Solvents, not grouped in Class-1, Class-2 and Class-3, are often required to attain desirable properties of drug substances, products and excipients. Their use is particularly important in drug substances where a specific polymorph determines the bioavailability of drug product. How the limit of of such solvents is determined in pharmaceuticals, is the topic and content of this video. Further what other strategies are made available to regulatory personnel to justify such solvents' limits in pharmaceuticals.

1. Residual Solvent Analysis, Part-3
Solvents’ Limit in Pharmaceuticals
with
“No Adequate Toxicological Data”;
Strategies & Approaches to
Regulatory Approvals
ICH-Q3C(R6)
Arvind Mittal, Ph.D

2. Scientific Literature: Solvent toxicity
 Google Scholar
 PubMed/MedLine/PubChem/ NLM (National Library of Medicine US)
 TOXNET/HSDB (Hazardous Substance Data Bank)/ HAZ-MAP
 Chemical Abstract Service (CAS Number Search)
 NIOSH TWA REL (National Institute for Occupational Safety and Health: Recommended Exposure
Limit)
 OSHA PEL (Occupational Safety and Health Administration; Permissible Exposure Limit)
 RTECS (Registry of Toxic Effects of Chemical Substances)
 ACGIH TLV (American Conference of Governmental Industrial Hygienists: Threshold Limit Value)
 ESIS – European Chemical Substances Information System
Literature is searched for NOEL [No Observed Effect Level]
or
LOEL [Lowest Observed Effect Level] values
Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects

3. Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects
Isopropyl Ether/Diisopropyl Ether: CAS 108-20-3
 Most relevant search for animal toxicity
 Dalbey W, Feuston M. Subchronic and developmental toxicity studies of
vaporized diisopropyl ether in rats . J Toxicol Environ Health. 1996; 49(1):29-43.
 Romanelli L, Evandri MG. Permitted Daily Exposure for Diisopropyl Ether as a
Residual Solvent in Pharmaceuticals. Toxicol Res. 2018;34(2):111-125. .
 Subchronic toxicity
 Developmental
 Neurological toxicity
 Carcinogenicity
 Genotoxicity
Animal: Rat
Mol. Wt 102.177 g/mol
O

4. Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects
 Experimental Parameters
 Animal : Rat
 Inhalation exposure concentration : 0, 480, 3300 & 7100 ppm
 Exposure duration : 6 Hr/Day, 5 Days/week for 13 weeks
 Temperature : 25° C (273 + 25 = 298 K)
 Result & Findings
 NOEL : 480 ppm
 Carcinogenicity (oral) : Hepatic (liver) & Renal (kidney)
 Genotoxicity : Non-genotoxic
 Teratogenicity : Unconfirmed teratogen (suspected teratogen)
 Conclusion : Non-genotoxic carcinogen & suspected teratogen

5.  Calculation of Permissible Daily Exposure (PDE)
Ideal Gas Equation PV = nRT
Where P = pressure of vapor (gas) atm
V = volume (L or m3)
n = amount of solvent in mg or g
R = Gas constant (0.082 L .atm .K-1.mol-1)
T = Temperature on Kelvin scale (273 + 25 = 298 K)
OR Conc. Of gas (solvent mg/L)
n
V
=
480 x 10-6 atm x 102.177 x 103 mg.mol-1
0.082 L. atm. K-1.mol-1 x 298 K
P
RT
= =
49.04 mg
24.44 L
= 2.007 mg/L
Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects

6. Daily dose (Rat) =
0.358mg/L x 290 L/Day
0.425 Kg
= 244.282 mg/Kg/Day » NOEL
Modifying
Factors
Permissible Daily Exposure (PDE) =
(Human)
NOEL (Rat) x Average Human wt (50 Kg)
F1 x F2 x F3 x F4 x F5
Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects
For Continuous dosing = 2.007 mg/L x
6 hr
24 hr
5 day
7 day
x = 0.358 mg/L
(Brief & Scala Model)

7. Modifying Factors/Safety Factors
 F1 = Extrapolation from animal to human
 F1 = 5 If animal is rat
 F1 = 12 If animal is mice
 F1 = 2 If animal is dog
 F1 = 2.5 If animal is rabbit
 F1 = 3 If animal is monkey
 F1 = 10 Other animals
F1 = 5
 F2 = Variability among human beings F2 = 10
Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects

8. Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects
 F3 = Duration of toxicity studies in animals
 F3 = 1 : If duration is ½ lifetime of an animal (1Yr =
Rodents/Rabbit; 7 Yrs = Cats/Dogs/ monkeys)
: reproductive studies in which the whole period of
organogenesis is covered
 F3 = 2 : 6 Months: Rodents; 3.5 Yrs: Non-Rodent
 F3 = 5 : 3 Months: Rodents; 2 Yrs: Non-Rodent
 F3 = 10: Less than 3 months
13 wks = 3 M
F3 = 5

9.  F4 = Nature of toxicity: Severe toxicity/Reproductive toxicity/Non-
Genotoxic carcinogenicity/ Nuerotoxicity/Teratogenicity
 F4 = 1 Fetal toxicity as well as maternal toxicity
 F4 = 5 Fetal toxicity without maternal toxicity
 F4 = 5 teratogenic effect with maternal toxicity
 F4 = 10 teratogenic effect without maternal
toxicity
Non genotoxic
carcinogen &
suspected
tertatogen
F4 = 10
Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects
 F5 = Nature of Study
 F5 = 1 If NOEL is determined
 F5 = 10 If LOEL is determined
NOEL Yes
F5 = 1

10. Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects
Permissible Daily Exposure (PDE) =
(Human)
244.282 mg.Kg-1.Day-1 x 50 Kg
5 x 10 x 5 x 10 x 1
= 4.885 mg/Day
Concentration (ppm) =
(in pharmaceuticals)
PDE (mg/Day) x 1000
Dose (10 g/Day)
= µg/g OR ppm
•
•
•
4.885 x 1000
10
= 488.5 µg/g OR 489 ppm OR 480 ppm
Concentration (ppm) =

11. Second Approach
NIOH/OSHA Permissible Exposure Limit (PEL)
Isopropyl Ether (TWA): 500 ppm
•
•
•
n
V
=
500 x 10-6 atm x 102.177 x 103 mg.mol-1
0.082 L atm. K-1.mol-1 x 298 K
P
RT
= =
51.09 mg
24.44 L
= 2.0907 mg/L
For Continuous dosing = 2.0907 mg/L x
8 hr
24 hr
5 day
7 day
x = 0.4978 mg/L
Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects
Daily dose (Human) =
0.4978mg/L x 28800 L/Day
60 Kg
= 238.944 mg/Kg/Day
» NOEL = 239 µg/g OR 230 ppm

12. Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects
ICH (PDE) vs NOISH (PEL)  NIOSH provides more restricted levels
Name CAS ICH (ppm) NIOSH (ppm)
Isopropyl ether 108-20-3 480 230
Methyl isopropyl ketone 563-8-4 260 80

13. Third Approach ICH Escape Window
ICH Q3C (R6) PART I: IMPURITIES: GUIDELINE FOR RESIDUAL SOLVENTS
Supporting safety data in a marketing application for a new drug product containing a
new solvent may be based on concepts in this guideline OR the concept of
qualification of impurities as expressed in the guideline for drug substance (Q3A,
Impurities in New Drug Substances) OR drug product (Q3B, Impurities in New Drug
Products), or all three guidelines.
1. INTRODUCTION
Known Impurity NMT 0.15% OR 1500 ppm??
Any Other Impurity NMT 0.10% OR 1000 ppm ??
Solvents with “No Adequate” Toxicological Data;
Strategies & Approaches to
Regulatory Aspects