The document discusses the importance of testing for pharmaceutical impurities. It defines impurities as any compound in a drug substance or preparation that is not the active ingredient or excipient. Impurities can derive from manufacturing or degradation processes. The document outlines the pharmacopeial and industry approaches to setting limits for different types of impurities, including organic, inorganic, and residual solvents. The pharmacopeial approach sets limits in individual drug substance monographs, while industry guidelines provide thresholds and procedures for identifying, qualifying, and setting limits for impurities according to ICH Q3 guidelines. Both approaches aim to ensure impurity levels do not negatively impact safety or efficacy.

1. The importance
of testing on
pharmaceutical impurities
Christian Zeine
Belgrad, April 17th 2008

2. Agenda
• Introduction
– Definition of the term impurity
– Reasons and times for testing
• Different types of impurities
• Approach to impurity limits from different sides
– Pharmacopeial approach
– Approach from industry
• for compounds described in the pharmacopeia(s)
• for non-pharmacopeial compounds (ICH guidelines)
• ICH vs. Pharmacopeias
• Summary

3. Introduction
• Definition of the term „impurity“
(according to ICH)
– Any compound in a drug substance or a drug preparation
which
• is not the active ingredient itself
• is not an excipient used to produce the drug preparation
• derives from the manufacturing and/or degradation processes
– Could be
• an organic impurity (from manufacturing and/or degradation processes)
• an inorganic impurity (from reagents, catalysts used during
manufacturing)
• a solvent

4. Introduction
• Reasons for testing and controlling impurities
– Overall reason:
Testing on impurities mandatory for registration purposes
and marketing authorisation
– Because of several risk potentials of impurities:
• Pharmacological effects
• Toxicity
• Adverse side effects
• Influence on the performance of the drug substance

5. Introduction
• Time points for testing
– Already during development of drug substances/products
• To change to a synthesis route with other, more advantageous impurity
profile
• For analytical method development parallel to drug product/drug
substance development
– Release testing/quality control ...
• ... of the drug substance and
as quality control of incoming goods
• ... of the drug preparation (e.g. tablets)
– During the anticipated shelf life of the preparation (stability
testing)

6. Agenda
• Introduction
– Definition of the term impurity
– Reasons and times for testing
• Different types of impurities
• Approach to impurity limits from different sides
– Pharmacopeial approach
– Approach from industry
• for compounds described in the pharmacopeia(s)
• for non-pharmacopeial compounds (ICH guidelines)
• ICH vs. Pharmacopeias
• Summary

7. Different types of impurities
• Organic impurities
– Starting materials (or intermediates) of the drug substance
Example Aspirin (Acetylsalicylic acid):
HOOC OOC-CH3
HOOC OH
HOOC-CH3
+
+ H2O
MM0133.07

8. Different types of impurities
• Organic impurities
– By-products during synthesis
Example Aspirin:
HOOC OOC-CH3
HOOC OH
HOOC-CH3
+
+ H2O

9. Different types of impurities
• Organic impurities
– By-products during synthesis
Example Aspirin:
HOOC OH
+
+ H2O
HOOC OH
HOOC OOC-CH3

10. Different types of impurities
• Organic impurities
– By-products during synthesis
Example Aspirin:
HOOC OH
+
+ H2O
HOOC OH
OH
HOOC OOC
MM0133.03: Salicylsalicylic Acid

11. Different types of impurities
• Organic impurities
– Degradation products of the drug substance
Example Aspirin (under influence of moisture):
HOOC OOC-CH3
HOOC OH
HOOC-CH3
+
H2O

12. Different types of impurities
• Inorganic impurities
– Residues from substances used during production
e.g.
• Phosphat salts from buffer solutions (used to maintain a certain
pH level during production)
• Chlorides from the use of hydrochloric acid
(common chemical used for several techniques
during production)
• Heavy metals from catalysts (used to ease a
chemical reaction)
• Filter aids, charcoal etc.

13. Different types of impurities
• Residual solvents
– Production of drug substances normally in solution
• Sometimes critical parameter
– Enhance yield
– Determine product characteristics: Crystal form,
purity, solubility
– After Production: Evaporation of solvents necessary
– In case of organic solvents:
Evaluation/Controlling of successful
evaporation mandatory because of health risks

14. Agenda
• Introduction
– Definition of the term impurity
– Reasons and times for testing
• Different types of impurities
• Approach to impurity limits from
different sides
– Pharmacopeial approach
– Approach from industry
• for compounds described in the pharmacopeia(s)
• for non-pharmacopeial compounds (ICH guidelines)
• ICH vs. Pharmacopeias
• Summary

15. Pharmacopeial approach
to impurity limits
• Overall rationale
– Providing limits not affecting the
human/animal organism in an unacceptable way

16. Pharmacopeial approach
to impurity limits
• Organic impurities
– General monograph and text on organic impurities in EP
– General chapter <466> and <1086> in USP
– Limits are set in the individual monographs in special
paragraphs
• „Related Substances“ (EP, BP)
• In paragraphs just stating the impurity´s name (EP, BP)
• „Related Compounds“ (USP)
• „Limit of ...“ (USP)
• „Chromatographic purity“ (USP)
– Limits differ from monograph to monograph
• sometimes from impurity to impurity
• due to different toxicological/pharmacological potencial

17. Pharmacopeial approach
to impurity limits
• Ibuprofen monograph EP 6.0

18. Pharmacopeial approach
to impurity limits
• Ibuprofen monograph EP 6.0

19. Pharmacopeial approach
to impurity limits
• Inorganic impurities
– Limits are set in the monographs in special paragraphs
• „Heavy metals“ (EP, BP, USP)
• In paragraphs just stating the impurity´s name e.g. „Iron.“ or
„Phosphates.“ (EP, BP, USP)
• Residual Solvents
– Limits are set in the monographs in special paragraphs
• „Loss on drying“ (EP, BP, USP)
– Special chapters describe the methods of LOD
• „Identification and control of residual solvents“; „residual solvent“ (EP,
BP)
– Special chapters describe the method of solvent controlling
• „Organic volatile impurities“ (USP)

20. Pharmacopeial approach
to impurity limits
• Ibuprofen monograph EP 6.0

21. Pharmacopeial approach
to impurity limits
• Omeprazol monograph EP 6.0

22. Agenda
• Introduction
– Definition of the term impurity
– Reasons and times for testing
• Different types of impurities
• Approach to impurity limits from
different sides
– Pharmacopeial approach
– Approach from industry
• for compounds described in the pharmacopeia(s)
• for non-pharmacopeial compounds (ICH guidelines)
• ICH vs. Pharmacopeias
• Summary

23. Industrial approach to
impurity limits
• For drug substances described in the
pharmacopeia(s)
– Industry normally following the monographs
or comparable measures
– In case of insufficient description by a monograph (due to a
manufacturing process with impurities not mentioned in a
monograph)
• Testing on such impurities is demanded by
European law (Directive 2001/83/EU, Attachment 1):
„However, where a starting material … has been prepared by a method liable to leave
impurities not controlled in the pharmacopoeia monograph, these impurities and their maximum
tolerance limits must be declared and a suitable test procedure must be described.“
• Industry is referring to other guidelines (ICH Guidelines, discussed on
the slides dealing with non-pharmacopeial drug substances)

24. Industrial approach to
impurity limits
• For non-pharmacopeial drug substances / products
• Could be
– New drug substances / products
– Drug substances / products with insufficient description
by pharmacopeial monograph (due to an
unknown production process)
• In this case: Industry is referring
to other guidelines (ICH Guidelines)

25. Industrial approach to
limits – ICH guidelines
• ICH: International Conference on Harmonisation
– Members from regulation authorities and industrial
pharmaceutical associations
– From Japan, USA and Europe
• Three ICH Guidelines important
– Q3A(R1): Impurities in new drug substances
– Q3B(R2): Impurities in new drug products
– Q3C(R3): Impurities – Guideline for residual solvents

26. Industrial approach to
limits – ICH guidelines
• Q3C: Impurities – Guideline for residual solvents
– Includes four lists with
• Solvents to be avoided
(due to unacceptable health risks)
• Solvents to be limited
(with detailed limits for each solvent)
• Solvents with low toxic potential
(with an overall limit for all solvents)
• Solvents with no toxicological data found
– Limits based on PDE (permitted daily exposure)

27. Industrial approach to
limits – ICH guidelines
• Q3A: Impurities in new drug substances
– Dealing with organic and inorganic impurities
• Inorganic impurity usually known,
no identification problem
• For inorganics only a short reference to pharmacopeial or other
scientifically sound limits
– For organic impurities:
Different thresholds for different actions
• Reporting
• Identification
• Qualification

28. Industrial approach to
limits – ICH guidelines
• Q3A: Impurities in new drug substances
– Originally intended for new drug substances and products
– FDA statement on applying ICH approach also to generic
products
Draft Guidance for Industry – ANDAs: Impurities in Drug
Substances (January 2005):
„The Q3A(R) [sic] was developed by the International Conference on
Harmonisation (ICH) to provide guidance on impurities in drug substances
for new drug applications (NDAs). However, the Agency believes that many
of the recommendations provided on impurities in drug substances also
apply to ANDAs."

29. Industrial approach to
limits – ICH guidelines
• Q3A: Impurities in new drug substances - thresholds

30. Industrial approach to
limits – ICH guidelines
• Q3A: Impurities in new drug substances – threshold
examples

31. Industrial approach to
limits – ICH guidelines
• Q3A: Impurities in new drug substances – decision
tree

32. Industrial approach to
limits – ICH guidelines
– Above ID threshold? => Identification
– When identified: Any risks known? => Reduce to „safe“ levels
• 10 ppm (0,001%) - for alkylating (carcinogenic) substances
• 1/10 NED (Nil Effect Dose, i.e. dose
with no observable tox./pharm. effects)
• 1/100 MED (Minimal Effect Dose, i.e. lowest dose
with any measurable tox./pharm. effect)
• Q3A(R1): Impurities in new drug substances – limit
setting
Not part of
Q3A(R1)
– When identified: Risks unknown? => Qualification of substance´s
risk potential when substance is above qualification level
(qualification by in vivo studies) => Results: NED or MED
– In case of impossible identification, although above ID threshold
=> Direct qualification of substance´s risk potential => Results:
NED or MED

33. Industrial approach to
limits – ICH guidelines
• Q3B: Impurities in new drug products
– Fulfillment of limit specifications
during the entire shelf life of product
– Q3B only looking on degradation impurities (i.e. no
discussion on inorganic impurities or „stable“ organic
impurities in the drug substance)
– Different thresholds for different actions again
• Reporting
• Identification
• Qualification

34. Industrial approach to
limits – ICH guidelines
• Q3B: Impurities in new drug products – thresholds

35. Industrial approach to
limits – ICH guidelines
• Q3B: Impurities in new drug products –
threshold examples

36. Industrial approach to
limits – ICH guidelines
• Q3B: Impurities in new drug products – decision tree

37. Industrial approach to
limits – ICH guidelines
• Q3B: Impurities in new drug products – limit
setting
Same procedure as with Q3A:
– When to identify: Any risks known? => Reduce to safe levels
• 10 ppm (0,001%) - for alkylating (carcinogenic) substances
• 1/10 NED (Nil Effect Dose, i.e. dose with
no observable tox./pharm. effects)
• 1/100 MED (Minimal Effect Dose, i.e. lowest dose
with tox./pharm. effect)
– When to identify: Risks unknown? => Qualification of
substance´s risk potential
when substance is above qualification level (qualification
usually done by in vivo studies) => Results: NED or MED
– In case of impossible identification, although above ID
threshold
=> Direct qualification of substance´s risk potential =>
Results: NED or MED
Not part of
Q3A(R1)

38. Overall conclusions
• Pharmacopeias provide impurity limits
• ICH guidelines provide thresholds, not limits
• Limit specifications have to be considered
individually, there are no rigid rules
• Expensive and time intensive
qualification studies should be avoided
– Extremely important:
• Identification of impurities
• Exact quantification of impurities

39. Agenda
• Introduction
– Definition of the term impurity
– Reasons and times for testing
• Different types of impurities
• Approach to impurity limits from different sides
– Pharmacopeial approach
– Approach from industry
• for compounds described in the pharmacopeia(s)
• for non-pharmacopeial compounds (ICH guidelines)
• ICH vs. Pharmacopeias
• Summary

40. ICH vs. Pharmacopeias
• ICH to be considered additionally
– e.g. Directive 2001/83/EU, Attachment 1
• „However, where a starting material … has been prepared by a method
liable to leave impurities not controlled in the pharmacopoeia
monograph, these impurities and their maximum tolerance limits must
be declared and a suitable test procedure must be described.“
– e.g. EP 6.0, General text 5.10.
Impurities in substances for pharmaceutical use
• General limits apply only to specified impurities
• Other detectable impurities must be considered according to general
monograph 2034 (Substances for pharmaceutical use)
• General monograph applies ICH threshholds
– e.g. USP 30 General notices, paragraph on impurities

41. ICH vs. Pharmacopeias
• Ibuprofen monograph EP 6.0

42. ICH vs. Pharmacopeias
• Ibuprofen monograph EP 6.0
– 0.3% by far above ICH threshhold for identification and
quantification
• Non-specified (“other”) impurities to be handled according to ICH
guidelines
– Only few impurity standards available from pharmacopoeias
• Used mainly for system suitability tests (resolution)
– Only on rare occasions for quantitative purposes
• No certificates of analysis
– No relative retention times
• Simple identification via monograph not possible
– Monograph’s method also not suitable for accurate
quantification of “other” impurities
• Not considering “relative response factors”

43. ICH vs. Pharmacopeias
• „Relative response factors“ Ibuprofen impurities
Prod.Nr. Impurity. m (mg) Area (abs) Area (rel) RRF Impurity Type
02.00 Ibuprofen 5,01 836236 166913 1,00 Drug Substance
02.13+.33 A+O 1,002+1,018 249869 121768 0,73 Byproduct of Synthesis
02.01 B 1,178 139326 118273 0,71 Byproduct of Synthesis
02.10 C 1,002 123074 122828 0,74 Intermediate
02.11 D 1,071 145838 136170 0,82 Byproduct of Synthesis
02.04 E 1,132 158918 140389 0,84 Degradation product
02.28 F 1,061 139326 131069 0,79 Byproduct of Synthesis
02.38 G 0,990 122549 123787 0,74 Byproduct of Synthesis
02.30 H 1,125 146650 130356 0,78 Byproduct of Synthesis
02.31 I 1,017 58323 57348 0,34 Byproduct of Synthesis
02.02 J 1,154 98309 85190 0,51 Degradation product
02.26 K 1,035 119590 115546 0,69 Degradation product
02.24 L 1,010 117993 116824 0,70 Degradation product
02.34 M 0,951 159398 167611 1,00 Intermediate
02.35 N 1,048 142022 135517 0,81 Byproduct of Synthesis
02.19 P 1,079 167505 155241 0,93 Byproduct of Synthesis
02.36 Q 1,125 146984 130652 0,78 Byproduct of Synthesis
02.37 R 1,196 163622 136808 0,82 Intermediate
02.03 - 0,995 52215 52477 0,31 Degradation product
02.08 - 1,011 35471 35085 0,21 Degradation product
02.09 - 0,969 142022 146566 0,88 Degradation product

44. ICH vs. Pharmacopeias
• Ibuprofen monograph EP suppl. 6.1
– New Related Substances part with new limits for impurities
– Retention times for specified impurities
– New wording in the impurity section

45. ICH vs. Pharmacopeias
• Key to accurate identification and quantification
– Special reference standards for impurities
– Via synthesis
– Isolation from matrix after forced degradation of API or
dosage form
– Carefully analysed with regard to identity and assay

46. Certificate of analysis

47. Certificate of analysis

48. Certificate of analysis

49. Certificate of analysis

50. Certificate of analysis

51. Certificate of analysis

52. Summary
• Defintion of the term „impurity“
• Rationales and times for testing
• Close look to certain types of impurities
– Organic, inorganic, residual solvents
• Setting specification limits on impurities
– From pharmacopeial side
– From industrial side
• Overall conclusions
– Accurate identification and quantification can prevent
expensive and time intensive qualification studies
– Accurate identification and quantification with help of special
impurity reference standards