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Category: QC SOP

Categories
QC SOP

SOP Title: Operation, Cleaning and Calibration of Vacuum Pump

SOP Title: Operation, Cleaning and Calibration of Vacuum Pump

 

  1. Objective:

To lay down the procedure for Operation, Cleaning and Calibration of Vacuum Pump.

  1. Scope:

This SOP is applicable for Operation, Cleaning and Calibration of Vacuum Pump located in Quality Control Laboratory

  1. Responsibility:
  • Quality Control: To prepare and review the SOP. To follow the procedures laid down for Operation, Cleaning and Calibration of Vacuum Pump as per this SOP.
  • Engineering Department: To carry out preventive maintenance as per schedule and procedure defined.
  • Quality Assurance Department: To review and approve the SOP and Annexures.
  1. Accountability:

Head Quality Control Department, Head Quality Assurance Department

  1. Procedure:

 

     5.1 Safety Precautions/Instructions:
5.1.1 Ensure all the electrical connections are properly earthed. Ensure the power plug of the vacuum pump is fixed in the socket properly.  
5.1.2 Wear personal protective equipments such as safety glasses during operation of equipment.  
5.1.3 Ensure that the ON/OFF switch is working properly by switching “ON” the vacuum pump.             
5.2 Operation:
5.2.1 Check the validity of calibration before starting any operations.  
5.2.2 Ensure that the equipment should be cleaned before operation.  
5.2.3 Connect the vacuum pump tube to the filtration assembly.  
5.2.4 Pour the solution to be filtered into the filtration assembly.  
5.2.5 Switch ON the main switch of the equipment.  
5.2.6 After completion of filtration put ‘OFF’ the main switch.  
5.2.7 Disconnect the vacuum pump tube from the filtration assembly.  
5.3 Cleaning Procedure:
5.3.1 Clean the vacuum pump with lint free cloth before and after use.  
   5.4 Calibration Procedure:
  Frequency:  Once in a year
5.4.1       Calibration is carried out by external agency as per SOP number QC/009 “Calibration of Instruments and Equipments”.  
5.4.2 Refer Annexure for calibration test to be performed and acceptance criteria.

Sr. No. Tests Set value Acceptance Criteria
1. Pressure Verification of vacuum gauge 0 inHg ± 2 %
– 5 inHg  ± 2 %
– 10 inHg ± 2 %
– 15 inHg ± 2 %
– 20 inHg ± 2 %
– 25 inHg ± 2 %
 
5.4.3 Generate the A. R. No. on the “Instrument/Equipment Calibration Register” as per SOP and give requisition to QA department for calibration formats of equipments on the due date of calibration.  
5.4.4 For issuance of calibration report refer SOP “Control of documents, Preparation, Approval, Issuance and Maintenance.  
5.4.5 If any breakdown occurs, follow procedure as per SOP.  
5.4.6 If preventive maintenance activity is outsourced, the observations are to be transcribed in the Annexure, and external party certificate to be attached.  

  

  1. Definitions / Abbreviations:
  • Definitions:
  • Breakdown: Any activity leading to operation of instrument/equipment other than the set parameters or unusual sound or vibration observed in the instrument/equipment.
  • Calibration: Tests performed to ensure that the instrument/equipment is functioning as per set parameters. These tests are performed as per predefined frequency and also after any major repair or replacement of parts.
  • Preventive Maintenance: Maintenance activity performed to ensure that the instrument/equipment will function smoothly and to avoid breakdowns. These activities are performed as per predefined frequency.

 

  • Abbreviations:
Abbreviation Expansion
No. Number
A. R. No. Analytical Reference Number

*Note – Ready to use SOP available in “DOWNLOAD” Section.

 

Categories
QC SOP

SOP Title: Operation, Cleaning and Calibration UV-Visible Spectrophotometer

SOP Title: Operation, Cleaning and Calibration UV-Visible Spectrophotometer

  1. Objective:

To lay down the procedure for Operation, Cleaning and Calibration of UV-Visible Spectrophotometer.

 

  1. Scope:

This SOP is applicable for Operation, Cleaning and Calibration of UV-Visible Spectrophotometer located in Quality Control Laboratory.

 

  1. Responsibility:
  • Quality Control Department: To prepare and review the SOP. To follow the procedures laid down for Operation, Cleaning and Calibration of UV-Visible Spectrophotometer as per this SOP.
  • Engineering Department: To carry out preventive maintenance as per schedule and procedure defined.
  • Quality Assurance Department: To review and approve the SOP and Annexures.

 

  1. Accountability:

Head Quality Control Department, Head Quality Assurance Department

  1. Procedure:
5.1          Safety Precautions/Instructions:
5.1.1 Ensure all the electrical connections are properly earthed. Ensure the power plug of the UV-Visible Spectrophotometer is fixed in the socket properly.  
5.1.2 Wear personal protective equipments such as safety glasses, hand gloves, nose mask during operation of instrument.  
5.1.3 Ensure that the ON/OFF switch is working properly by switching “ON” the UV-Visible Spectrophotometer.             
5.2        Operational  Procedure:
5.2.1 Check the validity of Calibration before starting any operations.  
5.2.2 Switch ON the instrument.  
5.2.3 The spectrophotometer performs various checks and initialization settings.  
5.2.4 The time required for initialisation is around 4-5 minutes.  
5.2.5 Wait for the initialization of the instrument.  
5.2.6 After normal completion of the initialization procedure the Main Menu will appear on the screen.  
  Photometric Absorbance/Transmittance Mode:
5.2.7 To select the Photometric MEASUREMENT, press “1”.  
5.2.8 To select Absorbance/Transmittance by Pressing the  key toggles between Absorbance and Transmittance.  
5.2.9 Set the wavelength [ l ] key. Enter the wavelength required and press [ENTER] key.  
5.2.10 Put the blank solution in both the cuvettes and place them in the cell holder compartment.  
5.2.11 Press the key [AUTO ZERO]. Blank will automatically give zero absorbance / Transmittance.  
5.2.12 Open the compartment and remove the first cuvette. Put the test solution in first cuvette and place it in the cell holder in the sample compartment.  
5.2.13 Read the Absorbance/ Transmittance from the screen. Press (PRINT) to take print of Absorbance/ Transmittance.  
5.2.14 Press the [RETURN] key to return to the preceding screen.  
5.2.15 Remove both the cuvettes, discard the solution and wash with purified water and then rinse with acetone.  
5.2.16 Scanning Range: Set the range of the wavelength scan. Enter the scan starting and ending wavelength in that order. The wavelength input is 190 nm to 1100 nm and the starting wavelength must be the longer wavelength of the two. The minimum scan range is 1 nm (Scan start wavelength) to greater than or equal to 1 nm (Scan end wavelength).  
5.2.17 The data sampling interval is determined from the scanning rate (1) and the wavelength range, so that the number of data pieces that are scanned by a single run is 1,000 minimum.  
5.2.18 As the data sampling interval becomes larger, the number of data pieces becomes smaller, which means that the practical scanning rate becomes faster.  
5.2.19 No. Of scans: Set the number of times a scan will be repeated. If this is set to 2 or More times, the interval setting will be displayed with the scanning repetitions on the same display line. When you press the START/STOP key once, measurement will be repeated only the set number of times.  
5.2.20 Display mode: This parameter will toggle between Sequential <-> Overlay each time this item is selected.  
5.2.21 Sequential: The screen is renewed for each scan and only the spectrum from that measurement is displayed.  
5.2.22 Overlay: The screen is not updated with each scanning result. The spectrum display for each scan is left as it is so that multiple spectra are overlaid in the display.  
5.2.23 Gain (E mode only): This will be displayed only in the E (energy) mode. This sets the gain for the photometer amplifier so that measurement can be performed without saturation of the energy curve.  The minimum setting is 1 and the maximum is 4. Sensitivity is increased by approximately 4 times with each level.  
5.2.24 Light Source: (E mode only): This will be displayed only in the E (energy) mode. Select a light source for the energy measurement. The selected light source will be used regardless of the parameter setting for the light source.  
5.2.25 W lamp: Selects the tungsten iodine lamp (halogen lamp) as the light source.  
5.2.26 D2 lamp: Selects the deuterium lamp as the light source.  
5.2.27 OFF: Turns OFF both of the W and D2 lamps. The light source mirror turns to the third light source.  
5.2.28 Put the blank solution in both the cuvettes and place them in the cell holder in the Compartment.  
5.2.29 Select the Meas. Mode, Scanning range, Rec. range, Scan speed etc as per requirement.  
5.2.30 Press the ‘F1’ key for [Base Corr.] base line correction.  
5.2.31 After competition of base line correction. Open the compartment and remove the first cuvette.  
5.2.32 Put the test solution in first cuvette and place it in the cell holder in the sample compartment.  
5.2.33 Press the START/ STOP Key. The measurement will be started with the measurement screen displayed.  
5.2.34 To stop the measurement, press the STRAT/ STOP Key again. After the measurement has been finished (stopped), the measurement screen will be displayed.  
5.2.35 The measurement result can be printed out as a hard copy of the screen on the printer (optional) by pressing the PRINT KEY. Pressing the RETURN key will return to the parameter configuration screen.  
5.2.36 After reading, take out both the cuvettes from the sample compartment.  
5.2.37 Press the [RETURN] key, to return to the preceding screen and switch OFF the instrument.  
5.2.38 Update the “Instrument/Equipment Usage Log Book” as per SOP.  
     5.3 Cleaning Procedure:
5.3.1 Wash both the cuvettes with distilled water and then dry with methanol. Place them back into the cuvette case.  
     5.4 Calibration Procedure:
  Frequency:  Quarterly or after carrying out any major maintenance work.
5.4.1 Generate the A. R. No. On the “Instrument/Equipment Calibration Register” as per SOP number and give requisition to QA Department for calibration formats of instruments on the due date of calibration.  
5.4.2 For issuance of calibration report refer SOP.  
5.4.3 Perform the calibration of instrument as per Annexure and procedure mentioned below.  
5.4.4 Calibration of UV-Visible Spectrophotometer is performed for below parameters:

1. Control of Wavelength

2. Control of Absorbance

3. Limit for Stray Light

4. Resolution

5. Derivative Spectrophotometry

6. Cell Check

  
  1. Control of Wavelength:
5.4.5 Control of Wavelength is done by using Holmium Perchlorate solution  
  5.4.6 Preparation of Holmium Perchlorate solution:

Dissolve 0.400 gm of Holmium Oxide in 6 ml of 1.4 M Perchloric acid solution and dilute to 10 ml with 1.4M Perchloric acid solution.

  
  5.4.7 Preparation of 1.4 M Perchloric acid solution:

Dilute 5.74 ml of Perchloric acid to 50 ml with purified water.

  
  5.4.8 Repeat the procedure given for operation under ‘Spectrum Mode’.  
  5.4.9 Read the absorbance of solution in spectrum mode from 200 nm to 400 nm and 400 nm to 600 nm, using 1.4M Perchloric acid solution as blank.  
  5.4.10 Check the wavelengths at 241.15 nm, 287.15 nm, 361.50 nm, 486.00 nm and 536.30 nm.  
  5.4.11 Enter the details in calibration report as per Annexure. Ensure that the results obtained, comply with the acceptance criteria.  
    2. Control of Absorbance:
  5.4.12 Control of Absorbance is done by using Potassium Dichromate.  
  5.4.13 Preparation of Potassium dichromate solution:

For UV range: Dissolve 0.060 gm of Potassium Dichromate previously dried to constant weight at 1300C in 500 ml of 0.005M sulphuric acid and dilute to 1000 ml with 0.005M sulphuric acid.

For Visible range: Dissolve 0.060 gm of Potassium Dichromate previously dried to constant weight at 130°C in 50 ml of 0.005M sulphuric acid and dilute to 100 ml with 0.005M sulphuric acid.

  
  5.4.14 Repeat the procedure given for operation under ‘Spectrum Mode’.  
  5.4.15 Take the spectrum scan with Meas. Mode ® absorbance (ABS), Scanning range® 220 nm to 460 nm, Rec. Range ® 0.200 to 0.980 Absorbance and scan speed ® medium or measure the absorbance at specified maximum wavelengths.  
  5.4.16 Take out the print and note the Absorbance at 235 nm, 257 nm, 313 nm, 350 nm and 430 nm and calculate A (1%, 1cm) using the formula given below.  
  5.4.17 Calculation for UV range: –    Absorbance x 1 x 1000

Weight of  K2Cr2O7 in gm x 100

  
  5.4.18 Calculation for Visible range: –    Absorbance x 1 x 100

Weight of  K2Cr2O7 in gm x 100

  
  5.4.19 Enter the details in calibration report as per Annexure No. 01. Ensure that the results obtained, comply with the acceptance criteria.  
    3. Limit for Stray Light:
  5.4.20 Limit for stray Light is detected by using 1.2 % w/v solution of Potassium Chloride (KCl) in distilled water with a path – length of 1cm at 200 nm when compared with purified water as reference liquid.  
  5.4.21 Limit for stray Light should be more than 2.0.  
  5.4.22 Enter the details in calibration report as per Annexure No. 01. Ensure that the results obtained, comply with the acceptance criteria.  
    4. Resolution:
  5.4.23 Record the spectrum of a 0.02%v/v solution of Toluene in Hexane.  
  5.4.24 Preparation of 0.02%v/v solution of Toluene in Hexane:

Pipette out 1.0 ml of Toluene in 50 ml dried volumetric flask and dilute to 50 ml with Hexane and shake well (solution A).

Pipette out 1.0 ml of (solution A) in 100 ml dried volumetric flask and dilute to 100 ml with Hexane (Solution B).

  
  5.4.25 The minimum ratio of the Absorbance at the maximum at 269 nm to that at the minimum at 266 nm is not less than 1.5.  
  5.4.26 Enter the details in calibration report as per Annexure No. 01. Ensure that the results obtained, comply with the acceptance criteria.  
    5.      Derivative Spectrophotometry:
  5.4.27 Record the spectrum of a 0.02 % v/v solution of Toluene in Methanol in the range 255 nm to 275 nm, using methanol as blank.  
  5.4.28 Preparation of 0.02 % v/v solution of Toluene in Hexane:

Pipette out 1.0 ml of Toluene in 50 ml dried volumetric flask and dilute to 50 ml with methanol and shake well (solution A).

Pipette out 1.0 ml of (solution A) in 100 ml dried volumetric flask and dilute to 100 ml with methanol (Solution B).

  
  5.4.29 A small negative extrema located between two large negative extrema at about 261 nm and at 268 nm should be clearly visible.  
  5.4.30 Enter the details in calibration report as per Annexure No. 01. Ensure that the results obtained, comply with the acceptance criteria.  
    6.      Cell check
  5.4.31 First make auto zero using air as a reference.  
  5.4.32 Measure the absorbance of each cell one by one by filling with methanol at 240 nm.  
  5.4.33 Keep the filled cell in sample compartment by keeping reference cell empty.  
  5.4.34 Enter the details in calibration report as per Annexure No. 01. Ensure that the results obtained, comply with the acceptance criteria.  
  5.4.35 Update the “Instrument/Equipment Usage Log Book”, “Annual Calibration Schedule” and “Monthly Calibration Schedule” as per SOP.  
  5.4.36 Affix the “Calibration Status Label” on the Instrument as per SOP  
  5.4.37 If calibration activity is outsourced, the values are to be transcribed in the Annexure and external party certificate to be attached.  

 

  1. Definitions / Abbreviations:
  • Definitions:
  • Breakdown: Any activity leading to operation of instrument/equipment other than the set parameters or unusual sound or vibration observed in the instrument/equipment.
  • Calibration: Tests performed to ensure that the instrument/equipment is functioning as per set parameters. These tests are performed as per predefined frequency and also after any major repair or replacement of parts.
  • Preventive Maintenance: Maintenance activity performed to ensure that the instrument/equipment will function smoothly and to avoid breakdowns. These activities are performed as per predefined frequency.

 

  • Abbreviations:
Abbreviation Expansion
UV Ultra Violet
ml millilitre
mg milligram
% Percentage
T Transmittance
l Wavelength
ABS Absorbance
D2 Deuterium
g gram
M Molar
nm nanometer
0C Degree Celsius
K2Cr2O7 Potassium Dichromate
w/v Weight by volume
v/v Volume by volume
F Function
A. R. No. Analytical Reference Number

 

*Note – Ready to use SOP available in “DOWNLOAD” Section.

 

Categories
QC SOP

SOP Title: Chromatographic Analysis, Trouble shooting and Documentation

SOP Title: Chromatographic Analysis, Trouble shooting and Documentation

  1. Objective:

To lay down the procedure for Chromatographic Analysis, Trouble shooting and Documentation in the Quality Control Department.

 

  1. Scope:

This procedure is applicable for Chromatographic Analysis, Trouble shooting and Documentation in the Quality Control Department.

 

  1. Responsibility:
  • Quality Control Department: To prepare and review the SOP. To follow the procedures laid down for Chromatographic Analysis, Trouble shooting and Documentation in Quality Control Department as per this SOP.
  • Quality Assurance Department: To review and approve the SOP and Annexure.

 

  1. Accountability:

Head Quality Control Department, Head Quality Assurance Department

  1. Procedure:
5.1         Mobile Phase :
5.1.1          The mobile phase shall be prepared as per respective standard test procedure.  
5.1.2          Always use HPLC grade chemicals & solvents. Always filter mobile phase through 0.45 µm filters.  
5.1.3          Filter buffer and organic solvent (if required) separately with 0.45 µm filter and then mix to avoid evaporation of organic solvent.  
5.1.4          If organic solvent already filtered through 0.45 µm or lesser then no need to filter.  
5.1.5          Shake the mobile phase bottle till the buffer and solvents gets properly mixed.  
5.1.6          Ensure that there is no phase separation.  
5.1.7          Degas the mobile phase by sonicating 2 – 5 minutes or as required.  
5.1.8          Mobile phase bottle should be labelled and filled as per Annexure No. 01.  
5.1.9          Use freshly prepared mobile phase for HPLC analysis which will be valid for three days only or till the completion of running sequence or based on mobile phase stability data whichever is letter and in case of sensitive mobile phase use freshly prepared mobile phase.  
5.1.10      Do not use any hazy mobile phase during HPLC analysis.  
5.2              Standard Preparation :
5.2.1          The standard shall be prepared as per respective standard test procedure, taking into consideration the Standard solution stability and storage requirement.  
5.3              Analysis :
5.3.1              Always use fresh HPLC vials & septa for analysis.  
5.3.2        Prepare the sequence as per respective standard test procedure.  
5.3.3        Prior to start the sequence analyst shall take the printout of sequence and shall sign with date. Reviewer shall review the sequence and put the sign and date. In case, reviewer is not available in the shift then another analyst shall review the sequence. In case, another analyst also not available then run the sequence by self-reviewing and sequence shall be reviewed by reviewer on next day.  
5.3.4        Pre-Evaluation injection: A system suitability check shall be injected at the beginning to check the chromatographic system suitability, mobile phase preparation and proper saturation of the HPLC column.  
5.3.5        Injection for system suitability check shall be processed and shall not be considered for calculation or reporting, it is just to ensure the system is ok. However repeat injection of standard avoided and no sample injection should be injected.  
5.3.6        The system suitability shall be established as per the standard test procedures, before starting the analysis.  
5.3.7        A printout of sequence shall be attached with analytical Analytical Work Report along with chromatograms.  
5.3.8     Injection sequence shall be as per the standard test procedure. If no specific sequence are mentioned in the standard test procedure then follow the sequence as mentioned below.  
   5.4 Preparation of sample Set/ Sequence:
5.4.1    Preparation of sequence is mainly separated in to two sets, i.e. Pre-Evaluation (PE) and Main Sequence set.  
5.4.2     Pre-Evaluation(PE): Sequence is prepared to check system suitability parameter by injecting, Blank, System Suitability Solution, Standard Solution  
5.4.3     Pre-Evaluation(PE) (Sequence – I)

 

Assay/ RS Content uniformity(CU) Dissolution
Blank Blank Blank
Standard Solution Standard Solution Standard Solution
System Suitability

(if applicable)

 System Suitability

(if applicable)

 System Suitability

(if applicable)
 
5.4.4  Main Sequence set (Sequence – II):-  
 

Assay Content uniformity Dissolution Related Substance
Blank Blank Blank Blank
System Suitability

(if applicable)

 System Suitability

(if applicable)

 System Suitability

(if applicable)

 System Suitability (if applicable)
Standard Solution-1 Standard Solution-1 Standard Solution-1 Blank (if required)
Standard Solution-2 Standard Solution-2 Standard Solution-2 Standard Solution-1
Standard Solution-3 Standard Solution-3 Standard Solution-3 Standard Solution-2
Standard Solution-4 Standard Solution-4 Standard Solution-4 Standard Solution-3
Standard Solution-5 Standard Solution-5 Standard Solution-5 Standard Solution-4
Standard Solution-6

(if applicable)

 Standard Solution-6

(if applicable)

 Standard Solution-6

(if applicable)

 Standard Solution-5
Blank Blank Blank Standard Solution-6(if applicable)
Sample Solution 1-Inj-1 Tablet-1 Tablet-7 Blank Blank
Sample Solution 1-Inj-2 Tablet-2 Tablet-8 Placebo Placebo
Sample Solution 2-Inj-1 Tablet-3 Tablet-9 Sample Solution 1 Sample Solution 1
Sample Solution 2-Inj-2 Tablet-4 Tablet-10 Sample Solution 2 Sample Solution 2
Sample Solution 3-Inj-1 Tablet-5   Sample Solution 3 Sample Solution 3
Sample Solution 3-Inj-2 Tablet-6   Sample Solution 4 Sample Solution 4
BKT_Standard Solution BKT_Standard Solution BKT_Standard Solution Sample Solution 5
Blank(if applicable) Blank(if applicable) Blank(if applicable) Sample Solution 6
– – – Blank
– – – BKT_Standard Solution
– – – System Suitability(if applicable)

Note: In case for any single batch testing is performed on 12 tablets then inject bracketing standard after 12 injection in that case no need to inject bracketing standard after 6 injections.
   5.5  
5.5 1     In case No. of injections for standard are not mentioned in standard test procedure then inject the five replicates of the standard. In case where diluted standard has to be injected then inject six replicates for the same.  

 

 

 
5.5 2     The system suitability shall be demonstrated throughout the run by bracketing standards RSD.  
5.5 3     After every six injections or end of the sample set, a single standard (Bracketing standard) solution injection shall be made and the cumulative/overall RSD of these standards with earlier system suitability standards shall be calculated. The acceptance criteria for system suitability shall be overall RSD not more than 2.0 % for assay and 5.0 % for RS or as per standard test procedure.  
5.5 4     In case, system suitability with bracketing standard is not meeting with acceptance criteria, then previous sample shall be invalidated with remarks.  
5.5 5     The retention time of standard and sample peaks should be within 10 % of actual retention time throughout the analysis for same concentration solutions.  
5.5 6     Resolution, tailing factor and theoretical plates shall comply with respective standard test procedure.  
5.6           Adjustment of Chromatographic Condition:
5.6.1    Composition of mobile phase: The amount of the minor solvent component may be adjusted by ± 30% relative to minor component or ±2% absolute, whichever is the larger, if required to meet the system suitability criteria, No other component is altered by more than 10% absolute.  
5.6.2    pH of the aqueous component of the mobile phase: ±0.2 pH, unless otherwise stated in the standard test procedure, or ± 1.0 pH when neutral substances are to be examined.  
5.6.3    Concentration of salts in the buffer component of a mobile phase: In the buffer component of a mobile phase: ± 10 per cent  
5.6.4       Detector wavelength: No adjustment permitted  
5.7               
5.7.1    Column length: ± 70 %  
5.7.2    Column internal diameter:  ± 25 %  
5.7.3    Particle size: Maximal reduction of 50 % of particle size, no increase permitted.  
5.7.4    Flow rate: ± 50 per cent. When in a monograph the retention time of the principle peak is indicated, the flow rate has to be adjusted if the column internal diameter has been changed.  
5.7.5    Injection Volume: The injection volume can be reduced as far as consistence with accepted precision and detection limits, no increase permitted.  
5.7.6    Gradient Elution: The configuration of the equipment employed may significantly alter the resolution, retention time and relative retention time described in the method.  If this occurs, it may be due to excessive dwell volume, which is the volume between the point at which the 2 eluents meets and the outlet of the column.  
5.8            
5.8.1        Stationary phase:

Column length : ± 70 %

Column internal diameter: ± 50 %

Particle size : Maximal reduction of 50 %, no increase permitted

Film thickness: -50 % to + 100 %

Flow rate : ± 50 %

Temperature: ± 10 %

  
5.8.2        Injection volume: May be decreased, provided detection and repeatability are satisfactory.  
5.9           Recording of Chromatograms for Assay/CU/ Dissolution Test:
5.4.1     Run the chromatogram as per run time given in STP.  
5.4.2     Unless otherwise specified, run the chromatogram at least 1.5 times of the main Peak Retention Time (RT).  
5.10       Integration, processing and printing of chromatograms for Assay/CU/ Dissolution Test:
5.10.1                         Set the integration parameter i.e. Peak Width, Peak Threshold, Minimum Height, Minimum Area, appropriately for proper marking of peak.  
5.10.2                         Before integration, adjust the scaling of chromatogram template such a way that main peak height should more 70% of full scale chromatogram.  
5.10.3                         Scaling of the chromatograms should be same for all chromatograms throughout the first to last injection of that particular sequence.  
5.10.4                         Changing of height of in between chromatogram not allowed unless and until justified.  
5.10.5                         Re-processing of chromatogram is not allowed unless and until justified.  
5.10.6                         Take the print out of processing method with set integration parameter at the end of chromatogram processing.  
5.10.7                         Take the chromatogram print out of standard solution (Sequence-I), Standard solution first Replicate (Sequence-II) and last bracketing standard with system suitability parameter as per STP.  
5.10.8                         The system suitability Chromatogram table should contain peak name, RT, Area, Tailing Factor/ Theoretical plates/ Resolution/ Capacity Factor etc. as applicable.  
5.10.9                         Rest of the other chromatogram table should contain peak Name, RT and Area.  
5.10.10                     The chromatograms which are disregarded shall be invalidated with reason. The reason for disregarding the chromatograms may be abnormal peak shape, system suitability failure due to variation in area count/inconsistent area, faulty integration, ghost peak or any other reason.  
5.10.11                     The analyst shall write the reason for disregarding with “INVALID /Invalid Data” remark/stamp on the chromatogram. The disregarded chromatogram shall be filed along with the valid chromatograms.  
5.10.12                        Recording of chromatograms for Related Substance/ Impurity/ Chromatographic purity Test:-
5.10.13                        Run the chromatogram as per run time given in STP.  
5.10.14                        Unless otherwise specified, Run the sample chromatograms at least 2.5 times of the main peak RT.  
5.10.15                        Run the 1st blank, System suitability solution, Placebo solution and last blank equal to sample run time.  
5.10.16                        Unless otherwise specified, Run the Standard solution replicate and other blanks chromatograms at least 1.5 times of the main peak RT.  
5.11       Integration/processing/printing of chromatograms for Related Substance/ Impurity/ Chromatographic purity Test:-
5.11 1    Before integration, adjust the scaling of chromatograms such a way that smallest peak on chromatogram to be seen.  
5.11 2    Set integration parameter i.e. peak width, peak threshold, Base to Base, Valley to valley, tangent peak etc.  
5.11 3    Same integration parameters shall be set for Blank, Placebo and sample chromatograms.  
5.11 4    Same scaling shall be set for Blank, Placebo and sample chromatograms.  
5.11 5    For standard solution, system suitability solution and other blanks different integration can be set according to requirement. However for standard replicates and bracketing standard processing same integration parameter and same scaling shall be used.  
5.11 6    Changing of height of in between chromatogram not allowed unless and until justified.  
5.11 7    Re-processing of chromatogram is not allowed unless and until justified.  
5.11 8    Take the print out of processing method with set integration parameter at the end of chromatogram processing.  
5.11 9    Take the chromatogram print out of standard solution (Sequence-I), Standard solution first Replicate (Sequence-II) and last bracketing standard with system suitability parameter as per STP.  
5.11 10                        The system suitability Chromatogram table should contain Peak Name, RT, Area, Tailing Factor/ Theoretical plates/ Resolution/ Capacity Factor etc. as applicable.  
5.11 11                        Rest of the other chromatogram table should contain peak Name, RT Area and Area %.  
5.11 12                        Manual integration allowed for small peaks wherever auto integration not possible.  
5.11 13                        Blank and placebo shall be integrated as per sample solution integration.  
5.11 14                        Do not consider the peak for calculation from sample solution which have same RT as that of Blank and placebo solution peak. Disregard Blank and placebo peaks from sample solution.  
5.11 15                        Calculate the impurities as mentioned in the STP.  
5.11 16                        Based on the RT or RRT name the impurities in chromatograms or calculation sheet.  
5.11 17                        Report the impurities as per specification.  
5.11 18                        During system suitability only initial replicate injections shall be considered for calculation of % RSD.  
5.11 19                        If necessary, Reprocessing of chromatograms shall be done and shall be documented with reason(s). Invalidate previous chromatograms with remark.  
5.11 20                        Any unknown peak found in the chromatogram other than the diluent, placebo and impurity peaks shall be integrated and considered as unknown peak.  
5.11 21                        Integration parameters such as peak width, slope sensitivity, minimum peak area / height etc. shall be recorded as used for each chromatogram or print out of integration parameters shall be attached with the chromatograms.  
5.11 22                        Attach the sequence print and method print for the entire analysis.  
5.11 23                        Sequence print shall contain Vial No, Sample Name, Sample ID, Method File, Data File, Injection Volume, column ID, Analyst Name etc.  
5.11 24                        Analyst should sign all the chromatograms with date.  
5.11 25                        Enter the usage details in instruments, Columns usages record and reference / working standard usage logbooks.  
5.12       Trouble Shooting in Chromatographic Analysis:-
Failing of Tailing Factor/ Theoretical Plates. Column bonding/packing detoriated due to continuous use. Flush the column with hot water, followed by 90% organic solvent, replace/ discard column if necessary. Take new column.
Wrong column selection. Connect correct column as per STP and start.
Not using HPLC Grade solvent in mobile phase Use of HPLC grade solvent and chemicals.
Column leakage Remove the ferrules/ tube fittings and refit it tightly. Replace if necessary.
Solution degradation. Prepare fresh solution and inject.
Ghost peak in Blank, Standard solution and sample solution Contamination in diluents Prepare new diluent. Make all fresh preparation with new diluents.
Vials Contamination or particular vial Contamination. Fill solution in new vials discard old vials.
Particular flask contamination. Make fresh solution with new flask.
Filtration Syringe contamination. Filter sample solution with new syringe.
Syringe filter contamination Filter sample solution with new syringe filter.
Mobile phase contamination Prepare new mobile phase and use.
No peak observed in Chromatograms. Blank/diluent solution filled instead of standard/sample solution. Fill new vial with standard/sample solution and inject.
Wrong standard solution selection. Prepare new standard and inject.
Wrong wavelength selection. Select correct wavelength and start.
Column leakage. Remove the ferrules/ tube fittings and refit it tightly. Replace if necessary.
Injector leakage. If yes, contact service engineer.
Injector needle broken. Contact service engineer.
Wrong mobile phase. Check and prepare new mobile phase.
Wrong column selection. Check and use proper column.
No vial in a tray at given position. Check vial tray & vial position. Keep vial at correct position.
 

  Broken/ leakage in vial. Check for vial intactness. Fill new vial.
Septa fall in vial. Check vial and fill new vial.
Wrong dilution to low concentration. Check dilutions. Make proper dilutions.
Leakage in detector tubing. Check detector tubing, replace if necessary.
Wrong instrument method selection. Check method properly selected.
Sequence interrupted/ aborted. Power failure. Check power failure data.
Software connectivity lost. Check connectivity. Restart the instrument and software.
Vail not detected. Check vials position in tray.
Computer shutdown/ malfunctioning. Check computer.
Malfunctioning of HPLC parts like, injector detector etc. Check for particular part. If yes, contact service engineer.
System over pressure/ Back pressure Check for Blockage in tubing/reservoir filters/ Column back pressure.
Flush the tubing with hot water or replace.
Sonicate reservoir filter with hot water and methanol.
Wash the column with hot water.
Peak split/ distorted peak. Column detoriation. Wash the column and check, replace column if necessary.
Solution degradation. Check solution stability, prepare fresh solution and inject.
Wrong column selection Check and use proper column.
Wrong diluent used Check diluent preparation, prepare new and inject

 
 

Failing resolution. Column bonding/packing detoriated due to continuous use. Flush the column with hot water, followed by 90% organic solvent, replace/ discard column if necessary. Take new column.
Wrong column selection. Connect correct column as per STP and start.
Not using HPLC Grade solvent in mobile phase Use of HPLC grade solvent and chemicals.
Solution degradation. Check solution stability,  prepare fresh solution and inject
Impurity degradation. Check impurity solution stability. Prepare fresh solution and inject.
Peak merging. Column detoriation. Wash the column and check, replace column if necessary.
Wrong column selection. Check and use proper column
Wrong mobile phase preparation. Check and prepare new mobile phase.
Wrong sequence preparation. Typo error in Standard/ sample name. Training to Analyst/ Reviewer.
Assess the impact of error on quality of product and make decision.
Wrong instrument method selection. Manual error or analyst error. Training to Analyst/ Reviewer.
Re-inject sequence if it is within solution stability or else prepare fresh solution
Wrong injection volume. Manual error or analyst error. Training to Analyst/ Reviewer.
Re-inject sequence if it is within solution stability or else prepare fresh solution
5.13          Procedure for Hypothetical Analysis:-  
5.13.1      Hypothetical analysis used when there is no assignable cause is identified during investigation of lab error, incidence of testing samples.  
5.13.2      Any evidence or ideas that may indicate a possible root cause can be explored or verified by hypothesis testing.  
5.13.3    Design a protocol for hypothetical testing and define the tentative steps that would follow to investigate the assignable cause.  
5.13.4    Hypothetical analysis protocol shall be designed by considering all possible suspected causes.  
5.13.5    1) Hypothesis testing must always be defined in a pre-approved protocol. This helps assure that testing is well planned, is scientifically sound and justified and prevents inadvertent use of inappropriate ad-hoc testing. Such testing can easily be interpreted as an attempt to “test into specification” and is likely to result in unfavourable scrutiny from regulatory authorities. Hypothesis testing is essentially a process of elimination. A well designed hypothesis testing protocol explores the possibilities, eliminates those proven as not the case and works in a structured manner towards defining the root cause or potential root cause(s) based on scientific and conclusive evidence.

2) The hypothesis testing protocol must define:

•A description of the hypothesis test

•The potential root cause being investigated

•The samples that will be tested

•Exact details on how to execute the test

•How the data will be evaluated

3) The results from hypotheses testing must only be used to confirm or discount a root cause. They cannot replace the original result or be reported as final analytical results.

  
5.13.6    Evaluate all suspected causes one by one step wise. If assignable causes found during first step then stop further testing close the investigation with proper scientific justification.  
5.13.7    Recommend corrective and preventive action wherever applicable.  
5.13.8    Hypothetical analysis may include but not limited to following points;  
5.13.9    Investigate sample Preparation error, sample degradation, sample contamination.  
5.13.10                        Hypothesis testing should be restricted to original samples wherever possible. It’s also advisable that hypothesis testing gives consideration to analysis by a second analyst.  
5.13.11  Re-injection of same sample, preparation of new sample, preparation of new mobile phase, changing analyst, changing column, changing chemicals and its make, Re-sampling of RM/FP/In-process sample,  
5.13.12  Where an assignable cause is not determined by the laboratory investigation then manufacturing error investigation must be undertaken.  
5.13.13  Investigation of manufacturing steps, handling and storage of sample in Production Area, Handling and storage of RM, Cross contamination in RM, Cross contamination in production, investigation of Packing steps, Effect of temperature on sample during packing, contamination of primary packing material, carryover of previous product manufactured.  
5.13.14  Cleaning verification of previous product, cross contamination in dispensing area, Quality of water used in manufacturing process, Any suspect on calibration of Equipment used in manufacturing and testing, health and hygiene of the personal involved in manufacturing and testing of product.  
5.13.15                        If that investigation does not reveal a manufacturing error, and sufficient analytical data exist from the retest to decide that the original out-of-specification result arose from an unassignable laboratory error, then one may conclude that the original out-of-specification result is not representative of the batch. Product history also should be considered at this point.  
5.14       HPLC System conversion for Reverse phase and Normal phase  :-  
  System conversion from Reverse phase to Normal phase:-
5.14.1    Purge and flush the HPLC system with water for 30 to 35 minutes all parts.  
5.14.2    Then Purge and flush the HPLC system with methanol for 30 to 35 minutes all parts.  
5.14.3    Then flush the HPLC system with IPA for 30 – 35 minutes  
  System conversion from Normal phase to Reverse phase:-
5.14.4    Purge and flush the HPLC system with IPA for 30 to 35 minutes all parts.  
5.14.5    Then Purge and flush the HPLC system with methanol for 30 to 35 minutes all parts.  
5.14.6    Then flush the HPLC system with water for 30 – 35 minutes  
5.15       Logging and Reporting Lab Error Report (LER):
5.15.1   Lab error report (LER) shall be filed for chromatographic day to day activity which does not have impact on quality of the product and need immediate corrective action in chromatographic errors before injecting sample solution.

For Example:- system suitability failure, column leakage etc.

  
5.15.2             Lab Error Report Log should be maintained as per annexure.  
5.15.3 In case sample solution is injected in HPLC then file an incident and proceed as per SOP “Incident Reporting and investigation”.  
5.15.4             Analyst shall report to Supervisor or Section Head immediately when error occur. The supervisor shall perform initial investigation to find out cause of error and shall suggest immediate corrective action.  
5.15.5             Error shall be logged in the “Lab Error Report Log” as per define format and number shall be assigned.  
5.15.6             Lab Error Report number shall be allotted to each error as mentioned below:

LER/YY/NNN where,

LER denotes Lab Error Report

YY denotes last two digit of the current year and

NNN denotes three digit serial number as (001, 002, 003….).

For example: – Lab Error Report Number for first error of year 2024 shall be assigned as LER/2024/001.

  
5.15.7          The “Lab Error Report” shall be maintained as per define format having the details like Lab Error Report No., Date/Time, Product, Batch No./A.R.No., Description of error, Initial Investigation and cause of error, Immediate corrective action, Impact Evaluation/further course of action, Preventive action, verified by QA, Closing Date, Closing remark by HOD/Designee.  
5.15.8             HOD/Supervisor shall evaluate impact of LER and based on outcome of immediate corrective action will suggest further course of action and preventive action.  
5.15.9             The LER shall be send to QA Department for review before final closure.  
5.15.10         If required, QA shall suggest further course of action in LER by considering regulatory aspects.  
5.15.11         The maximum time for investigation and closeout of LER shall be 30 working days from the date of filing.  
5.15.12         If the investigation is extended then justification shall be documented for the same.  

 

 

  1. Definitions / Abbreviations :
  • Definitions :
  • Quality Control Associate: Analyst, Supervisor, Executive of Quality Control Department or any personnel trained to perform duties as per this SOP.
  • Quality Assurance Associate: Executive of Quality Assurance Department or any personnel trained to perform duties as per this SOP.
  • Chromatography is defined as a procedure by which solute are separated by a dynamic migration process in a system consisting of two or more phases, one of which moves continuously in given direction and in which the individual substances exhibit different mobilities by reason of differences in adsorption, partition, solubility, vapour pressure, molecular size, or ionic change density. The individual substances thus separated can be identified or determined by analytical procedure.

 

  • Abbreviations:
Abbreviation Expansion
QC Quality Control
e.g. Example
No. Number

 

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QC SOP

SOP Title: Analytical Data Review and Result Transcription

SOP Title: Analytical Data Review and Result Transcription

  1. Objective:

To lay down the procedure for Analytical Data Review and Result Transcription in the Quality Control Department.

 

  1. Scope:

This procedure is applicable for Analytical Data Review and Result Transcription in the Quality Control Department.

 

  1. Responsibility:
  • Quality Control Department: To prepare and review the SOP. To follow the procedures laid down for Analytical Data Review and Result Transcription in Quality Control Department as per this SOP.
  • Quality Assurance Department: To review and approve the SOP and Annexure.

 

  1. Accountability:

Head Quality Control Department, Head Quality Assurance Department.

 

  1. Procedure:
5.1      Compilation of Analytical Data:  
5.1.1                          Analysis shall be carried out as per standard testing procedure and reporting of results shall be carried out with respect to specification.  
5.1.2                        All raw data like printouts of weight prints, chromatograms, spectrum, and contract testing laboratories reports shall be affixed.  
5.1.3                        Raw data sheet and all weight prints, chromatograms, spectrum shall be signed by the analyst and reviewed by reviewer.  
5.1.4                        Ensure that all entries shall be in respective log Books during analysis.  
5.1.5                        All relevant information shall be filled in respective raw data sheet.  
5.1.6                        Ensure that always use the current lot of working standard and reference standard, wherever applicable.  
5.1.7                        Ensure that correct factor used during the water content testing with Karl Fischer Titrator and correct molarity with Automatic Potentiometer Titrator.  
5.1.8                        Analytical results shall be carry forward to next stage in case of dose form of product is same like; results of coated tablets, uncoated tablet, Filled capsules, cream and ointment shall be transcribed during analysis finished product, wherever applicable.  
5.1.9                        Ensure that reference A.R. No. shall be mentioned in finished product report during the transcription of results from respective stage.

 

  
5.1.10                    In case data transcribed from previous stage, ensure that at least description and identification test to be carried out.  
5.1.11                    In case, identification test to be done for finished product by HPLC then, one Blank, one standard and one sample shall be injected in the HPLC.  
5.1.12                         In case, only identification test to be done for raw material by HPLC/GC then, one Blank, one standard and one sample shall be injected in the HPLC/GC.  
5.1.13                         Micro analysis shall be carried out in finished pack, if applicable.  
5.1.14                         If any customer, ask for the complete test after packing then all test shall be carried out after packing.  
    5.2 Review of Analytical Data :
5.2.1    Person having sufficient experience or subject expert shall be responsible for review of analytical data.    
5.2.2    Ensure that all relevant details of tested materials / product entered in raw data sheet.    
5.2.3    Ensure that all the relevant entries made in the respective log books.    
5.2.4    Ensure that analysis is completed as per respective current specification.    
5.2.5    Ensure that use of working standard and its potency is as per current/effective working standard.    
5.2.6       Ensure that analysis has been completed by using the corrected HPLC/GC columns.  
5.2.7    Ensure that all print outs / chromatograms / spectrum duly signed and dated by analyst and attached with raw data sheet.  
5.2.8    Ensure that correct Normality/Molarity of volumetric solution is used.  
5.2.9     Ensure that correct factor is used for water content testing by using Karl Fischer.  
5.2.10                         Ensure that all units mentioned correctly in raw data sheet.  
5.2.11                         Rounding of digits shall be done as per SOP ‘Rounding and Reporting of Test Results’.  
5.2.12                         Ensure the correctness of calculations.  
5.2.13   Reviewer shall check all raw data attached with report for its correctness and accuracy.  
5.2.14      Reviewer shall put the signature along with date on raw data sheet.  
5.2.15      Reviewer shall sign and date raw data, wherever applicable.  
5.2.16      Always follow approved specification and standard testing procedure for the review of document.  
  5.3 Reviewer Certification:
5.3.1    Before reviewing any data, reviewer shall be assessed by his/her supervisor to check sufficient knowledge and understanding of relevant records possessed by that particular person.  
5.3.2    Supervisor shall allocate one complete current analytical report for checking to the reviewer to do the assessment of his/her reviewing skills.  
5.3.3    After completion of review of analytical report, supervisor shall re-check same analytical report for its correctness and accuracy.  
5.3.4    If all data reviewed by new reviewer and supervisor are matching then supervisor shall recommend to the new reviewer for certification as per Annexure.  
5.3.5    Finally certification of reviewer shall be done by Head Quality Control/Designee.  

 

  1. Definitions / Abbreviations :
  • Definitions :

 

  • Abbreviations :
Abbreviation Expansion
SOP Standard Operating Procedure
QC Quality Control
QA Quality Assurance

 

 

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QC SOP

SOP Title: Analytical Method Validation, Analytical Method Verification and Method Transfer

SOP Title: Analytical Method Validation, Analytical Method Verification and Method Transfer

  1. Objective:

To lay down the procedure for analytical method validation, analytical method verification and method transfer in Quality Control Department.

 

  1. Scope:

This SOP is applicable for analytical method validation, analytical method verification and method transfer in Quality Control Department.

 

  1. Responsibility:
  • Quality Control: To prepare and review the SOP. To follow the procedures laid down for Validation of Analysts in Quality Control Department as per this SOP.
  • Quality Assurance Department: To review and approve the SOP and Annexures.

 

  1. Accountability:

Head – Quality Control / Head – Quality Assurance

 

  1. Procedure:

 

  • Operational Procedure:

 

5.1.1 The analytical method validation protocol shall be prepared for Method Validation and Method Transfer.  
5.1.2 The analytical method validation protocol shall contain the following parameter;

a.         Analytical method validation protocol cover page

b.      Protocol approval

c.       Revision history

d.      Objective

e.       Scope

f.       Responsibility

g.      Methods reference number

 

 

  
5.1.3 A.    Specificity

B.     Forced degradation (if applicable)

C.     Precision

·         Repeatability

·         Intermediate precision

·         Reproducibility

D.    Linearity

E.     Limit of detection and limit of quantitation in case of related substances and cleaning samples

F.      Accuracy

G.    Robustness

H.    Solution stability

I.       Filter suitability (if applicable)

J.       Swab recovery in case method validated for cleaning samples

  
5.1.4 Above all parameters are not limited during the analytical method validation. These parameters can be include and exclude on the basis of specific regulatory requirements/marketing authorization holders/customers.  
5.1.5 Recording of raw data during analytical method validation shall be recorded in worksheet issued by QA.  
5.1.6 After execution of analytical method validation as per their respective protocol, analytical method validation report shall be prepared.  
  Analytical method validation  
5.1.7 The analytical method validation report shall contain the following parameter;  
5.1.8 Analytical method validation report cover page

a.    Report approval

b.    Revision history

c.    Objective

d.   Scope

e.    Responsibility

f.     Methods reference

g.    Validation summary report

h.    Procedure

i.      Specificity

j.      Forced degradation if applicable.

k.    Precision

·      Repeatability

·      Intermediate precision

·      Reproducibility (If applicable)

l.      Linearity

m.  Range

  
5.1.9 Limit of detection (LOD) and limit of quantitation (LOQ)  in case of related substances and cleaning validation samples.

i.            Accuracy

ii.            Robustness

iii.             Solution stability

iv.            Filter compatibility

v.            Swab recovery (If applicable)

vi.            Deviation if any

vii.            Conclusion

  
5.1.10 Complete analytical method shall be included in the analytical method validation protocol and report as per respective standard test procedure.  
5.1.11 An approval of analytical method validation protocol / analytical method validation report shall be taken from marketing authorization holder/customer, in case of product manufactured for contract giver.  
5.1.12 Procedure for analytical method validation shall be as follows;  

 
5.1.13 Specificity:

Ability to asses unequivocally the analyte in the presence of components which may be expected to be present (Impurities, degradants)

  
 
5.1.14 For assay and impurity methods the samples shall contain materials which are potentially present during routine analysis and may interfere with the result, e.g. analysis sample containing potential interferences, e.g. impurities, Excipients.  
5.1.15 Sample shall prepared by spiking drug substance / drug product with potentially interfering material. The acceptance criteria shall be; No interference observed for response due to analyte or impurities or interest and no peaks interfering with analyte peak or the peaks due to the impurities of interest observed. Peak purity shall not be less than 0.995.  
5.1.16 When the impurities are available, the specificity of an assay method is determined by comparing the impurities, degradation products or placebo ingredients with those obtained from an analysis of sample without the impurities, degradation products or placebo ingredients.  
5.1.17 For the impurities test, the determination shall be established by spiking drug substances or drug product with appropriate levels of impurities and demonstration the separation of these impurities individually or from other components in the sample matrix.  
5.1.18 In case impurities are not available. Specificity shall be demonstrated by comparing test results with the blank and placebo ingredients.  
   
5.1.19 Forced degradation:

Forced degradation shall be done in presence of excipients, firstly performed during the pre-formulation stage to assist in the selection of the most formidable compounds and excipients. This shall lead to the development of more suitable formulation, packaging and change in storage and manufacturing conditions as the optimal formulation is defined to be used. Forced degradation studies are also in order to demonstrate specificity during the validation of stability indicating methods.

These studies are usually performed at conditions exceeding that of accelerated storage condition.

Forced degradation studies shall provide information to degradation pathway and degradation products that could form during storage of the drug product.

The main goal of forced degradation studies is to effectively produce samples containing representative and realistic degradation products. These degradation products shall be assessed whether they are a related to the excipients or due to drug substance- excipients interaction under certain forced degradation conditions. A delicate balance of efficiency

and severity / duration of stress conditions are needed. Overstressing shall destroy relevant compounds or generate irrelevant compounds.

Under stressing may fail to generate important degradation products.

The extent of targeted degradation shall be approximately anywhere from 5% to 20%. In some cases the degradation can be difficult to achieve 5%, in such cases statement shall be made in the validation report that the product quality / efficacy shall not be affected for such particular stress condition. The assessment of peak purity using diode array shall be employed.

The stress testing shall be performed as per the below table;

Sr. No. Stress Test Condition Duration Acceptance Criteria
1.0 Thermal Degradation Initially from 50°C to 80°C (Ambient RH). Start from 1 day to 2 week or up to desired degradation. Peak purity shall not be less than 0.995 or angle should be less than threshold.
 
     

 

 
Sr.

No.

 Stress Test Condition Duration Acceptance Criteria
2.0 Humidity From 40 ± 2°C / 75% ± 5% RH Start from one week to 2 week or up to

desired degradation in open petri plates

 Peak purity shall not be less than 0.995 or angle should be less than threshold.
3.0 Acid Initially from 0.01N Hydrochloric Acid to 5N Hydrochloric Acid. Start from 1 hr. to 3 hrs. Peak purity shall not be less than 0.995 or angle should be less than threshold
4.0 Base Initially from 0.01N Sodium Hydroxide to 5N Sodium Hydroxide Start from 1 hr. to 3 days Peak purity shall not be less than 0.995 or angle should be less than threshold.
 
 
Sr.

No.

 Stress Test Condition Duration Acceptance Criteria
5.0 Oxidation / Reduction Initially form 1% Hydrogen Peroxide to 3% Hydrogen Peroxide at room temperature in amber coloured volumetric flask or as per recommended storage condition Start from 1 hr. to 3 days Peak purity shall not be less than 0.995 or angle should be less than threshold.

 
6.0 Light Maximum 1.2 million lux hours and 200 watt hours / square meter or 365nm / fluorescent light Start from 1day to 7days Peak purity shall not be less than 0.995 or angle should be less than threshold
 
5.1.20 Precision:

Precision is the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample. There are following aspects to achieve for precision.

  
5.1.21 Repeatability:

Repeatability is a measure of precision under the same operating conditions over a short interval of time that is, under normal operating conditions of analytical method with the same equipment.

Repeatability to be accessed using a minimum of nine determinations covering the specified range for the procedure (e.g. three concentrations / three replicates as in the accuracy experiment) of using a minimum six determination at 100% of the test concentration. Standard deviation, relative standard deviation and confidence interval to be reported. The assay value of independent analysis of sample preparation to final test result. For the related substances, residual solvents precision shall be established at 100% specification level of know impurities / organic solvents and also to be established at the limit of quantification level.

  
5.1.22 Intermediate precision:

Intermediate precision is defined as the variation within the same laboratory. The extent to which intermediate precision needs to be established depends on the circumstances under which the procedure is intended to be used. Typical parameters that are investigated include day to day variation, analyst variation and equipment variation. Depending upon the extent of the study, the use of experimental design is encouraged. Experimental design shall be minimize the number of experiments that need to be performed.  It is important that exemption from doing intermediate precision when reproducibility is proven. It shall be expected that the intermediate precision shall show variability that is in same range or less than repeatability variation. The standard deviation, relative standard deviation (coefficient variation) and confidence interval to be established of data.

  
   
5.1.23 Reproducibility:

Reproducibility measures the precision between laboratories. This parameter shall be considered in the standardization of an analytical method (e.g. inclusion of procedures in pharmacopoeias and method transfer between different laboratories).

To validate this characteristic, similar study to be performed at different laboratories using the same homogeneous sample lot and the same experimental design. In case of method transfer between two laboratories, different approaches may be taken to achieve the successful transfer of the procedure. The approach is method transfer from the originating laboratory to the receiving laboratory. The originating laboratory is defined as the laboratory that has developed and validated analytical method. The receiving laboratory is defined as laboratory to which the analytical method to be transferred and that will participate in the method transfer studies. In the method transfer, it is recommended that protocol be initiated with details of the experiments to be performed and acceptance criteria (in term of the difference between the means of the two laboratories) for passing the method transfer.

  
 
5.1.24 Linearity:

Linearity of an analytical procedure as the ability (within the given range) to obtain test results of variable data (e.g. absorbance and area under the curve) which are directly proportional to the concentration (amount of analyte) in the sample. The data variables that shall be used for quantitation of the analyte are the peak area or ration of peak area of analyte to the internal standard peak. The working sample concentration and samples tested for accuracy shall be in the linear range.

  
5.1.25 There are two general approaches for determining the linearity of the method.  
5.1.26 The first approach is to weigh different amounts of standard directly to prepare linearity solutions at different concentrations. However, it is not suitable to prepare solution at very low concentration, as the weighing error shall be relatively high.  
5.1.27 Another approach is to prepare a stock solution of  high concentration. Linearity is then demonstrated directly by dilution of standard stock solution. This is more popular and the recommended approach.

Linearity is best evaluated by visual inspection of a plot of signals as a function of analyte concentration. Subsequently, the variable data are generally used to calculate a regression line by the least square method. At least five concentration levels shall be used. Under normal circumstances, linearity shall be with coefficient of determination (r2) of 0.995 the slope, residual sum of squares, and y intercept shall also be reported.

The slope of the regression line shall provide an idea of the sensitivity of the regression. The y intercept shall provide an estimate of the variability of the method. The ratios per cent of the y- intercept with the variable data at nominal concentration are used to estimate the method variability.

For determination of assay of drug substances of a drug product, the usual range of linearity shall be ±20% of the target or nominal concentration. For the determination of content uniformity, it shall be ±30% of the target of nominal concentration. For determination of related substances or residual solvents it shall be from the reporting level to 20% ahead of the target or nominal concentration. For dissolution testing: ±20% over the specified range.

  
 
5.1.28 Range:

The range of analytical procedure is the interval between the upper and lower concentration of analyte in the sample for which it has been demonstrated that the analytical procedure shall a suitable level of precision, accuracy, and linearity. The range shall normally expressed in the same units as test results (e.g. percent, parts per million) obtained by the analytical procedure.

  
 
5.1.29 For the assay of drug substance or finished drug product, it is normally recommended to have a range of 80 – 120% of the nominal concentration.  
  For content uniformity, a normal range shall cover 70 – 130% of the nominal concentration, unless a wider and more appropriate range is justified.

For dissolution testing, a normal range is ± 20% over the specified range. In case the acceptance criteria for a controlled – release product covers a region from 20% after1 h, and up to 90% after 24 h, the validated range would be 0 – 110% of the label claim. In this case, the lowest appropriate quantifiable concentration of analyte will be used as the lowest limit as 0% is not appropriate.

For the related substances / residual solvents of drug substance or finished drug product, it is normally recommended to have a range of limit of quantitation – 120% of the nominal concentration.

  
5.1.30 Limit of Detection (LOD):

The Limit of Detection (LOD)  is the lowest amount of analyte in a sample that shall be detected but not necessarily quantitated under the stated experimental conditions. The detection shall usually expressed as the concentration of the analyte in the sample, e.g. percentage, parts per million (ppm) or  parts per billion (ppb).

There are several approaches to establish the limit of detection. One approach to establish detection limit shall be determined by the analysis of a series of sample with known concentrations and establishing the minimum level at which analyte shall be reliably detected. Presentation of relevant chromatograms or other relevant data shall be sufficient for justification of the detection limit.

For instrumental procedures that exhibit background noise, it shall compare measured signals from samples with known concentrations of analyte with those of the blank samples. The minimum concentration at which the analyte shall reliably be detected, shall establish using an acceptable signal to noise ratio of 2:1 or 3:1. Presentation of relevant chromatograms shall be sufficient for justification of detection limit.

Another approach to estimate the detection limit from the standard deviation of the response and the slope of the calibration curve. The standard deviation shall be determined either from the standard deviation of multiple blank samples or from the standard deviation of the y intercepts of the regression lime done in the range of the detection limit. This estimate shall need to be subsequently validated by the independent analysis of a suitable number of samples near or at the detection limit;

  
 
 
 
    3.3 σ
LOD = ——————–
    S

 

Where,

σ = the standard deviation of the response

S = the slope of the calibration curve

 

  
5.1.31 Limit of Quantitation (LOQ):

The Limit of Quantitation  (LOQ) is a characteristic of quantitative assays for low levels of compounds in the sample matrices, such as impurities in bulk drug substances and degradation products in finished pharmaceuticals. LOQ shall be defined as the concentration of related substances in the sample that shall give a signal to noise ratio of 10:1; the LOQ of a method is affected by both the detector sensitivity and the accuracy of sample preparation at the low concentration of the impurities. In practice LOQ shall be lower than the corresponding report limit.

Generally, three approaches are to establish the quantitation limit.

           The first approach is to evaluate it by visual evaluation and shall be used for non instrumental methods and instrumental methods. Quantitation limit is determined by analysis of samples with known concentrations of analyte and by establishing the minimum level at which the analyte shall be quantitated with acceptable accuracy and precision.

The second approach determines the signal to noise ratio by comparing measured  signals from samples with known low concentration at which the analyte shall be  reliable quantified at the signal to noise ration 10:1.

The third approach estimates LOQ by equation as per limit of detection;

 

           10 σ
QL = —————-
             S

Where,

σ = the standard deviation of the response

S = the slope of the calibration curve

The slope shall be established from calibration curve of the analyte. The value of the σ shall be established by

·                  Calculating the standard deviation of the responses obtained from the measurement of the analytical background response of an appropriate number of blank samples or

·                  Calculating the residual standard deviation of the regression line from the calibration curve using samples containing the analyte in the range of LOQ.

Whatever approach is applied, the LOQ shall be subsequently validated by the analysis of a suitable number of samples prepared at the LOQ and determining the precision and accuracy at this level.

  
 
 
 
5.1.32 Accuracy:

Accuracy of an analytical procedure as the closeness of agreement between the values that are accepted either as conventional true values or an accepted references value and the value found. For the drug substances accuracy is defined by the application of the analytical procedure to an analyte of known purity (e.g. reference standard). For the drug product, accuracy shall be determined by application of the analytical procedure to synthetic mixtures of the drug product components to which amounts of analyte have been added within the range of the procedure. It is recommended to assess minimum of nine determinations over a minimum three concentration levels covering the specified range (e.g. three concentration / three replicates).

Accuracy shall be reported as percent recovery by assay (using the proposed analytical procedure) of known added amount of analyte in the sample of as the difference between the mean and the accepted true value together with the confidence intervals. The range for the accuracy limit shall be within the linear range.

Typically accuracy of the recovery of the drug substance is expected to be about 99 – 101%. Typical accuracy of drug product is expected to be 98 – 102%.

For the dissolution of drug product accuracy of recovery is expected to be 98 – 102%.

Values of accuracy of recovery data beyond this range need to be investigated as appropriate.

For the related substances / residual solvents recovery shall be performed from the quantitation limit by spiking the known concentration of known impurities / residual solvents in analyte and the accuracy of recovery can be up to 85 – 115%.

For Cleaning validation recovery shall be performed from the quantitation limit to minimum 120% by spiking the known concentration of known analyte and the accuracy of recovery should not be less than 70%.

  
 
 
5.1.33 Robustness:

Robustness of an analytical procedure is a measure of the analytical method to remain unaffected by small but deliberate variations in method parameter and provides an indication of its reliability during normal usage.

Common method parameters that can affect the analytical procedure shall be considered based on the analytical technique;

.  Sample preparation

. Extraction time

. Sample solvent (pH ±0.2, percent organic ± 5% absolute)

  
 
  ·   High performance liquid chromatography (HPLC) condition / spectrophotometric methods

Mobile phase composition (pH ±0.05, percent organic ± 2% absolute)

Column used (equivalent columns, lots and / or suppliers)

Temperature (± 5º C)

Flow rate (± 10 %)

·       Gas chromatography (GC) conditions

Column used (equivalent columns, lots and / or suppliers)

Temperature (± 10 %)

Flow rate (± 10 %)

When the results are affected by some critical experimental parameters, a precautionary statement shall be included in the analytical procedure to ensure that this parameter is tightly controlled between experiments. For example: in case percent ion pairing of mobile phase affects the results significantly, the analytical procedure shall explicitly be written with a precautionary statement for aqueous component.

Other robustness considering for ruggedness of the analytical procedure during validation include the following;

·         Sample extraction: mechanical shaking preferred over sonication as the latter is affected by a number of factors, for

·                 example, time for sonication.

·                 Dilution of sample and solvent, minimize the number of dilution steps to reduce introduction of error. Dilution solvent shall be as similar to mobile phase as possible.

  
 
5.1.34 Solution stability:

·         Stability of Standard and Sample Solution shall be performed at various time intervals and at room temperature.

·    Acceptance criteria shall be as follows :

For assay and dissolution, the relative standard deviation for peak area as obtained from standard solution and test solution shall not be more than 2.0%.

For related substance and residual solvents, the relative standard deviation for peak area as obtained from standard solution and test solution shall not be more than 10.0 % at various time intervals

  
 
5.1.35 Filter compatibility:

Filter compatibility shall be performed with different filter against the centrifuged solution. Acceptance criteria for filter compatibility shall be as follows:

The similarity factor for centrifuged standard and filtered standard solution

shall be between 0.98 and 1.02.

The similarity factor for centrifuged sample solution and filtered sample solution shall be between 0.98 and 1.02.

  
 
 
5.1.36 Following parameters to be established during the analytical method validation;  
 
Analytical Task Identification Quantitative Limit

Test

 Assay/dissolution/ content uniformity / potency
Accuracy

Precision

 No Yes No Yes
Repeatability No Yes No Yes
Intermediate Precision No Yes No Yes
Reproducibility No Yes No Yes
Specificity Yes Yes Yes Yes
Limit of Detection No Yes Yes No
Limit of quantitation No Yes Yes No
Linearity No Yes No Yes
Range No Yes No Yes
Robustness No Yes No Yes
Solution Stability No Yes No Yes
Filter compatibility No Yes No Yes

 
 
     

 

5.1.37 Method Verification:

Verification consists of assessing selected analytical validation characteristics described earlier to generate appropriate relevant data rather than repeating the validation process for commercial products. The method verification shall be done for the pharmacopeial methods (compendial methods) such as titrations, chromatographic procedures (related compounds, assay, dissolution and limit tests), and spectroscopic tests. However, general tests (water, heavy metals, residue on ignition) do not typically require verification.

  
 
5.1.38 The analytical method verification protocol shall be prepared.  
5.1.39 The analytical method verification protocol shall contain the following parameter;

Analytical method validation protocol cover page

Protocol approval

Revision history

Objective

Scope

Responsibility

Methods reference number

Procedure

Precision

·                 Repeatability

·                 Intermediate precision

·                  Reproducibility

  
 
5.1.40 Specificity :

 

Analytical task Verification
Accuracy No
Precision  
·      Repeatability Yes
·      Intermediate precision Yes

 

 
·      Reproducibility Yes
Specificity Yes
Limit of detection No
Limit of quantitation No
Linearity No
Range No
Robustness No
 
 
5.1.41 Method Revalidation:

The analytical method shall be revalidation under following circumstances; however these circumstances are not limited;

·      In case new impurity found that makes deficient in its specificity, this method needs to be modified and revalidated.

·      Changes in the excipients composition can change the product impurity profile.

·      Changes in equipment or supplier of critical supplies of the API (Active Pharmaceutical Ingredients) or final drug product shall have the potential to change their degradation profile and shall require the method to be redeveloped and revalidated.

  
 

 

 

  1. Definitions /Abbreviations:
  • Definitions:
  • Abbreviations:

 

Abbreviation Expansion
e.g. Example
No. Number
°C Degree Centigrade
RH Relative Humidity
% Percent
N Normal
ppm Parts per million
ppb Parts per billion
USP United State of Pharmacopoeia
  1. Reference:

 

References Description
Q2 (R1) Validation of analytical procedures : Text and Methodology.
USP <1224> Transfer of analytical procedures
USP <1225> Validation of compendial procedures
USP <1226> Verification of compendial procedures

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Categories
QC SOP

SOP Title: Operation, Handling and Cleaning of Stability Chamber

SOP Title: Operation, Handling and Cleaning of Stability Chamber

  1. Objective:

To lay down the procedure for Operation, Handling and Cleaning of Stability Chamber.

  1. Scope:

This SOP is applicable for Operation, Handling and Cleaning of Stability Chamber used to incubate stability samples located in stability section.

 

  1. Responsibility:
  • Quality Control Department: To prepare and review the SOP. To follow the procedures laid down for Operation, Handling and Cleaning of Stability Chamber as per this SOP.
  • Engineering Department: To carry out preventive maintenance as per schedule and procedure defined.
  • Quality Assurance Department: To review and approve the SOP and Annexures.

 

  1. Accountability:

Head Quality Control Department, Head Quality Assurance Department

 

  1. Procedure:
5.1.1                      Stability chamber has 2 sensor located inside the stability chamber

1) Temperature sensor

2)Relative Humidity  sensor

  
5.2  Operation  Of Stability Chamber
5.2.1 Before switching on the chamber check the Water level of Water tank, which is attached to the back side of the chamber.  
5.2.2 Put the main plug in to the socket provided behind the chamber and switched ‘ON’ the main switch.  
5.2.3 Now switch on the “Mains” from the front panel by rotating the knob at ‘ON’ position.  
5.2.4 Now Temperature and Relative Humidity controller will glow and will display the set parameter. Set the desire value of temperature and Relative Humidity  from controller display, as per define in operation manual.  
5.2.5 Set the safety controller temperature value above 2° C of   set temperature, as mentioned in operation manual.  
  Incubation of Stability Samples:
5.3.1 For the incubation of stability sample open the chamber door by provided key, keep the stability sample inside the chamber on trays.  
5.3.2 make the entries in respective stability register as per SOP of Sampling, Handling and Analysis of Stability Study Samples  
5.3.3 Do not over crowd the tray with more samples.  
5.3.4 Keep chamber always in lock and key. Only authorised and trained persons shall be allowed to open the chamber.  
5.4 Temperature and Relative Humidity Monitoring:
  Frequency : Daily Temperature and Relative Humidity  monitoring shall be done  twice a day
5.4.1 Daily Temperature and Relative Humidity Monitoring shall be done twice a day i.e. morning session and evening session as per Annexure.  
5.4.2 If Temperature and Relative Humidity  found out of limit for more than 24 hours then file a incidence and investigate the cause of failure along with Engineering Department  
5.4.3 If breakdown occurs to stability chamber then inform Engineering department for further action. If required, contact service Engineer.  
5.4.4 Incubation shall be maintained at ± 2° C of the Specified temperature and ± 5% of the Specified Relative Humidity. The daily monitoring data shall be reviewed fortnightly basis to check any excursion occurs.

Any deviation as mentioned below must be assessed for impact and reported to the Head of QA Department. Refer SOP Procedure for Stability Study of Drug Product.

Deviation of > ±2° C to ± 5°C from the set point for 48Hours.

Deviation of > ±5% RH to ± 10% from the set point for 48Hours.

Deviation of > ±5° C from the set point for 24Hours.

Deviation of > ± 10% RH from the set point for 24Hours.

  
5.5 Calibration Procedure:
  Frequency: Yearly Periodic Calibration by external agency
5.5.1 Periodic Calibration shall be done once in a year by external agency or after carrying out any major maintenance work.  
5.5.2 Calibration is carried out for set Temperature and Relative Humidity  RH for 24 Hours at the time interval of 10 minutes.  
5.5.3 Enter the details in calibration report. Ensure that the results obtained, comply with the acceptance criteria.  
5.5.4 Update the “Instrument/Equipment Usage Log Book”, as per SOP and Update the “Annual Calibration Schedule” as per SOP.  
5.5.5 Affix the Calibration status label as per Annexure  
5.5.6 If Calibration activity is outsourced, the values are to be transcribed as per SOP, and external party certificate to be attached.  
5.6 Preventive Maintenance
5.6.1 Perform the preventive maintenance monthly basis as per Annexure.  
5.6.2 If any breakdown occurs, follow procedure as per SOP “Calibration of Instruments and Equipments”.  
5.7 Cleaning of Stability Chamber:
5.7.1 Stability chamber should be cleaned once a month.  
5.7.2 Floor, internal walls and exterior shall be cleaned with dry lint free cloth.  
5.7.3 All empty shelves shall be wiped with dry lint free cloth.  

 

  1. Definitions / Abbreviations:
  • Definitions:
  • Breakdown: Any activity leading to operation of instrument/equipment other than the set parameters or unusual sound or vibration observed in the instrument/equipment.
  • Calibration: Tests performed to ensure that the instrument/equipment is functioning as per set parameters. These tests are performed as per predefined frequency and also after any major repair or replacement of parts.
  • Preventive Maintenance: Maintenance activity performed to ensure that the instrument/equipment will function smoothly and to avoid breakdowns. These activities are performed as per predefined frequency.

                                                                                                                                                               

  • Abbreviations:
Abbreviation Expansion
°C Degree Centigrade
RH Relative Humidity
% percent
v/v Volume by volume
LED Light Emitting Diode

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Categories
QC SOP

SOP Title: Operation, Cleaning and Calibration of Bulk Density Apparatus

SOP Title: Operation, Cleaning and Calibration of Bulk Density Apparatus

  1. Objective:

To lay down the procedure for Operation, Cleaning and Calibration of Bulk Density Apparatus.

  1. Scope:

This SOP is applicable for Operation, Cleaning and Calibration of Bulk Density Apparatus located in Quality Control Laboratory.

 

  1. Responsibility:
  • Quality Control: To prepare and review the SOP. To follow the procedures laid down for Operation, Cleaning and Calibration of Bulk Density Apparatus as per this SOP.
  • Engineering Department: To carry out preventive maintenance as per schedule and procedure defined.
  • Quality Assurance Department: To review and approve the SOP and Annexures.
  1. Accountability:

Head Quality Control Department, Head Quality Assurance Department

 

  1. Procedure:
    5.1 Safety Precautions/Instructions:
5.1.1 Ensure all the electrical connections are properly earthed. Ensure the power plug of the bulk density apparatus is fixed in the socket properly.  
5.1.2 Wear personal protective equipment’s such as safety glasses, hand gloves during operation of instrument.  
5.1.3 Ensure that the ON/OFF switch is working properly by switching “ON” the bulk density apparatus.             
  5.2 Operation  Procedure:
5.2.1  Check the validity of Calibration before starting any operations  
5.2.2 Introduction to the Keys:

ON/OFF Mains: To ON and OFF the instrument.

  
5.2.3 Switch ON the main switch of instrument.  
5.2.4 Weigh the required quantity of sample and transfer it into empty clean and dry measuring cylinder.  
5.2.5 Wrap cylinder mouth with aluminium foil or rubber stopper.  
5.2.6 Open the rings of the holder provided on the instrument.  
5.2.7 Place the measuring cylinder on the round surface of the instrument and slightly screw up the rings.  
5.2.8 Set the desired number of strokes by pressing SET key.  
5.2.9 Switch ON the ‘ON/OFF Mains’ button on the instrument.  
5.2.10 The piston will rise up & down till the set number of strokes are completed.  
5.2.11 At the end of the process the burger will indicate for completion of process.  
5.2.12 Switch OFF the ‘ON/OFF Mains’ button and open the rings of the holder and remove the measuring cylinder.  
5.2.13 Switch OFF the main switch of instrument.  
5.2.14 Record the volume and calculate the bulk density of the sample as per standard testing procedure.  
5.2.15 Update the “Instrument/Equipment Usage Log Book” as per SOP.  
   5.3 Cleaning Procedure:
5.3.1 Switch ON the main switch of instrument.  
5.3.2 Clean the surface of the instrument with lint free cloth before and after use.  
5.4 Calibration Procedure:
5.4.1 Frequency: Half Yearly or after carrying out any major maintenance work.
5.4.2 Generate the A. R. No. as per SOP and give requisition to QA department for calibration formats of instruments on the due date of calibration.  
5.4.3 For issuance of calibration report refer SOP.  
5.4.4 Perform the calibration of instrument as per Annexure and procedure mentioned below.  
5.4.5 Switch ON the main switch of instrument.  
5.4.6 Switch ON the ‘ON/OFF Mains’ button on the instrument.  
5.4.7 Set the strokes to 100 by pressing SET key.  
5.4.8 Check the number of strokes on digital display.  
5.4.9 At the end of the process the beep sound will indicate for completion of process.  
5.4.10 Follow the same procedure for 50 strokes.  
5.4.11 Switch OFF the ‘ON/OFF Mains’ button and switch OFF the main switch.  
5.4.12

 

 

 

 

 

 

 

 Enter the details in calibration report as per Annexure. Ensure that the results obtained, comply with the acceptance criteria.

Sr. No. Parameters Set value Acceptance Criteria Observed Values  
1. No. of Strokes 50 ± 1 Stroke    
100 ± 2 Stroke  

 

  
 
5.4.13 Update the “Instrument/Equipment Usage Log Book.  
5.4.14 Affix the “Calibration Status Label” on the Instrument as per SOP.  
5.4.15 If calibration activity is outsourced, the values are to be transcribed in the Annexure, and external party certificate to be attached.  
5.4.16 If any breakdown occurs, follow procedure as per SOP.  

  

  1. Definitions / Abbreviations:
  • Definitions:
  • Breakdown: Any activity leading to operation of instrument/equipment other than the set parameters or unusual sound or vibration observed in the instrument/equipment.
  • Calibration: Tests performed to ensure that the instrument/equipment is functioning as per set parameters. These tests are performed as per predefined frequency and also after any major repair or replacement of parts.
  • Preventive Maintenance: Maintenance activity performed to ensure that the instrument/equipment will function smoothly and to avoid breakdowns. These activities are performed as per predefined frequency.
  • Abbreviations:
Abbreviation Expansion
SOP Standard Operating Procedure
QC Quality Control
QA Quality Assurance
No. Number
A.R.No. Analytical Reference Number

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Categories
QC SOP

SOP Title: Operation, Cleaning and Calibration of Karl Fischer Apparatus

SOP Title: Operation, Cleaning and Calibration of Karl Fischer Apparatus

  1. Objective:

To lay down the procedure for Operation, Cleaning and Calibration of Karl Fischer Apparatus. 

 

  1. Scope:

This SOP is applicable for Operation, Cleaning and Calibration of Karl Fischer Apparatus located in Quality Control Laboratory.

 

  1. Responsibility:
  • Quality Control: To prepare and review the SOP. To follow the procedures laid down for Operation, Cleaning and Calibration of Karl Fischer Apparatus as per this SOP.
  • Engineering Department: To carry out preventive maintenance as per schedule and procedure defined.
  • Quality Assurance Department: To review and approve the SOP and Annexures.

 

  1. Accountability:

Head Quality Control Department, Head Quality Assurance Department

  1. Procedure:
5.1          Safety Precautions/Instructions:
5.1.1 Ensure all the electrical connections are properly earthed. Ensure the power plug of the Karl Fischer Apparatus is fixed in the socket properly.  
5.1.2 Wear personal protective equipments such as safety glasses, hand gloves, nose mask during operation of instrument.  
5.1.3 Ensure that the ON/OFF switch is working properly by switching “ON” the Karl Fischer Apparatus.             
5.2 Operational  Procedure:
5.2.1 Check the validity of Calibration before starting any operations.  
5.2.2 Switch ON the mains of the instrument.  
5.2.3 ON/OFF switch is provided on the front panel. This switch puts the instrument ‘ON’ and LCD screen will glow.  
5.3 Preparing the instrument for titration:
5.3.1 Add as per requirement K/F Reagent in the reservoir bottle fitted with the adaptor.  
5.3.2 Needless to state that the glassware used should be well dried; otherwise reagent will become useless before use.  
5.3.3 Remove the large rubber cork and add some K/F grade methanol to the reaction beaker to such an extent that the metal wires of sensors in the beaker are fully immersed.  
5.3.4 Replace the cork immediately to prevent moisture from atmosphere entering in the beaker.  
5.3.5 Connect the leads of the Pt – Sensors to the sockets provided on the instrument.  
5.3.6 Connect the titrator to mains supply and put the mains switch ‘ON’. The four line LCD display will ‘GLOW’.  
5.3.7 Adjust the speed of the magnetic stirrer such that the sensor wires do not get exposed to air.  
5.3.8 The height of the sensors in the beaker should be so adjusted that the magnetic stirrer does not hit them while rotating.  
5.4.17 This indicates that the methanol is neutralised and 1st stage of titration is over.  
  To test the sample:
5.4.47 Carry out the operation as per define in operation manual.  
5.4.48 Update the “Instrument/Equipment Usage Log Book” as per SOP.  
5.5 Cleaning Procedure:
5.5.1 Fill methanol in the second reservoir of amber colour 250 ml bottle. Lift the (glass) Adapter from the K/F Reagent bottle and attach the adapter to the methanol bottle.  
5.5.2 Press ‘CLEAN’ key; the dispensing unit will start sucking the methanol from the bottle.  
5.5.3 When clear drops from the dispensing tube start falling in the titration vessel, just detach the tube from the glass adapter.  
5.5.4 The remaining methanol in the dispensing tube will empty into the titration vessel and after few minutes the system will stop automatically.  
5.5.10 The dispensing unit will start sucking the methanol. To ‘stop’ in between, press ‘STOP’ key again. OR the system will stop automatically after few minutes.  
5.5.13 Take some acetone in a small beaker and dip the wires of the sensors in it, shake the beaker gently so that the sensors get cleaned. Wash the reaction beaker and dry it in the oven.  
   5.6 Calibration Procedure:
  Frequency:  Quarterly or after carrying out any major maintenance work.  
5.6.1 Generate the A. R. No. on the “Instrument/Equipment Calibration Register” as per SOP and give requisition to QA department for calibration formats of instruments on the due date of calibration.  
5.6.2 For issuance of calibration report refer SOP.  
5.6.3 Perform the calibration of instrument as per Annexure and procedure mentioned below.  
5.6.4 Calibration of Karl Fischer Apparatus is performed for below parameters:

1. Water content of Sodium tartrate

2. Dispenser calibration

  
  1. Water content of Sodium tartrate:
5.6.5 Weigh about 5mg to 50mg of Sodium tartrate. Titrate with KF reagent. Note down reading in annexure. Calculate % moisture content. Operate the instrument as per SOP.  
5.6.6 Water equivalent Factor for Karl Fischer reagent is determined by using about 25mg of purified water in triplicate.  
5.6.7 Enter the details in calibration report as per Annexure. Ensure that the results obtained, comply with the acceptance criteria.

 

  
  Dispenser calibration:
5.6.8 Allow the dispenser to run for sometime so that the Inlet and Outlet tubes are filled with water. This can be done by running the clean cycle of the dispenser.  
5.6.9 Thus the dispenser is now ready for calibration after air bubble is removed. Now weigh the empty beaker accurately and note down its weight.

 

  
5.6.24 Dispense 10mL of water in beaker from dispenser. Note down the weight of beaker with water.  The same experiment is repeated thrice and the average volume is calculated.  
5.6.25 Each time calculate the dispensed volume and record in annexure.  
5.6.28 Enter the details in calibration report as per Annexure. Ensure that the results obtained, comply with the acceptance criteria.  
5.6.29 Update the “Instrument/Equipment Usage Log Book”, “Annual Calibration Schedule” and “Monthly Calibration Schedule” as per SOP.  
5.6.30 Affix the “Calibration Status Label” on the Instrument as per SOP.  
5.6.31 If calibration activity is outsourced, the values are to be transcribed in the Annexure, and external party certificate to be attached.  
5.6.32 If any breakdown occurs, follow procedure as per SOP number.  
  1. Definitions /Abbreviations:
  • Breakdown: Any activity leading to operation of instrument/equipment other than the set parameters or unusual sound or vibration observed in the instrument/equipment.
  • Calibration: Tests performed to ensure that the instrument/equipment is functioning as per set parameters. These tests are performed as per predefined frequency and also after any major repair or replacement of parts.
  • Preventive Maintenance: Maintenance activity performed to ensure that the instrument/equipment will function smoothly and to avoid breakdowns. These activities are performed as per predefined frequency.
  • Abbreviations:

 

Abbreviation Expansion
secs seconds
K/F Karl Fischer
LCD Liquid Crystal Diode
i.e. That is
Pt. Platinum
g gram
Lit Litre
Av. Average
EX. Extra
e.g. Example
K.F.R. Karl Fischer Reading
ml millilitre
PPM Parts Per Million
A.R.No. Analytical Reference Number
mg milligram
Conf. Confirmation

 

 

Calibration Report

 

Note: Carry out the calibration of the instrument as per SOP for the following parameters:

 

Quantity of Water

Weighed

W (mg)

 Burette Reading

BR (ml)

 Karl Fischer Reagent Water equivalent Factor F = W / BR  

% RSD

 Acceptance

Criteria
         

NMT 2.0 %
     
     

 

Mean Factor = F =__________

 

Quantity of Sodium Tartarate weighed

W1 (gms)

 Burette Reading

Y ml

 % Moisture Content

(% w/w)

 Acceptance Criteria
      15.35 – 15.97 %w/w

  Calculation:

% Moisture Content = Y x F x 100    = ———– w/w

W1 x 1000

 

Dispenser calibration:

Parameters Observations Acceptance Criteria Complies / Does Not Complies
Weight of the empty beaker (A)   Not more than ± 0.20 ml of  volume of water taken  
Required volume of water to be dispensed  
Weight of the empty beaker + volume dispensed (B)  
Actual volume of water dispensed (B – A)/0.99707  

 

Remark: The result Complies/Does not complies as per acceptance criteria.

 

 

*Note – Ready to use SOP available in “DOWNLOAD” Section.

 

Categories
QC SOP

SOP Title: Operation, Cleaning and Calibration of Precision Weighing Balance

Title: Operation, Cleaning and Calibration of Precision Weighing  Balance

  1. Objective:

To lay down the procedure for Operation, Cleaning and Calibration of Electronic Weighing Balance.

  1. Scope:

This SOP is applicable for Operation, Cleaning and Calibration of Electronic Weighing Balance in the Quality Control Department.

  • Responsibility :
    • Quality Control Department: To prepare and review the SOP. To follow the procedures for the Operation, Cleaning and Calibration of Electronic Weighing Balance.
    • Engineering Department: To carry out preventive maintenance as per schedule and procedure defined.
    • Quality Assurance Department: To review and approve the SOP and Annexure.

 

  1. Accountability:

Head Quality Control Department, Head Quality Assurance Department.

 

  1. Procedure:
    5.1 Safety Precaution:
5.1.1 Inspect electrical cables and connectors for any sign of damage or wear prior to use.
5.1.2 Do not disconnect electrical connection during weighing operation.
5.1.3 Never overload Electronic Weighing Balance  (EWB) beyond its capacity to avoid potential damages to load cells.
    5.2 Checks before switching “ON” the Electronic Weighing Balance
5.2.1 Do not keep the EWB near source of vibration /strong air drift.
5.2.2 Ensure that the EWB is clean and if not, clean the balance using a non-static brush.
5.2.3 Always start the weighing balance 30 minutes prior to use.
5.2.4 Do not keep weight on balance during “OFF” condition.
    5.3 Weighing Operation:
5.3.1 Connect the power supply cord to the switch board and switch on the balance and allow the balance to warm up for about 30 minutes.
5.3.2 The balance shall perform a self-test in which all display segments light up.
5.3.3 Ensure that, the balance is calibrated by checking the calibration status label on the balance.
5.3.4 Ensure balance is in clean condition.
5.3.5 Place appropriate container on the centre of the pan of the Electronic Weighing Balance.
5.3.6 Tare the weight of the container by pressing the ‘ZERO’ key.
5.3.7 Check that the display shows zeros.
5.3.8 If the display is not showing zero reading then press ‘ZERO’ key to zero the display.
5.3.9 To take tare weight, remove the tarred container from the balance, display shows the tare weight of the container.
5.3.10 Transfer the required quantity of the material to be weighed onto the container by means of a clean dry spatula and allow the display to stabilize.
5.3.11 The display shows the net weight of the material/product.
5.3.12 To check the gross weight, remove the container including the material and press the “ZERO” key for auto zero. Check that the display shows zeros and keep the container with material, display will show the sum of weights of the both container and material.
5.3.13 After completion and before weighing of every container, balance should be display Zero. (applicable during gross weight checking) If shows zero error, make it zero by pressing “ZERO” key of the balance.
5.3.14 After completion of weighing, remove the weighed material/ container from the balance. At end of the shift, switch “OFF” the balance and then switch ‘OFF’ the main supply.
    5.4 Calibration:
5.4.1 Generate the A. R. No. as per SOP and give requisition to QA Department for quarterly calibration formats of instrument on the due date of calibration.
5.4.2 Get the  calibration record format issued from QA.
5.4.3 Daily calibration: Calibration to be performed every day before the starting the weighing in the morning or start of shift.
5.4.4 Calibration is performed using standard calibrated weight box.
5.4.5 Place 2 gram of calibrated weight on the pan of the balance using forceps and record the weight as per Annexure. Ensure that the value meets with the acceptance limits.
5.4.6 Place 20 gram of calibrated weight on the pan of the balance using forceps and record the weight as per Annexure. Ensure that the value meets with the acceptance limits.
5.4.7 Place 50 gram of calibrated weight on the pan of the balance using forceps and record the weight as per Annexure. Ensure that the value meets with the acceptance limits.
5.4.8 Place 100 gram of calibrated weight on the pan of the balance using forceps and record the weight as per Annexure. Ensure that the value meets with the acceptance limits.
5.4.9 Permissible tolerance for verification should be as per define in Annexure.
5.4.10 If daily calibration complies with permissible tolerance, affix / update ‘Calibration Status Label’ as per SOP.
    5.5 Quarterly or after carrying out any major maintenance work:
5.5.1 Perform the complete calibration once in three months., Refer Annexure
5.5.2 Following parameters shall be checked:

  • Weighing performance / Accuracy across the operating range,
  • Repeatability / Precision, and
  • Eccentricity / Corner

 
    5.6 Weighing performance / Accuracy Across the Operating Range:
5.6.1 Set the balance to Zero before the start of the weighing performance, do not set zero in between two consecutive weighing operations.
5.6.2 The standard weights should be distributed evenly on the balance pan.
5.6.3 Calibration shall be carried out by using calibrated standard weights as per Annexure.
    5.7 Repeatability / Precision:
5.7.1 Load standard calibrated weight [500 gram] on weighing pan and record the reading displayed after stabilization.
5.7.2 Remove the weight and ensure that reading returns back to Zero.
5.7.3 Again place the same weight and repeat the above steps 5 more times.
5.7.4 Record the reading displayed in Annexure.
5.7.5 Permissible tolerance for verification should be as per Annexure.
    5.8 Eccentricity / Corner :
5.8.1 Load standard calibrated weight [500 gram] in the centre of weighing pan and record the stabilized reading displayed.
5.8.2 Repeat the procedure by placing the standard weight at different corners [as displayed below] of weighing pan.
5.8.3  

 

 

 

Weighing Pan 

C – Centre, 1, 2, 3, 4 – Corners.
5.8.4 Record the readings displayed in each location of weight placement.
5.8.5 Update the “Instrument/Equipment Usage Log Book”, as per SOP.
5.8.6 Affix the “Calibration Status Label” on the Instrument as per SOP.
5.8.7 If calibration activity is outsourced, the values are to be transcribed in the Annexure, and external party certificate to be attached.
5.8.8 Switch “OFF” the balance after completion of weighing at the end of the shift.
    5.9 Cleaning:
5.9.1 Switch “OFF” the balance during cleaning.
5.9.2 Cleaning of the balance should be done daily before calibration, after each weighing activity or whenever necessary.
5.9.3 First remove the dust and powder with the help of soft nylon brush.
5.9.4 Clean the balance with soft cloth soaked and squeezed in IPA to remove any oily substances or spots from the balance and clean with lint free cloth.
   5.10 Action Plan During Break Down of Balance:
5.10.1 If any breakdown occurs, follow procedure as per SOP “Calibration of Instruments and Equipments”.
5.10.2 After rectification calibrate the balance with all suitable weights before use.

 

  1. Definitions / Abbreviations:
  • Definitions:
  • Breakdown: Any activity leading to operation of instrument/equipment other than the set parameters or unusual sound or vibration observed in the instrument/equipment.
  • Calibration: Tests performed to ensure that the instrument/equipment is functioning as per set parameters. These tests are performed as per predefined frequency and also after any major repair or replacement of parts.
  • Preventive Maintenance: Maintenance activity performed to ensure that the instrument/equipment will function smoothly and to avoid breakdowns. These activities are performed as per predefined frequency.
  • Abbreviations:

 

Abbreviation Expansion
SOP Standard Operating Procedure
QC Quality Control
IPA Isopropyl alcohol

 

*Note – Ready to use SOP available in “DOWNLOAD” Section.

 

  

 

 

 

       Daily  Performance check 

 Acceptance Criteria: +0.1%                                                                 Standard weight box ID no.  _____________

 

 

Date

 Standard Weights  

Remark

 Done by Checked by
2.000 g 20.000 g 50.000g 100.000g

 

Categories
QC SOP

Title: Operation, Cleaning and Calibration of pH/Conductivity Meter

Title: Operation, Cleaning and Calibration of pH/Conductivity Meter

  1. Objective:

To lay down the procedure for Operation, Cleaning and Calibration of pH/Conductivity Meter.

  1. Scope:

This SOP is applicable for Operation, Cleaning and Calibration of pH/Conductivity Meter used to check pH and conductivity of samples and is located in Quality Control Laboratory.

  1. Responsibility:
  • Quality Control Department: To prepare and review the SOP. To follow the procedures laid down for Operation, Cleaning and Calibration of pH/Conductivity Meter as per this SOP.
  • Engineering Department: To carry out preventive maintenance as per schedule and procedure defined.
  • Quality Assurance Department: To review and approve the SOP and Annexures.

 Accountability:

Head Quality Control Department, Head Quality Assurance Department

  1. Procedure:
5.1 Safety Precautions/Instructions:
5.1.1        Ensure all the electrical connections are properly earthed. Ensure the power plug of the pH/Conductivity Meter is fixed in the socket properly.
5.1.2 Wear personal protective equipments such as safety glasses, hand gloves during operation of instrument.
5.1.3 Ensure that the ON/OFF switch is working properly by switching “ON” the pH/Conductivity Meter.
   5.2 OPERATION UNDER “pH MEASUREMENT MODE”:
5.2.1 Press “MODE” key to select measurement mode i.e. “pH measurement mode”
a) pH MODE:
5.2.2 Ensure that the pH electrode is connected to the instrument.

Select “pH mode” and the display shows

  
5.2.3 Note: “Wait! Stabilizing” indicates that the instrument is checking Electrode signal stability and once the signal is steady it shows the measured pH, mV and temperature.  
5.2.4 Remove the pH electrode from the storage solution and rinse it with purified water 2 to 3 times, soak the excess water with tissue paper and insert the pH electrode and temperature sensor into the beaker containing sample solution.  
5.2.5 Stir the sample solution keeping the pH electrode and temperature sensor immersed in it.  
5.2.6 Note: Instrument will print report of single reading taken if printer is connected properly otherwise it will ignore printing and continue the pH measurement. Check if printer is “ON” and paper is loaded in the tray.
Update the “Instrument/Equipment Usage Log Book” as per SOP  
5.3 pH Meter Calibration Procedure:
Frequency: Daily or after carrying out any major maintenance work.
5.3.1 For issuance of calibration report refer SOP.  
5.3.2 Perform the calibration of instrument as per Annexure and procedure mentioned below.  
5.3.3 Calibrate the instrument using standard buffers pH 1.68, pH 4.01, pH 7.00, pH 9.18 and pH 12.45.  
5.3.4 Ensure that the pH- electrode is connected to the instrument and properly activated and stored.  
5.3.5 Ensure that the temperature sensor and printer is connected to the instrument.  
5.3.6 Rinse the pH electrodes 2 to 3 times, remove the excess water by soaking it with tissue paper and insert the pH electrode and Temperature sensor in the beaker having pH buffer 1.68.  
5.3.7 Now remove the pH electrode from the 1.68 pH buffer and rinse it thoroughly with purified water, soak the excess water with tissue paper. Insert the pH electrode and temperature sensor in the beaker having 4.01 pH buffer.  
5.3.8 Note: The next buffer should not be more than 4 pH unit.  
5.3.9 Enter the second calibration buffer value 4.01 with the numeric keys.  
5.3.10 Repeat the procedure for the calibration buffers 7.00, 9.18 and 12.45.  
5.3.11 When the last (5th) buffer is completed, instrument checks slope obtained i.e. 90% to 105 %.  
5.3.12 Full calibration report is printed with values, buffers used and the slope obtained.  
5.3.13 Enter the details in calibration report as per Annexure. Ensure that the results obtained, comply with the acceptance criteria.  
5.3.14 Update the “Instrument/Equipment Usage Log Book”as per SOP.  
5.3.15 Affix the “Calibration Status Label” on the instrument as per SOP.  
5.4 Operation Under “Conductivity Measurement Mode”:
5.4.1 Press “MODE” key to select measurement mode i.e. “Conductivity measurement mode” and the instrument will display as:
a)   Conductivity MODE:
5.4.2 Ensure that the conductivity electrode is connected to the instrument.

Select “Conductivity mode” and the display reads,
5.4.3 Stir the sample solution keeping Conductivity electrode and temperature sensor immersed in it.
5.4.4 Display will read the Conductivity of the sample solution.
5.4.5
Sample Name

*

Press “ENTER” and the display will read
 

5.4.6

 Enter the sample name by using alphanumeric keys, followed by ID No and the press “ENTER”.
5.4.7  Note: Instrument will print report of single reading taken if printer is  connected properly otherwise it will ignore printing and continue the pH measurement. Check if printer is “ON” and paper is loaded in the tray.
5.4.8 After printing is over, automatically the instrument Display returns to the measurement function.
5.4.9 Update the “Instrument/Equipment Usage Log Book” as per SOP.
5.5 Calibration Procedure:
5.5.1 Frequency: Daily or after carrying out any major maintenance work.
5.5.2 For issuance of calibration report refer SOP.
5.5.3 Perform the calibration of instrument as per Annexure and procedure mentioned below.
5.5.4 Ensure that the Conductivity- electrode is connected to the instrument and properly activated and stored.
5.5.5 Ensure that the temperature sensor and printer is connected to the instrument.
5.5.6 Rinse the Conductivity electrodes 2 to 3 times with purified water, remove the excess water by soaking it with tissue paper and insert the Conductivity electrode and Temperature sensor in the beaker having conductivity standard solution 100 μS/cm.
5.5.7 Press “CAL”
5.5.8 Press “ENTER” and the instrument checks the calibration limit.
5.5.9 If the obtained cell constant is within limit, then the display will show the conductivity value of conductivity standard solution.
5.5.10
Incorrect buffer or

Faulty probe

If the obtained cell constant is out of limit, the display reads as
5.5.11 Full Calibration report is printed with values of standard used, measured value and Cell constant.
5.5.12 Enter the details in calibration report as per Annexure. Ensure that the results obtained, comply with the acceptance criteria.
5.5.13 Update the “Instrument/Equipment Usage Log Book” as per SOP.
5.5.14 Affix the “Calibration Status Label” on the instrument as per SOP.
5.5.15 If calibration activity is outsourced, the values are to be transcribed in the Annexure, and external party certificate to be attached.
  5.6 Electrode Storage:
5.6.1 Store the pH electrode in 3 M KCl solution between routine measurements.
5.6.2 Store the conductivity electrode in Purified Water.
5.6.3 After use, the tips of the pH electrode shall be covered with wetting caps filled with KCl solution to prevent damage.
5.6.4 Activation of pH Electrode:
5.6.5 Dip the pH electrode in a beaker containing 0.1 M Hydrochloric acid for about 1-2 hours.
   5.7 Cleaning Procedure:
5.7.1 Clean the instrument with lint free cloth before and after completion of test.
5.7.2 Change the storage solution of pH electrode once in a week.
5.7.3 Change the storage solution of Conductivity electrode every day.
5.7.4 Replace the filled KCl solution in the electrode with 3M KCl solution once in a week.  
5.7.5 If any breakdown occurs, follow procedure as per SOP.

 

  1. Definitions / Abbreviations:
  • Definitions:
  • Breakdown: Any activity leading to operation of instrument other than the set parameters or unusual sound or vibration observed in the instrument.
  • Calibration: Tests performed to ensure that the instrument is functioning as per set parameters. These tests are performed as per predefined frequency and also after any major repair or replacement of parts.
  • Preventive Maintenance: Maintenance activity performed to ensure that the instrument will function smoothly and to avoid breakdowns. These activities are performed as per predefined frequency.

 

  • pH: pH is defined as the negative logarithm of the hydrogen ion concentration. Measurement of pH of any aqueous sample solution gives the degree of acidity or alkalinity of the solution.
  • Conductivity: Conductivity is the measurement of materials ability to conduct electric current. Measurement of conductivity of sample solution gives the degree of electrical conductance in a defined volume of the solution.

 

  • Abbreviations:
Abbreviation Expansion
pH Power of hydrogen
KCl Potassium Chloride
% Percentage
mm millimetre
GLP Good Laboratory Practices
N Normal
No. Number
μS/cm micro Siemens per centimeter
± Plus or minus
ID No. Identification Number

 

Calibration Report (pH Mode)

 

Observations:

Buffers used for calibration Observed pH Slope obtained
pH 1.68
pH 4.01
pH 7.00
pH 9.18
pH 12.45

 

Acceptance Criteria:

  1. The observed pH of buffer solutions should not be more than ± 0.05.
  2. Slope obtained should be between 90% to 105%.

 

Calibration Report (Conductivity Mode)

 

Sr. No. Conductivity standard solution at 25oC Batch No. Validity
1. 100 µS/cm

 

Observations:

Cell constant of electrode (K) Conductivity standard solution used at 25oC Observed Conductivity

 

Acceptance Criteria:

  1. Displayed value of conductivity should not differ ± 0.5 µS/cm.

 

 

*Note – Ready to use SOP available in “DOWNLOAD” Section.

 

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