ADDITIONAL DRAFT AMENDMENTS
UPDATED ON: 01.07.2011
The IPC has received inputs from its stakeholders on IP 2010 which require upgradation/change. The draft
amendments (PROPOSED) are put on the website (www.ipc.gov.in) for comments of the users. It is expected that if
no comments are received within 15 days, please note- the draft amendments will be taken for finalization.
2.2.11. Sterility. Page 56
Insert after para 4,
“This sampling is, however, applicable at manufacturers and not for Inspectors under the Drugs and Cosmetics Act
for drawing statutory samples and for Government Analysts.”
Method A- Membrane Filtration. Validation of Tests, last line
Change from: 7 days to: 14 days
Method B- Direct Inoculation. Para 4, last line
Change from: 7 days to: 14 days
2.3.50. Fatty Acid Composition by Gas Chromatography
The test for foreign oils is carried out on the methyl esters of the fatty acids contained in the oil under examination
by gas chromatography (2.4.13).
Method A. This method is not applicable to oils that contain glycerides of fatty acids with an epoxy-, hydroepoxy-,
hydroperoxy, cyclopropyl or cyclopropenyl group, or those that contain a large proportion of fatty acids of chain
length less than 8 carbon atoms or to oils with an acid value greater than 2.0.
Test solution. When prescribed in the monograph, dry the oil under examination before the methylation step. Weigh
1.0 g of the oil into a 25-ml round-bottomed flask with a ground-glass neck fitted with a reflux condenser and a gas
port into the flask. Add 10 ml of anhydrous methanol and 0.2 ml of a 6.0 per cent w/v solution of potassium
hydroxide in methanol. Attach the reflux condenser, pass nitrogen through the mixture at a rate of about 50 ml per
minute, shake and heat to boiling for about 10 minutes. When the solution is clear, continue heating for a further 5
minutes. Cool the flask under running water and transfer the contents to a separating funnel. Rinse the flask with 5
ml of heptane and transfer the rinsings to the separating funnel and shake. Add 10 ml of a 20 per cent w/v solution
of sodium chloride and shake vigorously. Allow to separate and transfer the organic layer to a vial containing
anhydrous sodium sulphate. Allow to stand, then filter.
Reference solution (a). Prepare 0.5 g of the mixture of calibrating substances with the composition described in one
of the tables, as prescribed in the individual monograph (if the monograph does not mention a specific solution, use
the composition described in Table-1). Dissolve in heptanes and dilute to 50.0 ml with the same solvent.
Reference solution (b). Dilute 1.0 ml of reference solution (a) to 10.0 ml with heptane.
Reference solution (c). Prepare 0.5 g of a mixture of fatty acid methyl esters that corresponds in composition to the
mixture of fatty acids indicated in the monograph of the substance under examination. Dissolve in heptane and
dilute to 50.0 ml with the same solvent. Commercially available mixtures of fatty acid methyl esters may also be
used.
Chromatographic system
– a capillary column 30 m x 0.8 mm, packed with fused silica coated with macrogol 20000 (film thickness 0.5
µm),
– temperature:
– column. 170°, then raised at the rate of 3° per minute to 230°,
– inlet port and detector. 250°,
– flame ionization detector,
– flow rate. 1.3 ml per minute and a split ratio of 1:100.
System suitability when using the mixture of calibrating substances in Table-1 or Table-3:
Inject reference solutions (a) and (b). The resolution between the peaks due to methyl oleate and methyl stearate in
the chromatogram obtained with reference solution (a) is not less than 1.8 and the theoretical plates for the peak due
to methyl stearate is not less than 30,000. In the chromatogram obtained with reference solution (b), the signal-tonoise ratio for the peak due to methyl myristate is not less than 5.0.
System suitability when using the mixture of calibrating substances in Table-2:
Inject reference solutions (a) and (b). The resolution between the peaks due to methyl caprylate and methyl caprate
in the chromatogram obtained with reference solution (a) is not less than 4.0 and the theoretical plates for the peak
due to methyl caprate is not less than 15,000. In the chromatogram obtained with reference solution (b), the signalto-noise ratio for the peak due to methyl caproate is not less than 5.0.
Assessment of chromatograms. Avoid working conditions tending to give masked peaks (presence of constituents
with small differences between retention times, for example linolenic acid and arachidic acid).
Qualitative analysis. Identify the peaks in the chromatogram obtained with reference solution (c) (isothermal
operating conditions or linear temperature programming).
When using isothermal operating conditions, the peaks may also be identified by drawing calibration curves using
the chromatogram obtained with reference solution (a) and the information given in Tables-1, 2 or 3.
Table 1- Mixture of calibrating substances (for gas chromatography with capillary column and split inlet system it is
recommended that the component with the longest chain length of the mixture under examination to be added to the
calibrating mixture, when qualitative analysis is done using calibration curves)
Mixture of following substances
Methyl laurate
Methyl myristate
Methyl plamitate
Methyl stearate
Methyl arachidate
Methyl oleate
Composition (per cent m/m)
5
5
10
20
40
20
Table-2. Mixture of calibrating substances (for gas chromatography with capillary column and split inlet system, it
is recommended that the component with the longest chain length of the mixture under examination to be added to
the calibrating mixture, when qualitative analysis is done using calibration curves)
Mixture of following substances
Methyl caproate
Methyl caprylate
Methyl caprate
Methyl laurate
Methyl myristate
Composition (per cent m/m)
10
10
20
20
40
Table-3. Mixture of calibrating substances (for gas chromatography with capillary column and split inlet system, it
is recommended that the component with the longest chain length of the mixture under examination to be added to
the calibrating mixture, when qualitative analysis is done using calibration curves)
Mixture of following substances
Methyl myristate
Methyl palmitate
Composition (per cent m/m)
5
10
Methyl stearate
Methyl arachidate
Methyl oleate
Methyl eicosenaote
Methyl behenate
Methyl lignocerate
15
20
20
10
10
10
Measure the reduced retention time (t' R) of each peak in the chromatogram obtained with reference solution (a).
t' R is the retention time measured from the solvent peak and not from the time of injection. Plot the straight line:
log (t' r)= f(equivalent chain length)
The logarithms of t' R of unsaturated acids are situated on this line at points corresponding to non-integer values of
carbon atoms known as 'equivalent chain lengths'; the equivalent chain length is the length of the theoretical
saturated chain that would have the same t' R as the fatty acid to be identified. For example, linoleic acid has the
same t' R as the theoretical saturated fatty acid having 18.8 carbon atoms.
Identify the peaks in the chromatogram obtained with the test solution by means of the straight line and the reduced
retention times. Equivalent chain lengths are given in Table 2.4.22.-4.
Quantitative analysis. In general, the normalisation procedure is used in which the sum of the areas of the peaks in
the chromatogram, except that of the solvent, is set at 100 per cent. The content of a constituent is calculated by
determining the area of the corresponding peak as a percentage of the sum of the areas of all the peaks. Disregard
any peak with an area less than 0.05 per cent of the total area.
In certain cases, for example in the presence of fatty acids with 12 or less carbon atoms, correction factors can be
prescribed in the individual monograph to convert peak areas in per cent m/m.
Table-4. Equivalent chain lengths (this value, which is to be calculated using calibration curves, is given as an
example for a column of macrogeol 20000)
Fatty Acid
Caproic acid
Caprylic acid
Capric acid
Lauric acid
Myristic acid
Palmitic acid
Palmitoleic acid
Margaric acid
Stearic acid
Oleic acid
Linoleic acid
Gamma-linolenic acid
Alpha-linolenic acid
Arachidic acid
Elcosenoic acid
Arachidonic acid
Behenic acid
Erucic acid
12-Oxostearic acid
Ricinoleic acid
12-Hydroxystearic acid
Lignoceric acid
Nervonic acid
equivalent chain length
6.0
8.0
10.0
12.0
14.0
16.0
16.3
17.0
18.0
18.3
18.8
19.0
19.2
20.0
20.2
21.2
22.0
22.2
22.7
23.9
23.9
24.0
24.2
Method B. This method is not applicable to oils that contain glycerides of fatty acids with an epoxy-, hydroepoxy-,
hydroperoxy-, cyclopropyl or cyclopropenyl group or to oils with an acid value greater than 2.0.
Test solution. Introduce 0.1 g of the substance under examination into a 10-ml centrifuge tube with a screw cap.
Dissolve with 1 ml of heptane and 1 ml of dimethyl carbonate and mix vigorously under gentle heating (50-60°).
Add, while still warm, 1 ml of a 1.2 per cent w/v solution of sodium in anhydrous methanol, prepared with the
necessary precautions, and mix vigorously for about 5 minutes. Add 3 ml of water and mix vigorously for about 30
seconds. Centrifuge for 15 minutes at 1500 g. Inject 1 µl of the organic phase.
Reference solutions and assessment of chromatograms. Where there is no specific prescription in the individual
monograph, proceed as described under Method A.
Chromatographic system
– a capillary column 30 m x 0.25 mm, packed with fused silica coated with macrogol 20000 (film thickness 0.25
µm),
– temperature:
Time
Temperature
(min)
(°)
column
0-15
100
15-36
100-225
36-61
225
- injection port and detector 250°,
– flame ionization detector,
– flow rate. 0.9 ml per minute and a split ratio of 1:100.
Method C. This method is not applicable to oils that contain glycerides of fatty acids with epoxy- , hydroepoxy-,
hydroperoxy-, aldehyde, ketone, cyclopropyl and cyclopropenyl groups and conjugated polyunsaturated and
acetylenic compounds because of partial or complete destruction of these groups.
Test solution. Dissolve 0.1 g of the substance under examination in 2 ml of a 2 per cent w/v solution of sodium
hydroxide in methanol in a 25-ml conical flask and boil under a reflux condenser for 30 minutes. Add 2.0 ml of
boron trifluoride-methanol solution through the condenser and boil for 30 minutes. Add 4 ml of heptane through the
condenser and boil for 5 minutes. Cool and add 10.0 ml of saturated sodium chloride solution, shake for about 15
seconds and add a quantity of saturated sodium chloride solution such that the upper phase is brought into the neck
of the flask. Collect 2 ml of the upper phase, wash with 3 quantities, each of 2 ml, of water and dry over anhydrous
sodium sulphate.
2.4.13. Gas Chromatography
Adjustment of chromatographic conditions. Lines 12 and 13
Change from: Injection volume. May be decreased provided detection and repeatability are satisfactory. to: Injection
volume. May be decreased provided detection and repeatability of the peak(s) to be determined are satisfactory: no
increase permitted.
Note: Query received from Sridhar Rao. Chem-Decided by SD of IPC. Harmonized on the lines of EP.
2.4.14. Liquid Chromatography
Adjustment of chromatographic conditions. Line 11
Change from: ± pH to: ± 1.0 pH
Line 24
Change from: Temperature. ± 10 per cent, to a maximum of 60°; to: Temperature. ± 10°, where the operating
temperature is specified unless otherwise prescribed;
Lines 25 and 26
Change from: Injection volume. May be increased if detection and repeatability of peak(s) to be determined are
satisfactory. to: Injection volume. May be decreased provided detection and repeatability of the peak(s) to be
determined are satisfactory: no increase permitted.
2.4.26. Solubility
Atorvastatin Calcium. Page 149
Change from: Freely soluble in methanol to: Slightly soluble in methanol
Clomifene. Page 153
Change from: Clomifene to: Clomifene Citrate
Page 156
Insert before Ethyl Chloride
“Ethylcellulose. Insoluble in water, in glycerin, and in propylene glycol. Ethylcellulose containing less than 46.5
per cent of ethoxy groups is freely soluble in tetrahydrofuran, in methyl acetate, in chloroform, and in mixtures of
aromatic hydrocarbons with ethanol (95 per cent). Ethylcellulose containing not less than 46.5 per cent of ethoxy
groups is freely soluble in ethanol (95 per cent), in methanol, in toluene, in chloroform, and in ethyl acetate.”
Poloxamers. Page 165
Change to: Freely soluble in water and in ethanol (95 per cent).
2.4.29. Weight Per Millilitre and Relative Density.
Page No. 174
Relative Density. Insert the following before Alcohol Table.
Oscillating transducer density meter:- The apparatus consists of (i) a U-shaped tube, usually of borosilicate
glass, which contains the liquid under examination; (ii) a magneto-electrical or piezo-electrical excitation system
that causes the tube to oscillate as a cantilever oscillator at a characteristic frequency depending on the density of
the liquid under examination; (iii) a means of measuring the oscillation period (T), which may be converted by the
apparatus to give a direct reading of density, or used to calculate density using the constants A and B described
below.
The resonant frequency (f) is a function of the spring constant (c) and the mass (m) of the system:
Hence:
ρ
M
V
=
=
=
density of the liquid under examination
mass of the tube,
inner volume of the tube.
Introduction of 2 constants A = c /(4p2 × V) and B = M/V, leads to the classical equation for the oscillating
transducer:
The constants A and B are determined by operating the instrument with the U-tube filled with 2 different samples of
known density, for example, degassed water and air. Control measurements are made daily using degassed water.
The results displayed for the control measurement using degassed water shall not deviate from the reference value
(ρ25 = 0.997043 g·cm-3, d2525 = 1.000000) by more than its specified error. For example, an instrument specified to ±
0.0001 g·cm-3 shall display 0.9970 ± 0.0001 g·cm-3 in order to be suitable for further measurement. Otherwise a readjustment is necessary. Calibration with certified reference materials is carried out regularly. Measurements are
made using the same procedure as for calibration. The liquid under examination is equilibrated in a thermostat at
25° before introduction into the tube, if necessary, to avoid the formation of bubbles and to reduce the time required
for measurement.
Factors affecting accuracy include (i) temperature uniformity throughout the tube; (ii) non-linearity over a range of
density; (iii) parasitic resonant effects; (iv) viscosity, whereby solutions with a higher viscosity than the calibrant
have a density that is apparently higher than the true value.
The effects of non-linearity and viscosity may be avoided by using calibrants that have density and viscosity close to
those of the liquid under examination (± 5 per cent for density, ± 50 per cent for viscosity). The density meter may
have functions for automatic viscosity correction and for correction of errors arising from temperature changes and
non-linearity.
Precision is a function of the repeatability and stability of the oscillator frequency, which is dependent on the
stability of the volume, mass and spring constant of the cell.
Density meters are able to achieve measurements with an error of the order of 1 × 10-3 g·cm-3 to 1 × 10-5 g·cm-3 and
a repeatability of 1 × 10-4 g·cm-3 to 1 × 10-6 g·cm-3.
2.5.10. Validation of Analytical Procedures
Change to:
2.5.10. Validation of Analytical Procedures
Validation of an analytical procedure is performed in order to demonstrate that the procedure is suitable for its
intended use. Validation is performed in order to show that the result(s) generated by a particular analytical
procedure are reliable and accurate.
Types of procedures to be validated
The objective of validation of an analytical procedure is to demonstrate that it is suitable for its intended purpose. A
tabular summation of the characteristics applicable to identification, control of impurities and assay procedures is
included.
- signifies that this characteristic is not normally evaluated
+ signifies that this characteristic is normally evaluated
(1) in cases where reproducibility has been performed, intermediate precision is not needed
(2) lack of specificity of one analytical procedure could be compensated by other
procedure(s)
supporting analytical
(3) may be needed in some cases
Specificity
Specificity is the ability to assess unequivocally the analyte in the presence of components that may be expected to
be present. Typically these might include impurities, degradants, matrix, etc.
Specificity may often be expressed as the degree of bias of test results obtained by analysis of samples containing
added impurities, degradation products, related chemical compounds, or placebo ingredients when compared to test
results without added substances.
Specificity is usually demonstrated by measuring the response of the sample matrix and any expected or known
species (for example excipients, impurities or degradation products). It would normally be expected that no
significant response would be obtained that interferes with the measurement of the analyte(s). However it is not
always possible that an analytical procedure is specific for a particular analyte. In this instance a combination of
two or more analytical procedures may be necessary to achieve the required discrimination.
Linearity
The linearity of an analytical procedure is its ability (within a given range) to obtain test results that are directly
proportional to the concentration (amount) of analyte in the sample.
Linearity is usually demonstrated by visual inspection of a plot of signals as a function of analyte concentration or
content. If there is a linear relationship, test results should be evaluated by appropriate statistical methods, for
example, by calculation of a regression line by the method of least squares. In some cases, to obtain linearity
between assays and sample concentrations, the test data may need to be subjected to a mathematical transformation
prior to the regression analysis. Data from the regression line itself may be helpful to provide mathematical
estimates of the degree of linearity.
The correlation coefficient, y-intercept, slope of the regression line and residual sum of squares should be
calculated. A plot of the data should be included. In addition, an analysis of the deviation of the actual data points
from the regression line may also be helpful for evaluating linearity.
A minimum of five concentrations is recommended. Other approaches should be justified.
Accuracy
The accuracy of an analytical procedure expresses the closeness of agreement between the value which is accepted
either as a conventional true value or an accepted reference value and the value found. This is sometimes termed
trueness. Accuracy should be established across the specified range of the analytical procedure.
Accuracy is usually demonstrated by adding known amounts of analyte(s) to the sample matrix and determining the
measured result using the analytical procedure. The recovery of measured against actual amounts is then calculated.
Usually a minimum of three determinations at each of three concentrations across the intended range is
recommended.
Accuracy may also be demonstrated by the method of standard additions, or by cross-correlation of results with a
second, independent, procedure. Accuracy may be inferred once precision, linearity and specificity have been
established.
Precision
The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of
measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions.
Precision may be considered at three levels: repeatability, intermediate precision and reproducibility.
Precision should be investigated using homogeneous, authentic samples. However, if it is not possible to obtain a
homogeneous sample it may be investigated using artificially prepared samples or a sample solution.
The precision of an analytical procedure is usually expressed as the variance, standard deviation or coefficient of
variation of a series of measurements.
Repeatability (Intra-Assay Precision)
Repeatability expresses the precision under the same operating conditions over a short interval of time. Repeatability
is also termed as intra-assay precision.
Repeatability is usually demonstrated by repeated measurements of a single sample (e.g. use of the analytical
procedure within a laboratory over a short period of time using the same analyst with the same equipment). A
minimum of three determinations at each of three concentrations across the intended range, or a minimum of six
determinations at the test concentration is recommended.
Intermediate Precision
Intermediate precision expresses within-laboratory variations: different days, different analysts or equipment, etc.
Intermediate precision is usually demonstrated by repeated measurements of the sample used in the repeatability
experiment within the same laboratory. Usually the repeatability experiment is repeated on the same sample by a
different analyst, on a different day, using different equipment if possible.
Reproducibility
Reproducibility expresses the precision between laboratories (collaborative studies, usually applied to
standardisation of methodology).
Reproducibility is usually demonstrated by means of an inter-laboratory trial.
Detection Limit
The detection limit of an analytical procedure is the lowest concentration of analyte in a sample that can be detected
but not necessarily quantitated as an exact value.
The detection limit is usually expressed as the concentration of analyte (e.g., percentage, parts per billion) in the
sample.
The detection limit is usually demonstrated by measuring low concentrations of the analyte and showing that a
response is obtained.
Quantitation Limit
The quantitation limit of an individual analytical procedure is the lowest amount of analyte in a sample which can
be quantitatively determined with suitable precision and accuracy. The quantitation limit is a parameter of
quantitative assays for low levels of compounds in sample matrices, and is used particularly for the determination of
impurities and/or degradation products.
It is usually expressed as the concentration of analyte (e.g., percentage, parts per billion) in the sample.
The quantitation limit is usually demonstrated by measuring low concentrations of the analyte and showing that a
repeatable response is obtained.
Robustness
The robustness of an analytical procedure is a measure of its capacity to remain unaffected by small but deliberate
variations in method parameters and provides an indication of its reliability during normal usage.
Robustness is usually demonstrated by making small deliberate changes to one of the operating parameters of the
method, analysing samples and comparing the results to those obtained using the prescribed method.
Range
The range of an analytical method is the interval between the upper and lower concentration (amounts) of analyte
(including these concentrations) for which it has been demonstrated that the analytical procedure has a suitable level
of precision, accuracy and linearity.
The specified range is normally derived from linearity studies and depends on the intended application of the
procedure. It is established by confirming that the analytical procedure provides an acceptable degree of linearity,
accuracy and precision when applied to samples containing amounts of analyte within or at the extremes of the
specified range of the analytical procedure.
For assays the range is usually not less than 80 to 120 per cent of the test concentration.
For determination of content uniformity the range is usually not less than 70 to 130 per cent of the test
concentration.
For determination of impurities the range is usually not less than the reporting limit of the impurity to 120 per cent
of the specification.
For dissolution testing the range is usually +/- 20 per cent over the expected concentrations.
Range is usually demonstrated by confirming that the analytical procedure provides an acceptable degree of
linearity, accuracy and precision when applied to samples containing amounts of analyte within or at the extremes of
the specified range.
3.3. Liquid/HPTLC/Gas chromatograms of Herbs
Senna Dry Extract. Page 543
HPLC Chromatogram of calcium sennosides RS and Senna Dry Extract
Change from: Sennoside A
Change from: Sennoside B
to: Sennoside B
to: Sennoside A
Senna Tablets. Page 544
HPLC Chromatogram of calcium sennosides RS and Senna Tablets.
Change from: Sennoside A
Change from: Sennoside B
to: Sennoside B
to: Sennoside A
5.4. Residual Solvents. Page 650
Class 1 solvents. Table 1
Change to:
Solvent
Benzene
Carbon Tetrachloride
1, 2-Dichloroethane
1, 1-Dichloroethene
1, 1, 1-Trichloroethane
Class 2 solvent. Table 2
Change to:
Table 1
Concentration Limit
(ppm)
2
4
5
8
1500
Concern
Carcinogen
Toxic and environmental hazard
Toxic
T oxic
Environmental hazard
Solvent
Acetonitrile
Chlorobenzene
Chloroform
Cyclohexane
1,2-Dichloroethene
Dichloromethane
1,2-Dimethoxyethane
N,N-Dimethylacetamide
N,N-Dimethylformamide
1,4-Dioxane
2-Ethoxyethanol**
Ethyleneglycol**
Formamide**
Hexane
Methanol
2-Methoxyethanol**
Ethylbutylketone
Methylcyclohexane
N-Methylpyrrolidone**
Nitromethane
Pyridine
Sulpholane**
Tetrahydrofuran
Tetralin
Toluene
1, 1, 2-Trichloroethene
Xylene*
Table 2
PDE
(mg/day)
4.1
3.6
0.6
38.8
18.7
6.0
1.0
10.9
8.8
3.8
1.6
6.2
2.2
2.9
30.0
0.5
0.5
11.8
5.3
0.5
2.0
1.6
7.2
1.0
8.9
0.8
21.7
Concentration Limit
(ppm)
410
360
60
3880
1870
600
100
1090
880
380
160
620
220
290
3000
50
50
1180
530
50
200
160
720
100
890
80
2170
Insert before Class 3 solventsOptions for describing limits of class 2 solvents-Two options are available when setting limits for Class 2
solvents.
Option 1. The concentration limits in ppm stated in Table 2 can be used. They were calculated using equation (1)
below by assuming a product mass of 10 g administered daily.
Concentration (ppm) = 1000 x PDE
dose
Here, PDE is given in terms of mg/day and dose is given in g/day.
(1)
These limits are considered acceptable for all substances, excipients, or products. Therefore this option may be
applied if the daily dose is not known or fixed. If all excipients and drug substances in a formulation meet the limits
given in Option 1, then these components may be used in any proportion. No further calculation is necessary
provided the daily dose does not exceed 10 g. Products that are administered in doses more than 10 g per day should
be considered under Option 2.
Option 2. It is not considered necessary for each component of the drug product to comply with the limits given in
Option 1. The PDE in terms of mg/day as stated in Table 2 can be used with the known maximum daily dose and
equation (1) above to determine the concentration of residual solvent allowed in a drug product. Such limits are
considered acceptable provided that it has been demonstrated that the residual solvent has been reduced to the
practical minimum. The limits should be realistic in relation to analytical precision, manufacturing capability,
reasonable variation in the manufacturing process, and the limits should reflect contemporary manufacturing
standards.
Option 2 may be applied by adding the amounts of a residual solvent present in each of the components of the drug
product. The sum of the amounts of the solvent per day should be less than that given by the PDE.
Consider an example of the use of Option 1 and Option2 applied to acetonitrile in a drug product. The permitted
daily exposure to acetonitrile is 4.1 mg/day; thus the Option 1 limit is 410 ppm. The maximum administered daily
mass of a drug product is 5.0 g , and the drug product contains two excipients. The composition of the drug product
and the calculated maximum content of residual acetonitrile are given in the following table.
Component
Amount in
Acetonitrile
Daily
formulation
content
exposure
Drug substance
0.3 g
800 ppm
0.24 mg
Excipient 1
0.9 g
400 ppm
0.36 mg
Excipient 2
3.8 g
800 ppm
3.04 mg
Drug product
5.0 g
728 ppm
3.64 mg
_____________________________________________________________________________________________
Excipient 1 meets the Option 1 limit, but the drug substance, excipient 2, and drug product do not meet the Option 1
limit. Nevertheless, the product meets the option 2 limit of 4.1 mg per day and thus conforms to the
recommendations in this guideline.
Consider another example using acetonitrile as residual solvent. The maximum administered daily mass of a drug
product is 5.0 g, and the drug product contains two excipients. The composition of the drug product and the
calculated maximum content of residual acetonitrile is given in the following table.
Component
Amount in
Acetonitrile
Daily
formulation
content
exposure
Drug substance
0.3 g
800 ppm
0.24 mg
Excipient 1
0.9 g
2000 ppm
1.80 mg
Excipient 2
3.8 g
800 ppm
3.04 mg
Drug product
5.0 g
1016 ppm
5.08 mg
_____________________________________________________________________________________________
In this example, the product meets neither the Option 1 nor the Option 2 limit according to this summation. The
manufacturer could test the drug product to determine if the formulation process reduced the level of acetonitrile. If
the level of acetonitrile was not reduced during formulation to the allowed limit, then the manufacturer of the drug
product should take other steps to reduce the amount of acetonitrile in the drug product. If all of these steps fail to
reduce the level of residual solvent, in exceptional cases the manufacturer could provide a summary of efforts made
to reduce the solvent level to meet the guideline value, and provide a risk-benefit analysis to support allowing the
product to be utilized with residual solvent at a higher level.
Class 3 solvent. Table 3
Change to:
Table 3
Acetic Acid
Acetone
Anisole
1-Butanol
2-Butanol
Butyl Acetate
Tert-Butylmethyl Ether
Cumene
Dimethyl Sulphoxide(DMSO)
Ethanol
Ethyl acetate
Ethyl ether
Ethyl formate
Formic acid
Heptane
Isobutyl acetate
Isopropyl acetate
Methyl acetate
3-Methyl-1-Butanol
Methylethylketone
Methylisobutylketone
2-Methyl-1-Propanol
Pentane
1-Pentanol
1-Propanol
2-Propanol
Propyl acetate
Method. Chromatographic system
Change from: Chromatographic system to: Chromatographic system 1
Page 655. Paragraph 3and 4
Delete: “Inject 1 ml of the gaseous phase of reference solution (a1) into the column of system 2. The peaks due to
Class 1 residual solvents are still detectable.
Inject 1 ml of the gaseous phase of reference solution (b) into the column of system 2 and record the chromatogram
under such conditions that the resolution between acetonitrile and trichloroethene can be determined. The system is
suitable if the chromatogram obtained resembles the chromatogram shown in Figure 4 and the resolution between
acetonitrile and trichloroethene is at least 1.0.’’
Insert before 5.5. Impurities
Appendix 1. List of solvents included in the
guideline
Aceclofenac Tablets. Page 770
Dissolution. Line 2
Change from: 900 ml of phosphate buffer pH 7.5, 0.33 M Mixed to: 900 ml of phosphate buffer pH 7.5,
Aminophylline. Page 799
Heavy metals. Line 1
Change from: A 8.0 per cent w/v solution to: 1 g
Atorvastatin Calcium. Page 849
Identification. B
Change to: Determine by atomic absorption spectrophotometry (2.4.2). A 0.005 per cent w/v solution of the
substance under examination in a mixture of 75 volumes of methanol, 25 volumes of water and 2 volumes of
hydrochloric acid using air-acetylene flame, shows absorption at the calcium emission line at 422.7 nm.
Betahistine Tablets. Page 898
Dissolution. Line 2
Change from: 900 ml of phosphate citrate buffer pH 6.8, to: 900 ml of phosphate citrate buffer pH 6.8 prepared by
dissolving 21.9 g of anhydrous sodium dihydrogen orthophosphate and 4.83 g of citric acid in 1000 ml of water,
adjust the pH to 6.8 with 1M sodium hydroxide solution,
Betamethasone Cream. Page 903
Assay. Test solution
Change to: Test solution. Shake a quantity of Cream containing about 2 mg of Betamethasone Dipropionate with
50.0 ml of the solvent mixture containing 1.0 ml of internal standard solution. Heat in a water-bath at 60°, shaking
intermittently, until the cream melts. Remove from the bath, and shake vigorously until the specimen has
resolidified. Repeat the heating and shaking. Freeze in an ice-methanol bath for about 15 minutes, and centrifuge at
2500 rpm for about 5 minutes. Transfer a portion of the supernatant to a suitable vial.
Reference solution
Change to: Reference solution. Dissolve 4 mg of betamethasone dipropionate RS in 100.0 ml of the solvent mixture
containing 1.0 ml of internal standard solution.
Dibasic Calcium Phosphate. Page 970
Identification. A
Change from: reaction B to: reaction A
Cefoperazone Sodium. Page 1014
Acetone. Chromatographic system, line 8
Change from: flow rate. 30 ml per minute of the carrier gas. to: split ration 1:5 with a linear velocity of about
35cm/s of the carrier gas.
Crospovidone. Page 1141
Impurity A. Reference solution (b), line 2
Change from: 50 mg to: 500 mg
Diacerein. Page 1191
Related substances. Reference solution (b), line 3
Insert at the end
“Dilute 5.0 ml of this solution to 200.0 ml with the solvent mixture.
Diazepam Injection. Page 1196
Description. Line 1
Change from: A clear, colourless or almost colourless solution. to: A clear, colourless to pale yellow solution.
Esomeprazole Tablets. Page 1296
Dissolution. Change to:
Dissolution (2.5.2).
A. Apparatus No. 1,
Medium. 900 ml of 0.1 M hydrochloric acid,
Speed and time. 75 rpm and 120 minutes.
At the end of 120 minutes, drain the acid solution slowly without losing any tablet fragments. Transfer the entire
content to a 100-ml volumetric flask (in the case of 20 mg tablets) or a 200-ml volumetric flask (in the case of 40 mg
tablets), add about 80 ml of methanol (in the case of 20 mg tablets) or 160 ml (in the case of 40 mg tablets), and
disperse the tablets with the aid of ultrasound for 15 minutes. Dilute to volume with methanol. Mix well with the aid
of ultrasound to disperse the tablets further for 5 minutes and centrifuge at 4000 rpm for 10 minutes. Dilute 5.0 ml of
the supernatant liquid to 25.0 ml with the mobile phase.
Using the resulting solution as the test solution, carry out the determination as described in the Assay. Calculate the
content of C34H36N6O6S2 in the supernatant liquid. Calculate the percentage of esomeprazole released in the acid
medium by subtracting the content of C34H36N6O6S2 in the test solution from the total content determined in the
Assay.
Not more than 10 per cent of the stated amount of C34H36N6O6S2 is dissolved in 120 minutes.
B. Apparatus No. 1,
Medium. 900 ml of phosphate buffer pH 6.8,
Speed and time. 75 rpm and 60 minutes.
Transfer another 6 tablets and run the apparatus for 60 minutes. Decant the solution and centrifuge. Using the
supernatant liquid as the test solution, carry out the determination as described in the Assay. Calculate the content of
C34H36N6O6S2 in the medium.
D. Not less than 70 per cent of the stated amount of C34H36N6O6S2.
Flucocinolone Acetonide. Page 1361
Related substances. Last para, lines 6 and 7
Change from: reference solution (b) (0.5 per cent) to: reference solution (b) (1.0 per cent); not more than one such
peak is more than 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b)
(0.5 per cent)
Hydrochlorothiazide. Page 1451
Chlorides. Line 2
Change from: 7.5 ml of the resulting solution to: The resulting solution
Lamivudine and Zidovudine Tablets. Page 1561
Dissolution. Reference solution
Change to: Reference solution. Dissolve an accurately weighed quantity of lamivudine RS and zidovudine RS in the
mobile phase and dilute with the mobile phase to obtain a solution having a known concentration similar to the
expected concentration of the test solution.
Levonorgestrel and Ethinyloestradiol Tablets. Page 1582
Assay. Test solution, lines 2 and 3
Change from: 3 mg of Levonorgestral in a 200-ml volumetric flask to: 1.5 mg of Levonorgestral in a 100-ml
volumetric flask
Magnesium Stearate. Page 1625
Fatty acid composition
Change to: Fatty acid composition. Determine by gas chromatography (2.4.13).
Test solution. Dissolve 100 mg of the substance under examination in 5 ml of boron trifluoride-methanol solution.
Boil under a reflux condenser for 10 minutes, add 4.0 ml of heptane through the condenser for 10 minutes, and add
20.0 ml of a saturated sodium chloride solution. Shake and allow the layers to separate. Dry the organic layer over
0.1 g of anhydrous sodium sulphate. Dilute 1.0 ml of the solution to 10.0 ml with heptane.
Reference solution. Dissolve 50 mg each of palmitic acid RS and stearic acid RS in 5.0 ml of boron trifluoridemethanol
solution.
Boil
under
a
reflux
condenser
for
10
minutes,
add
4.0 ml of heptane through the condenser for 10 minutes, and add 20.0 ml of a saturated sodium chloride solution.
Shake and allow the layers to separate. Dry the organic layer over 0.1 g of anhydrous sodium sulphate. Dilute 1.0
ml of this solution to 10.0 ml with heptane.
Chromatographic system
– a stainless steel column 30 m x 0.32 mm, packed with fused silica coated with macrogol 20000 (film thickness
0.5 µm);
– temperature:
Column
time
temperature
(min)
(º)
0-2
70
2-36
70-240
36-41
240
– Inlet port at 220º and detector at 260º,
– flame ionization detector,
– flow rate. 2.4 ml per minute, helium as the carrier gas.
Inject 1µl of the reference solution. The relative retention with reference to methyl stearate for methyl palmitate is
about 0.9. The test is not valid unless the resolution between the peaks due to methyl stearate and methyl palmitate
is not less than 5.0.
Inject 1µl of the test solution and the reference solution.
Calculate the percentage content of stearic acid and palmitic acid.
Mannitol Injection. Page 1634
Identification. B. Test solution, line 2
Change from: 10 ml to: 100 ml
Metronidazole Tablets. Page 1686
Related substances. Chromatographic system, lines 5 and 6
Change from: 0.1 M potassium dihydrogen orthophosphate to: 0.01 M potassium dihydrogen orthophosphate
Oral Rehydration Salts. Page 1820
Description. Line 2
Delete: “odourless”
Poloxamers.
Page No. 1928
Average relative molecular mass. Insert at the end
Oxypropylene:oxyehtylene ratio. Insert at the end
Praziquantel. Page 1947
Related substances. Last para, lines 11 and 13
Change from: reference solution (b) to: reference solution (c)
Rabeprazole Tablets. Page 2037
Dissolution Change to:
Dissolution (2.5.2).
A. Apparatus No. 1,
Medium. 900 ml of 0.1 M hydrochloric acid,
Speed and time. 50 rpm and 120 minutes.
Withdraw a suitable volume of the medium and filter. Measure the absorbance of the filtered solution immediately,
suitably diluted with the dissolution medium, if necessary, at the maximum at about 291 nm (2.4.7). Calculate the
content of C18H20N3O3SNa in the medium from the absorbance obtained from a solution of known concentration
of rabeprazole sodium RS, prepared by dissolving in minimum quantity of a mixture of 75 volumes of acetonitrile
and 25 volumes of methanol and suitably diluted with the dissolution medium.
D. Not more than 10 per cent of the stated amount of C18H20N3O3SNa.
B. Apparatus No. 1,
Medium. 900 ml of phosphate buffer pH 7.4,
Speed and time. 75 rpm and 45 minutes.
Withdraw a suitable volume of the medium and filter. Measure the absorbance of the filtered solution immediately,
suitably diluted with the dissolution medium, if necessary, at the maximum at about 291 nm (2.4.7). Calculate the
content of C18H20N3O3SNa in the medium from the absorbance obtained from a solution of known concentration
of rabeprazole sodium RS, prepared by dissolving in minimum quantity of a mixture of 75 volumes of acetonitrile
and 25 volumes of methanol and suitably diluted with the dissolution medium.
D. Not less than 70 per cent of the stated amount of C18H20N3O3SNa.
Rifampicin Capsules. Page 2055
Related substances. After chromatographic system, para 2, line 2
Change from: 2.61 to: 3.56
Roxithromycin. Page 2073
Related substances. After chromatographic system, para 1, lines 4 and 5
Change from: not more than 2.0 to: not less than 2.0
Roxithromycin Tablets. Page 2075
Asssay. After chromatographic system, para 1, line 5
Change from: not more than 1.5 to: not less than 1.5
Saccharin Sodium. Page 2082
Inset before Category
“It may contain a variable quantity of water.”
Salbutamol Inhalation. Page 2084
Assay. Para 2, line 8
Insert before
Change from: following order, to: following order, add 4 ml of a 5 per cent w/v solution of sodium bicarbonate,
Sodium Metabisulphite. Page 2132
Acidity.
Change to: pH (2.4.24). 3.5 to 5.0, determined in 5.0 per cent w/v solution in carbon dioxide-free water.
Blood and Blood-related Products
Human Albumin. Page 2568
Abnormal toxicity. Line 2
Change from: using Method B to: for antisera and vaccines