Bundesinstitut für Arzneimittel

und Medizinprodukte

Impurity Profiles in Active

Pharmaceutical Ingredients

EU/Swissmedic GMP Workshop

Beijing University, Sept. 20 – 22, 2006

Dr. Susanne Keitel

Federal Institute for Drugs and Medical Devices (BfArM),
Germany
 Bundesinstitut für Arzneimittel
und Medizinprodukte

Structure

I. General principles
II. Dossier Requirements: NCE vs. Existing Substances,
ASMF vs. CEP
III. Specification of Impurities in the API
IV. Residual Solvents
V. Metal Catalysts and Genotoxic Impurities
VI. Need more Information?
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und Medizinprodukte

Definition “Impurity”

“(1) Any component of the new drug substance

which is not the chemical entity defined as the
new drug substance. (2) Any component of the
drug product which is not the chemical entity
defined as the drug substance or an excipient in
the drug product.”
( ICH Q6A: Specifications)

International Conference on Harmonisation

of Technical Requirements for Registration of Pharmaceuticals
for Human Use
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Classification of Impurities I

• Organic impurities
(process- and drug-related)
• Inorganic impurities
• Residual solvents
• Polymorphic forms
• Enantiomeric impurities
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Classification of Impurities II

Organic impurities can arise during the

manufacturing process and/or storage of the API.
They can be identified or unidentified, volatile or non volatile
e.g.:
• Starting materials
• By-products
• Intermediates
• Degradation products
• Reagents, ligands and catalysts
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Classification of Impurities III

Inorganic impurities can result from the

manufacturing process, they are normally known
and identified and include
e.g.:
• Reagents, ligands, catalysts
• Heavy metals or other residual metals
• Inorganic salts
• Other materials, e.g. filter aids, charcoal….
 Bundesinstitut für Arzneimittel
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Structure

I. General principles
II. Dossier Requirements: NCE vs. Existing Substances,
ASMF vs. CEP
III. Specification of Impurities in the API
IV. Residual Solvents
V. Metal Catalysts and Genotoxic Impurities
VI. Need more Information?
 Bundesinstitut für Arzneimittel
und Medizinprodukte

API Documentation in the Licensing Process I

S Drug Substance
S.1 General Information:
• Nomenclature
• Structure
• General Properties
S.2 Manufacture
• Manufacturer(s)
• Description of Manufacturing Process and Process Controls
• Control of Materials
• Controls of Critical Steps and Intermediates
• Process Validation and/or Evaluation
• Manufacturing Process Development
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API Documentation in the Licensing Process II

S.3 Characterisation
• Elucidation of Structure and Other Characteristics
• Impurities
S.4 Control of Drug Substance
• Specification
• Analytical Procedures
• Validation of Analytical Procedures
• Batch Analyses
S.5 Reference Standards or Materials
S.6 Container Closure System
S.7 Stability
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Classification of APIs
• New chemical entities (NCE),
used for the first time in a
medicinal product for human or
veterinary use
• Existing substances,
– not covered by a monograph in the
European Pharmacopoeia or the
national pharmacopoeia of an EU
Member State
– Existing substances covered by a
monograph in one of above
pharmacopoeia
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API Documentation in the Application

File

• Complete part 3.2. S

• Active Substance Master File (ASMF) for new and
existing APIs, not for biotech or biologicals!
• Certificate of Suitability of the European Directorate for
the Quality of Medicines – EDQM - (CEP; only for
APIs covered by a Ph. Eur. monograph and for
demonstration of TSE-safety)
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New Chemical Entities I

• 3.2. S 3.2: Information on impurities
• Discussion of potential impurities arising from the
synthesis, indication of their origin
• Statement whether actual samples of such impurities
have been synthesized for test purposes. Structural
analysis data and information which of the analytical
methods described have been used to detect that
impurity
• Discussion of possible routes of degradation
• Analytical methods (LOD and LOQ) used to detect
likely impurities or other related impurities
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New Chemical Entities II

• Copies of relevant chromatograms

• Summary on the nature and levels of actual
impurities detected in the batch samples
• Justification for selecting the limits based on
safety and toxicity data as well as on the
methods used to control impurities

?
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New Chemical Entities III

• 3.2. S 7.3: Stability Data

• Forced degradation studies as integral part of
the dossier. Aim: to generate degradation
products and elucidate degradation pathways,
e.g. hydrolysis, photolysis, thermal stress,
oxidation….
• Information on the analytical methods and
their validation
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Existing Substances - ASMF vs. CEP

Identical requirements on the documentation, i.e.

pharmacopoeial monograph is able to detect all
impurities resulting from the specific synthesis
used

Assessment: Competent Authority ⇒ ASMF

EDQM ⇒ CEP
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ASMF

Open (applicant’s) part, closed (confidential) part,

letter of access
• Intended to keep trade secrets/know-how of
API manufacturer confidential
• Submission only possibly in connection with a
marketing authorisation application or variation!
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ASMF ASMF AP RP
Section Section Name

3.2.S.1 General information 9

3.2.S.2 Manufacture 9
3.2.S.2.1 Manufacturer(s) 9
3.2.S.2.2 Description of manufacturing process and process 9 9
controls
3.2.S.2.3 Control of materials 9
3.2.S.2.4 Control of critical steps and intermediates 9 9
3.2.S.2.5 Process validation and evaluation 9
3.2.S.2.6 Manufacturing process development 9
3.2.S.3 Characterisation 9
3.2.S.4 Control of Drug Substance 9
3.2.S.5 Reference standards or materials 9
3.2.S.6 Container closure system 9
3.2.S.7 Stability (9)
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EDQM Certification Scheme

• API-manufacturer (or representative or broker) submits dossier
to EDQM
• Dossier assessment based on the current pharmacopoeial
monograph and ICH-/CHMP- guidelines done by experts
nominated by national competent authorities, [Link]
assessors of NCAs (rapporteur/ co-rapporteur)
• Deficiency letter sent to the applicant, where relevant, and
submission of response document to clarify open
issues/deficiencies
• Granting of a Certificate of Suitability (CEP) by EDQM.
Inclusion of additional tests/specifications/test methods, where
relevant
• Marketing authorisation applicant submits CEP issued to the
API-manufacturer in the dossier to demonstrate API quality
NO “CARTE BLANCHE“!
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EDQM Certification Scheme

Basis for Assessment:

• Knowledge of the syntheses which the
monograph is based upon
• Current relevant ICH/ CHMP-guidelines, use
of toxicological expertise, where relevant
• Revision of monographs may be initiated
based on the information gained from the
application for CEPs
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Pharmacopoeial Substances without

CEP or ASMF

Demonstration that pharmacopoeial monograph is

able to detect all impurities resulting from the
specific synthesis used

ÖLiterature data not sufficient

ÖData to demonstrate that all impurities are
detected and separated from the main peak
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Specification of Impurities in the API

• Impurities Testing Guideline: Impurities in

New Drug Substances (ICH Q3A (R2))
• Specific pharmacopoeial monograph and
general monograph “Substances for
pharmaceutical use”
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Use of [Link]. Monographs for API

Specific monograph, e.g.

Gentamicine sulphate, Acetazolamide
+ General texts:
e.g. residual solvents
impurities in substances for pharmaceutical use
+ General monographs
– Products of fermentation
– Products with a risk of transfer of spongiform
encephalopathies of animal origin
– Substances for pharmaceutical use
 Bundesinstitut für Arzneimittel
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Structure

I. General principles
II. Dossier Requirements: NCE vs. Existing Substances,
ASMF vs. CEP
III. Specification of Impurities in the API
IV. Residual Solvents
V. Metal Catalysts and Genotoxic Impurities
VI. Need more Information?
 Bundesinstitut für Arzneimittel
und Medizinprodukte

Definition of Impurities I
Identified Impurity:
An impurity for which a structural characterisation has been
achieved
Specified Impurity:
An impurity that is individually listed and limited with a specific
acceptance criterion in the specification. Can be either
identified or unidentified
Unidentified Impurity:
An impurity for which a structural characterisation has not
been achieved and that is defined solely by qualitative
analytical properties (e.g. chromatographic retention time)
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Definition of Impurities II

Unspecified Impurity:
An impurity that is limited by a general acceptance criterion,
but not individually listed with its own specific acceptance
criterion in the specification

Qualification:
Process of acquiring and evaluating data that establishes the
biological safety of an individual impurity or a given impurity
profile at the level(s) specified
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Specification of Impurities

Organic Impurities
– Each specified identified impurity
– Each specified unidentified impurity
– Any unspecified impurity with an acceptance
criterion of not more than the identification
threshold
– Total impurities
Residual Solvents
Inorganic Impurities
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Thresholds for Impurities

Thresholds
Maximum Reporting Identification Qualification
Daily Dose Threshold Threshold Threshold

≤ 2 g/day > 0.05 % > 0.10 % or 1.0 mg/day > 0.15 % or 1.0mg/day
(whichever is lower) (whichever is lower)

> 2 g/day > 0.03 % > 0.05 % > 0.05 %

♦ number of decimal digits: two below 1.0 %, one above 1.0 %

♦ application of conventional rounding rules
♦ total impurities > 0.05 %
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Illustration of Reporting Impurity

Results
Action
Raw Result Reported Identification Qualification
(%) Result (%) (0.10 %) (0.15 %)

0.066 0.07 - -
0.0963 0.10 - -
0.12 0.12 + -
0.1649 0.16 + +

It may be appropriate to re-measure the actual amount of the impurity

present and re-evaluate against the qualification threshold if the response
factor is determined to differ significantly from the original assumptions
 Bundesinstitut für Arzneimittel
und Medizinprodukte

Structure

I. General principles
II. Dossier Requirements: NCE vs. Existing Substances,
ASMF vs. CEP
III. Specification of Impurities in the API
IV. Residual Solvents
V. Metal Catalysts and Genotoxic Impurities
VI. Need more Information?
 Bundesinstitut für Arzneimittel
und Medizinprodukte

Classification of Residual Solvents

Known human carcinogens, strongly
suspected human carcinogens, and
environmental hazards
• Class I
⇒ solvents to be avoided

Non-genotoxic animal carcinogens or

possible causative agents of other
• Class II irreversible toxicity. Solvents suspected of
other significant but reversible toxicities
⇒ solvents to be limited

Solvents with low toxic potential to man;

no health-based exposure limit is needed
• Class III
⇒ solvents with low toxic potential
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Classification of Residual Solvents

Benzene, carbon tetrachloride,
1,2-dichloroethane, 1,1-dichloroethene, 1,1,1-
trichloroethane
• Class I
⇒ solvents to be avoided

Acetonitrile, chloroform, cyclohexane,

dioxane, methanol, methylbutylketone,
• Class II tetrahydrofurane, toluene, ...

⇒ solvents to be limited

Acetone, butanol, butyl acetate, DMSO,

ethanol, ethyl acetate, ethyl ether, heptane,
isopropanol, methylethyl ketone, ...
• Class III
⇒ solvents with low toxic potential
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Specification of Residual Solvents in

the API
• Class 1 residual solvents to be avoided, BUT
are they always avoidable?

™ Starting material:
e.g. benzene, 1,2-dichloroethane in early steps in
synthesis
™ By-products from chemical reaction:
e.g. benzene as a Grignard-by-product
™ Impurity in another residual solvents:
e.g. benzene as an impurity in toluene

NO – Need for control!

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Class 1 Solvents as Impurity

• Routine test on a suitable intermediate or the final API

OR
• Control of the “solvent impurity” in the originator
solvent: level below limit specified in guideline
(volatility of both solvents in drying processes must be
taken into account!)
• NMT 30% of the specified limit in a suitable
intermediate of final API, supporting data on 6
consecutive pilot scale- or 3 production scale batches
• Specification for originator solvent includes routine test
and limit for the class 1 solvent
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Specification of Class 2 Solvents

• Use in the last step of synthesis

& need for routine control in the final API

• Use prior to the last step of synthesis

& exemption from need for routine test if
demonstrated on a suitable intermediate of the final
API that content of solvent is NMT 10 % of the
acceptable concentration limit stated in the ICH
guideline (e.g. acetonitrile 41 ppm).

Supporting data on 6 consecutive pilot scale or 3

production scale batches required!
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Specification of Residual Solvents in

the API
Changes to the manufacturing process of an API
in which it has been demonstrated initially that a
Class 1 or Class 2 solvent is below the defined
threshold for routine testing:

& Need to consider impact of process changes

on solvent levels and revalidation, as
necessary!
 Bundesinstitut für Arzneimittel
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Structure

I. General principles
II. Dossier Requirements: NCE vs. Existing Substances,
ASMF vs. CEP
III. Specification of Impurities in the API
IV. Residual Solvents
V. Metal Catalysts and Genotoxic Impurities
VI. Need more Information?
 Bundesinstitut für Arzneimittel
und Medizinprodukte

Residues of Metal Catalysts

• Draft EU-guideline on the Specification Limits for Residues
of Metal Catalysts, scope: Metal catalysts in API and
excipients
• 14 different elements
• PDE - „maximum patient exposure“ – tabulation of
recommendations on oral and parenteral PDEs, taking
oral bioavailability into account
• Routine control, based on suitable validated method
Exception: validated reduction method for a specific
catalyst established
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Genotoxic Impurities

EU-Guideline on the Limits of Genotoxic

Impurities, addition to ICH Q 3 A and B

„For impurities known to be unusually potent or to produce toxic

or unexpected pharmacological effects, the quantitation/detection
limit of the analytical methods should be commensurate with the
level at which the impurities must be controlled.“
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Genotoxic Impurities
Scope:
• NCEs
• new applications for existing active substances where
assessment of the route of synthesis, process control and
impurity profile does not provide reasonable assurance
that no new or higher levels of genotoxic impurities are
introduced…
• known genotoxic activity -
normally based on positive findings in in-vivo mammalian
test(s), supplemented by respective finding from in-vitro-
test(s)
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Genotoxic Impurities

Establishment of two classes

I. genotoxic substances with sufficient evidence for a

threshold-related mechanism
e.g. topoisomerase inhibition,
inhibition of DNA -synthesis,
interaction with the spindle apparatus of cell division,
...

⇒ establishment of exposure levels without appreciable

risk of genotoxicity according to the procedure for class 2
solvents. Calculation of a PDE, derived from the “no-
observed-effect-level” (NOEL) or the „lowest-observed-
effect level“ LOEL
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Genotoxic Impurities

II. Genotoxic compounds without sufficient

evidence for a threshold-related mechanism,
e.g. alkylating agents

ALARP principle – as low as reasonably

practicable
⇒ Case-by-case decision
a) pharmaceutical assessment
b) toxicological assessment
Overall Risk-Benefit Evaluation
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Genotoxic Impurities

TTC concept (threshold of toxicological concern)

• Definition of a common exposure level for any unstudied

chemical that will not pose a risk or significant
carcinogenicity or other toxic
• TTC estimated as 1.5 µg/person/day

- Not applicable to highly potent genotoxic carcinogens:

aflatoxin-like - , N-nitroso -, azoxy – compounds. This group
requires compound-specific toxicity data!!

- Not applicable to carcinogens where adequate toxicity data

(long-term studies) are available and allow for a compound-
specific risk assessment!
 Bundesinstitut für Arzneimittel
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Structure

I. General principles
II. Dossier Requirements: NCE vs. Existing Substances,
ASMF vs. CEP
III. Specification of Impurities in the API
IV. Residual Solvents
V. Metal Catalysts and Genotoxic Impurities
VI. Need more Information?
 Bundesinstitut für Arzneimittel
und Medizinprodukte

Need More Information?

• ICH Harmonised Tripartite Guideline Q3A(R): Impurities in New

Drug Substances. (February 2002). CPMP/ICH/2737/99
• ICH Harmonised Tripartite Guideline Q3C: Impurities: Residual
Solvents. CPMP/ICH/283/95
• ICH Harmonised Tripartite Guideline Q3C(M): Impurities:
Residual Solvents (Maintenance) PDE for N-Methylpyrrolidone
(NMP) and PDE for Tetrahydrofurane. CPMP/ICH/1940/00 corr.
(Nov 2002) und CPMP/ICH/1507/02 (April 2002).
• Annexes to: CPMP/ICH/283/95 Impurities: Guideline for
Residual Solvents ...
Annex 1: Specifications for class 1 and class 2 residual solvents
in active substances. Annex 2: Residues of solvents used in the
manufacture of finished products. CPMP/QWP/450/03 (July
2004)
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• Note for Guidance on specification limits for residues of metal

catalysts (June 2002). CPMP/SWP/4446/00 - Draft
• Guideline on the limits of genotoxic impurities (June 2006).
CPMP/SWP/5199/02
• ICH Harmonised Tripartite Guideline Q6A: Specifications: Test
Procedures and Acceptance Criteria for New Drug Substances
and New Drug Products: Chemical Substances.
CPMP/ICH/367/96
• Guideline on active substance master file procedure.
CPMP/QWP/227/02 (January 2004)
• ICH Harmonised Tripartite Guideline Q1A(R2): Stability Testing
of New Drug Substances and Products (February 2003)
CPMP/ICH/2736/99
• ICH Harmonised Tripartite Guideline Q1B: Photostability Testing.
CPMP/ICH/279/95
• ICH Harmonised Tripartite Guideline Q1C: Stability Testing for
New Dosage Forms. CPMP/ICH/280/95
• ICH Harmonised Tripartite Guideline Q1E: Evaluation of Stability
Data. (February 2003)
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• Note for Guidance on stability testing: stability testing of existing

active substances and related finished products.
CPMP/QWP/122/02, corr.
• ICH Harmonised Tripartite Guideline Q2A: Text on Validations of
Analytical Procedures. CPMP/ICH/381/95
• ICH Harmonised Tripartite Guideline Q2B: Methodology.
CPMP/ICH/281/95
• Guideline on the chemistry of new active substances.
CPMP/QWP/130/96, Rev.1
• Note for Guidance: Investigation of Chiral Active Substances. EC
Document III/3501/91-EN
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Need for more information?

• [Link]
• [Link]
• [Link]
dralex/[Link]
• [Link]
• [Link]
• [Link]
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Abbreviations
• ALARP as low as reasonably practicable
• ASMF active substance master file
• CEP Certificate of Suitability
• CTD Common Technical Document
• EDQM European Directorate for the Quality of Medicines
• LOEL lowest-observed-effect level
• NCA national competent authority
• NCE new chemical entity
• NMT not more than (≤)
• NOEL no-observed-effect level
• PDE permitted daily exposure
• QWP Quality Working Party
• SWP Safety Working Party
• TTC Threshold of Toxicological Concern