QUALITY MANAGEMENT OF
ANTIMALARIAL MEDICINES
Experience in prequalification of
antimalarial medicines (product dossier
assessment)
János Pogány, Ph.D., WHO consultant
Bangkok, 19 October 2004
E-mail: pogany@axelero.hu
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ABBREVIATIONS and NOTES
API
Active pharmaceutical ingredient
BP
British Pharmacopoeia
EOI
Expression of interest
FDC(s)
fixed-dose combination(s)
FPP(s)
Finished pharmaceutical product(s)
Ph.Eur.European Pharmacopoeia
Ph.Int.
International Pharmacopoeia
USP
United States Pharmacopeia
Text in green refers to WHO documents or requirements
Text in light blue indicates a quality assessment issue
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SUBJECTS FOR DISCUSSION
1.
2.
3.
4.
5.
Interchangeability of FPPs
Artemisinin-based antimalarials
Requirements for submission of pharmaceutical data
Main gaps observed in the evaluation of dossiers

Regulatory aspects

Correspondence with FPP manufacturers
A few conclusions
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INTERCHANGEABILITY
OF FPPs
Pharmaceutical
equivalence
INTERCHANGEABILITY (IC)
INTERCHANGEABILITY OF
MULTISOURCE FPPs (IC) = (ESSENTIAL
SIMILARITY WITH INNOVATOR) =
PHARMACEUTICAL EQUIVALENCE (PE) +
BIOEQUIVALENCE (BE)
IC = PE + BE
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PHARMACEUTICAL EQUIVALENCE

FPPs MEET SAME OR COMPARABLE
STANDARDS




SAME API (chemical and physical equivalence)
SAME DOSAGE FORM AND ROUTE OF
ADMINISTRATION
SAME STRENGTH
COMPARABLE LABELING

WHO-GMP (batch-to-batch uniformity of quality)
 STABILITY EQUIVALENCE
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FACTORS INFLUENCING PE
INACTIVE
INGREDIENTS
Manufacturin
g
authorization
ACTIVE
INGREDIENTS
GMP
standards
FPP
MANUFACTURER
Marketing
authorization
Pharmacopeia
standards
NATIONAL
DRA1
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PACKING
MATERIALS
NATIONAL
DRA2
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ARTEMISININ-BASED FPPs
EXPRESSION OF INTEREST
(March 2003)
ARTEMISININ-BASED FPPs





Artemether, oral preparations
Artemether, intramuscular preparations
Artemether + lumefantrine, oral
preparations
Artemotil, injectable forms
Artenimol (dihydroartemisinin) tablets,
capsules, paediatric granules, suppositories
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ARTEMISININ-BASED FPPs





Artesunate injection for IV and IM
Artesunate, oral preparations
Artesunate + amodiaquine, oral preparations
Artesunate + mefloquine, oral preparations
Artesunate + sulphadoxine/pyrimethamine
(SP), oral preparations
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PREQUALIFICATION
PROJECT OF WHO
Requirements for submission
of pharmaceutical data
PREQUALIFICATION GUIDES
1.
1.
2.
3.
http://www.who.int/medicines/library/qsm/
manual-on-marketing/who-dmp-rgs-985.doc
http://www.who.int/medicines/organization/qsm
/activities/qualityassurance/gmp/gmpcover.html
WHO/HTP/EDM/QSM/2001: Standard
Operating Procedure: Assessing Product Files
International Conference on Harmonization
(ICH) guidelines
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WHO-GMP General Considerations

Licensed pharmaceutical products
(marketing authorization) should be
manufactured only by licensed
manufacturers (holders of a manufacturing
authorization) whose activities are regularly
inspected by competent national authorities.
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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
SOP 020/00 - Assessing Product Files
8.4 Addendum D – Product
Assessment Report – Generic FPPs
SCOPE OF THE GUIDELINE

This guideline applies only to APIs
manufactured by chemical synthesis or semisynthetic processes and to FPPs containing
such APIs.

APIs manufactured by fermentation and cell culture processes should
comply with the general requirements and specific monographs of the
Ph.Eur..or the USP. Corresponding FPPs should be assessed by the
monographs of the BP or the USP; for non-compendial APIs and FPPs, the
ICH-Q6B guide “Specifications: Test Procedures and Acceptance Criteria
for Biotechnological/Biological Products” should be used.
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Section 1. CHARACTERISTICS OF THE FPP
1.1 Details of the product
1.1.1 Name, dosage form and strength of the product
1.1.2 Approved generic name(s) [use International Nonproprietary Name (INN), if any]
1.1.3 Visual description of the FPP
1.1.4 Visual description of the packaging
1.2 Sample
1.3 Regulatory situation in other countries
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Section 2.
API quality issues
Illustrative examples of
requirements
APIs UNDER DISCUSSION
NON-COMPENDIAL APIs
Lumefantrine
Sulfamethoxypyrazine
INTERNATIONAL PHARMACOPOEIA
Artemether
Artemotil
Artesunate
Proguanil HCl
Artemisinin
Artenimol
Mefloquine hydrochloride
INTERNATIONALLY USED PHARMACOPOEIAE
Amodiaquine HCl (USP)
Proguanil HCl (BP)
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Pyrimethamine (Ph.Eur., USP)
Sulfadoxine (Ph.Eur.)
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LOW-RISK APIs
1.
CERTIFICATE OF SUITABILITY (DRA)
2.
DRUG MASTER FILE


3.
PHARMACOPEIA MONOGRAPH



4.
OPEN PART (APPLICANT)
CLOSED PART (DRA)
LITERATURE EVIDENCE OF STABILITY
SYNTHESIS IMPURITIES ARE CONTROLLED BY
MONOGRAPH (toxicology of additional impurities)
CLASS1 SOLVENTS EXCLUDED, CLASS2 SOLVENTS
CONTROLLED
FPP IS REGISTERED IN THE ICH REGION
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HIGH-RISK, ARTEMISININ-BASED APIs


NO INNOVATOR API/FPP IN THE ICH REGION.
NO REFERENCE STANDARD/COMPARATOR IS
AVAILABLE FOR:


PHARMACEUTICAL EQUIVALENCE STUDIES
BIOEQUIVALENCE STUDIES

THE APIs and FPPs ARE NOT OFFICIAL IN THE
INTERNATIONALLY USED MAJOR PHARMACOPOEIAS

WHO GUIDES/SOPs APPLY TO MULTISOURCE FPPs.
ICH GUIDES SHOULD BE USED FOR EVALUATION.
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Section 2. APIs
2.1 Nomenclature
2.1.1 International Nonproprietary Name (INN)
2.1.2 Compendial name if relevant
2.1.3 Chemical name(s)
2.1.4 Company or laboratory code, if applicable
2.1.5 Other non-proprietary name(s), e.g., national name,
United States Adopted Name (USAN), Japanese
Accepted Name (JAN); British Approved Name (BAN)
2.1.6 Chemical Abstracts Service (CAS) registry number
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CHEMICAL NAME(s)

ARTESUNATE
(3R,5aS,6R,8aS,9R,10S,12R,12aR)-Decahydro3,6,9-trimethyl-3,12-epoxy-12H-pyrano[4,3-j]1,2benzodioxepin-10-ol, hydrogen succinate;
therefore eight (8) stereogenic centres exist, or
128 pairs of enantiomers and 256 diastereoisomers are possible. Only one used in therapy.
 CAS Reg. No: 88495-63-0
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Section 2. APIs
2.2 Properties of API(s)
2.2.1 API not described in BP, Int.Ph., JP,
Ph.Eur., or USP
2.2.2 API described in BP, Int.Ph., JP, Ph.Eur., or
USP
2.2.3 Information from literature.
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NON-COMPENDIAL APIs
No reference standard/spectrum. Documented
evidence of structure and stereochemistry -such
as clearly visible, quality assurance (QA)-certified
copies of infrared, nuclear magnetic resonance
(proton and C-13), ultraviolet and mass spectrashould be submitted together with professional
interpretation of the relevant parts of spectra, Xray diffractograms, thermograms, and so on.
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(NON)-COMPENDIAL API(s)
No/insufficient information from pharmacopoeia
and manuals. Physicochemical and other relevant
properties of the API, such as solubility in water,
other solvents and buffers of different pH; partition
coefficient; existence/absence of polymorphs and
water/solvent of crystallization; results of
hygroscopicity testing; particle size and so on.
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Section 2. APIs
2.3 Site(s) of manufacture
2.4 Route(s) of synthesis
2.4.1 API not described in BP, Int.Ph., JP,
Ph.Eur., or USP
2.4.2 API described in BP, Int.Ph., JP, Ph.Eur.,
or USP
2.4.3 Specifications of starting materials and
intermediates used in the synthesis
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COMPENDIAL API(s)
The official monograph of an API in a
pharmacopoeia does not necessarily control
the quality of the API. Impurities, including
residual solvents, depend on the synthesis
route (steps, conditions, catalysts, byproducts, batch size, process control, etc.)
and this may differ from manufacturer to
manufacturer.
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2.4 ROUTE(S) OF SYNTHESIS

European certificate of suitability (CEP) together
with annexes.
 Flow diagram of the synthetic process(es) that
includes batch size, molecular formulae, chemical
structures; description of operating conditions,
purification steps, catalysts and solvents.
 Sequential procedural narrative of the
manufacturing process with detailed description of
purification and crystallization.
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ARTESUNATE SYNTHESIS – Step 1
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ARTESUNATE SYNTHESIS – Step 2
Dihydroartemisinine
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Section 2. APIs
2.5 Specifications
2.5.1 API not described in BP, Int.Ph., JP, Ph.Eur.,
or USP
2.5.2 API described in BP, Int.Ph., JP, Ph.Eur., or
USP
2.6 Container closure system
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CHEMICAL EQUIVALENCE
 OFFICIAL COMPENDIA
 BATCH-TO-BATCH UNIFORMITY




IMPURITY PROFILE
RESIDUAL SOLVENTS
ASSAY
PHYSICOCHEMICAL PROPERTIES
 GMP and STABILITY EQUIVALENCE
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IMPURITIES
Concept of impurities has changed with time and
the development of analytical methods.

IDENTIFIED IMPURITY

UNIDENTIFIED IMPURITY

SPECIFIED IMPURITY

UNSPECIFIED IMPURITY
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IMPURITY EQUIVALENCE

NO NEW IMPURITY IS OBSERVED IN THE
KEY 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
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POTENTIAL SYNTHESIS IMPURITIES OF
ARTESUNATE
STARTING MATERIALS and REACTANTS
 Potential impurities of artemisinin (pesticides)
 Unreacted artemisinin
 Unreacted artenimol (dihydroartemisinin), mixture
of α- and β-epimers
 Unreacted succinic acid
(POTENTIAL) BY-PRODUCTS
 Deoxy-artemisin
 Dimers of artesunate
 β-Artesunate
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RESIDUAL SOLVENTS

EACH EXISTING RESIDUAL SOLVENT (methanol,
methylene chloride and heptane) 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
 SKIP TESTING IS PERMITTED IF DOCUMENTED
EVIDENCE HAS BEEN PROVIDED ON ABSENCE OF
NOT LESS THAN ??? BATCHES
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ASSAY BY TITRATION
During stability studies, the assay was increasing.
The hydrolysis may yield artenimol and succinic
acid. The latter can justify the increase in assay.
+
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Artesunate – identification, impurities and
assay
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CRITICAL DEFICIENCIES

Synthesis impurities, including residual solvents,
which may be present in API, have not been
characterised and analysed.
 Analytical validation information -including
experimental data for the analytical procedures
used for testing the API and impurities- have not
been provided.
 The preparation and quality specification of
primary (absolute) and secondary (working)
standards has not been described.
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Section 2. APIs
2.7 Stability testing
2.7.1 Stress testing (forced degradation)
2.7.2 Regulatory stability testing
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FORCED DEGRADATION STUDIES
1.
Intrinsic stability of the molecule (sensitivity of the
API to potential effects of the external environment –
selection of containers)
2.
Identification of likely degradants
Stability-indicating power of assay method
 Stability studies of the FPP

3.
4.
No standard method, 10-30% degradation, stress
factors, conditions and time
Solid state degradation (supporting information)
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REGULATORY STABILITY TESTING
1.
2.
3.
4.
It is not necessary to examine specifically for
certain degradation products if it has been
demonstrated that they are not formed at 50-60 oC
under moderate stress conditions.
Photostability (ICH Q1B, non-compendial APIs)
Stability protocol, report with professional
evaluation of data is required.
A re-test period should be derived from the
stability information, and the approved retest date
should be displayed on the container label.
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DATA OF STABILITY BATCHES
Batch numbers
Date of manufacture
Site of manufacture
Batch size (kg)
Date of initial analysis
The batches should be representative of the manufacturing process and should
be manufactured from different batches of key intermediates.
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TEST PARAMETERS

CHEMICAL CHARACTERISTICS (ASSAY
AND IMPURITIES INCLUDING
DEGRADANTS)
 PHYSICAL CHARACTERISTICS
(PHOTOSTABILITY, APPEARANCE AND
WATER)
 MICROBIOLOGICAL ATTRIBUTES
(STERILE APIS AS A RULE)
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GENERAL CONDITIONS

REAL TIME
25 ± 2oC and 60 ± 5 % RH, 12 months
 INTERMEDIATE
30 ± 2oC 65 ± 5% RH, 6-12 months
 ACCELERATED
40o ± 2oC 75 ± 5% RH, 3-6 months
(There may be justified exceptions with
grandfathered drugs.)
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OBJECTIVE: RETEST PERIOD
Regulatory stability studies provide documented
evidence that an API remains within specification
during the re-test period if stored in the original
container under prescribed conditions.
An API is considered as stable if it is within the
defined/regulatory specifications when stored at 30
± 2 oC / 65 ± 5 % RH for 2 years and at 40 ± 2 oC /
75 ± 5 % RH for 6 months.
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STABILITY and LABELING
NOTE FOR GUIDANCE ON
DECLARATION OF STORAGE
CONDITIONS IN THE PRODUCT
PARTICULARS. (LABELING OF
PRODUCTS SENSITIVE TO
TEMPERATURE, LIGHT AND HUMIDITY).
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FPP quality issues
Illustrative examples of
requirements
Part 3. FPP(s)
3.1 Manufacturing and marketing
authorization
3.2 Pharmaceutical development
3.2.1 Company research and development
3.2.2 Information from literature
3.3 Formulation
3.4 Sites of manufacture
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MARKETING AUTHORIZATION


If the FPP has been locally developed and
manufactured, the national drug regulatory
authority (NDRA) must evaluate the data set
itself (p. 23).
If an evaluation report —critical summary and
interpretation of the data, with conclusions— is
not available, it is not possible to seek a WHOtype certificate (p. 23).
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Part 3. FPP(s)
3.5 Manufacturing process
3.6 Manufacturing Process Controls of
Critical Steps and Intermediates
3.7 Process Validation and Evaluation
3.7.1 New generic FPPs
3.7.2 Established generic FPPs
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CONCURRENT VALIDATION
NEW GENERIC FPPs

Full validation studies should be completed for
each FPP at the production scale.
 Short description of the process with a summary
of the critical processing steps or critical
parameters to be monitored during validation.
 FPP specification (release) including IPC
acceptance criteria should be derived from
validation batches
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RETROSPECTIVE VALIDATION
ESTABLISHED GENERIC FPPs
Annual quality review data and analysis
were not submitted to prove that the
manufacturing processes —including
equipment, buildings, personnel and
materials— are capable of achieving the
intended results on a consistent
and continuous basis.
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Part 3. FPP(s)
3.8 Specifications for excipients
3.8.1 Excipients not described in Int.Ph., JP, BP, Ph.Eur., or USP
3.8.2 Excipients described in Int.Ph., JP, BP, Ph.Eur., or USP
3.9 Control of the FPP
3.9.1 Specifications for the FPP
3.9.2 Analytical procedures
3.9.3 Validation of analytical procedures
3.9.4 Batch analyses
3.10 Container/closure system(s) and other packaging
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SPECIFICATIONS FOR THE FPP





The maximum acceptable deviation in the API
content of the FPP shall not exceed ±5% of the
label claim at batch release.
Degradation products, synthesis impurities
(typically not applicable) and residual solvents
(rarely applicable).
Dissolution against disintegration time.
All analytical methods should be validated or
verified (compendial methods).
Microbiological purity (skip testing)
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Part 3. FPP(s)
3.11
Stability testing
3.11.1
3.11.2
3.11.3
3.11.4
3.11.5
3.11.6
3.11.7
3.11.8
2.11.9
2.11.10
2.11.11
2.11.12
Stability-indicating quality parameters
Photostability Testing
Selection of Batches
Container Closure System
Testing Frequency
Storage Conditions
General case
Finished products packaged in impermeable containers
Finished products packaged in semi-permeable containers
Evaluation
Extrapolation of data
Core Storage Statements
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STABILITY OF FPPs

Characteristics studied should be those in the FPP
specification that are likely to be affected by
storage and/or not monitored routinely at the time
of manufacture.
 Whether and to what extent replication should be
performed will depend on the results of validation
studies.
 It may be appropriate to have justifiable differences
between the shelf life and release acceptance
criteria based on the stability evaluation and the
changes observed on storage.
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DATA OF STABILITY BATCHES
Batch number
Date of manufacture
Site of manufacture
Batch size (kg)
Batch size (number of units)
Date of initial analysis
Batch number of the (API)
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STABILITY OF FPPs

A systematic approach should be adopted in the
presentation and evaluation of the stability
information.
 Organize data for all attributes separately and
evaluate each attribute in the report.
 Shelf life acceptance criteria should be derived
from consideration of all available stability
information.
 Unless otherwise justified, 30°C ± 2°C / 65% ±
5% RH is the preferred real-time condition for the
prequalification project.
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EVALUATION OF STABILITY DATA
– BEST CASE
Tabulate and plot stability data on all
attributes at all storage conditions and
evaluate each attribute separately.
2. No significant change at accelerated
conditions within six (6) months.
3. Long-term data show little or no variability
and little or no change over time.
1.
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EVALUATION OF STABILITY DATA
– BEST CASE
Long-term data show little or no variability
and little or no change over time.
5. Statistical analysis is normally unnecessary.
6. Proposed retest period = period covered by
long-tem data + 12 months
4.
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Part 3. FPP(s)
3.12 Container labelling
3.12.1 Outer packaging or, where there is no outer
packaging, on the immediate packaging
3.12.2 Blisters and strips
3.13 Product information for health professionals
3.14 Patient information and package leaflet
3.15 Justification for any differences to the product
in the country or countries issuing the
submitted WHO-type certificate(s).
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WHOPAR

Propose a copy of the Summary of Product
Characteristics (SmPC) aimed at medical
practitioners and other health professionals and
preferably approved by the competent authority at
the time of licensing. The SmPC is an essential part
of pre-qualification and it can only be changed with
the consent of WHO.
 Provide copies of all package inserts distributed to
the patients. The package leaflet should be in
conformity with the SmPC. It should be written in
English, should be legible and comprehensible.
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Main gaps observed in the
evaluation of dossiers
Regulatory aspects and
correspondence with
manufacturers
GLOBAL REGULATORY ISSUES
API or FPP originate „LEGALLY” from countries
where:


Manufacture of APIs is not
regulated
Pharmaceutical exports and
imports are not regulated
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GLOBAL REGULATORY ISSUES

National requirements for MA do not meet WHO
requirements. E.g., stability and biostudies
are/were not required
 MA of FPPs is issued without evaluation by the
national drug regulatory authority (NDRA)

Certificate of Pharmaceutical Product (CPP) is
issued by the NDRA without assessment of the
FPP quality.
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CORRESPONDENCE WITH MANUFACTURERS
Impurities: “Further efforts are made to improve the
process.”
 Individual impurity limits were not based on batch
analysis results and they were not in line with the ICH
guidelines (e.g., NMT 1.0% instead of NMT 0.1%).
 Residual solvents were included in the monograph but
not in the DMF.
 Class2 solvents: pyridine and chloroform are used in
the synthesis and not tested in the API.

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CORRESPONDENCE WITH MANUFACTURERS
The melting point is 143-145oC (p.4) as opposed
to 131-134oC ± 1.5oC in the DMF.
 No adequate information was provided on the
preparation and quality specification of primary
(absolute) and secondary (working) standards.
(For instance, lack of complete CoA, assay by
two different validated methods, detailed
information on storage, etc.).

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CORRESPONDENCE WITH MANUFACTURERS

FPP - HPLC method is described as an alternative
assay to titration but acceptance limits are 97103% as opposed to 98-102% in the DMF.
 FPP - Analysis of the tests for microbiological
purity on „two (2) batches showed contamination
with an invading yeast.”
 Stress stability (forced degradation) tests on the
API were not submitted.
 Substantial degradation was observed at high
temperature and under intensive light.
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CORRESPONDENCE WITH MANUFACTURERS
“Room temperature and accelerated tests are in
progress.” Results were not submitted.
 The stress data on FPP show that the blister pack
does not protect the tablets even if overwrapped
by additional protective packing. Supplier
reduced expiry date.
 The currently available stability data reveal
possible decomposition and justify only a one (1)
year re-test date.

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A FEW CONCLUSIONS
1.
2.
Artemisinin-derived FPPs had been on the market
for decades but most of them did not meet basic
standards of quality at the beginning of the project.
It takes time to get into compliance



3.
4.
Develop new formulations
Data to be generated, tests carried out
GMP upgrade needed
One FPP is prequalified from a DC; another one is
registered in the ICH region.
Evaluation of dossiers is still free of charge.
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