Regulatory Requirements
with Relevance for Quality
of API
Beijing, March 2010
Jean-Louis ROBERT
National Health Laboratory
L – 1011 LUXEMBOURG
CHMP co-opted member
Chair CHMP/CVMP QWP
1
Topics addressed



General considerations – CTD-Q
Manufacturing: API starting materials
Impurities








Related substances
Residual solvents
Genotoxic impurities
Residual metal catalysts/reagents
Stability
EU Assessment Policy: known active substance
Conclusion
Back-up: References relevant guidelines



Application file CTD-Q structure
Decision tree identification/qualification impurities
Example of structure of genotoxic impurities
2
S.1 General Information



S.1.1 Nomenclature
S.1.2 Structure
S.1.3 General Properties



Physicochemical properties
Properties affecting pharmacological efficacy
…………..
3
S.2 Manufacture (1)


S.2.1 Manufacturer(s)
S.2.2 Description of Manufacturing Process and
Process Controls




Flowchart
Sequential procedural narrative
Scale, range, yield……..
S.2.3 Control of Materials


API starting material
Information on all materials of biological origin, incl.
viral safety
4
S.2.3 Manufacture: API starting material (2)






API starting material incorporated as a significant structural
fragment into the structure of the AS
Proposal and justification by the applicant
Full characterisation
Description of a one step synthesis not acceptable, unless
described in the European Pharmacopoeia (CEP or
compliance with EP monograph to be demonstrated)
Name of supplier has to be submitted
Detailed description of the synthesis and GMP compliance
(ICH Q7) should go together.
5
S.2.3 Manufacture: API starting material
only flow chart
AS
SM
AS
SM3
detailed
description
AS
AS
SM
n
6
Example: Ibuprofen

N-Butyl-Ibuprofen as an impurity of Ibuprofen
(n-butylbenzene present in starting material
isobutylbenzene)
CH3
H3C C C
H H2
Isobutyl-benzol
CH3
CH3
H3C C C
H H2
C
H
COOH
Ibuprofen
7
Résolution test
8
9
S.2 Manufacture (2)

S.2.4 Controls for Critical Steps and Intermediates


S.2.5 Process Validation and/or Evaluation


Tests and acceptance criteria to be provided
Sterilisation process
S.2.6 Manufacturing Process Development


Changes in manufacturing occurring during
development (pre-clinical, clinical, commercial)
Development of e.g. a design space, real time release
testing
10
S.3 Characterisation


S.3.1 Elucidation of Structure and other Characteristics
 Full elucidation or with reference to a pharmacopoeial
standard
S.3.2 Impurities
 Classification of Impurities
 Organic impurities, Inorganic impurities, Residual
solvents
 Drug substance impurities:
 Process (synthetic) and drug related impurities
(degradation);
 Drug product impurities:
 Degradation products
11
Impurities: General Considerations





The ICH guidelines Q3A (R), [Q3B (R)], Q3C are the
general basis for the control of impurities in active
substances and medicinal products
 Consideration of chemistry and safety aspects
 Glossary
Initial scope: new active substances and corresponding
products.
Extension to existing active substances and corresponding
medicinal products.
European Pharmacopoeia: general monographs (e.g.
Substances for Pharmaceutical Use) and chapters
New synthesis can generate new impurities (imp. profile)


Not necessarily qualified
In addition EU guidelines
 Genotoxic Impurities Testing
 Residual metal catalysts/ metal reagents
12
Q3A/B(R) and Q6A are complementary

Q3A-B:

Q6A:
address the chemistry aspects and
the safety aspects of impurities and
defines different thresholds
 reporting,
 identification,
 qualification.
addresses the setting and justification of
acceptance criteria and the selection of
test procedures
13
Listing of 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
14
Thresholds (active substance)
Reporting T
Identificat. T
MDD < 2g
MDD>2g
> 0.05%
> 0.10% or
> 0.03%
> 0.05%
1.0 mg per day intake,
whichever is lower
Qualificat. T
> 0.15%
> 0.05%
1.0 mg per day intake,
whichever is lower
15
Active substances outside of the scope of the
ICH guideline

For active substances outside of the scope of ICH
guideline:


The applicant should justify adequate thresholds taking into
account the nature of the active substance, the maximal daily
dose, the duration of therapy, the ability of the analytical
methods (current scientific status).
European Pharmacopoeia:

Organic impurities in peptides obtained by chemical
synthesis:
Reporting threshold:
> 0.1%
Identification threshold:
> 0.5%
Qualification threshold:
> 1.0%
16
Scientific Discussion on Impurities





Summary of actual and potential impurities (sound scientific
appraisal).
Potential impurity: an impurity that can arise during manufacture or
storage. It may or may not appear in the new drug substance.
Risk based approach (see also ICH Q9)
Thorough discussion by the applicant based on synthesis,
reagents used, stability,...
Summary of laboratory studies conducted to detect impurities
 Negative results can be helpful !
Discussion on the impurity profiles found in preclinical and
clinical trials: impurities above the qualification threshold have
to be qualified.
17
Impurities to be specified - Rationale for the
inclusion or exclusion of impurities


Scientific knowledge/understanding about the manufacturing process of the
active substance
 Knowledge about how an impurity is generated
Establishment of a control strategy
 Specifications of AS starting materials
 Control of impurities at intermediates rather than on final AS
 Identification of critical process parameters influencing the impurity
profile
 Process controls
 Purification steps: influence on the impurity profile of the final active
substance
 Knowledge about the degradation pathway
18
Reminder: Control Strategy (ICH Q10)


A planned set of controls, derived from current product and
process understanding, that assures process performance and
product quality. The controls can include parameters and
attributes related to drug substance and drug product materials
and components, facility and equipment operating conditions,
in-process controls, finished product specifications, and the
associated methods and frequency of monitoring and control.
Consider each unit operation but also an overall control strategy.
19
Acceptance criteria for impurities



Acceptance criteria should be based on
 Relevant development data
 Test data for the active substance used in
toxicological and clinical studies
 Results from long term and accelerated stability data
 Range of expected analytical and manufacturing
variability
Actual results obtained should form the primary basis
for establishing the acceptance criteria
They should not be higher than the qualification level
20
Reporting impurities content of batches

Results to be provided for batches used for clinical,
safety and stability testing, as well as batches
representative of the proposed commercial process.


To be reported: > Reporting threshold.
Batches: detailed information to be provided.
Identity / size
 Date and site of manufacture
 Manufacturing process
 Impurities content, single, total
 Use of batches
 Reference to analytical procedure used

21
New Impurities

Decision Tree for Identification and Qualification (ICHQ3A R2)
 Description of considerations for the qualification and
identification of impurities when thresholds are
exceeded.
 Recommendation what to do when new impurities
appear during later stage of development or after
authorisation.
22
Residual Solvents: Q3C

Residual Solvents: Q3C




Defines safety limits for solvents (class 1, 2, 3 and (4)
solvents)
Option 1 based on concentration
Option 2 based on MDD and PDE
When the acceptance criteria are identical to the safety
limits (as indicated in the NfG): no justification is needed
(option 1).
23
Residual Solvents: Q3C

Class 1 solvents
In all cases, the limit of a class 1 solvent in the final active
substance should comply with the requirements of the NfG,
even if initially not used as a solvent.
e.g. benzene:
- use as starting material (synthesis)
- present as contaminant e.g. toluene
- by-product from a chemical reaction
24
Residual Solvents: some comments
CHMP position paper

Class 2 solvents

As a principle:


Last step of the synthesis:


Should be routinely controlled either in an intermediate
or in the active substance;
Routine control in the final active substance
Prior to the last step:

If <10% present in a suitable intermediate or in the
active substance, need not be controlled routinely.
25
Genotoxic Impurities

Joint SWP-QWP “Guideline on the Limits of Genotoxic
Impurities”



published 2006
came into 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”.
26
Genotoxic Impurities

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.
27
Genotoxic Impurities

Principles



Identifications guided by existing genotoxic data or the
presence of structure alerts
Genotoxic compounds with sufficient evidence for a
threshold-related mechanism
Genotoxic compounds without sufficient evidence for a
threshold-related mechanism
Threshold of Toxicological concern:
TTC value: 1.5 µg/day
28
Genotoxic impurities


Pharmaceutical considerations
 Try to avoid genotoxic reagents
 Limitations (if possible) at an intermediate rather at the
end active substance
 Introduction of a specific purification step (destruction
of genotoxic impurity)
 Assessment from the applicant justifying the potential
presence or non presence of the genotoxic impurity
Discussion/collaboration with safety experts important.
29
Genotoxic impurities
SWP – QWP Q&As

Revision 1 issued June 2008

The aim of the Q&As document is to provide
clarification and harmonisation of interpretation of
the Guideline on the Limits of Genotoxic Impurities

Addresses 7 key areas
30
Genotoxic impurities

“Cause for concern”:


If a manufacturing procedure for API remains essentially
unchanged, a re-evaluation with respect to the presence
of potentially genotoxic impurities is generally not
needed. However, new knowledge may indicate a
previously unknown “cause for concern”.
e.g. mesylate salt
31
Metal Catalysts/Metal Reagents
Recommendation of acceptable concentration limits for the
residues of metal catalysts or metal reagents that may be
present in pharmaceutical substances or in drug products.
32
Metal Catalysts/Metal Reagents


EMEA/145858/2006
General considerations






Same principles as for Residual Solvents ICH Q3C
Conservative approach compared to food additives
3 classes
Class limit for class 1B
Reporting similar to ICH Q3C
Implementation 5 years (for existing products)
33
Metal Catalysts/Metal Reagents

Concept

Class 1 Metals: metals of high toxic potential


Class 2 Metals: metals with low toxic potential


Known carcinogens
Nutritional trace metals, common in food and food additives
Class 3 Metals: metals with no significant toxicity
Ubiquitous in environment, plants and animals
 No need for health based exposure limit


Difference is made between oral, parenteral and inhalation
exposure (class 1)
34
Metal Catalysts/Metal Reagents

Expectation:



The relevant residual metal should be controlled with a suitable
method
Pharmacopoeial heavy metal test generally not acceptable
Further discussion at international level ongoing both on the
methodology and the limits
35
Setting Specifications –
Considerations Control of Impurities

Drug substance:


Identification of process parameter(s) (CQP) in the synthesis
influencing the generation of a specific impurity in the final
product: introduction of a specific in-process control:
tightening of pH range.
Introduction of a specific purification step e.g. to limit a
potential genotoxic impurity below TTC (degradation of this
impurity).
36
Synthesis Indinavir Sulfate
37
Setting specification: GTI
(case centralised authorised product)
Intermediate II + Compound III
Compound IV
Final
AS
suspected GT
comp. III < 10 ppm
< TTC
(detection limit)
(target)
38
S.4 Control of Drug Substance





S.4.1 Specification
S.4.2 Analytical Procedures
S.4.3 Validation of Analytical Procedures
S.4.4 Batch Analyses
S.4.5 Justification of Specification
39
S.5 Reference Standards of Materials


Full characterisation
Pharmacopoeial standards
40
S.6 Container Closure System

Brief description of bulk container closure system
41
S.7 Stability (1)



S.7.1 Stability summary and Conclusions
S.7.2 Post-approval Stability Protocol and Stability
Commitment
S.7.3 Stability Data
42
S.7 Stability (2)



EU in climatic zone I/II
Storage conditions according to ICH
Guidelines:



ICH 1A (R2): new active substances
CHMP: existing active substances derived from ICH
guideline
In principle no difference in requirements between new
active substances and existing active substances.
43
Stability: Storage conditions

General case
Study
Storage condition
Minimum time period covered
by data at submission
Long term*
25°C ± 2°C/60% RH ± 5%
RH or
30°C ± 2°C/65% RH ± 5%
RH
New AS. 1 year
Exi. AS: 6 mo. (opt. a and b)
Intermediate 30°C ± 2°C/65% RH ± 5%
RH
6 months
Accelerated
6 long
months
± 2°C/75%
RH ±whether
5%
* It is up to 40°C
the applicant
to decide
term stability
studies areRH
performed at 25°C ± 2°C/60% RH ± 5% RH or
30°C ± 2°C/65% RH ± 5% RH. In the latter case, no additional
data under intermediate conditions will have to be generated.
44
Stability: Storage conditions

Refrigerator
Study
Storage condition
Minimum time period
covered by data at
submission
Long term
25°C ± 2°C/60% RH ± 5%
RH or
New AS. 1 year
Exi. AS: 6 mo. (opt. a and b)
Accelerated
25°C ± 2°C/60% RH ± 5%
RH
6 months

Freezer
Study
Storage condition
Minimum time period covered by data
at submission
Long term
-20°C ± 5°C
New AS. 1 year
Exi. AS: 6 mo. (opt. a and b)
45
Stability: Further Considerations


Retest period to be defined
Pharmacopoeial substances: monographs cover
synthetic and degradation products: if no retest date,
batch has to be controlled immediately prior to be
manufactured in the medicinal product.
46
Declaration Storage Conditions (CPMP)
Testing conditions where
stability has been shown
25°C/60%RH
alt. 30°C/65%RH
40°C/75%RH
Required label
None
Additional label,
where relevant
Do not refrigerate
or freeze
25°C/60%RH +
30°C/60%RH (interm)
or 30°C/65%RH
Do not store above
30°C
Do not refrigerate
or freeze
25°C/60%RH
Do not store above
25°C
Do not refrigerate
or freeze
5°C±3°C
Store at 2-8°C
Do not freeze
Below 0°C
Store in freezer
47
Setting Specifications:
future position paper




Harmonisation approach for residual solvents, heavy
metals, genotoxic impurities
Last step of the synthesis
Prior to the last step of the synthesis
…..
48
EU Assessment Policy (known ASs)


From a pharmaceutical quality point of view no difference
is made between new active substances and “existing or
known” active substances (and their corresponding
products).
This is also highlighted in the European Pharmacopoeia
where relevant ICH or CHMP guidelines or the policy
adopted have been adopted:
 Impurities
 Residual solvents
 Genotoxic impurities (EP policy)
 Residual metal catalysts/reagents (EP policy)
49
EU Assessment Policy (known ASs) (2)



Applications for a MA of medicinal products containing
existing active substances are assessed according to their own
merit (based on quality risk management).
A summary of impurities present in batches of the active
substance(s) …………..(and decomposition products arising
during storage) as proposed for use in the product to be
marketed together with an evaluation of these impurities.
For existing/known active substances, the European
Pharmacopoeia general monograph “Substances for
pharmaceutical use” is applicable.
50
EU Assessment Policy (known ASs) (3)

Each active substance with regard to impurities has ultimately
to be assessed on its own merits. If the impurity profile of the
proposed product is different from that of the reference
product, this fact is not a ground for rejection of the
application if the impurities are considered qualified.

In the development part of the application, it is expected to
find a discussion whether the product is likely to have a
different impurity profile as compared to the original product.
51
EU Assessment Policy (known ASs) (4)

It is expected that the applicant of a generic product justifies
why he considers the impurities in his product safe for the
intended use and qualified, either by reference to expected
similarity with the originator or by other means e.g.
compliance with relevant (V)ICH guidelines.

In the case where the impurity profile of a generic product
differs qualitatively from the originator, or where higher
amount of impurities are seen, the full qualification or other
adequate information about the safety of these impurities will
be requested.
52
Outlook

Preparation of an ICH API (chemical and
biotechnological origin) guideline (Q11) taking into
account the concepts and principles described in Q8R
(Pharmaceutical Development).




enhanced/systematic development
establishment of design space
establishment of real time release testing
New Paradigm: combination of enhanced process
understanding, formal use risk management tools and
establishment of an efficient quality system
53
Conclusion





The pharmaceutical quality requirements for the API (AS)
are very much guided by the harmonised ICH guidelines:
Impurities, stability, analytical validation,………
From a pharmaceutical quality point of view there is no
difference between new ASs and existing/known ASs.
The section on impurities is one of the most important
section in an application file. Thorough preparation and
presentation of this section is most helpful for the assessor.
During lifetime of the product, attention has to be paid to
changes in the manufacturing process including change in
suppliers of starting materials.
Impurities profile depends very much on the route of
synthesis.!!
54
Back-up slides
55
References - Relevant Guidelines (API)
From a pharmaceutical quality point of view no difference is made between new
active substances and “existing or known” active substances (and their
corresponding products).







CHMP NfG:
CHMP NfG:
Chemistry on new active substances
Summary of requirements for Active
Substances in the Quality Part of the Dossier
Q3A (R2):
Impurities Testing in new drug substances
Q3C:
Impurities: Guideline for Residual Solvents
CHMP position paper class 1/class 2 solvents
CHMP NfG:
Testing on Genotoxic Impurities
CHMP HfG:
Specification limits for residues of metal
catalysts or metal reagents
56
References - Relevant Guidelines (API)





Q6A:
Specifications: Test Procedures and
Acceptance Criteria for New Drug
Substances and New Drug Products
Q2R:
Validation of analytical procedures
Q1A (R2):
Stability: new active substances…….
CHMP NfG:
Stability: existing active substances…….
European Pharmacopoeia


General monograph: Substances for pharmacopoeial use
General chapter:



Control of Impurities (5.10)
Residual Solvents (5.4)
EMEA Website: www.emea.europa.eu including Q&As
57
Application file: CTD-Q: Drug Substances 3.2.S

S.1 General Information




S.1.1 Nomenclature
S.1.2 Structure
S.1.3 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
58
Applicatin file: CTD-Q: Drug Substances 3.2.S

S.3 Characterisation



S.3.1 Elucidation of Structure and other Characteristics
S.3.2 Impurities
S.4 Control of Drug Substances





S.4.1 Specification
S.4.2 Analytical Procedures
S.4.3 Validation of Analytical Procedures
S.4.4 Batch Analyses
S.4.5 Justification of Specification
59
Application file: CTD-Q: Drug Substances 3.2.S



S.5 Reference Standards of Materials
S.6 Container Closure System
S.7 Stability



S.7.1 Stability Summary and Conclusions
S.7.2 Post-approval Stability Protocol and Stability
Commitment
S.7.3 Stability Data
60
Decision Tree for Identification and Qualification
Is impurity greater than identification
Threshold?
No action
Yes
No
Yes
Any known human
relevant risks?
Structure identified?
Yes
No further
Reduce
to save
level
action
No
No
Yes
Yes
Reduce to not
more than (≤)
identification threshold
Reduce to not
more than (≤)
identification threshold
Greater
than qualification
Threshold?
No
Yes
No
No
No
action
Consider patient population and duration of use and consider conducting:
- Genotoxicity studies (point mutation, chromosomal aberration)
- General toxicity studies (one species, usually 14 to 90 days)
- Other specific toxicity endpoints, as appropriate
Reduce to save
level
Any clinically relevant
adverse effects?
Yes
Qualified
No
61
Examples of Structure of Genotoxic Impurities
Group 1: Aromatic Groups
A
N
OH
N
A
A
N
A
N
O
Purines,
Pyrimidines,
Intercalators,
PNAs or PNAHs
A
O
N-hydroxyaryls
N-Acylated aminoaryls
(Alkylated) Aminoaryls
Aza-aryl N-oxides
Group 2: Alkyl and Aryl Groups
OH
O
A
N
A
H
Aldehydes
A
A
N-methylols
A
Epoxides
EWG
Micheal-reactive
Acceptors
A
NO
A
N-Nitrosoamines
A
NO2
Nitro compounds
O
NH2
Propiosultones
Group 3: Heteroatomic Groups
O
O
A
S
P
X
OR
OR
Alkyl esters of
phosphonates or sulfonates
S or N Mustards
(beta haloethyl)
A
R
N N
A
A
O
O S
A
Propiolactones
S or N
Carbamates
(Urethanes)
O
O
Aziridines
X
O
H
N
O
A
A
N
Hydrazines and
Azo compounds
X
Halo-alkenes Primary halides
(Alkyl and Aryl-CH2)
Legend:
A = Alkyl, Aryl or H
X = F, Cl, Br, I
EWG = Electron withdrawing group
(CN, C=O, ester, etc.)
62