RSD ≤ 0.3%

[][]Return to the ‘Flame Control’ window and extinguish the flame by pressing Flame On/Off.

Wavelength Accuracy Using As:

Test Conditions:

[][]Open the default Arsenic method (File-New-Method-Ni)
[][]Open the continuous Graphics window so the system will set up for Arsenic.
[][]Ensure the lamp has been on for 15 minutes before measuring absorbance.

Test prerequisites:

[][]Burner position Optimized and Nebulizer adjusted using Copper.

Test Steps:

[][]Under the tool bar, double click on the instrument icon in the ‘Spectrometer status panel’ to open the diagnostic/spectrometer window.
[][]Select the ‘Optical Position’ button at the button of the diagnostics window.
[][]A graphic plot of the peaked positions for the prism and Grating will be displayed.
The Prism Tolerance is ±200 motor steps
The Grating Tolerance is ±380 motor steps

[][]Select the ‘X’ in the upper right hand corner to exit the ‘Optical position’ window. Select the X in the Upper right corner to close the window.

AA-BG Baseline Noise at 1 Abs. Using As:

Test Steps:

Edit the Arsenic default method and enter/verify the following parameter:

Signal type:AA-BG
Read time: 2
Replicates: 99

[][]In the Manual Analysis Control window, select the ‘Analyze blank’ button. The system will take 99 readings and perform an autozero.
[][]Insert the 1.0 A neutral density filter into the filter holder.
[][]In the Manual Analysis Control window, select the ‘Analyze Sample’ button. When the reading is complete, record the SD value. It should be ≤ 0.005.

AA Baseline Noise and Drift using Cu:

Test prerequisites:

[][]Burner position Optimized and Nebulizer adjusted using Copper.
[][]Copper lamp should be warmed up at least 15 minutes.

Test Steps:

[][]Open the default Copper method (File-New-Method-Ni)
[][]Open the continuous Graphics window so the system will set up for Copper.
[][]Edit the Copper default method and enter/verify the following parameter:
Signal type: AA
Read time: 0.5
Replicates: 99

[][]In the Manual Analysis Control window, select the ‘Analyze blank’ button. The system will take 99 readings and perform an autozero.
[][]In the Manual Analysis Control window, select the ‘Analyze Sample’ button. Data collection for 99 replicates will begin.
[][]At the end of 99 replicates, record the standard deviation (SD) value in the table below. It should be ≤0.001. Record the mean absorbance value as well.
[][]Wait 15 minutes and repeat the measurement. Record the mean absorbance value for the second measurement.
[][]Calculate the difference between the absorbance measurements. It should be ≤ 0.002 Abs.

Wavelength Accuracy Using Cu:

Test Steps:

[][]Under the tool bar, double click on the instrument icon in the ‘Spectrometer status panel’ to open the diagnostic/spectrometer window.
[][]Select the ‘Optical Position’ button at the button of the diagnostics window.
[][]A graphic plot of the peaked positions for the prism and Grating will be displayed.

The Prism Tolerance is ±120 motor steps
The Grating Tolerance is ±380 motor steps

[][]Select the ‘X’ in the upper right hand corner to exit the ‘Optical position’ window. Select the X in the Upper right corner to close the window.

Copper Capacitance:

The Optical position box also displays two capacitances values. Cap: in the upper left corner. The first value is the cap: used for peaking and the last value is the Final Cap: Record the Final Cap. It should be ≥1.0 pF

Flame Sensitivity and Precision using Cu:

Apparatus:

Volumetric flask with stopper, 1000 ml
Glass pipette 2 ml
Beaker 10 to 200 ml

Reagents:

1000 ppm Cu AAS standard solution.
Nitric acid.

Preparation for 2ppm Cu standard solution:

[][]Pour a small quantity of 1000 ppm Cu AAS standard solution in the beaker. Use it to rinse the 2 ml Pipette and the beaker, then discard it.
[][][][]Pour another 5ml (minimum) 1000ppm Cu AAS standard solution into the beaker
Pipette 2 ml standard from the beaker into the 1000 ml volumetric flask.
[][]Half fill the volumetric flask with de-ionized water.
[][]Pour 10 ml (approximately) of nitric acid into the volumetric flask.
[][]Fill the volumetric flask with de-=ionized water exactly to the mark.

Note: 2ppm Ni standard should be produced before the day of test.

Test Steps:

[][]Edit the Copper default method and enter/verify the following parameter:
Signal type: AA
Read time:10.0
Replicates: 10
[][]In the ‘Flame Control’ window, select the ‘Flam On/off’ icon to light the flam.
[][]In the ‘Manual Analysis Control’ window, aspirate blank and select ‘Analysis Blank’. 10 Replicates will be measured and autozero will occur.
[][]Aspirate a 2ppm Cu standard and select ‘Analysis Sample’. 10 Replicates will be measured.
[][]The results will be displayed in the result window. Record the values for mean absorbance and relative standard deviation (RSD).The value should meet following requirements.
Mean Absorbance ≥ 0.250
RSD ≤ 0.30%
[][]Select the Spectrometer- Setting tab and enter/verify the following parameter:
[][]Signal type: AA

Read time:0.1
Replicates: 10

[][]In the ‘Flame Control’ window, select the ‘Flam On/off’ icon to light the flam.
[][]In the ‘Manual Analysis Control’ window, aspirate blank and select ‘Analysis Blank’. 10 Replicates will be measured and autozero will occur.
[][]Aspirate a 2ppm Cu standard and select ‘Analysis Sample’. 10 Replicates will be measured.
[][]The results will be displayed in the result window. Record the value for relative standard deviation (RSD).The value should meet following requirements.
RSD ≤ 3.0%
[][]Return to the ‘Flame Control’ window and extinguish the flame by pressing Flame On/Off.

Calibration for Flame System:

Chromium Baseline Noise For Furness:

Test Steps:

[][]Click on the File pull down menu, then on Open. Select Method.
[][]Click on Browse. Go up 2 levels and double-click on Service. Then double click on Method.
[][]Double click on HGA Cr Test method. Select the Method Ed icon to open the Method Editor window.
[][]In the spectrometer section, select set. Select 2.7 Slit Width and 0.8 Slit Height. Select OK. Click on the file pull down menu, then on Save. Select Method. Close the Method Editor window.
[][]Click on the Tools pull down menu and then select Continuous Graphics. This will set up the Lamp. Close the Continuous Graphics window.
[][]Open the Align lamps window. Look at the Bar Graph status window and verify that the Cr HCL Lamp current is 15 mA and the Slit is se4t to 2.7/0.8. Also verify that the Background corrector is On. Allow the lamp to warm up for 30 minutes.
[][]Close the Align Lamps window.
[][]From the Tools pull down menu open the windows Results, Peaks and Automated Analysis. Arrange and align the windows as desired.
[][]Open the Furness control window and select the Furness ON/Off button to run at least one dry firing (without any sample) to make sure that there is no residual signal (Peak area less than 0.005) from any previous injections or tube contamination.
[][]Make sure position 3 of the Autosampler is empty. Type in 3 as the sample lactation in the setup page of the Automated Analysis window, click on the Analyze tab and then on the Analyze Samples button to measure 5 Furness dry firings (without any sample).
[][]Ensure that the AA and BG signals do not diverge from the baseline. Realign the Furness into the optical beam if necessary.
[][]The standard deviation of the mean dry-firing result in integrated absorbance (Peak area) for the Cr wavelength must not exceed a maximum value of 0.002. Record the result.

Chromium Characteristic Mass and Precession:

Test Steps:

[][]Use the same method as in the previous test. Demonized water should be in position 1 and Cr standard should be in position 2 of the Autosampler.
[][]Type in 2 as the sample lactation in the setup page of the Automated Analysis window, click on the analyze tab and then on the Analyze Samples button to measure 5 furnace firings using 20 µl sample injections.
[][]Calculate the characteristic mass using the Calculate characteristic mass tool from the Analyses pull down menu.

Characteristic Mass Result:

The characteristic mass (m0) results in pg and calculated from the mean integrated absorbance (Peak area) values should lie within the following ranges:

Element: Cr

Lower Limit (pg): 2.3

Target Value (pg): 3.0

Upper Limit (pg): 3.8

Note: If the characteristic mass exceeds the lower limit, check for possible contamination of the water used for sample preparation. Prepare a new solution if required.

Precision:

[][]The relative standard deviation (%RSD) of the mean sample solution readings calculated from the integrated absorbance (peak area) values for Cr must not exceed the maximum value of 2.0%.
[][]Record the results in the OQ Test Certificate on page 40.
[][]AS-800 Autosampler Linearity
[][]Click on the File pull down menu, then on Open. Select Method.
[][]Verify that you are in the Service\Methods directory. If not, click on Browse. Go up 2 levels and double-click on Service. Then double click on Method.
[][]Double click on HGA AS-800 Lin method.
[][]Select the Method icon to open the Method Editor window.
[][]In the spectrometer section, select Set. Select 2.7 Slit Width and 0.8 Slit Hight. Select OK.
[][]On the right side of the Method window select the Settings tab.
[][]In the Lamp Current section, select Use current (mA) and then type 15 in the Lamp Current box.
[][]Click on the File pull down menu, then on Save. Select Method.
[][]Close the Method Editor window.
[][]Clock on the Tools pull down menu and then select Continuous Graphics. This will set up the Lamp. Close the Continuous Graphics windows.
[][]Open the Align lamps windows. Look at the Bar Graph status window and verify that the Cr HCL Lamp current is 15mA and Slit is set to 2.7/0.8. Also verify that the Background Correction is ON. Allow the lamp to warm up for 30 minutes (if not already warmed up).
[][]Close the Align Lamps window.
[][]From the Tools pull down menu open the windows Results, Peaks, Examine Calibration and Automated Analysis. Arrange and align the windows as desired.
[][]Click on the Analyze tab of the Automated Analysis window and then on the Calibration button top start the calibration.
[][]When the calibration is finished check the Correlation Coefficient Result in the Examine Calibration window.
[][]The Correlation Coefficient Result Cr must exceed the minimum value of 0.999.

Annexure: Atomic Absorption Spectrophotometer Calibration

Annexure-I: Calibration Information Sheet for Wavelength Accuracy, Sensitivity and Precision using Ni
Annexure-II: Calibration Information Sheet for Wavelength Accuracy and AA-BG Baseline Noise at 1 Abs. using As
Annexure-III: Calibration Information Sheet for Baseline Noise, Wavelength Accuracy, Copper Capacitance, Flame Sensitivity and Precision using Cu
Annexure-IV: Calibration Information Sheet for Baseline Noise, Characteristic Mass and Precession, Autosampler Linearity using Cr
Annexure-V: Operation logbook for Atomic Absorption Spectrophotometer

Wash Water, Purpose:

Wash Water, The purpose of this SOP (Standard Operating Procedure) is to define the Sampling and analytical procedure for wash water.

Wash Water, Scope:

This procedure is applicable for sampling of wash water from production equipments and analysis of wash water in the Quality Control laboratory  of XX Pharmaceuticals Ltd.

Definition:

None

Responsibilities:

The roles and responsibility is as follows:

Executive, Production

[][]To co-ordinate to collect the sample as per defined procedure
[][]To send duly filled Wash Water Sampling Advice Form to QC/QA Department.
[][]To maintain the proper documentation.

Sr. Executive/Executive, Quality Assurance

[][]To withdraw the sample as per the defined procedure.

Sr. Executive/Executive, QC

[][]To analyze the sample as per defined procedure
[][]To ensure that this procedure is kept up to date.

Manager, Quality Control

[][]To ensure appropriate personnel from the section are trained on this procedure.
[][]To confirm that SOP is technically sound and reflects the required working practices.

Head of Quality Assurance

[][]To ensure the overall implementation of the SOP.
[][]Approval of the SOP.

Procedure:

[][]Production personnel clean the equipment as per standard cleaning procedure, intimates QC/QA for wash water sampling with the “Wash Water Sampling Advice Form” in duplicate.
[][]Quality Compliance representative inspects the equipment and its parts for cleanliness and then collects the sample as follows:

Vibratory Shifter:

[][]Attach the sieve on the body of the sifter and wash with 3.0 L of Purified water and collect the sample at the receiver into a clean bowl. Rinse the dismantled parts (Lid, clamp, hopper and silicon gasket) with 2 liters of purified water and collect into the same bowl. Collect approx. 30 ml of the sample into an amber colored bottle for analysis.

Container Blender:

[][]Rinse the colloid mill with 3.0 L of Purified water and collect it into a clean bowl. Collect 30ml of the sample into an amber colored bottle from the bowl for analysis.

Rapid Mixer Granulator:

[][]Rinse the equipment bowl and top lid with 30.0L of Purified water and collect the water into a clean bowl through the discharge taking care that the whole surface of the bowl and top lid is rinsed properly and rinse the dismantled parts (clamp for binder addition, charging port, spray nozzle, vent filter, chopper blade, impeller blade discharge valve and all gaskets) with 5 liters of purified water and collect into the same bowl. Collect approximately 30 ml of sample into an amber colored bottle for analysis.

FBD (Fluid Bed Drier):

[][]Rinse the retarding chamber internally with 10.0 L of Purified water and collect it into a clean bowl. Collect approximately 30 ml of the sample into an amber colored bottle for analysis. Similarly rinse the FBD trolleys with 10.0 L of Purified water each and collect 30ml of the sample separately from the two bowls. Rinse the cartridge filters/FBD bag with 5-liters of purified water and collect the water into the clean bowl. Collect approximately 30 ml of the sample into an amber colored bottle for analysis.

Tablet Coating Machine:

[][]Rinse the pan with 10.0L of Purified water and collect the sample into a clean bowl through the discharge taking care that the whole surface and the Baffles are rinsed properly. Rinse the dismantled parts (Silicon tube, Gun assembly, inlet duct and outlet duct) with 5 liters of purified water and collect into the same bowl. Collect approximately 30 ml of the sample into an amber colored bottle for analysis.

Compression machine:

[][]Rinse the hoppers, butterfly valve, triclover clamp, force feeder, inlet connector, Turret guards, Powder scrapper, Acrylic guards, feeder shaft, Exhaust pipes with 5 liters of purified water and collect in a clean bowl. Collect approximately 30 ml of this sample into an amber colored bottle for analysis. Similarly rinse the y – chute, Gravity pipe with 5 liters of purified water and collect in the clean bowl. Collect approximately 30 ml of this sample into an amber colored bottle for analysis.

Capsule Filling Machine:

[][]Rinse the capsule loading channel, hopper, Loading ring, Auger, Locking pin assembly with 5 liters of purified water and collect in to clean bowl. Collect approximately 30 ml of this sample into an amber colored bottle for analysis.

Capsule polishing Machine:

[][]Rinse S.S cover of polishing Machine and polishing brush with 2 liters of purified water and collect in to clean bowl. Collect approximately 30 ml of this sample into an amber colored bottle for analysis.
[][]While collecting wash water sample, collect Purified water about 30 ml into an amber colored bottle.
[][]Use this as blank.

Note: For the equipments, which are not specified above, use 2.0 L, 5.0 L, & 10.0 L as the rinsing water quantity depending on the size i.e. small, medium & big.

Analysis:

[][]After getting sampling advice form from production department, QC personnel will entry in the wash water register and assign a lab control number as WW-000X/MM/XX(where WW for Wash Water, 000X- Sequential number of four digits, MM-Month and YY-Last two digits of year. For example: WW-0001/08/XX). Then the compliance personnel will collect the sample and send to Quality Control department for analysis.
[][]QC analyses the sample by scanning through 190-400 nm on UV-VIS Spectrophotometer, using Purified water (collected as explained earlier) as blank.
[][]Observe for any abnormal peaks and/or peaks having same wavelength maximum of active material of previous product.
[][]Reject the sample in case of any abnormal peak or if a peak of previous product having more absorbance that of a 10 ppm standard solution of active of previous product and send the information to the concerned department.
[][]Take the spectrum print out on the back side of the wash water report copy (QC copy) and inform production for rewash.
[][]If absorbance is less than that observed in standard graph, intimate the concerned department by sending the original copy of the report after making necessary entries and approving the clean card. Retain the duplicate copy of the report and file it after making necessary entries in the register.

Annexure:

Annexure-I: Wash Water Sampling Advice Form.
Annexure-II: Wash Water Register.

Out Of Specification (OOS), Purpose :

Out Of Specification (OOS), The purpose of this SOP is to define the procedure for handling of OOS results in the Quality Control Laboratory of XX Pharmaceuticals Ltd.

Out Of Specification (OOS),Scope :

[][]This SOP is applicable for all Out of Specification (OOS) results detected during testing of any product or materials in Quality Control Laboratory of general block of XX Pharmaceuticals Limited.
[][]If an out of specification results is generated for dissolution/ Drug release, uniformity of dosage units, weight variation, disintegration test, In process sample and any other test which is used to measure variability in a lot this SOP does not apply. In such cases respective Pharmacopoeial guidelines or criteria shall be apply.
[][]This SOP does not apply to samples of various stages like In process samples, Intermediate samples, scale up batches, method validation, method development, solvents, packaging material, wash water, decontamination samples, evaluation samples, raw material received from new vendor, description and solubility test, tests where tentative limits given.
[][]This SOP does not apply for OOS to tests like Bulk density, Sieve analysis, Particle size and other physical parameters.
[][]This SOP does not apply when system suitability failure, bracketing standard, transcriptional errors or processing method errors (In case of failure due to the integration parameters for the HPLC).
[][]This SOP does not apply to incomplete analysis where result is not derived.
[][]Out of Specification is not applicable for out laboratory testing.

Definitions / Abbreviation:

[][]Standard Operating Procedure (SOP): Standard Operating Procedure. A written authorized procedure, which gives instructions for performing operations.
[][]QC: Quality Control.
[][]CAPA: Corrective action and preventive action.
[][]OOS result: An OOS result is a result from a defined test procedure that fails to meet established specifications or criteria. An OOS result does not constitute a failure unless further investigation confirms this result.
[][]Atypical result: Results that are still within specification but are unexpected, questionable, irregular, deviant or abnormal.
[][]Obvious error : Obvious error can be occurred due to:
Calculation Error
Laboratory error
[][]Laboratory Error: A mistake that occurs within the test laboratory caused by an analyst or piece of equipment. Examples include use of incorrect standards, improper sample or standard preparation, improperly calibrated balances, equipment failure and miscalculations.
[][]Laboratory Investigation: The investigation that is conducted within the laboratory to determine the cause of the OOS results.
[][]Assignable Cause: An identified reason for obtaining an OOS or aberrant/anomalous result.
[][]No Assignable Cause: When no result could be identified.
[][]Review: To check all critical parameters involved in the test which may cause of the OOS results.
[][]Reanalysis: Further analysis with the same dilution of sample or of same aliquots which produced OOS results.
[][]Retest: Re-examining the material from the original sample that was used as the source of the aliquot that produced OOS result.
[][]Resample: A new sample from the original container where possible, required in the event of insufficient material remaining from original sample composite or proven issue with original sample integrity.

Responsibilities:

The roles and responsibility is as follows:

Executive, QC

[][]Analysis of any product or materials and to notify the OOS results to supervisor.

Sr. Executive, QC

[][]To ensure the initial investigation of the test parameters and to organize the testing.

Manager, Quality Control

[][]To ensure that this procedure is kept up to date.
[][]To confirm that the SOP reflects the required working practices.
[][]To make decision for re-sampling.
[][]To arrange training on the SOP to all concerned personnel and to ensure implementation of the SOP after training.

Head of Quality Assurance

[][]Approval of the SOP.
[][]To take the final decision to release the batch.
[][]To ensure the overall implementation of the SOP.

Procedure:

[][]The procedure mentioned below shall be followed if a Laboratory result for raw materials sample, In-process Sample or Finished Product sample fails to meet the Specification.
[][]Analyst shall not destroy the sample preparation / solution and shall retain the prepared solutions, Standards and Sample solutions until the investigations have been concluded.
[][]Retain all Glassware, Blend & Finished Product Sample.
[][]Check the whole analysis for compliance (Self-check).
[][]Inform immediately to the Supervisor about the OOS result.
[][]Supervisor will discuss with the analyst about the test method and confirm analyst knowledge of and performance of the correct procedure.
[][]Check if a laboratory error could be the cause of OOS results and inform Manager, QC.
[][]Check and record the present conditions in Notification of out of specification (OOS) result as per Annexure-I.
[][]Follow the Flow Chart (Annexure-II) for OOS Investigation
[][]The QC Manager should assess the data promptly to ascertain if the results may be attributed to laboratory error, or whether the results could indicate problems in the manufacturing process.

[][]It is to be clarified together with the QC Manager whether there is an apparent analytical error. A formal check is to be carried out (Investigation stage 1) using Out of Specification (OOS) Results Investigation Checklist (Annexure – IV) which shall be issued by QC Manager making entry in the Out of specification investigation register (Annexure – III) and assigning sequential number as below:
e.g. OOS-001/xx
Where, OOS is the abbreviation of Out of Specification
001 is the sequential number of Out of Specification investigation
/ is separator
xx is last two digits of year 20xx

[][]At the first step, the QC Manager along with Analyst shall immediately try to find out any obvious Error (Example: Calculation error, Power outage, Equipment failure, Testing Error, Incorrect Instrument Parameters etc.)
[][]If any calculation error is found out, make correction the calculation and release the material/product; analyst shall be re-trained for the error parts.
[][]If the calculation / documentation are correct, proceed with the investigation of the stepwise analysis which may include re-examination of the actual solutions, test units, glassware used in the original measurements and preparations.
[][]The following steps should be taken as part of the investigation:
[][]Discuss the test method with the analyst; confirm analyst knowledge of and performance of the correct procedure.
[][]Examine the raw data obtained in the analysis, including chromatograms and spectra, and identify anomalous or suspect.
[][]Confirm the performance of the instruments.
[][]Determine that appropriate reference standards, solvents, reagents, and other solutions were used and that they meet quality control specifications.
[][]Evaluate the performance of the testing method to ensure that it is performing according to the standard expected based on method validation data.
[][]Document and preserve evidence of this investigation.
[][]Where a transient equipment malfunction or other problem in the dosage form (e.g. incomplete extraction) is suspected, re-inject the retained sample preparations to assign a cause for OOS results.
[][]When laboratory error is identified, determine the source of that error (root cause) generating CAPA as per the SOP for ‘Corrective and Preventive Action’  and take corrective action to ensure that it does not occur again. Recommend on Out of Specification (OOS) Results Investigation Checklist (Annexure – IV) for performing a repeat analysis on the same sample with the same analyst. If the repeat analysis result is passing, void the initial result and approve the batch based on the re-test result.
[][]If no apparent analytical error can be found, i.e. evidence of laboratory error remains unclear, investigation stage 2 should be conducted to determine what caused the unexpected results, which may include re-testing and/or re-sampling and further investigation.
[][]Before further investigations are carried out during the next step, the subsequent procedure has to be written down in the testing protocol (Annexure – IV).
Tasks in testing protocol:
“What” is to be done (retesting, re-sampling, etc.)?
“Who” will be carrying out the investigations (1st analyst, 2nd analyst, etc.)?
“How” will the investigations be carried out, which equipment, which reagents, additional analysis of reference samples (state batch and number of analysis)?
“How often” will the analysis be repeated (final criterion to prevent “analysis” into
“compliance”)?
[][]A justification for the procedure must be given by the QC manager prior to implementation of the testing protocol and the test plan must be approved.
The number of retests should be 3 times or more
[][]The investigation may involve re-testing a portion of the original sample. The sample used for the retesting should be taken from the same homogeneous material / product that was originally collected for the lot/batch, tested and yielded the OOS result. For a liquid, it may be from the original unit liquid product or composite of the liquid product; for a solid it may be an additional weighing from the same sample composite that had been prepared by the analyst.
[][]Decisions to retest should be based on the objectives of the testing and sound scientific judgment. Retesting should be performed by an analyst other than the one who performed the original test.
[][]If the result is within specification (passes), the material/product shall be re-analyzed by first analyst with the same sample and to investigate the first analyst.
[][]If investigation of first analyst found satisfactory then release the material/product
[][]If the material/product fails by the second analyst also, simultaneously analyze after re-sample with the previously approved material/product.
[][]Re-sampling should involve analyzing a specimen from the collection of a new sample from the batch. A re-sampling of the batch should be conducted if insufficient quantity of the original sample remains to perform all further testing or if the investigation shows that the original sample was not representative of the batch. This would be indicated, for example, by widely varied results obtained from several aliquots of the original composite (after determining there was no error in the performance of the analysis). Re-sampling should be performed by the same qualified, validated methods that were used for the initial sample. However, if the investigation reveals that the initial sampling method was in error, a new accurate sampling method must be developed, qualified and documented.
[][]If previously approved material/product passes within the specification and material/product under investigation meets the specification, release the material/product.
[][]In case of material if previously approved material passes within the specification and material under investigation fails to meet the specification, material shall be rejected.
[][]In case of product if previously approved product passes within the specification and product under investigation fails to meet the specification, the laboratory investigation may be extended to review the quality of the materials (raw & primary packaging) used in manufacturing of the finished product. If any problem in quality of the materials is identified which may have potential effect on the OOS scenario, the root cause will be attributed to that problem.
[][]The procedure is then to be implemented and the results be evaluated. The results are to be summarized in Annexure – VI (report level 2).
[][]Conclusion must be drawn and it must be stated which individual values will be entered in the result (on Certificate of Analysis).
[][]The error category of the initial OOS result must also be recorded.
[][]At measures, a statement must be made explaining how similar OOS results are to be avoided in future.
[][]During investigation of an OOS result, review the previous investigation reports to determine whether a similar occurrence has taken place.
[][]When the laboratory investigation does not determine that laboratory error caused the OOS result and testing result appears to be accurate, the laboratory investigation/report to be handed over to QA manager for a full-scale failure investigation as per the SOP for ‘Deviation Procedure’.
[][]In case the process error is identified during failure investigation, suitable corrective action shall be taken. Sample shall then be analyzed as per routine procedure and accordingly release, if the results are okay.
[][]Quality Assurance Manager will initiate the CAPA based on root cause found in the failure investigation. CAPA must be implemented within agreed time lime. All CAPAs must be implemented based on criticality.

Annexure:

Annexure-I: Notification of Out of Specification Result
Annexure-II: Flow Chart for OOS Investigation
Annexure-III: Out of Specification (OOS) Register
Annexure-IV: Out of Specification (OOS) Investigation Checklist
Annexure-V: Out of Specification (OOS) Testing Protocol
Annexure-VI: Out of Specification (OOS) Investigation Report

Shaking Water Bath Calibration, Purpose :

Shaking Water Bath Calibration, The purpose of this SOP is to describe the operation, calibration and cleaning of Shaking Water Bath (Model: Clifton, NE5-28D).

Shaking Water Bath Calibration, Scope :

This procedure is applicable for Shaking Water Bath (Model: Clifton NE5-28D), installed in the quality control laboratory of XX Pharmaceuticals Limited.

Definitions / Abbreviation:

[][]SOP: Standard Operating Procedure
[][]QC: Quality Control
[][]LED: Light-emitting diode

Responsibilities:

The roles and responsibility is as follows:

Sr. Executive/Executive, QC

[][]To ensure that the instructions of this procedure are correctly followed.
[][]To maintain the record properly as per SOP.
[][]To ensure cleaning of shaking water bath maintaining safety rules.

Manager, Quality Control

[][]To ensure that this procedure is kept up to date.
[][]To confirm that the SOP is technically sound and reflects the required working practices.
[][]To arrange training on the SOP to all concerned personnel and to ensure implementation of the SOP after training.
[][]Schedule calibration of the instrument at the defined intervals.

Head of Quality Assurance

[][]Approval of the SOP
[][]To ensure the overall implementation of the SOP.

Procedure:

General precautions or operational safety:

[][]Laboratory coat, hand gloves and safety glasses must be worn while handling the instrument.
[][]Always follow good laboratory practice by ensuring substances being heated offer no risk of a hazard (explosion, implosion or release of toxic or flammable gases) or that these have been addressed. When heating substances where liberating of gases occurs suitable extraction should be used.
[][]If this product is not used in accordance with these instructions, then basic safety protection afforded by the water bath may be affected.
[][]Check the operation of over temperature device regularly.
[][]The main supply cord fitted to this product is a heat resistant type and should be replaced by an equivalent type.
[][]Always use the display or a thermometer to check the temperature. Never touch the liquid within the bath as it may be very hot.
[][]Always disconnect the bath from the electric supply before cleaning.
[][]Allow the liquid in the bath to cool down to 40°C before draining.
[][]Do not operate water bath without water.
[][]Do not open the lid during operation.
[][]Always use the lid when the instrument is not in use to avoid contaminants landing in the bath liquid.

Operation:

[][]Check the calibration sticker to ensure that the instrument is within due date of calibration.
[][]Check the water level, if required, the bath is filled to an appropriate level with purified water prior to switching it on.
[][]Switch on the bath using the ‘O/I’ switch, located at the right side of back of the shaking water bath.
[][]At first display will show “Clifton”.
[][]Press [Enter] button for Menu.
[][]To create a program, select “Do nothing” by using [UP/DOWN] key and press [Enter] button.
[][]Set the required temperature by [UP/DOWN] key and press [Enter] button.
[][]Select “Disable” by using [UP/DOWN] key and press [Enter] button.
[][]Then display will show “Stopped”.
[][]Press [Enter] button for next step.
[][]Set delay start time, ramp time by using [UP/DOWN] key and press [Enter] for next step.
[][]Set the set temperature by using [UP/DOWN] key and press [Enter] button to set the dwell time by using [UP/DOWN] key.
[][]Press [Enter] button.
[][]Select “English” by using [UP/DOWN] key and press [Enter] button for two times.
[][]Display will show a graph.
[][]Press [Enter] button for three times.
[][]Select “Start” by using [UP/DOWN] key and press [Enter] button.
[][]Select “Yes” to conform by using [UP/DOWN] key and press [Enter] button.
[][]Select “Local” by using [UP/DOWN] key and place the beaker containing sample into the shaking water bath and press [Enter] to start the instrument.
[][]LED indicator will illuminate when the bath temperature is either 4°C above or below set temperature.
[][]After completion of work, switch off the bath using ‘O/I’ switch, located at the right side of back of the shaking water bath.

Calibration:

[][]Calibrate the Shacking water bath once in a year.
[][]Fill purified water in water bath to an appropriate level.
[][]Switch on the bath using the ‘O/I’ switch, located at the right side of back of the shaking water bath.
[][]Set the desired temperature against calibrated standard thermometer at 37⁰C, 50⁰C, 90⁰C.
[][]Allow 30 minutes to equilibrate.
[][]Check the temperature using a calibrated standard thermometer and record the temperature in the calibration information sheet for shaking water bath (as per Annexure-I).

Cleaning:

[][]Clean the instrument once in a week or in between when water becomes dirty.
[][]Switch ‘OFF’ the instrument.
[][]Open the lid of the shaking water bath.
[][]Wash the lid properly with purified water.
[][]Remove the water from water bath to reduce potential biological contamination.
[][]Wash the shaking water bath with soapy water and then purified water.
[][]Mop with clean dry cotton cloth.
[][]Use 10% nitric acid on a cloth (wear suitable gloves) to remove any deposits.
[][]Add 1 litre of vinegar to water in the stainless steel tank, gently heat to 50°C for an hour, empty and brush the lime away for descaling. Rinse thoroughly afterwards.
[][]Fill with purified water up to desired level of the shaking water bath.
[][]Close the lid of bath.

Annexure:

Annexure-I: Calibration Information Sheet for Shaking Water Bath.

Calibration of Polarimeter , Purpose :

Calibration of Polarimeter , The purpose of this SOP is to describe the operation, calibration and cleaning of Polarimeter (Model: Rudolph, AUTOPOL IV) used for the determination of the optical rotation in quality control laboratory at XX Pharmaceuticals Ltd.

Calibration of Polarimeter , Scope :

This procedure describes the application of Polarimetric determinations of optical rotation of raw materials (active & excipients), intermediates and drug product etc. in the quality control laboratory of general block at XX Pharmaceuticals Limited.

Definitions/Abbreviation:

Standard Operating Procedure (SOP): A written authorized procedure, which gives instructions for performing operations.

Responsibilities:

The roles and responsibility is as follows:

Officer/Executive/ Sr. Executive, Quality Control

[][]To ensure that this procedure is followed.
[][]To maintain the records properly as per SOP.

Manager, Quality Control

[][]To ensure that this procedure is kept up to date.
[][]To confirm that the SOP is technically sound and reflects the required working practices.
[][]Arrange training on the SOP to all concerned personnel.
[][]To ensure implementation of the SOP after training.
[][]Schedule calibration of the instrument at the defined intervals.

Head of Quality Assurance

[][]Approval of the SOP.
[][]To ensure overall implementation of this SOP.

Procedure:

Precaution(s):

[][]The equipment should not be set near to room heating equipment or direct sunlight.
[][]Not to spill water or sample on the main body of the instrument.
[][]Use the instrument at an ambient temperature of 5°C to 35°C and RH lower than 90%.
[][]Disconnect the power supply before moving or cleaning of the instrument.

General procedure:

Polarimetry is used to measure the effect that an optically active molecule in solution has on polarized light. Specific Optical Rotation is defined as an Observed Optical Rotation, measured at a specific wavelength and temperature, corrected for the path length of the optical cell and concentration of the solution. The sample is normally presented to the Polarimeter as a solution, contained in a thermally controlled optical cell. A beam of polarised light is then passed through this cell and any rotation of this polarised light is measured via a detector

Reagent quality:

[][]If water is used in the preparation of sample solutions, it must be purified by distillation or deionization process.

Instrument equilibration:

[][]The instrument must be equilibrated before use. The polarimeter (set to required wavelength), must be switched on for a minimum of at least 30 minutes before use.

Preparation and storage of samples:

[][]Sample solutions must be prepared in accordance with the analytical method. Sample solutions must be discarded at the end of the working day, unless solution stability has been demonstrated.

Preparation for measurement:

[][]Connect the power cable and turn the Polarimeter ON.
[][]Press Menu to select the measurement settings.
[][]Press Scale button and select the specific optical rotation.
[][]Press Temperature correction and select off mode.
[][]Press Statistics button and select on (n-1).
[][]Exit from the Menu by pressing Exit button.
[][]Fill the Polarimeter cell with sample blank and place it into the sample chamber.
[][]Press Zero button for zeroing the sample blank.
[][]Then remove the cell from the sample chamber and discard the sample blank and rinse the cell with the sample.
[][]Fill the cell with the sample and press Measure.
[][]Type the Lot ID and press Enter.
[][]Input the sample weight and press Enter.
[][]Type the Sample Name again presses Enter.
[][]When the measurement completed, press Print Option to the results.
[][]Remove the polarimeter cell from the chamber.

Calculation of Specific Optical Rotation:
The specific optical rotation of a sample is calculated as follows:

A=αx100/I x c

Where,
[α] = Specific Rotation at Temperature, T°C and wavelength, λ nm
Α = Observed Rotation in degrees (°)
l = Path length in decimeters (dm)
c = Concentration of analyte (g /100 ml)

Cleaning of the instrument:

Cleaning of the cell:

[][]The cell must be cleaned after use. Thoroughly rinse the cell with the same solvent used for the sample, then rinse with purified water followed by methanol.

Cleaning of the sample compartment:

[][]The sample compartment should be cleaned immediately if anything is spilled into it in order to preserve the black matt finish and prevent corrosion or contamination.
[][]Use a soft cloth impregnated with a soapy solution to rub away any foreign material.
[][]Use a clean soft cloth dampened with water to rinse the cleaned surfaces thoroughly.
[][]Finally dry with a lint free cloth or tissue.

Calibration check with sucrose solution:

[][]Frequency: Yearly
[][]The check consists of determining the specific optical rotation of sucrose solution, using 20% w/v solutions. The method is detailed below. All results and calculations must be recorded on the calibration information sheet for Polarimeter.

Procedure:

Apparatus:

1dm Polarimeter tube.
Thermostat bath 20°C ± 0.2°C.

Reagent:

Sucrose Solution

Loss on Drying:

[][]Accurately weigh approximately 1g of sucrose into a clean dry weighing bottle that has previously been dried at 105°C, cooled in a dessicator for half an hour and weighed.
Dry in an oven at 105°C±2°C for 2 hours, then cool in a desiccator and reweigh.
[][]Calculate the loss in weight as a percentage and record the result on the polarimeter calibration check sheet using the following calculation:

LOD=Weight loss(g)/Weight taken(g)x100

Determination of Specific Optical Rotation at 20°C:

[][]Accurately weigh about 20 g of Sucrose into three separate 100 ml volumetric flasks. Dissolve in 80 ml of water and dilute to 100 ml with water.
[][]Zero the polarimeter using purified water in the 1dm polarimeter tube.
[][]Determine the optical rotation of each solution at 20°C ± 0.5°C in the 1dm tube.
[][]Record and calculate the results obtained for each solution on the polarimeter calibration check sheet using the following calculation:

A=αx100x100/I x c x(100-%LOD)

Where,
[α] = Specific Rotation at Temperature, 20°C and wavelength, 589.3 nm
A = Observed Rotation in degrees (°)
l = Path length in decimeters (dm)
c = Concentration of analyte (g/100 ml)
The specific optical rotation for each solution should be in the range +66.3° to +67.0° (reference the current European Pharmacopoeia).

Calibration check with Quartz Control Plate:

Frequency: Yearly
Apparatus:
Quartz Control Plate
[][]Check that the instrument and the Quartz Control Plate are at room temperature and that the instrument has been on for at least 10 minutes with the Quartz control Plate resting in the back of the sample chamber.
[][]Press Menu button to select Measurement Settings.
[][]Press Scale to select Optical Rotation.
[][]Press Temperature Correction and select Quartz.
[][]Press Statistics and select on (n-1).
[][]Press Exit button to return Manu.
[][]Press zero for zeroing the instrument.
[][]Place the Quartz Control Plate in to the sample chamber.
[][]Press Measure to measure the Quartz Control Plate.
[][]Type the Lot ID and press Enter.
[][]Type the Sample ID and press the Enter.
[][]Type the Sample Name and press the Enter.
[][]When the measurement completed press Print/Send key to print the measurement results.
[][]Remove the Quartz Control Plate form the chamber and return it to its container.
[][]Review the measurement results. Verify the Quartz Control Plate measure is within the tolerance specification.

Annexure:

[][]Annexure-I: Calibration Information Sheet for Polarimeter with Sucrose Solution
[][]Annexure-II: Calibration Information Sheet for Polarimeter with Quartz Control Plate
[][]Annexure-III: Log Book for Polarimeter