by PROTOCOL FOR VALIDATION OF METHOD OF ANALYSIS FOR CLEANING SAMPLE OF CITALOPRAM TABLETS
| Superseded Protocol No. | Nil |
| Effective Date |
TABLE OF CONTENTS :
| Sr. No. | Subject | Page No. |
| Protocol Approval | ||
| Objective | ||
| Scope | ||
| Responsibility | ||
| Product profile | ||
| Methodology | ||
| Validation Parameter | ||
| Incident/Deviation | ||
| Summary | ||
| Revision History |
- PROTOCOL APPROVAL:
Prepared By:
| Functional Area | Name | Designation | Signature/ Date |
| Quality Control |
Reviewed By:
| Functional Area | Name | Designation | Signature/Date |
| Quality Assurance | |||
| Head Quality Control |
Approved By:
| Functional Area | Name | Designation | Signature/Date |
| Head QA |
Authorized By:
| Functional Area | Name | Designation | Signature/Date |
| Head Quality |
- Objective:
The objective of this validation is to provide documentary evidence that analytical methodology used in the analysis of cleaning samples of Citalopram and reliable results within the predetermined acceptance criteria.
Analytical method validation will be performed by considering thefollowing parameters:
| Parameters | |
| Specificity | |
| Precision | |
| System Precision | |
| Method Precision | |
| Linearity | |
| Limit of Detection ( LOD) | |
| Limit of Quantification ( LOQ ) | |
| Accuracy | |
| Stability of Analytical Solution | |
| Robustness | |
| Recovery Study |
Following parameters mention will be seen during system suitability:
| Sr. No. | Parameters | Limit |
| 1. | Tailing Factor of Citalopram peak | Not more than 2.0 |
| 2. | Theoretical plate of Citalopram peak | Not Less than 2000 |
| 3. | % RSD for peck area of Citalopram in Citalopram Tablets from 5 replicate injections of standard solution. | Not more than 2.0 |
When the above parameters meet the method after that the actual experiments should be started.
- Scope :
This protocol is applicable for the validation of method of analysis of cleaning samples of Citalopram tablets.
- Responsibility of Validation Team:
| Departments | Responsibilities |
| QC | Preparation and Review of Validation protocol. |
| Perform the validation as per approved protocol and recording of data. | |
| Compilation and checking of data. | |
| Preparation and review of Validation report. | |
| To impart training of protocol to concerned department/persons. | |
| QA | Review and approval of Validation protocol. |
| Co-ordination with QC to carry out Validation. | |
| Review and approval of Validation report. | |
| Head Quality | Authorization of protocol. |
- Product Profile:
| Category (% API Content) | Antidepressant |
| Reason for Validation | First Validation (To validate the analytical method for cleaning sample analysis) |
| Active Ingredient | Citalopram Hydrobromide |
| Method Reference |
- Methodology:
Chromatographic conditions (By HPLC):
Instrument : High Performance Liquid Chromatography (UV Visible/DAD Detector)
Column : Symmetry (C8), 150 x 3.9 mm, 5µ or equivalent
Flow rate : approx. 1.1 ml/min
Detector : 240nm
Column Temperature : 40ºC
Injection Volume : 10µl
Chromatogram time : 12.0 minutes
Program : Isocratic Method
Reagents required: following mention chemical reagents in Table 1 required in method analysis used for cleaning method validation of Citalopram.
Table 1
| Reagents | Grade |
| Methanol | HPLC Grade |
| Acetonitrile | HPLC Grade |
| Trihydrate sodium acetate | AR Grade |
| Water | HPLC Grade or Milli Q water |
Preparation of the mobile phase and Diluents:
Solution 1 : Dissolve 1.6 g of Trihydrate sodium acetate in 1000 ml of HPLC Grade
Water/ Milli-Q water.
Solution 2 : Acetonitrile: Methanol (50:50)
Mobile Phase : Solution 1: Solution 2 (50:45)
Diluent : Mobile Phase
Preparation of Solutions:
Standard solution:
1st Standard Dilution: Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60.0 ml of mobile phase and dilute to volume with the mobile phase. (Stock concentration of Citalopram base = 0.5 mg/ml or 500 ppm)
2nd Standard Dilution: Dilute 2.0 ml of 1st standard Dilution to 100.0 ml volumetric flask and dilute with the mobile phase. (Final concentration of Citalopram base = 0.01 mg/ml or 10ppm).
System suitability criteria:
Inject 10 µl of the standard solution in five replicate injections and check the system suitability parameters as mentioned below Table 2:
Table 2
| Sr. No. | Parameters | Limit |
| 1. | Tailing Factor | Not more than 2.0 |
| 2. | Theoretical plate | Not Less than 2000 |
| 3. | % RSD for peck area of Citalopram from 5 replicate injections of standard solution. | Not more than 2.0 |
Calculations:
At Ws 2 10 P 324.44
% Citalopram = ——— x ———- x ————- x ———— x —————- x —————-100
AS 100 100 1 100 405.35
Where:
At : Area of Citalopram in the Sample Solution
As : Area of Citalopram in the Standard Solution
Ws : Weight of Working Standard of Citalopram Hydrobromide
324.44 : Molecular weight of Citalopram
405.35 : Molecular weight of Citalopram Hydrobromide
P : Potency of Citalopram Hydrobromide
- VALIDATION PARAMETERS:
This method validation report describes the methodology which is used in the analysis for cleaning sample of Citalopram Tablets for the following parameters.
- Specificity
- Precision
- Linearity
- Accuracy
- Range
- Stability of solution
- Robustness
- System Suitability
- Specificity:
Specificity of analytical method is its ability to assess unequivocally the analyte in presence of components that may be expected to be present in the Swab and Rinse.
Prepare blank solution, swab blank solution, swab standard solution and standard solution 10 mcg/ml as per procedure given below.
Standard solution
1st Standard Dilution: Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60 ml of mobile phase and dilute to volume with the mobile phase. (Stock concentration of Citalopram base = 0.50 mg/ml or 500ppm)
2nd Standard Dilution: Dilute 2.0 ml of 1st standard Dilution to 100.0 ml volumetric flask and dilute with the mobile phase. (Final concentration of Citalopram base = 0.01 mg/ml or 10ppm).
Blank Solution: Mobile phase and Water.
Placebo Solution: Transfer 220 mg of Placebo into 100.0 ml of volumetric flask and add 70 ml of the mobile phase. Sonicate for 5min and dilute to volume with mobile phase. Filter through 0.45 µm nylon membrane filter.
Swab Blank Solution: Take 10.0 ml of diluent in a test tube, dip fresh swab stick in test tube and sonicate for 5 minutes.
Swab Standard Solution: Take 10.0 ml of standard solution of 0.01 mg/ml or 10ppm in a test tube, dip fresh swab stick in test tube and sonicate for 5 minutes.
Specificity of test method should be established by injecting Blank Solution, Placebo solution, Standard solution Swab blank solution and swab standard solution. The sequence prepared as mention below in Table 3.0. Record the chromatogram and check as per acceptance criteria.
Table 3.0
| Solutions | No of Injection to be injected in Sequence |
| Blank mobile phase | 1 |
| Blank Water | 1 |
| Placebo solution | 1 |
| Standard Solution | 5 |
| Swab Blank Solution | 1 |
| Swab Standard Solution | 1 |
| Standard Solution Bracketing | 1 |
Acceptance criteria
The diluent, excipient compounds and swab stick must not interfere with the analysis of the targeted analyte.
No any peak should elute at the retention time Citalopram in blank and placebo solution. Peak purity of the main peak should pass in test and standard solution.
- Precision:System Precision:
The system precision is the closeness of agreement between the responses of detector. It is usually expressed as the standard deviation (SD) or the relative standard deviation (RSD). Standard solution will be prepared as per method of analysis of cleaning validation and injected. Five replicate injections and recorded the area response of main analyte peak. Relative standard deviation will be calculated of response of Citalopram for six replicate injections. The following sequence will be prepared for system precision as mention in Table 4.0.
Table 4.0
| Solutions | No of Injection to be injected in Sequence |
| Blank | 1 |
| Standard Solution | 6 |
Acceptance criteria
The Area % Relative standard deviation for six replicate injections of standard solution should be not more than 2.0% and RT % Relative standard deviation for six replicate injections of standard solution should be not more than 1.0%.
- Method Precision:
The precision of an analytical method is the degree of agreement among individual test results when the procedure is applied repeatability to multiple samplings of homogenous sample. It is usually expressed as the standard deviation and the relative standard deviation.
Prepare six individual spiked samples of 10ppm and analyze as per Methodology.
Standard solution:
1st Standard Dilution: Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60.0 ml of mobile phase and dilute to volume with the mobile phase. (Stock Concentration of Citalopram base = 0.5mg/ml 500ppm)
2nd Standard Dilution: Dilute 2.0 ml of 1st standard Dilution to 100.0 ml volumetric flask and dilute with the mobile phase. (Final concentration of Citalopram base = 0.01 mg/ml or 10ppm).
Placebo Solution: Transfer 220.0 mg of Placebo into 100.0 ml of volumetric flask and add 70 ml of the mobile phase. Sonicate for 5min and dilute to volume with mobile phase. Filter through 0.45 µm nylon membrane filter.
Spiked test solution: Transfer 220.0 mg of placebo weight into 100.0 ml of volumetric flask and add 2.0 ml of 1st standard dilution, add 70 ml of the mobile phase. Sonicate for 5min and dilute to volume with mobile phase. Filter through 0.45 µm nylon membrane filter.(Final concentration of Citalopram base = 0.01 mg/ml or 10ppm), Solution prepared to be injected as given below in sequence Table 5.
Table 5
| Solutions | No of Injection to be injected in Sequence |
| Blank | 1 |
| Placebo | 1 |
| Standard Solution | 5 |
| Spiked Sample Solution 1 | 2 |
| Spiked Sample Solution 2 | 2 |
| Spiked Sample Solution 3 | 2 |
| Standard Solution Bracketing | 1 |
| Spiked Sample Solution 4 | 2 |
| Spiked Sample Solution 5 | 2 |
| Spiked Sample Solution 6 | 2 |
| Standard Solution Bracketing | 1 |
Acceptance criteria
The Area % Relative standard deviation for six determination of spiked sample should be not more than 2.0%.
- Limit Of Detection And QuantificationPredictive Linearity
For determining LOQ, prepare a series of seven dilutions of linearity solutions with increasing concentrations. Inject in duplicate progressively lower concentrations and determine the areas. Plot a graph of concentration v/s area and determine slope of the line. Also determine the STEYX of this line. The Predictive linearity by preparing and inject the standard solution of 0.02ppm, 0.05ppm, 0.5ppm, 1.0ppm, 5.0ppm, 10.0ppm, 20ppm of concentration.
Standard solution:
1st Standard Dilution: Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60 ml of mobile phase and dilute to volume with the mobile phase. (Stock Concentration of Citalopram base = 0.5mg/ml 500ppm)
2nd Standard Dilution: Dilute 2.0 ml of 1st standard Dilution to 100.0 ml volumetric flask and dilute with the mobile phase. (Final concentration of Citalopram base = 0.01 mg/ml or 10ppm).
Preparation of standard linearity stock solution (I) of Citalopram:
Accurately weigh and transfer about 31.2 mg of Citalopram Hydrochloride working standard (equivalent to 25 mg Citalopram) in a 100 ml volumetric flask, add 60 ml of mobile phase, sonicate to dissolve, make volume with mobile phase, mix. (250 ppm of Citalopram)
Preparation of standard linearity stock solution (II) of Citalopram:
Dilute 2.0 ml of standard stock solution I into 200.0 ml of volumetric flask with mobile phase, mix well. (2.5 ppm of Citalopram)
Table 6: Dilutions for prediction linearity
| Citalopram Linearity stock Solution (I) to be added (mL) | Volume to be diluted with Diluent (mL) | Citalopram Linearity stock Solution (II) to be added (mL) | Volume to be diluted with Diluent (mL) | Theoretical Concentration (ppm) for Citalopram |
| Refer to Preparation of standard stock solution (II) of Citalopram | 2.0 | 250.0 | 0.02 | |
| 5.0 | 250.0 | 0.05 | ||
| 5.0 | 25.0 | 0.50 | ||
| 10.0 | 25.0 | 1.00 | ||
| 2.0 | 100.0 | NA NA | 5.00 | |
| 2.0 | 50.0 | 10.00 | ||
| 2.0 | 25.0 | 20.00 |
Table 7: Prediction linearity for Citalopram
| Sr. No. | Theoretical Concentration (ppm) for Citalopram | Actual conc. (ppm) | Peak Area | Mean Peak Area | |
| I | II | ||||
| 1 | 0.02 | ||||
| 2 | 0.05 | ||||
| 3 | 0.50 | ||||
| 4 | 1.00 | ||||
| 5 | 5.00 | ||||
| 6 | 10.00 | ||||
| 7 | 20.00 | ||||
| Correlation Coefficient (r) | |||||
| Standard Error | |||||
| Slope | |||||
| Limit of detection (LOD), ppm | |||||
| Limit of quantitation (LOQ), ppm |
The LOD and LOQ are calculated based on the following formula
LOD = Standard Error (σ) x 3.3
————————————
Slope (S)
LOQ = Standard Error (σ) x 10
——————————–
Slope (S)
- LOQ and LOD Precision
To confirm the values of LOQ and LOD obtained from prediction linearity, prepare solution at LOQ and LOD concentration by using stock solutions with suitable dilutions and inject six replicate injections to check the %RSD. Summaries the data obtained in the following tables
Table 8: Precision at LOD
| COMPONENT® | Citalopram | |
| Peak Area | Signal/Noise Ratio | |
| Theoretical Conc. (ppm) | ||
| Actual Conc. (ppm) | ||
| 1 | ||
| 2 | ||
| 3 | ||
| 4 | ||
| 5 | ||
| 6 | ||
| Mean | ||
| SD | ||
| % RSD | ||
| Acceptance criteria | NMT 30.0% | 3:1 |
Table 9: Precision at LOQ
| COMPONENT® | Citalopram HBr | |
| Theoretical Conc. (ppm) | ||
| Actual Conc. (ppm) | ||
| Peak Area | Signal/Noise Ratio | |
| 1 | ||
| 2 | ||
| 3 | ||
| 4 | ||
| 5 | ||
| 6 | ||
| Mean | ||
| SD | ||
| % RSD | ||
| Acceptance criteria | NMT 10.0% | 10:1 |
Acceptance criteria:
The correlation coefficient of predictive linearity of Citalopram HBr from LOD or LOQ to 200% should not less than 0.99. should be not The % RSD of Peak Area should be NMT 10.0% for Limit of Quantitation and % RSD of Peak Area should be NMT 30.0% Limit of Detection. Signal to Noise Ratio for LOD should be 3:1 and Signal to Noise Ratio for LOQ should be 10:1.
- Accuracy:
The accuracy of an analytical procedure express the closeness of agreement between the value which accepted either as a conventional true value or an accepted reference value and the value found. The accuracy should be established across the specified range of the analytical procedure.
Test Procedure:
Prepare the sample solution by spiking the Citalopram (Drug substances) to the placebo at about 50%, 100% and 150% of test concentration level in triplicate in each level and analyze as per cleaning protocol. Calculate the % RSD for recovery obtained at each level separately and overall %RSD.
Preparation of solutions for accuracy:
Standard solution:
1st Standard Dilution: Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60.0 ml of mobile phase and dilute to volume with the mobile phase. (Stock Concentration of Citalopram base = 0.5mg/ml 500ppm)
2nd Standard Dilution: Dilute 2.0 ml of 1st standard Dilution to 100.0 ml volumetric flask and dilute with the mobile phase. (Final concentration of Citalopram base = 0.01 mg/ml or 10ppm) and filter with 0.45 µm nylon filter.
Preparation of standard accuracy stock solution of Citalopram:
Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60.0 ml of mobile phase and dilute to volume with the mobile phase. (Stock Concentration of Citalopram base = 0.5mg/ml 500ppm)
Sample solutions:
Level I (50%): Transfer 220.0 mg of placebo weight into 100.0 ml of volumetric flask and add 1.0 ml of accuracy standard stock solution of Citalopram, add 70.0 ml of the mobile phase. Sonicate for 5.0 min and dilute to volume with mobile phase. Filter through 0.45 µm nylon membrane filter. (Final concentration of Citalopram base = 0.005 mg/ml or 5.0ppm),
Level II (100%): Transfer 220.0 mg of placebo weight into 100.0 ml of volumetric flask and add 2.0 ml of accuracy standard stock solution of Citalopram, add 70.0 ml of the mobile phase. Sonicate for 5.0 min and dilute to volume with mobile phase. Filter through 0.45 µm nylon membrane filter. (Final concentration of Citalopram base = 0.005 mg/ml or 5.0ppm),
Level III (150%): Transfer 220.0 mg of placebo weight into 100.0 ml of volumetric flask and add 3.0 ml of accuracy standard stock solution of Citalopram, add 70.0 ml of the mobile phase. Sonicate for 5.0 min and dilute to volume with mobile phase. Filter through 0.45 µm nylon membrane filter. (Final concentration of Citalopram base = 0.005 mg/ml or 5.0ppm),
Table 10: Accuracy of Citalopram
| % Level | Solution preparations | Theoretical Conc. (ppm) | |
| Volume of Standard stock Soln. withdrawn (mL) | Total volume (mL) | ||
| 50% : Test 1 | 1.0ml | 100.0ml | 5.0ppm |
| 50% : Test 2 | 1.0ml | 100.0ml | 5.0ppm |
| 50% : Test 3 | 1.0ml | 100.0ml | 5.0ppm |
| 100% : Test 1 | 2.0ml | 100.0ml | 10.0ppm |
| 100% : Test 2 | 2.0ml | 100.0ml | 10.0ppm |
| 100% : Test 3 | 2.0ml | 100.0ml | 10.0ppm |
| 150% : Test 1 | 3.0ml | 100.0ml | 15.0ppm |
| 150% : Test 2 | 3.0ml | 100.0ml | 15.0ppm |
| 150% : Test 3 | 3.0ml | 100.0ml | 15.0ppm |
Calculation:
Amount added in ppm
Ws2 X P 324.44
Amount added = ——— x ———- x ————- x ————- x 1000
100 100 100 405.35
At Ws1 2 P 324.44
Amount Recovered= ——— x ———- x ————- x ———— x —————- x 1000
AS 100 100 100 405.35
Amount Recovered in ppm
%Recovery = ——————————————– x 100
Amount added in ppm
Where:
At : Area of Citalopram in the Sample Solution
As : Area of Citalopram in the Standard Solution
Ws1 : Weight of Citalopram taken in standard solution
Ws2 : Weight of Citalopram taken in standard stock solution to be spike
X : Volume of standard stock withdrawn in ml for spiking (i.e.1ml, 2ml, 3ml)
P : Potency of Citalopram Hydrobromide
324.44 : Molecular weight of Citalopram
405.35 : Molecular weight of Citalopram Hydrobromide
Acceptance criteria
The mean recovery at each level should be between 70% to 130% of the theoretical value and the % RSD not more than 10%.
- Range:
The range of an 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 has a suitable level of precision, accuracy and linearity. The range is normally expressed in the same units as test results obtained by the analytical method. (E.g. percent, parts per million).
- Stability of Analytical solution:
It is essential when validating an analytical method to confirm that the analyte has adequate stability in standard solution during analytical measurement stages of the testing.
Test Procedure:
Prepare the standard solution as per cleaning testing protocol and analyze the solution at the different time intervals i.e. 6.0 hour, 12.0 hour, 18.0 hour, 24.0 hour, 30.0 hour, 36.0 hour,42.0 hour, 48.0 hour and calculate the relative standard deviation.
Standard solution:
1st Standard Dilution: Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60.0 ml of mobile phase and dilute to volume with the mobile phase. (Stock Concentration of Citalopram base = 0.5mg/ml 500ppm)
2nd Standard Dilution: Dilute 2.0 ml of 1st standard Dilution to 100.0 ml volumetric flask and dilute with the mobile phase. (Final concentration of Citalopram base = 0.01 mg/ml or 10ppm) and filter with 0.45 µm nylon filter.
Acceptance criteria
The relative standard deviation of standard solution at each time interval should not be more than 2.0%.
- Robustness:
The method should show reliability of an analysis with respect to deliberate variation in method parameters of cleaning.
Following deliberate variations should be done in method parameters:
- By changing the flow rate by ±10%.
- By changing the Column oven temperature by ±5°C.
- By Changing the Organic Solvent ±5%.
System suitability parameters shall be performed as per cleaning testing procedure for each deliberate variation.
Test Procedure:
Prepare the standard solution as per the method by deliberate variations made in the method for each condition as mentioned in protocol and analyze.
Standard solution:
1st Standard Dilution: Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60.0 ml of mobile phase and dilute to volume with the mobile phase. (Stock Concentration of Citalopram base = 0.5mg/ml 500ppm)
2nd Standard Dilution: Dilute 2.0 ml of 1st standard Dilution to 100.0 ml volumetric flask and dilute with the mobile phase. (Final concentration of Citalopram base = 0.01 mg/ml or 10ppm)
Acceptance criteria
System suitability parameter should meet as per acceptance limit of system suitability criteria.
- Plates Recovery:
Standard solution:
1st Standard Dilution: Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60 ml of mobile phase and dilute to volume with the mobile phase. (Stock Concentration of Citalopram base = 0.5mg/ml 500ppm)
2nd Standard Dilution: Dilute 2.0 ml of 1st standard Dilution to 100.0 ml volumetric flask and dilute with the mobile phase. (Final concentration of Citalopram base = 0.01 mg/ml or 10ppm)
Recovery Stock Solution:
Accurately weigh, approximately 62.45 mg of Citalopram Hydrobromide WS (equivalent to 50.0 mg of Citalopram base) in a 100.0 ml volumetric flask, completely dissolve in 60 ml of mobile phase and dilute to volume with the mobile phase. (Stock Concentration of Citalopram base = 0.5mg/ml 500ppm)
- Spike the 0.5 ml, 1.0 ml and 1.5 ml of recovery stock solution into the area of 10 x 10 cm2 in three different SS Plates for each concentration.
- Allow the solutions to dry in air.
- Take the Swab wipe and moisten with diluents, swab one SS plate in the area of 10 x 10 cm2. Collect the swab in the 50 ml volumetric flask containing already 40.0 ml of diluent and sonicate for 10.0 minutes with swirling. Squeeze the swab and discard after makeup volume to 50.0 ml with the diluents. Filter through 0.45 µm filter. Final concentrations of recovery solutions are 5.0 ppm, 10.0 ppm, and 15.0 ppm.
- Similarly do the recovery on 10 × 10 cm2 Acrylic plates, PVC, Silicone and Conveying belt.
Acceptance criteria:
Recovery at each level should not less than 70%
- Incident/Deviation:
Any Incident or Deviation observed during Analytical Method validation shall be recorded and reported in Validation Report.
- Summary/Conclusion:
Final Conclusion shall be drawn from analytical method validation for its use to analyze the cleaning samples of Citalopram tablets by HPLC.
Summary of validation report shall be prepared.
Revision History :
| Revision No. | Details of changes | Reason for change |
| 00 | Nil | New Document |
