EU requirements for quality of APIs in
Marketing Authorisation Application
Latest developments
Maryam MEHMANDOUST, PhD
ANSM, France
Current Challenges in Global Regulatory Compliance –
Quality of Pharmaceutical Ingredients
28- 29 September 2012, Mumbai, INDIA
Glossary

ALARP
As low as reasonably practicable
 API
Active pharmaceutical ingredient
API = active substance (AS) = drug substance
 CEP
Certificate of European Pharmacopoeia
 CPP
Critical process parameters
 CQA
Critical quality attribute
 CTD
Common technical documentation
 DP
Drug product
 DS
Design space
 GMP
Good manufacturing practices
 GTI
Genotoxic impurity
 IPC
In process control
 MA
Marketing autorisation
 mfg
Manufacturing
 nfg
Note for guidance
 PDE
Permitted daily exposure
 Ph. Eur.
European Pharmacopoeia
 ppm
Part per million
 Q
Quality
 QP
Qualified person
 QWP
Quality working group
 RT
Retention time
 SM
Starting material
 SWP
Safety working party
 TTC
Threshold of toxicological concern
Agence nationale de sécurité du médicament et des produits de santé
1
Topics addressed
EU Different options for submission of information on APIs
 CTD quality part: Drug substance 3.2.S.
 Manufacture S.2.
 Manufacturers GMP status
 Manufacture of mixtures
 API Starting material (EU requirements, examples, ICH Q11)
 Manufacture: validation & mfg process development
 Impurities S.3.2.
 Control of API S.4.
 Specifications for highly toxic impurities: genotox, class 1
metal catalysts and solvents
 Specifications for related impurities in antibiotics
 Stability
 Conclusion

Agence nationale de sécurité du médicament et des produits de santé
2
Submission of data on APIs: Module 3
EU nfg Summary of requirements for AS in the Q part of the dossier,
CHMP/QWP/297/97 Rev 1 corr

Full documentation on the API provided in the MA dossier
Certificate European Pharmacopoeia (CEP)
EDQM Certification procedure in order to confirm compliance with the
Ph. Eur. monographs


Active Substance Master File (ASMF)
 New developments

For a pharmacopoeial substance demonstration of compliance with
the monograph
Option no more used
Agence nationale de sécurité du médicament et des produits de santé
3
Active substance master File (ASMF)
New developments (CHMP/QWP/227/02 Rev 3)

ASMF Working Party established (CMDh, CMDv, CHMP, CVMP)

Mandate: to find solutions for a worksharing system of ASMF
assessments between EU Members States

ASMFs involved in EU procedures (CP, DCP and MRP)

Development of a database to host ASMF assessment reports
 Creation of the EU ASMF number

Revision of the ASMF nfg regarding annexes (now 4 annexes)
coming into force from October 1, 2012

Paper on the rules of worksharing between MSs under preparation
Agence nationale de sécurité du médicament et des produits de santé
4
Active substance master File (ASMF)
New developments (CHMP/QWP/227/02 Rev 3)

Annex 2, Letter of access amended to inform ASMF holders about
share of ASMF assessment reports between all EU MSs & EDQM

Annex 3, Submission letter & administrative details

Annex 4, Withdrawal of letter of access (when the ASMF holder
does not wish anymore to use the ASMF submitted in support of a
specific DP)

Guidance for new annexes developped and soon available for
ASMF holders

Much insistance to have the latest version of the ASMF in different
concerned MSs
Agence nationale de sécurité du médicament et des produits de santé
5
CTD quality part: Drug substance 3.2.S.

S.1 General Information
(Nomenclature, Structure, General Properties)

S.2 Manufacture
 S.2.1 Manufacturer(s)
 S.2.2 Description of Manufacturing Process and Process Controls
 S.2.3 Control of Materials
 S.2.4 Controls for Critical Steps and Intermediates
 S.2.5 Process Validation and/or Evaluation
 S.2.6 Manufacturing Process Development
S.3 Characterisation
 S.3.1 Elucidation of Structure and other Characteristics
 S.3.2 Impurities
S.4 Control of Drug Substances
S.5 Reference Standards of Materials
S.6 Container Closure System
S.7 Stability





Agence nationale de sécurité du médicament et des produits de santé
6
S.2. Manufacture
S.2.1. Manufacturers / GMP status of sites

EU Directive 2001/83/ EC revised in October 2005, art 46f (50f in
2001/82/EC)
 Obligation of MA holders: Use as starting materials* only active
substances manufactured in accordance with guidelines on
GMP of starting materials

QP declaration: responsibility on QP in the site responsible for
batch release of drug product to audit the API manufacturer and
verify the above requirement

Manufacture of active substance begins from the use of the API
starting material according to ICH Q7/ EU GMP Part II
 QP declaration includes logically also mfg sites of intermediates
(see selection and outcome of assessment of the SM API)
* The term starting material clarified now in Directive 2011/62/EC
Agence nationale de sécurité du médicament et des produits de santé
7
S.2. Manufacture
S.2.1. Manufacturers / GMP status of sites

For sterile API a QP declaration is not sufficient.
 A GMP certificate or a valid mfg authorisation from an EEA
Authority or from the Authority of countries having Mutual
Recognition Agreement (MRA) with EU is to be submitted.
 Data on sterilisation and validation to be submitted to the MA
holder/ applicant for inclusion in the MA file (regardless of the
option of submission of data: CEP, ASMF)
See at EMA website, scientific guidelines, Q&A on quality part 1,
active substance
Agence nationale de sécurité du médicament et des produits de santé
8
S.2. Manufacture
Mixture(s) of API(s) and excipients
QWP Q&A Quality, Part 1 and 2

A mixture of an active substance with an excipient cannot be
submitted through an ASMF
 Blending of AS and excipient considered as the 1st step in mfg of the
medicinal product
 Exceptions: where the active substance cannot exist on its own, e.g.,
due to insufficient stability without a stabilising agent, or in the case of
herbal dry extracts if it is not possible to produce a solid extract without
excipients

Mixing of different active substances produced at different mfg sites
cannot be considered as active substance manufacture
 mixing of active substances that can exist and produced on their own
should be considered as the first step of the manufacture of the finished
product.
GMP + dossier consequence: mixture of active substances OR active
substance + excipient is subject to compliance with part I of the EU GMP
Guide (GMP of finished products), to be described in P.3.
Agence nationale de sécurité du médicament et des produits de santé
9
S.2.2. Description of the manufacturing process and
process controls
EU nfg chemistry of new active substance, CPMP/ QWP/ 130/96
Rev 1

Description of the process represents the applicant / manufacturer’s
commitment

Any step of the process having an impact on the quality of the API
and classified as « critical » to be identified and described in this
section

Flow diagram
 Should include molecualr formulae, weights, yield ranges,
chemical structures of starting materials, intermediates, API
reflecting stereochemistry
Agence nationale de sécurité du médicament et des produits de santé
10
S.2.2. Description of the manufacturing process and
process controls
EU nfg chemistry of new active substance, CPMP/ QWP/ 130/96
Rev 1
 Sequential procedural narrative including operating conditions,
quantities of materials used for a representative commercial scale
batch, yields



IPCs for each step
Scale of manufacture
Reprocessing
ICH Q11
 Any design space in the mfg process should be included as part of
the mfg process description i.e. under S.2.2.: description of CPPs and
non CPPs, identification of stages/unit operations covered by DS

Design space is proposed by the applicant and subject to regulatory
assessment and approval
Agence nationale de sécurité du médicament et des produits de santé
11
S.2.3. Control of materials

API Starting material (still important topic)

Information on quality and controls of all other materials used in the
process (appropriate specifications for their intended use)

If quality of a specific input material critical for the quality of final
API, validation data for non compendial methods used for its control
(consider implications for API starting material)

Biologically sourced materials
 Viral and TSE aspects to be addressed for all materials of
biological origin
Agence nationale de sécurité du médicament et des produits de santé
12
API Starting Material/ important topic, why?
Current situation and issues

Context of globalisation
 Fragmentation of the API manufacturing chain

More and more applicants/ manufacturers of API submit a very
short synthesis (reduced nb of steps 1 or 2)

Proposal for API SM with a structure very close to the final API
where the API can be a complex molecule

Lack of information OR poor information on potential impurities
arising from the API SM synthesis and their carry over into the API
 insufficient information to ensure full control of the final API

Manufacturers of the proposed API SM are often external suppliers
 Do manufacturers of the API, ASMF and CEP holders have sufficient
control on them?
Agence nationale de sécurité du médicament et des produits de santé
13
API Starting Material/ important topic, why?
Current situation and issues

Regulatory changes in EU only applicable to manufacturer of API
SM and its specifications

Concerns for GMP application: short syntheses may not include
critical steps that normally should be performed under GMP.
Difficulties for inspectors to verify these steps

ICH Q11 now adopted: The time where it was possible to say
“assessment needs and GMP inspectors needs should not be
confused ” is over.

More and more request of reviewers to re-define the API SM to
simpler molecules
Agence nationale de sécurité du médicament et des produits de santé
14
API Starting Material
ICH Q7 / EU GMP part II definition
A raw material, intermediate, or an API that is used in the production
of an API and that is incorporated as a significant structural
fragment into the structure of the API.
An API Starting Material can be an article of commerce, a material
purchased from one or more suppliers under contract or commercial
agreement or purchased in-house. API starting materials are
normally of defined chemical properties and structure.

ICH Q7 does not intend to define registration requirements and do
not affect the ability of the responsible competent authority to
establish specific registration requirements regarding APIs within
the context of MA.
Agence nationale de sécurité du médicament et des produits de santé
15
API Starting material
EU nfg chemistry of new active substance,
CPMP/ QWP/130/96, Rev 1

Description of the process and synthesis schematic should include
all the steps proceeding from the API starting material to the
isolated intermediates and ultimately to the final API.

Use of the API starting material marks the beginning of the detailed
description of the process.
 This is also where GMP starts according to ICH Q7 and ICH
Q11

Description of the process should cover all the synthetic steps
critical for the safety (impurities) and the efficacy (structural part for
the activity) of the API.
Agence nationale de sécurité du médicament et des produits de santé
16
API Starting material
EU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1
API SM to be proposed and justified by the applicant
 Incorporated as “significant structural fragment”
 Name and address of suppliers (to be understood as mfg sites)
 Full characterisation, complete specifications including an
impurity profile/ method validation if not pharmacopoeial
 Information about the SM synthesis (not detailed, flow-chart) to
enable assessors to judge of the suitability of the proposed
specifications
 Discussion on impurities present in the API SM and possibility of
their carry over or as derivatives into the final API
 Acceptance criteria for API SM to be set based on evaluation of
the fate of impurities when subject to the normal process/
synthesis
Agence nationale de sécurité du médicament et des produits de santé
17
API Starting material
EU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1
Agence nationale de sécurité du médicament et des produits de santé
18
API Starting material
EU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1
 Relevant viral safety and TSE data to be provided if any animal
derived material used the API mfg process (e.g. fermentation,
enzymes, amino acids, etc)
 API SM of vegetable origin: full characterisation including
contaminant profile (microbial contamination, pesticides,
mycotoxins, etc)
. See risk assessment for mycotoxins/aflatoxins in Q&A on quality
of herbal medicinal products, EMA/HMPC/41500/2010 Rev 1
Publication date Feb 2012 (Q 6 for routine or skip testing)
. Q&A of QWP on SM of herbal origin available on EMA website
(scientific guidelines, Q&A on quality part 1, active substance, starting
material of herbal origin)
Agence nationale de sécurité du médicament et des produits de santé
19
API Starting material
EU nfg chemistry of new active substance, CPMP/QWP/130/96, Rev 1
A route of synthesis of one step is not acceptable unless in
certain circumstances

If API SM described in Ph.Eur. and covered by a CEP presented in S.2.3.
 If API SM authorised as an active substance in a MA
 If proof of conformity with the monograph is provided (testing according to
the monograph)
Option no more acceptable ! the nfg should be amended for
clarification
Reagents, solvents
Agence nationale de sécurité du médicament et des produits de santé
20
API Starting material
Experience of EU assessors
Clopidogrel 5-Sulfosalicylate: not acceptable
Agence nationale de sécurité du médicament et des produits de santé
21
API Starting material
Experience of EU assessors
Methy prednisolone hemisuccinate: not acceptable
Agence nationale de sécurité du médicament et des produits de santé
22
API Starting material
Experience of EU assessors
Donepezil hydrochloride hydrate: not acceptable
Agence nationale de sécurité du médicament et des produits de santé
23
API Starting material
Experience of EU assessors
Famciclovir: no more acceptable while absence of carry
over of impurities of SM API was justified under S.2.3
Agence nationale de sécurité du médicament et des produits de santé
24
API Starting material
Experience of EU assessors

Impossible to define an acceptable number of steps that may fit all the situations as it
depends on nb of factors (complexity of the molecule, control strategy, etc): case by
case assessment

Generally 1 or 2 steps are not sufficient to provide assurance of final API quality and
not acceptable unless justified by API structure

Some APIs are of so simple structure that it is obvious a process in one step is
acceptable e.g.: chloroxylenol
pirfenidone

Commercial availability on its own is not a criterion of selection of the API SM
contrary to what can be concluded from ICH Q7, now ICH 11 applicable

API SM prepared by custom synthesis should meet not only the requirements of the
nfg but also GMP consideration

Purification, salt formation, salt transformation or milling are not considered synthesis
step

When API SM not acceptable, redefinition is requested however difference of view
about application of this measure to already accepted ASMFs and MAs
Agence nationale de sécurité du médicament et des produits de santé
25
API Starting material
ICH Q11 adopted (applicable in EU in November 2012)
Selection of API SM, section 5


Principles to determine where the AS mfg process begins
Accent on control strategy

Main principle: Changes in material attributes or in operating
conditions occuring near the beginning of the mfg process have
lower potential to impact the quality of final API

Relationship between risk and number of steps from the end of the
mfg process to be considered for 2 aspects
 Physical properties of the drug substance
 Formation, fate and purge of impurities
Agence nationale de sécurité du médicament et des produits de santé
26
API Starting material
ICH Q11 adopted (applicable in EU in November 2012)
Selection of API SM, section 5

Risk and number of steps from the end of the mfg process to be
considered for 2 aspects
 Physical properties of the drug substance
 final crystallisation and subsequent operations, all occuring usually
at final stages therefore always described in S.2.2. part of applicant
commitment and subject to GMP
 Formation, fate and purge of impurities
 Principle: consider risk of carry over to the final API. More chance
to remove impurities generated early in the mfg process in
purification steps (washings, crystallisation of intermediates) than
those generated late in the process
 Fate: whether the impurity reacts and changes its chemical
structure
 Purge: whether the impurity is removed via crystallisation,
extraction, etc
Agence nationale de sécurité du médicament et des produits de santé
27
API Starting material
ICH Q11 adopted (applicable in EU in November 2012)
Selection of API SM, section 5

To perform assessment of suitability of mfg process and controls
(including on impurities) in place, enough of the API mfg process
is to be described in the application
 To understand how impurities are formed, what could be the
impact of changes in the process on their formation, fate and
purge
 To understand why the control strategy proposed is suitable
for the API mfg process
This will include typically description of multiple chemical
transformation steps.
Agence nationale de sécurité du médicament et des produits de santé
28
API Starting material
ICH Q11 adopted (applicable in EU in November 2012)

Principles to be applied together in selction of SMs rather than
applying them in isolation
Mfg steps that impact the impurity profile of the API should normally
be included in the mfg process described in S.2.2.

Application of GMP provisions described in ICH Q7 to each branch
of a convergent synthesis beginning from the 1st use of a starting
material.

A SM is of defined chemical property and structure
Non isolated intermediates are not appropriate SMs
SM incorporated as a significant structural fragment and in this
context, different from raw materials


Agence nationale de sécurité du médicament et des produits de santé
29
API Starting material
ICH Q11 adopted (applicable in EU in November 2012)

Principles to be applied together in selction of SMs rather than
applying them in isolation
Justification for appropriateness of selected API SM
 Ability of analytical methods to detect impurities in SMs
 Fate and purge of these impurities and their derivatives in the process
 How the specification of each SM will contribute to the control strategy

No need to justify use of commercially available SM however
 Commercially available chemical is one that is sold as a commodity in a
NON Pharmaceutical market
 Chemicals prepared by custom synthesis are not considered as
commercially available
Selection of a chemical prepared by custom synthesis is to be justified
according to the general principles described in ICH Q11
Agence nationale de sécurité du médicament et des produits de santé
30
API Starting material
ICH Q11 adopted (applicable in EU in November 2012)

Semi synthetic APIs: obtained by combination of chemical
synthesis & fermentation or extraction from botanical material

Possible to describe the mfg process from one of the isolated
intermediates (as SM API) in the synthetic process

The selected isolated intermediate should comply with the
principles outlined before for selection of API SM
 Analytical characterisation of the selected SM including its impurity
profile, impact of fermentation or botanical material/extraction on the
impurity profile of the API

If not, description of the mfg process should be from the source
material (microorganism producer or plant)
Agence nationale de sécurité du médicament et des produits de santé
31
API Starting material
ICH Q11 adopted (applicable in EU in November 2012)
Assurance of quality of API: application of GMP to mfg process
together with appropriate control strategy
A control strategy can include but is not limited to

Controls on material attributes (raw materials, SM, intermediates, primary
packaging, etc)
 Controls implicit in design of the mfg process (order of steps or addition of
reagents)
 In-process controls (IPC tests and process parameters)
 Controls on drug substance (e.g. release testing)
Definition of control strategy: A planned set of controls, derived from current
product and process understanding, that assures process performance and
product quality. Every API mfg process, whether developed through a
traditional or enhanced approach (or some combination thereof), has an
associated control strategy.
Agence nationale de sécurité du médicament et des produits de santé
32
API Starting material
ICH Q11: example of application of principles of API SM selection
together and not in isolation
Why D can be selected as API SM instead of A?
1st step generation of chiral centre, control of undesired enantiomer in D
 Stereocentre stable up to the end
 Steps 4,5 & 6 generation of impurities
 Steps 2 and 3 no impact on impurity profile
Agence nationale de sécurité du médicament et des produits de santé
33
S.2. Manufacture

S.2.5 Process Validation and/or Evaluation
 Sterilisation process
 For non sterile API, validation should be carried out but not needed to
provide in the file (see ICH Q11)

S.2.6 Manufacturing Process Development
 Changes in manufacturing occurring during development (pre-clinical,
clinical, scale up, commercial)
 Development of e.g. a design space, real time release testing
 Risk assessment & assignment of criticality: Identification of CQAs
and CPP
 Establishing a Design space: design of experiments & design
space verification
 Defining a control strategy
Agence nationale de sécurité du médicament et des produits de santé
34
S.3. Characterisation
S.3.2. Impurities

Classification of impurities
 Organic impurities ICH Q3 A (R)
 Residual solvents ICH Q3C and EU nfg CPMP/QWP/450/03
 Inorganic impurities
 Metal catalysts (EU nfg EMEA/CHMP/SWP/4446/2000)
 Genotoxic impurities (EU nfg CPMP/SWP/5199/02)
These texts are applicable in EU to new active substances (NAS =
New chemical entities NCE) and also to existing active
substances
(ICH Q3A and Q3C by application of Ph. Eur. general monograph
2034)
Agence nationale de sécurité du médicament et des produits de santé
35
S.3. 2. Impurities
Related substances & thresholds to apply


Each specified identified impurity
Each specified unidentified impurity but identified at least by an analytical
character e.g. RT in a chromatographic system


Any unspecified impurity with an acceptance criterion of not more
than (<) the identification threshold
Total impurities
Agence nationale de sécurité du médicament et des produits de santé
36
S.3. 2. Impurities
APIs outside the scope of ICH and EU guidelines

Organic impurities in peptides obtained by chemical synthesis,
Ph. Eur. general monograph 2034
Reporting threshold
> 0.1%
Identification threshold > 0.5%
Qualification threshold > 1.0%

For other type of APIs, Justification to be provided for adequate
thresholds
 the nature of the active substance,
 the maximal daily dose of drug product,
 the duration of therapy,
 the ability of the analytical methods (current scientific status)
Agence nationale de sécurité du médicament et des produits de santé
37
S.3. 2. Impurities
Scientific discussion on impurities & rationale for setting
acceptance criteria

Summary of actual and potential impurities & discussion on their origin and
generation

Discussion on impurity profiles found in preclinical and clinical batches for
new APIs

Discussion on impurity profile found in development, pilot, commercial
batches for existing APIs
 Comparison to the pharmacopoeial monograph

Impurities above the qualification thresholds have to be qualified, acceptance
criteria cannot be higher than qualified level

Actual results obtained including stability data should be the basis for setting
the acceptance criteria i.e. specifications have to reflect results

Decision Tree for Identification and Qualification of new impurities in Q3A
 Demonstration of similarity with the reference product possible
Agence nationale de sécurité du médicament et des produits de santé
38
S.3. 2. Impurities
Residual solvents
Safety limits for 3 classes of solvents
 Class 1 solvents highly toxic, to be avoided, suitable justification
needed for their use
 Class 2 solvents to be limited with 2 options
 Concentration limit (ppm) and PDE (mg/day)
 NEW: cumene classified now in class 2
 option 1 limit of NMT 70 ppm
 option 2 limit (PDE) of 0.7 mg/day
 See rules of omission of testing in EU nfg CPMP/QWP/450/03 as annex
to Q3C. These rules do not preclude that if the API is tested, it should
anyhow meet the requirement of the ICH Q3C nfg


Class 3 solvents, low toxic potential
Table 4, a non exhaustive list of solvents for which safety data are
not available
Agence nationale de sécurité du médicament et des produits de santé
39
S.3. 2. Impurities
Residues of metal catalysts, metal reagents
EU nfg EMEA/CHMP/SWP/4446/2000 objectives
 To recommend maximum acceptable concentration limits for
residues of metal catalysts/reagents in pharmaceutical substances or
in drug products

Control of residual metal with a suitable method

Pharmacopoeial heavy metal test generally not acceptable

Implementation 5 years for existing products
ICH guideline for metal impurities ICH Q3D under preparation
Agence nationale de sécurité du médicament et des produits de santé
40
S.3. 2. Impurities
Residues of metal catalysts, metal reagents
EU nfg EMEA/CHMP/SWP/4446/2000 objectives
 Class 1 Metals: metals of high toxic potential
 Known carcinogens
 3 sub-classes
 Class 1B: not individual limit but total limit for whole class
 Class 2 Metals: metals with low toxic potential
 Nutritional trace metals, common in food and food additives:
Cu, Mn
 Class 3 Metals: metals with no significant toxicity
 Ubiquitous in environment, plants and animals: Fe, Zn
Difference is made between requirements for oral, parenteral
and inhalation exposure
Agence nationale de sécurité du médicament et des produits de santé
41
S.3. 2. Impurities
Genotoxic impurities (GTIs)
EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006

Joint SWP-QWP “Guideline on the Limits of Genotoxic Impurities”
with effect on 1 January 2007

Basis: ICH Q3A/B guideline
“For impurities known to be unusually potent or to produce toxic or
unexpected pharmacological effects, the quantification - detection
limit of the analytical procedures should be commensurate with the
level at which the impurities should be controlled”.

An ICH guideline is under preparation, genotoxic impurities M7
Agence nationale de sécurité du médicament et des produits de santé
42
S.3. 2. Impurities
Genotoxic impurities (GTIs)
EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006

Scope
 New active substances
 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 GTIs are introduced as compared to
products currently authorised in the EU containing the same
active substance (idem variations)
 No need for retrospectively application to authorised products,
unless there is a specific cause for concern
Agence nationale de sécurité du médicament et des produits de santé
43
S.3. 2. Impurities
Genotoxic impurities (GTIs)
EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006

Principles
 Identification guided by existing genotoxic data or the presence of alert
structures
 Genotoxic compounds with sufficient evidence for a threshold related
mechanism e.g. data from long term carcinogenocity studies (PDE)
 Genotoxic compounds without sufficient evidence for a threshold related
mechanism, ALARP principle
IF data not available
 Application of a generally applicable approach as defined by the
threshold of Toxicological Concern TTC
 Threshold of Toxicological concern:
TTC value: 1.5 µg/day
TTC not applicable to high potency genotoxic carcinogens such as
aflatoxins, N-nitroso and azoxy compounds
Agence nationale de sécurité du médicament et des produits de santé
44
S.3. 2. Impurities
Genotoxic impurities (GTIs)
EU nfg CPMP/SWP/5199/02 and EMEA/CHMP/QWP/251344/2006

Pharmaceutical considerations
 Try to avoid genotoxic reagents or their generation (design of
synthesis)
 Limitations (if possible) at an intermediate rather at the end active




substance
Introduce a specific purification step (destruction of genotoxic
impurity)
Assessment from the applicant justifying the potential presence or
non presence of the genotoxic impurity
If not possible to avoid GTIs then go through relevant safety
studies
See decision trees in the EU nfg on GTIs
Agence nationale de sécurité du médicament et des produits de santé
45
S.3. 2. Impurities
Genotoxic impurities (GTIs)
Joint SWP-QWP Q & A, EMA/ CHMP/ SWP/ 431994/ 2007 Rev . 3

Revision 3 adopted in September 2010
The aim of the Q&As, is to provide clarification and harmonisation of
interpretation of the Guideline on the Limits of Genotoxic Impurities

Addresses several key areas including amongst others






An explanation for cause of concern e.g. mesylate esters
When ALARP should be applied
Ames test overruling alert structures but to be conducted to regulatory
acceptable standards
How to control GTIs in clinical trials and concept of staged TTC
In presence of several GTIs, TTC should be applicable individually if
impurities are structurally unrelated and to the sum if they are
structurally similar (e.g. group of mesylates)
Agence nationale de sécurité du médicament et des produits de santé
46
S.3. 2. Impurities
Potentially genotoxic impurities with alert structures, Muller and al.
Gro up 1 : Aro m at ic gro up s
OH
N
A
A
N
A
N
A
N
O
N -H y d ro xy ary l s
A
O
N -A cy l at ed ami n o ary l s A za-ary l N -o xi d es A mi n o ary l s an d al k y l at ed ami n o ary l s
P u ri n es o r P y ri mi d i n s , In t ercal at o rs , P N A s o r P N A H s
Gro up 2 : Alk y l an d Ary l Gro up s
O
H
A
O
OH
A
A l d eh y d es
N
A
N
A
A
N -Met h y l o l s
A
E p o xi d es
O
A
A
A zi ri d i n es
Halo gen
C (o r S)
P ro p i o l act o n es
P ro p i o s u l t o n es
Mi ch ael -react i v e
A ccep t o rs
O
O
P
S
OR
A
A
N
N
A
S or N
N o r S Mu s t ard s
(b et a h al o et h y l )
A= Alk y l, Ary l, o r H
Halo gen = F, Cl, Br, I
Gro up 3 : Het ereo at o m ic gro up s
EW G= CN, CO, est er, et c
EW G
NH2
A
O
N
A
O
NO 2
N -N i t ro s ami n es N i t ro co mp o u n d s Carb amat es (U ret h an es )
H
O
NO
A
A
H y d razi n es an d
A zo Co mp o u n d s
Halogen
A
Halogen
OR
A l k y l E s t ers o f
P h o s p h o n at es o r Su l fo n at es
H al o -al k en es
P ri mary H al i d es
(A l k y l an d ary l -CH
2)
Agence nationale de sécurité du médicament et des produits de santé
47
S.4. Control of API
Harmonisation of policies on setting specifications to
highly toxic impurities
QWP Q&A, part 1, June 2012, EMA website
Same principles (3 scenarios/cases) apply to
 Genotox impurities
 Class 1 metal catalysts
 Class 1 solvents
Example is given in following slides for GTIs
Target limit is the limit in the corresponding guideline
Agence nationale de sécurité du médicament et des produits de santé
48
S.4. Control of API
Harmonisation of policies on setting specifications (GTI)
QWP Q&A, part 1, June 2012, EMA website
What is a reasonable policy for setting specifications for potentially GTI
that are theoretical or actual impurities in the API mfg process

Case 1 – A potential genotoxic impurity
 If a potential genotoxic impurity is just a theoretical impurity i.e.
based on theoretical considerations but not found in practice at
any key stage in the mfg process as demonstrated by studies
during development of the manufacture, the impurity does not
need to be included in the drug substance specification OR a
specification of an intermediate.
 This implies availability of a suitable method and testing to show
absence of such impurity
Agence nationale de sécurité du médicament et des produits de santé
49
S.4. Control of API
Harmonisation of policies on setting specifications (GTI)
QWP Q&A, part 1, June 2012, EMA website

Case 2 – A (potentially) genotoxic impurity actually formed or
introduced prior to the final step of the synthesis
Possible not to include such impurity in the drug substance specification
 Controlled by a suitable limit in a synthesis intermediate and
demonstration by analysis results (use of spiking experiments) that it
does not exceed 30 % of the limit, derived either from TTC or otherwise
defined acceptable limit etc, in the drug substance.
Agence nationale de sécurité du médicament et des produits de santé
50
S.4. Control of API
Harmonisation of policies on setting specifications (GTI)
QWP Q&A, part 1, June 2012, EMA website

Case 2 (cont.) – A (potentially) genotoxic impurity actually formed or
introduced prior to the final step of the synthesis
Possible not to include such impurity in the drug substance specification
 Skip testing possible if level of the impurity in a synthesis intermediate
does not exceed 30% of the limit, either TTC or otherwise defined
acceptable limit etc, in the intermediate. Data to be presented for at
least 6 consecutive pilot scale or 3 consecutive production scale lots.
 If this condition is not fulfilled, a routine test in the intermediate is
needed.
 If the impurity exceeds 30% of the limit, either TTC or otherwise defined
acceptable limit etc., in the drug substance the impurity to be included
in the drug substance specification and routinely
 No control of genotoxic impurity at the intermediate stage, then the
scenario of example 3 applies.
Agence nationale de sécurité du médicament et des produits de santé
51
S.4. Control of API
Harmonisation of policies on setting specifications (GTI)
QWP Q&A, part 1, June 2012, EMA website

Case 3 – A (potentially) genotoxic impurity is formed or introduced
in the last step of the synthesis
Such impurity should be included in the drug substance specification
 Possible to apply skip testing if the level of the impurity does not
exceed 30 % of the limit, derived from either TTC or otherwise defined
acceptable limit etc, in the drug substance.
 Data should be presented for at least 6 consecutive pilot scale or 3
consecutive production scale batches if skip testing is applied.
 If this condition is not fulfilled, a routine test in the drug substance
specification is needed.
Agence nationale de sécurité du médicament et des produits de santé
52
S.4. Control of API
Setting specifications for impurities in antibiotics
NEW, EU nfg EMA/CHMP/CVMP/QWP/199250/2009, effective end June 2013

Applicable to new antibiotics and new sources of existing
antibiotics
Not applicable to residues from fermentation process

Active substances manufactured by semi-synthesis

 Reporting threshold: 0.05%/ 0.03%
 Identification threshold: 0.10% / 0.05%
 Qualification threshold: 0.15% / 0.05%

Active substances manufactured by fermentation, single compound
 Reporting threshold: 0.10%
 Identification and qualification threshold: 0.15%

Active substances manufactured by fermentation, family of compounds
 Reporting threshold: 0.10%
 Identification threshold: 0.15%
 Qualification threshold: 0.50% / 0.2%
(structurally close related compounds versus other related compounds)
Agence nationale de sécurité du médicament et des produits de santé
53
S.7. Stability
EU located in climatic zone I/II
 Storage conditions according to ICH
 Guidelines:
 ICH Q1A (R2): new active substances
 EU nfg for existing active substances, derived from ICH,
CPMP/QWP/122/02, rev 1
 Same requirements between new active substances and existing
active substances UNLESS for length of data at time of submission

Retest period to be defined
 If no retest period, API should be tested against its specifications
before use in production of DP
 Declarations of storage conditions according to
CPMP/QWP/609/96/Rev 1 (different from WHO rules)

Agence nationale de sécurité du médicament et des produits de santé
54
Conclusion

From a pharmaceutical quality point of view, no difference is made
between new active substances and existing or known active
substances
 Adoption of certain ICH texts in Ph. Eur. general monograph 2034

Much emphasis on “Impurities”: each API should be assessed with
regard to impurities on its own merits. Thorough discussion needed.

Justification from the applicant why impurities in the product are
considered qualified and safe for the intended use

API starting material, very important topic
 Justify selection in view of EU nfg chemistry of new active
substances & ICH Q11
 Critical steps of the synthesis should be GMP
 Consider steps of generation and removal of impurities
 Attention to change of suppliers of SM API impacting the
impurity profile of final API
Agence nationale de sécurité du médicament et des produits de santé
55
Thank you for your attention
Agence nationale de sécurité du médicament et des produits de santé
56
Avertissement
• Lien d’intérêt : personnel salarié de l’ANSM (opérateur de l’Etat).
• La présente intervention s’inscrit dans un strict respect d’indépendance et
d’impartialité de l’ANSM vis-à-vis des autres intervenants.
• Toute utilisation du matériel présenté, doit être soumise à l'approbation préalable
de l’ANSM.
Warning
• Link of interest: employee of ANSM (State operator).
• This speech is made under strict compliance with the independence and
impartiality of ANSM as regards other speakers.
• Any further use of this material must be submitted to ANSM prior approval.
Avertissement
• Lien d’intérêt : personnel salarié de l’ANSM (opérateur de l’Etat).
• La présente intervention s’inscrit dans un strict respect d’indépendance et
d’impartialité de l’ANSM vis-à-vis des autres intervenants.
• Toute utilisation du matériel présenté, doit être soumise à l'approbation préalable
de l’ANSM.
Warning
• Link of interest: employee of ANSM (State operator).
• This speech is made under strict compliance with the independence and
impartiality of ANSM as regards other speakers.
• Any further use of this material must be submitted to ANSM prior approval.