1. Residual Solvent
Options for Describing Limits of
Class 2 Solvents
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2. Why
Objective –
To understand Options for Describing Limits of Class 2 Solvents

3. Calculation of concentration limits in ppm for Residual Solvent
Concentration (ppm) = ----------------
1000 X PDE
Dose
PDE =Permitted Daily Exposure, given in terms of mg/day.
Dose is given in g/day.
The concentration were calculated using equation by assuming a
product mass of 10 g administered daily.

4. Calculation of concentration limits in ppm for Residual Solvent
PDE = 4.1 mg per day, Dose = 10 g
Acetonitrile Limit (ppm) = ---------------- = --------------- = 410 ppm
1000 X PDE
Dose
1000 X 4.1
10
Example - Acetonitrile Limit Calculation
PDE = 4.1 mg per day, Dose = 20 g
Acetonitrile Limit (ppm) = ---------------- = --------------- = 205 ppm
1000 X PDE
Dose
1000 X 4.1
20
PDE = 4.1 mg per day, Dose = 5 g
Acetonitrile Limit (ppm) = ---------------- = --------------- = 820 ppm
1000 X PDE
Dose
1000 X 4.1
5

5. Options for Describing Limits of Class 2 Solvents
Option 1
Option 2

6. Option 1
The concentration limits in ppm stated in ICH/USP/Guidelines can be used. These
limits are considered acceptable for all substances, excipients or products.
Example 1 - Acetonitrile Limit Calculation
Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.6 200 0.12 Pass as per option 1
Excipient 1 1.0 400 0.40 Pass as per option 1
Excipient 2 5.0 100 0.50 Pass as per option 1
Drug Product 6.6 155 1.02 Pass as per option 1

7. Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.3 200 0.06 Pass as per option 1
Excipient 1 0.9 400 0.36 Pass as per option 1
Excipient 2 3.8 100 0.38 Pass as per option 1
Drug Product 5.0 160 0.80 Pass as per option 1
Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.6 200 0.12 Pass as per option 1
Excipient 1 1.8 400 0.72 Pass as per option 1
Excipient 2 7.6 100 0.76 Pass as per option 1
Drug Product 10.0 160 1.60 Pass as per option 1
Option 1Example 2 - Acetonitrile Limit Calculation
Example 3 - Acetonitrile Limit Calculation

8. 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 greater than 10 g per day should be
considered under Option 2.
Therefore this option may be applied if the daily dose is not known or fixed.
Option 1

9. Option 2
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 solvent
per day should be less than that given by the PDE.
Example 4 - Acetonitrile Limit Calculation
Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.3 800 0.24 As per option 1=?
Excipient 1 0.9 400 0.36 Pass as per option 1
Excipient 2 3.8 800 3.04 As per option 1=?
Drug Product 5.0 728 3.64 Pass as per option 2

10. Component
Amount in
formulation (g)
Acetonitrile
Content (ppm)
Daily exposure
(mg)
Acetonitrile Limit
(4.1 mg/day)
Drug Substance 0.3 800 0.24 As per option 1 or 2 =?
Excipient 1 0.9 2000 1.80 As per option 1 or 2 =?
Excipient 2 3.8 800 3.04 As per option 1 or 2 =?
Drug Product 5.0 1016 5.08 As per option 1 or 2 =?
Option 2
Example 5 - Acetonitrile Limit Calculation

11. Option 2
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 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.
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.

12. Than
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