PCI VI sem

1. As Per PCI Regulations /B. Parm. VI
Sem./Pharmaceutical Quality Assurance
UNIT-1
ICH Q 3 GUIDELINE
• Presented By: VIVEK JAIN
• M.Pharm. (Pharmaceutical Analysis)
• Associate Professor
• ADINA Institute Of Pharmaceutical Sciences,
Sagar (M.P.)
• EMAIL:pharmamakers2010@gmail.com

2. ICH Q 3 GUIDELINE
IMPURITIES DRUG PRODUCT & DRUG
SUBSTANCE

3. Objective of the guideline
• The impurities in pharmaceuticals are unwanted
chemicals that remain with the active pharmaceutical
ingredients (APIs) or develop during formulation or
upon aging of both API and formulation. The presence
of these unwanted chemicals even in trace amount may
influence the efficacy and safety of pharmaceutical
product. The control of impurities is currently a critical
issue to the pharmaceutical industry
• Objective: To makes recommendation to applicant on
reporting, identifying & qualifying information on
impurities in new drug substance

4. What is Impurity
• ICH defines impurities as substances in the API that are
not the API itself.
• OR Any component of drug substance that is not the
chemical entity
• Or for drug product that is not the drug substance or an
excipient
• ICH Status: Q3A- Q3D Impurities
• Q3A (R2) Impurities in New Drug Substances
• Q3B (R2) – Impurities in New Drug Products
• Q3C (R5) – Impurities : Guideline for Residual Solvents
• Q3D – Impurities : Guideline for Elemental Impurities

5. Definitions
• Impurity: Any component of the new drug
product that is not the drug substance or an
excipient in the drug product.
• Impurity Profile: A description of the identified
and unidentified impurities present in a drug
product.
• Qualification: The process of acquiring and
evaluating data that establishes the biological
safety of an individual degradation product or a
given degradation profile at the level(s) specified.

6. • Degradation Product: An impurity resulting from
a chemical change in the drug substance brought
about during manufacture and/or storage of the
new drug product by the effect of, for example,
light, temperature, pH, water, or by reaction with
an excipient and/or the immediate container
closure system.
• Degradation Profile: A description of the
degradation products observed in the drug
substance or drug product.

7. • Identified Degradation Product: A degradation
product for which a structural characterisation
has been achieved.
• Unidentified Degradation Product: A
degradation product for which a structural
characterisation has not been achieved and
that is defined solely by qualitative analytical
properties (e.g., chromatographic retention
time).

8. • Qualification Threshold: A limit above (>)
which a degradation product should be
qualified.
• Reporting Threshold: A limit above (>) which a
degradation product should be reported.
• Identification Threshold: A limit above (>)
which a degradation product should be
identified.

9. Types of impurity
• Organic
• Inorganic
• Residual solvents

10. Organic
• Organic impurities mainly arise during the
synthesis, purification(manufacturing process
)and or storage of the drug substance
• Organic imps can be classified like...
Starting materials
Intermediate
Degradation products
Reagents, ligand and catalysts

11. Inorganic
Inorganic impurities derive from the
manufacturing process and excipients. Generally,
excipients contain high levels of heavy metals
such as arsenic, bismuth, cadmium, chromium,
copper, iron, lead, mercury, nickel and sodium.
Sometimes they might present in the product
during processing or they leached from packing
material
 Heavy metals
Inorganic salts
Other materails like filter aids, charcoal

12. Residual solvents (ICH Q3 C guideline)
• Residual solvents are potentially undesirable substances.
They either modify the properties of certain compounds
or may be hazardous to human health. The residual
solvents also affect physicochemical properties of the
bulk drug substances such as crystallinity of bulk drug,
which in turn may affect the dissolution properties, odor
and color changes in finished products
• Residual solvents are those solvents which are used as
vehicles for the preparation of solution / suspensions in
the synthesis of a new drug substance

13. objective of this guideline
• The is to recommend acceptable amounts for residual solvents
in pharmaceuticals for the safety of the patient. The guideline
recommends use of less toxic solvents and describes levels
considered to be toxicologically acceptable for some residual
solvents
• Residual solvents in pharmaceuticals are defined here as organic
volatile chemicals that are used or produced in the manufacture
of drug substances or excipients, or in the preparation of drug
products.
• Since there is no therapeutic benefit from residual solvents, all
residual solvents should be removed to the extent possible to
meet product specifications, good manufacturing practices, or
other quality-based requirements. Drug products should
contain no higher levels of residual solvents than can be
supported by safety data.

14. As per the ICH guidelines, the solvents used in the
manufacturing of drug substances classified in to four
types
• Class 1 solvents: Solvents to be avoided
• Class 2 solvents: Solvents to be limited
• Class 3 solvents: Solvents with low toxic
potential
• Class 4 solvents: Solvents for which No
Adequate Toxicological Data was Found

15. As per the ICH guidelines, the solvents used in the
manufacturing of drug substances classified in to four
types
• a) Class I solvents: Solvents to Be Avoided
Solvents in Class 1 should not be employed in the
manufacture of drug substances, excipients, and
drug products because of their unacceptable
toxicity or their deleterious environmental effect.
However, if their use is unavoidable in order to
produce a drug product with a significant
therapeutic advance, then their levels should be
restricted as shown in Table 1.

16. Residual solvent Concentration limit (ppm)
Benzene 2 ( Carcinogenic)
Carbon tetrachloride 4 (Toxic)
1,1 Dichloro ethene 8 (Toxic)
1,2 Dichloro ethene 5 (Toxic)
1,1,1 trichloro ethane 1500 (Environmental hazard)

17. • b) Class II solvents: Solvents to Be Limited Class II
solvents usage should be limited in
pharmaceutical products because of their
inherent toxicity.
• Table 2 lists class II solvents with their daily
permissible exposure.

18. Solvent PDE (mg/day) Concentration limit (ppm) Acetonitrile 4.1
410 Chlorobenzene 3.6 360 Chloroform 0.6 60 Cumene 1 0.7 70
Cyclohexane 38.8 3880 1,2-Dichloroethene 18.7 1870
Dichloromethane 6.0 600 1,2-Dimethoxyethane 1.0 100 N,N-
Dimethylacetamide 10.9 1090 N,N-Dimethylformamide 8.8 880
1,4-Dioxane 3.8 380 2-Ethoxyethanol 1.6 160 Ethyleneglycol 6.2
620 Formamide 2.2 220 Hexane 2.9 290 Methanol 30.0 3000 2-
Methoxyethanol 0.5 50 Methylbutyl ketone 0.5 50
Methylcyclohexane 11.8 1180 Methylisobutylketone2 45 4500 N-
Methylpyrrolidone3 5.3 530

19. • c) Class III Solvents: Solvents with Low Toxic
Potential These are less toxic and possess lower
risk to human health than class I or class II
• Long-term toxicity or carcinogenicity not
reported, which is evident from the available data
for the solvents under this category. The use of
class III solvents in pharmaceuticals does not
have any serious health hazard. Some of the
solvents are; Acetic acid, anisole, butanol,
2butanol, isopropyl acetate, methylacetate,
butylacetate, ter-butyl methyl ether, pentene,
cumene, Dimethyl sulfoxide, ethanol,
ethylacetate, formicacid, heptane, isobutyl
ketone, tetrahydrofuran, 1-pentanol, 2propanol,
methyl isobutyl ketone, propylacetate, 3methyl-
1-butanol, methyl ethylketone.

20. • d) Class IV Solvents: Class IV solvents, adequate
toxicological data is not available. The
manufacturers should justify the residual levels
for these solvents in pharmaceutical products.
The solvents under class IV are 1, 1-diethoxy
propane, 1-1-dimethoxy propane, 2-2
• 2dimethoxy propane, methyl isopropyl ketone,
isooctane, isopropyl ether, methyl
tetrahydrofuran, petroleum ether, trichloro acetic
acid.

21. Thresholds for Degradation Products in New
Drug Products
• Reporting Thresholds
Maximum Daily Dose Thresholds
≤ 1 g
0.1%
> 1 g 0.05%

22. Identification Thresholds
•
Maximum Daily Dose Thresholds
< 1 mg 1.0% or 5 µg TDI, whichever is
lower
1 mg - 10mg 0.5% or 20 µg TDI, whichever
is lower
>10 mg - 2 g 0.2% or 2 mg TDI, whichever is
lower
> 2 g 0.10%

23. Qualification Thresholds
Maximum Daily Dose Thresholds
< 10 mg 1.0% or 50 µg TDI, whichever is
lower
10 mg - 100 mg 0.5% or 200 µg TDI, whichever
is lower
>100 mg - 2 g 0.2% or 3 mg TDI, whichever is
lower
> 2 g 0.15%