APIs

Active pharmaceutical ingredients
Presented By
Rutendo Kuwana
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and
.assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda
Presentation approach
Discuss aspects of the information that is required for the
API for WHO Prequalification
Use examples from literature as well as experience from
the WHO PQ Project
2|
Active Pharmaceutical Ingredients - Artemisinin based therapy
Some definitions
Active Pharmaceutical Ingredient (API)
A substance or compound that is intended to be used in

the manufacture of a pharmaceutical product as a
therapeutically active compound (ingredient)
3|
Some definitions (2)
Enantiomers
cpds with same molecular formula as substance but differ in spatial
arrangement of atoms and are non-superimpossable mirror images
Polymorphism occurrence of different crystalline forms of the same

substance
Degradation product molecule resulting from chemical change in

substance due to e.g. light, temperature, pH, water, reaction with
excipient, immediate container/closure
4|
Some definitions (3)
Impurity any component of the medicinal product which is not the

chemical entity defined as the active substance or an excipient of
the product
Identified Impurity an impurity for which structural characterisation

has been achieved
Unidentified degradation product an impurity defined only by

qualitative properties e.g. Rt
5|
Available information on API

Applicants should collect and analyse available information
of the API in a systematic approach. This approach
Leads to a sound scientific understanding of the API, with
respect to properties, stability, specifications, etc.
Assists in API manufacture and DMF compilation
Leads to the appropriate choice of API manufacturer (source)
Assists in dossier compilation
Is important for FPP pharmaceutical development
Leads to reduction of time / cost
6|
Literature information on API
Standard works / series / books such as:
(Analytical) Profiles of Drug Substances and Excipients [eds: Florey / Brittain

31 volumes]
The Merck Index (for structures, properties)
Pharmaceutical Codex (12th edition) (old APIs)
Journals through search facilities such as
International Pharmaceutical Abstracts, Chemical Abstracts, Analytical

Abstracts & internet
Pharmacopoeial monographs (current)

Analysis of structure & stereochemistry
7|
Information from
literature and structures
APIs which are organic compounds, have unique

chemical structures & stereochemistry
These structures, together with the solid/liquid state
conditions, are basically responsible for chemical and
physical properties of the APIs
8|
Guidelines
Guideline on Submission of Documentation for Prequalification of Multi-Source
(Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS,
Malaria and Tuberculosis [GuideGeneric]
Guidance on Variations to a prequalified Dossier [Variation Guide]
Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02 Rev1]
Guideline on Active Pharmaceutical Ingredient Master File (APIMF) Procedure
[Draft]
Guideline on Summary of Requirements for Active Substances in the Quality Part of
the Dossier [CPMP/QWP/297/97 Rev 1 corr]
ICH Q3A [R] Impurities Testing Guideline: Impurities in New Drug Substances
[CPMP/ICH/2737/99]
ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug
Substances and New Drug Products: Chemical Substances [CPMP/ICH/367/96 corr]
ICH Q2A Validation of Analytical Procedures: Definitions and Terminology
[CPMP/ICH/381/95]
ICH Q2B Validation of Analytical Procedures: Methodology [CPMP/ICH/281/95]
9|
Literature support
Literature information used in the dossier should always be

accompanied by
Full traceable reference citations
Photocopies of publication or relevant pages
10 |
Properties of APIs
Scenarios:
API not described in BP, Ph., JP, Ph.Eur., or USP (non - compendial)
Considered new
(?) information on (adverse) drug reaction
Risk estimation high
Profound information necessary
API described in BP, Int.Ph., JP, Ph.Eur.,or USP (compendial)
Considered in use
Information on (adverse) drug reaction (monitored)
Risk estimation based on available data
Information necessary limited to data beyond the monograph
Essential control by the monograph
11 |
Properties of API(s)
APIs not described in BP, PhInt, PhEur or USP
a) evidence of chemical structure
spectral data
Single crystal X-ray structure (sufficient) or
Spectrometric data (IR, 1H & 13C NMR, MS, etc.): QA certified
copies of the spectra and tabulated data with
assignments against structure/interpretation of data (narrative)
b) evidence of chemical structure
Isomerism
Stereochemistry
Discussion of potential isomeric forms
12 |
Properties relevant/critical for the performance of the API

c) potential polymorphic forms
Influence on physicochemical and physical characteristics (solubility,
hardness, compressibility, density, melting point, etc.) Must be
controlled
d) particle size distribution
requirement for low solubility drugs (dissolution, bioequivalence)
e) additional characteristics
critical characteristics to be controlled to ensure consistent
performance of the API (e.g. hygroscopicity)
13 |
Properties: non-compendial APIs
Proof of structure/stereochemistry correctness

correlation against API spectral data from peer reviewed literature,
preferable innovator publication (in tabulated form!!). Strongly
recommended
14 |
APIs described in BP, PhInt, PhEur or USP
Evidence of chemical structure
control of structure by suitable compendial identification tests
Properties relevant/critical for the performance of the API (not necessarily
covered by the monograph)
a) potential polymorphic forms
Influence on physicochemical and physical characteristics (solubility,
hardness, compressibility, density, melting point, etc.) Must be
controlled
b) particle size distribution
requirement for low solubility drugs (dissolution, bioequivalence)
c) additional characteristics
critical characteristics to be controlled to ensure consistent
performance of the API (e.g. hygroscopicity)
15 |
Properties: Compendial APIs
Physico-chemical and other relevant properties, e.g.

Solubility in water (effect of pH), other solvents such as ether,
ethanol, acetone and dichloromethane
pKa, partition coefficient
Existence/absence of polymorphs and pseudo-polymorphs e.g.
solvates (with XRPD, DSC, IR)
e.g. Rifampicin polymorphs I and II
Hygroscopicity
Particle size
16 |
Categories of Antimalarials
APIs described in monographs of major international
pharmacopoeias ( 10 years)
Amodiaquine, Chloroquine, Dapsone, Quinine, Mefloquine,
Sulfadoxine/Pyrimethamine, Trimethoprim
APIs described in monographs of major international
pharmacopoeias (recently)
Arthemether, Artemisinin, Artemotil, Artenimol, Artesunate
APIs not described in monographs of major international
pharmacopoeias
Chlorproguanil, Lumefantrine, Naphthoquine, Piperaquine, Pyronaridine
17 |
Malaria APIs: Table of occurrence
API
BP
EP
US
Int
JP
MI
Artemether
Artemisinin
Artemotil (arteether)
Artenimol
Artesunate
18 |
APr
Cod
18
Malaria APIs: Table of occurrence (con.)
API
BP
EP
Amodiaquine
US
Int
Lumefantrine
JP
MI
APr
Cod
Mefloquine
Pyrimethamine
Sulfadoxine
Lumefantrine only malaria API without monograph
19 |
19
Properties of Artemisinins
Artemisinin (C15H22O5)
7 centers of asymmetry
27 potential isomers
One isomer in biosynthesis
Chemical synthesis
Feasible but uneconomical
Chemical derivatization at
C-10 (carbonyl-moiety) converts
C-10 into an additional
stereoisomeric center:
20 |
- and -isomers are formed
8
9
8a
12a
10
11
12
5a
5
1
4
2
Properties of Artemisinins
Manufacturer proposals
Melting range
Specific optical rotation
a-Artemether
100C
b-Artemether
84 - 86C, 86 90C
+166-+173, +168-+173
20mg/ml C2H5OH
a-Artesunate
144C, 143C, 142-146C

132-135C, 131-134C
+2.5-+3.5, +4.5-+6.5, +11-+14

10mg/ml CH2Cl2
+11-+14, 40mg/ml CH3Cl, +10-+14
(CH3Cl)
b-Artesunate
132-135C
+2.5-+3.5
a~b~Artenimol
+146 (15C)
(?mg/ml MeOH)
Diastereomers
may differ in their melting point/specific optical rotation
(in solution)
21 |
Route(s) of synthesis
API not described in BP, Int.Ph., JP,Ph.Eur., or USP (non-compendial APIs)

Controls of critical steps and intermediates
Potential impact on the quality of the API and intermediates
Process conditions, test requirements and other relevant parameters to be
controlled within predetermined limits
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Examples of potentially critical steps

Mixing of multiple components
Phase change and phase separation steps
Steps where control of pH and temperature are critical
Introduction of an essential structural element or major chemical
transformation
Introduction/removal of significant impurities to the API
Final purification step
Steps with an impact on solid state properties/homogeneity of the API
API described in BP, Int.Ph., JP, Ph.Eur.,

or USP (compendial APIs)
Route(s) of synthesis (cont.)
Requirements: The synthesis should
23 |
lead to the correct structure, stereochemistry and crystal form

& size (if relevant)
be well controlled and validated (GMP)
produce an API which meets acceptable standards of quality,
including limits of impurities (organic, inorganic, residual
solvents)
The information required for the synthesis of the API may

depend on
24 |
Availability of a valid CEP - no synthesis information is then

required. CEP must however have all appendices and applicant
to submit other info not covered by CEP
Whether the quality of the is API controlled by a monograph in

an acknowledged pharmacopoeia?
No official monograph is available for quality control

- Detailed information required e.g. Open Part of DMF (from API
manufacturer)
- Also signed declaration from API manuf that synthesis and purification
are as described in the dossier
Certification Scheme /EDQM

CEP Option
Issued by EDQM for substances described in the Ph. Eur.
www.edqm.eu under Certification.Pharm.Substances
Information which can be found on a quality CEP

- CEP reference Number,
- CEP holder,
- Site of manufacture of the API, site of manufacture of declared starting
material
- Grade (particle size or sterile) (if applicable)
- Ph. Eur. monograph according to which the Certification dossier has been
evaluated,
- Additional impurities and residual solvents not mentioned in the
monograph,
- Additional methods to those of the monograph as annexes,
- If sterile API, Method of sterilization + mention that process and validation
have been assessed
- Re-test period (if applicable)
- Packaging system and storage condition (if re-test period mentioned),
- Date of validity of the CEP
25 |
Certification Scheme /EDQM

CEP Option
A quality CEP certifies that the quality of the

substance can be checked according to the Ph. Eur.
by applying the analytical methods described in the
specific Ph. Eur. monograph supplemented by those
appended to the CEP.
26 |
Synthesis : non-compendial APIs
A flow diagram of the synthesis process

including structures & stereochemistry of starting materials & intermediates;
reagents; catalysts; solvents
A full description of each step / process, including:
27 |
Reaction conditions (temp., time, moisture control, etc.)

Quantities of reagents/solvents
Size of production scale
Purification of intermediates
Final API purification method / crystallisation / solvent(s)
Reprocessing (has to be justified, validated)
Process controls
Validation of critical steps, e.g. aseptic processes
Discussion of (possible) process impurities
Organic, residual solvents and catalysts/inorganic
API described in BP, PhInt, PhEur or USP

Impurities that are not included in the monograph
Process related impurities
Key intermediates
Residual solvents
Potential organic impurities not covered by the monograph
28 |
Specifications of raw materials and intermediates used in

synthesis
Provide specifications for
starting materials and intermediates (if isolated)

reagents, solvents & catalysts
Class 1 solvents should not be used (ICH Q3C)
Benzene, Carbon tetrachloride, 1,2-Dichloroethane,

1,1-Dichloroethene & 1,1,1-Trichloroethane
Provide a declaration on the use/non-use of material of animal or

human origin (TSE)
Risk of Transmitting Animal Spongiform Encephalopathy Agents (WHO TRS

908, Annex 1 or EMEA/410/01 Rev.2)
To limit impurities in the API (For safety reasons)

29 |
WHAT IS A STARTING MATERIAL?
Contributes an important structural part of the API

Available in free trade
Compound well defined in chemical literature (name, chemical
structure, chemical and physical properties, and impurity profile)
Synthesized by commonly known process
30 |
RE-DEFINITION OF STARTING MATERIAL

MARKS THE START OF THE MANUFACTURING PROCESS
DESCRIBED IN AN APPLICATION
Manufacturing steps before are not described
Manufacturing steps before need not be performed in
accordance with GMP
Changes in manufacturing steps before need not be reported
to WHO
EACH BRANCH OF A SYNTHESIS WILL BEGIN WITH ONE OR MORE
STARTING MATERIALS
31 |
API specifications
API not described in BP, Int.Ph., JP, Ph.Eur., or USP (non-compendial

APIs)
API described in BP, Int.Ph., JP, Ph.Eur.,

or USP (compendial APIs)
General note
An API has only one set of specifications applicable at release and
throughout the re-test period
an FPP may have two sets of specifications release and shelf-life
32 |
Specifications: Non-Compendial APIs
ICH Q6A (new APIs and products) for instance:
Requires justification for proposed specifications
Impurities to be characterised and limits set
synthesis and degradation according to ICH Q3A(R)

residual solvents according to ICH Q3C
Analytical methods with validation
Preparation and potency determination/specification of primary

and secondary (working) standards, with CoAs
Valid CoAs for at least 2 batches

33 |
Non-compendial APIs
Typical set of specifications
Appearance/description
Identification (at least one specific, e.g. IR spectrum)
Moisture content (or LOD: moisture + residual solvents)
Impurities
- Related organic substances (synthesis or degradation)
specified
unspecified and
total organic impurities
- Inorganic impurities, including catalysts
- Residual solvent(s)
Assay
Additional parameters important for specific API
34 |
such as particle size, polymorphic form, microbial limits
Specs: Compendial APIs
The current monograph always applicable

Additional critical specifications that are not included in monograph
e.g.
particle size & polymorphic form
synthesis related impurities resulting from specific process which may be
additional to monograph
residual solvents (specific to process)
Valid CoAs for at least 2 batches required

CEP normally states tests additional to the monograph
e.g. residual solvents & impurities
35 |
IMPURITIES
Extraneous contaminant (foreign substances)

Toxic impurities
Concomitant components
Signal impurities
36 |
Classes of Impurities
Organic
Inorganic
Residual solvents
37 |
Organic Impurities
May arise during manufacturing process and storage
Starting materials
By products
Intermediates
Degradation products
Reagents, ligands and catalysts
38 |
Inorganic Impurities
May be from manufacturing process and are normally
known and identified:
Reagents, ligands and catalysts

Heavy metals
Inorganic salts
other materials (e.g. filter aids, charcoal etc.)
39 |
Solvents
Organic or inorganic liquids used during the manufacturing

process
Toxicity generally known, therefore controls achievable
Limits to be based on pharmacopoeial standards or known

safety data
40 |
IMPURITIES
Identified impurity
Unidentified impurity
Specified impurity
Unspecified impurity
41 |
Impurity Thresholds
Identification threshold Limit above which, impurities found are to be identified
either structurally or by a qualitative parameter e.g. RT in HPLC system
Qualification threshold Limit above which, impurities found are to be
toxicologically qualified
Reporting threshold Limit from which, impurities should be analytically reported
Maximum Daily
Dose
Reporting
Threshold
Identification
Threshold
Qualification
Threshold
2g/day
0.05%
0.10% or 1mg per
0.15% or 1mg per
day intake (whichever is
day intake (whichever is
lower)
lower)
0.05%
0.05%
2g/day
42 |
0.03%
ICH Guidelines for Identification and Qualification of

impurities in bulk drugs and FPPs
43 |
IMPURITY EQUIVALENCE
To demonstrate that different sources of the API or routes of
synthesis are equivalent, checks on impurities are required to
show that
No new impurity is observed in the intermediate above 0.1%
No new impurity is observed in API above the qualification
threshold
Each existing impurity is within its stated limit
Total impurities are within the stated limit
44 |
IMPURITY EQUIVALENCE (2)

Each existing residual solvent is within its stated limit
New residual solvents, in either an intermediate or the

API, are at or below the levels recommended in the ICH
guide
45 |
IMPURITY EQUIVALENCE (3)

Ideally, impurities should be evaluated in isolated
intermediates immediately following the process step in
which they are produced
The impurity search can be extended to the next

downstream intermediate and the evaluation process
repeated until the final intermediate, even to the API
46 |
Potential impurities of Artemisinins

Starting material (extracted from herbal sources)
GuideGeneric:
Starting materials from vegetable origin should be fully characterized and
a contaminant profile should be established and submitted.
CPMP/QWP/297/97 Rev 1 corr:
In the case of substances isolated form herbal sources, the potential for
impurities arising from cultivation and/or preparation (e.g. pesticide
residues, fumigants, mycotoxins) should be addressed.
47 |
Potential impurities of Artemisinins II

Impurities contained in the starting material - Artemisinin
Biosynthetic by-products
Arteannuin B , Artemisitene, Artemisinic acid,
Extraction from fresh leaves with CHCl 3 within 1 min > 97%
Localisation in subcuticular space of the glands on the
surface of the leaves
Cultivation reagents
Pesticide residues, fumigants, mycotoxins
Solvents from the extraction process

Hexane, benzene, acetonitril, ether, pentane, chloroforme..(?) diesel, fuel
(?) [ICH Q3A (R)]
48 |
Potential impurities of Artemisinins III

Unreacted starting material
Artemisinin (starting material for derivatives)
Artemisinic acid (starting matrial for dihydroartemisinin)
Dihydroartemisinin (starting material for derivatives)
Unreacted intermediates, by-products
-Arthemether, -Artheether
/-Dihydroartemisinin
-Artesunate
49 |
Potential impurities of Artemisinins III cont.

Reagents, catalysts, residual solvents
Methanol, acetonitril, chloroforme, acetone
NaBH4, succinic acid/anhydride, triethylamine,
dimethylaminopyridine
Degradants
Stability of
ester-derivative (Artesunate)
ether-derivative (Artemether, Arteether)
lactone (Artemisinin)
Stability of artenimol (oxidation)
Susceptibility of endoperoxide bond to reduction
Deoxyartemisinine (loss of active principle!)
Zn / AcOH or FeBr2 / THF
50 |
Site(s) of manufacture
The quality of APIs is dependent on
Manufacturing site
Equipment, personal, technology
Route of synthesis, operational conditions, IPCs
Impurity profile, stability (API & FPP)
The quality of an API may consequently impact the quality of a FPP
Change in manufacturing site
Alternate API-manufacturers
Change in route of synthesis
Alternate API-manufacturers
51 |
Stability testing
Stress testing of API (forced degradation) helps
to identify the likely degradation products and pathways
to establish stability of the molecule
To verify specificity of stability assay method
e.g. Diode array detection for API peak purity !
Stability testing (regulatory) to provide evidence on

how the quality of an API varies with time
under the influence of a variety of environmental factors such as
temperature, humidity, and light; and
to establish a re-test period for the API and
to recommended storage conditions
52 |
Stress testing (forced degradation)

Typical conditions
The conditions should
Stress factor
Conditions (e.g.)
partially (e.g. 10-30%)

decompose the API to
primary degradation
products
Humidity
75% RH (solid)
Heat **
60C (solid)
Heat
water
Acid
0.1 M HCl
Conditions can be
changed to get required
degree of degradation
Base
0.1 M NaOH
Oxidative
3% H2O2
Photolytic
ICH Q1B
** Temperature should not

come closer than 10C
from melting point
Metal ions
(optional)
0.05 M Fe2+ or Cu2+
53 |
Stress testing (forced degradation)

Literature
Literature information and/or CEP
54 |
in support of and/or
to replace experimental data
Important Elements
The API must be of required structure & stereochemistry
The physical properties must be well understood, e.g.

hygroscopicity, crystal properties and solubility
The synthesis process must be according to GMP to

consistently produce an API of required chemical and physical
quality
limit impurities according to defined standards
55 |
Important Elements (2)
The set of specifications should
56 |
be based on validated analytical methods

with appropriate acceptance criteria
to which an API should conform to be considered acceptable for
its intended use throughout the retest period in the proposed
packaging

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Active pharmaceutical ingredients

Active Pharmaceutical Ingredients - Artemisinin based therapy

Active Pharmaceutical Ingredient (API)

A substance or compound that is intended to be used in

Active Pharmaceutical Ingredients - Artemisinin based therapy

Some definitions (2)

Polymorphism occurrence of different crystalline forms of the same

Degradation product molecule resulting from chemical change in

Active Pharmaceutical Ingredients - Artemisinin based therapy

Some definitions (3)

Impurity any component of the medicinal product which is not the

Identified Impurity an impurity for which structural characterisation

Unidentified degradation product an impurity defined only by

Active Pharmaceutical Ingredients - Artemisinin based therapy

Available information on API

Active Pharmaceutical Ingredients - Artemisinin based therapy

Literature information on API

Standard works / series / books such as:

(Analytical) Profiles of Drug Substances and Excipients [eds: Florey / Brittain

Journals through search facilities such as

International Pharmaceutical Abstracts, Chemical Abstracts, Analytical

Pharmacopoeial monographs (current)

Active Pharmaceutical Ingredients - Artemisinin based therapy

APIs which are organic compounds, have unique

Active Pharmaceutical Ingredients - Artemisinin based therapy

Active Pharmaceutical Ingredients - Artemisinin based therapy

Literature information used in the dossier should always be

Active Pharmaceutical Ingredients - Artemisinin based therapy

Active Pharmaceutical Ingredients - Artemisinin based therapy

Active Pharmaceutical Ingredients - Artemisinin based therapy

Properties relevant/critical for the performance of the API

Active Pharmaceutical Ingredients - Artemisinin based therapy

Properties: non-compendial APIs

Proof of structure/stereochemistry correctness

Active Pharmaceutical Ingredients - Artemisinin based therapy

Active Pharmaceutical Ingredients - Artemisinin based therapy

Properties: Compendial APIs

Physico-chemical and other relevant properties, e.g.

Active Pharmaceutical Ingredients - Artemisinin based therapy

Active Pharmaceutical Ingredients - Artemisinin based therapy

Malaria APIs: Table of occurrence

Active Pharmaceutical Ingredients - Artemisinin based therapy

Malaria APIs: Table of occurrence (con.)

Lumefantrine only malaria API without monograph

Active Pharmaceutical Ingredients - Artemisinin based therapy

- and -isomers are formed

Active Pharmaceutical Ingredients - Artemisinin based therapy

Specific optical rotation

144C, 143C, 142-146C

+2.5-+3.5, +4.5-+6.5, +11-+14

Active Pharmaceutical Ingredients - Artemisinin based therapy

API not described in BP, Int.Ph., JP,Ph.Eur., or USP (non-compendial APIs)

Examples of potentially critical steps

API described in BP, Int.Ph., JP, Ph.Eur.,

Active Pharmaceutical Ingredients - Artemisinin based therapy

Route(s) of synthesis (cont.)

Requirements: The synthesis should

lead to the correct structure, stereochemistry and crystal form

Active Pharmaceutical Ingredients - Artemisinin based therapy

The information required for the synthesis of the API may

Availability of a valid CEP - no synthesis information is then

Whether the quality of the is API controlled by a monograph in

No official monograph is available for quality control

Active Pharmaceutical Ingredients - Artemisinin based therapy