Pharmaceutical Quality

Information Form
(PQIF) - API

Guilin, January, 9 -13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

Abbreviations
API
ASMF
CHMP
CPMP
DMF
EDQM
FPP
ICH
OOS
PQIF
QWP

Active Pharmaceutical Ingredient

Active Substance Master File
Committee for Medicinal Products for Human Use
Committee for Proprietary Medicinal Products
Drug Master File
European Directorate for the Quality of Medicines
Finished Pharmaceutical Product
International Conference on Harmonization
Out Of Specification
Pharmaceutical Quality Information Form
Quality Working Party

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

Guidelines
Guideline on Submission of Documentation for Prequalification of MultiSource (Generic) Finished Pharmaceutical Products (FPPs) Used in the
Treatment of HIV / AIDS, Malaria and Tuberculosis [GuideGeneric]
Guideline on Active Substance Master File Procedure [CPMP/QWP/227/02
Rev 1]
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]
Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2. Active Pharmaceutical
Ingredient(s) [API(s)]
Presentation of information on the API

Full details as required according to Section 2 of the:

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]

Full details according to the Drug Master File (Active

Substance Master File) Procedure
Guideline on Active Substance Master File Procedure
[CPMP/QWP/227/02 Rev 1]

With or without certification (EDQM)

(applicable only to Ph. Eur. - APIs)

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2. Active Pharmaceutical
Ingredient(s) [API(s)] II
Advantages of the use of a DMF (ASMF)

Full details of chemistry, manufacturing

process, quality controls during manufacture
process validation, quality controls at batch
release and stability
Once the DMF (ASMF) is prequalified,
reference may be made to it in subsequent
applications
Conditions for the reference

Information on regular updates must be provided

Version number and date must be assigned

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

Deficiencies from prequalification

DMF (ASMF)

No version number and no date assigned

Deficiency letters from WHO/prequalification are not
addressed
Instead an update without reference to the deficiency list is
submitted

No tabular overview is provided to WHO outlining the

nature and the extent of the changes (updates)
compared to the previous version
Updates are not properly justified/explained
Change in the route of synthesis
Change in the last step of purificaton/crystallization

No transparency with the use of DMFs

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.2 Properties of API(s)

Categories of APIs

2.2.1 API not described in BP, PhInt, PhEur or USP

Considered new, used for the first time in a FPP
Risk estimation high
Full information necessary

2.2.2 API described in BP, PhInt, PhEur or USP

In use for a certain period of time
Information on safety and efficacy available
Risk estimation low(er)
Control by the monograph, additional information beyond the
scope of the monograph necessary

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.2 Properties of API(s) II

Categories of Antimalarials

APIs with existing monographs in major international

pharmacopoeias
Amodiaquine, Chloroquine (-phospate, -sulfate), Dapsone,
Quinine (-sulfate, -phosphate), Mefloquine,
Sulfadoxine/Pyrimethamine, Trimethoprim

APIs with existing monographs in major international

pharmacopoeias (recently)
Arthemether, Artemisinine, Artemotil, Artenimol
(Dihydroartemisinine), Artesunate,

APIs without existing monographs in major

international pharmacopoeias
Chlorproguanil, Lumefantrine, Naphthoquine, Piperaquine,
Pyronaridine

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.2 Properties of API(s) III

2.2.1 APIs not described in BP, PhInt,
PhEur or USP
a) evidence of chemical structure

spectral data
interpretation of data (narrative)

b) evidence of chemical structure

Isomerism
Stereochemistry
discussion of potential isomeric forms

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.2 Properties of API(s) III cont.

2.2.1 APIs not described in BP, PhInt, PhEur or
USP

Properties relevant/critical for the performance of the

API
c) potential polymorphic forms

physicochemical and physical characteristics (solubility,

hardness, compressibility, density, melting point, etc.) may
differ
polymorphism 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)

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.2 Properties of API(s) IV

2.2.1 APIs described in BP, PhInt, PhEur or USP
chemical structure elucidated [a) b)], control of structure by
suitable identification tests

Properties relevant/critical for the performance of the

API (not necessarily covered by the monograph)
a) potential polymorphic forms

physicochemical and physical characteristics (solubility,

hardness, compressibility, density, melting point, etc.) may
differ
polymorphism 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)

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.3 Site(s) of manufacture

Each API-manufacturer to be listed

Information on the quality of the API must be

clearly linked to the respective manufacturing
site (synthesis, production)
Name
Street address
Phone, Fax, Email

If applicable
referenced DMFs
letters of access

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

Deficiencies from prequalification

Quality of API missing

Detailed quality description on the API provided by
one manufacturer, alternative manufacturers are
named without presentation of information on the
API

API-manufacturer and quality of API missing

Alternative API-manufacturers are not listed, but
are revealed from the FPP-part of the dossier

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis

2.4.1 API not described in BP, PhInt, PhEur or USP

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

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

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis II

2.4.1 API not described in BP, PhInt,
PhEur or USP

Process Validation and/or Evaluation

All steps that are identified as critical for the API to
be validated
All steps covering aseptic processing or
sterilization to be validated

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis III

2.4.1 API not described in BP, PhInt,
PhEur or USP

Manufacturing process development

Description and discussion of any change to the
manufacturing process and/or manufacturing site
in developmental order:

Clinical
Comparative
Stability
Scaleup
Pilot
Production

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis IV

2.4.1 API not described in BP, PhInt, PhEur or
USP

Impurities
Identification of potential and actual impurities arising from
synthesis, manufacture and/or degradation

Potential sources of origin in sequential order

impurities contained in the starting material
starting material unreacted
intermediates unreacted
by-products (unwanted reaction products)
reagents
catalysts
residual solvents
degradants
Elucidation of origin may help to minimize impurities

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis V

Potential impurities of Artemisinines

Starting material (extracted from herbal

sources)
GuideGeneric:

Starting materials from vegetable origin should be fully

charcterized 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.

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis VI

Potential impurities of Artemisinines

Subsequent chemical reactions

Application of the scheme provided in
PQIF 2.4.1, a) Impurities

Critical process steps to be controlled

Stereochemistry of the hydration step

- stereoselective control method?
Derivatisation/Ether-/Esterification (stereoselectivity?)
Artemether, Artesunate, Artemotil
- stereoselective purification procedure?
- stability of the - ether versus -ester
Transformation Artenimol>>>Artemisinine?

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis VII

2.4.1 API not described in BP, PhInt, PhEur or
USP

Setting the acceptance criteria for impurities

Maximum daily dose (total daily intake)
ICH thresholds for drug-related impurities
Concentration limits for process related impurities

Residual solvents
Heavy metals

Available safety and toxicity data

Documented impurity levels according to the scheme provided

Reference to the analytical procedures used

Specificity, sensitivity

Justification of proposed acceptance criteria

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis VIII

2.4.1 API not described in BP, PhInt, PhEur or
USP

Setting the acceptance criteria for impurities

ICH thresholds for drug related impurities [ICH Q3A (R)]
Maximum Reporting Identification Qualification
Daily Dose Threshold Threshold
Threshold
2g/day
2g/day

Guilin, January, 9 13, 2006

0.05%
0.03%

0.10% or 1mg

0.15% or 1mg

per day intake

(whichever is lower)

per day intake

(whichever is lower)

0.05%

0.05%

Dr. Birgit Schmauser, BfArM, Bonn

Deficiencies from prequalification

Methods to assess impurities are not sensitive
enough to assess impurities

Quantitation limit (1%) far above the identification and

qualification threshold
(0.05 0.15%)

Listing of impurities limited to those actually

detected

Potential impurities are not discussed

Impurity levels are far above the qualification

limit without justification
Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis IX

2.4.2 Specifications of raw materials and
intermediates used in the synthesis

Quality and controls of materials coming into the

process
Starting materials
Raw materials
Intermediates
Reagents
Catalysts
Solvents

Specifications

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis X

2.4.2 Specifications of raw materials and
intermediates used in the synthesis

Particularly addressing the TSE-safety of all

materials coming into the process
Proof of safety by relevant data

CEP
Letter of attestation

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.4 Route(s) of synthesis XI

2.4.3 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

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications
2.5.1 API not described in BP, PhInt, PhEur or
USP

Presentation of the API-specification

Standard claimed

(e.g. in-house, BP,

PhInt, PhEur, USP

Reference or version

number

Specific test parameter

Analytical procedure
used

Acceptance criteria

Any test that is not performed on a batch to batch-basis must

be indicated (periodic testing or skip testing)

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications II
2.5.1 API not described in BP, PhInt, PhEur or
USP

Skip testing
ICH Q6A

performance of specified tests at release on pre-selected

batches and/or predetermined intervals, rather than on a batchto-batch basis with the understanding that those batches not
being tested must still meet all acceptance criteria established
for that product.
As this represents less than full testing it should be justified.
Any failure to meet acceptance criteria established for the
periodic test should be handled by proper notification (inform
WHO immediately). If the data demonstrate a need to restore
routine testing, batch-by-batch release testing should be
reinstated.

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications III

2.5.1 API not described in BP, PhInt, PhEur or
USP

Skip testing
ICH Q6A

The concept may be applicable to, f.ex., residual solvents and

microbiological testing, for solid oral dosage forms.
Since only limited data may be available at the time of
submission, the concept should generally be implemented postapproval ( post prequalification)

GuideGeneric

Where testing for possible impurities is omitted, particular

attention must be given to its justification
f. ex. particular method of production
f.ex. impuritiy has never been detected

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications IV
2.5.1 API not described in BP, PhInt, PhEur or USP

Batch analyses
Description of the batches
Batch
number

Batch size

Date and site

of production

Use (e.g.
clinical,
comparative

Results of the batches

Certificates of Analysis

Discussion of the results with respect to the use of the batch

Clinical, Comparative etc.

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications V
2.5.1 API not described in BP, PhInt,
PhEur or USP

Justification of Specifications
Evolution of tests
Evolution of analytical procedures
Evolution of acceptance criteria
Differences from compendial standards

f.ex. assay and impurities, heavy metals, residue on

ignition

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5. Specifications VI
2.5.1 API not described in BP, PhInt, PhEur or USP

Justification of Specifications
ICH Q6A

Justification for each procedure and each acceptance criterion with

reference to
relevant development data
pharmacopoeial standards
Test data for batches used in toxicology and clinical studies
Results from accelerated and long term studies
Reasonable range of analytical and manufacturing variability
Alternate justified approaches

Actual results obtained should form the primary basis for any
justification

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications VII

2.5.1 API not described in BP, PhInt, PhEur or
USP

Reference standards or materials

ICH Q2B

Reference standards/materials should be well characterized

with documented purity

Source

Official pharmacopoeial standards

In-house standards

Characterization and evaluation of non-official standards

Method of manufacture
Elucidation of structure
Certificate of analysis
Calibration against an official standard (if available)

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications VIII

2.5.1 API not described in BP, PhInt, PhEur or USP

Reference standards or materials (in-house)

Primary (absolute) standard

Documented purity (with purification procedure)

Assay by two independent procedures, one of which must be specific
Mass balance must be achieved
Assay value and all impurities found must amount to 100%
(relative to the analytical procedure)
All further impurities (residue on ignition/inorganic substances, loss on
drying etc.) must be considered to determine the absolute assay value

Secondary (working) standard

Documented purity with reference to the primary (absolute) standard

Intervals of control of content and duration of use

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications IX
2.5.1 API not described in BP, PhInt, PhEur or USP

Validation of analytical procedures

Stability indicating potential

Any in-house analytical procedure needs to be validated

ICH Q2A, ICH Q2B

Assay and impurities

Stress testing provides degradants that may occur during storage

Isolation of impurities and (stable) degradants in the development

phase
In situ generation of potential degradants

Validation of analytical procedures for assay and

impurities/degradants

Spiking experiments with isolated degradants/impurities

In situ use of stressed samples
Peak purity analysis of API-peaks

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications X
2.5.2 API described in BP, PhInt, PhEur or USP

Name the monograph

Name any test methods referenced in the monograph but not
appearing in it

List of tests beyond the scope of the monograph

Residuals, particle size, polymorphs, loss on drying

Generic guide:
Whenever an API has been prepared by a method liable to
leave impurities not controlled in the pharmacopoeial
monograph, these impurities (based on 3 to 10 batch
analysis results) including residual organic solvents, as well
as their maximum tolerance limits should be declared and
controlled by a suitable test procedure.

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

Specifications XI
2.5.2 API described in BP, PhInt, PhEur or
USP

Additional requirements
Generic guide:

The quality of the API should meet not only the

requirements of specific monographs but also those
described in the general monographs of a
pharmacopoeia on APIs, excipients and other substance
for pharmaceutical use.
f. ex. Substances for pharmaceutical use (PhEur)
f. ex. Control of impurities for substances for
pharmaceutical use (PhEur)

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.5 Specifications XII

2.5.2 API described in BP, PhInt, PhEur or USP

Validation of analytical methods

Pharmacopoeial methods are considered validated, however,
there is common understanding that certain parameters need
to be adapted:

New chapter USP <1226> Verification of analytical procedures

Pharmacopoeial Forum 31, No. 2, March/April 2005
System suitability test
PhEur 2.2.46
Insufficient Precision (RSD=s) leads to OOS results
3 x s 2% (assay specification)

Validation with respect to the stability indicating

nature of the methods
For impurities/degradants not covered by the monograph
If the pharmacopoeial method is modified

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

Deficiencies from prequalification

Pharmacopoeial acceptance criteria are not considered
for APIs described in the pharmacopoeia

API cannot be adequately controlled by wider ranges

Acceptance ranges of test parameters are much wider

than actual test results.

Acceptance ranges do not control the quality of the API

Only one type of Reference standard is provided and

simply represents API from a normal batch.
In-house absolute reference standards are not validated
against available official standards.
Pharmacopoeial methods are modified but impurity
profile is not adapted.

f.ex. Impurity A (in-house method) is different from Impurity A

(pharmacopoeial method)

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.6 Container closure system

Description of the container closure system
(for storage and shipment of the API)

Primary packaging material

Identity of materials of construction of each primary
packaging component
Reference to specification for each packaging component

Description
Identification
Drawings of critical dimensions

Secondary packaging material

Non-functional (briefly)
Functional

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.6 Container closure system II

Discussion of the suitability of the
container closure system

Choice of material
Function of material
f.ex. protection

Moisture, light, oxygen

Safety of material
Compatibility with API
Sorption
Leaching

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn

2.6 Container closure system III

Artemisinines

Storage conditions PhInt:

Should be kept in a well closed container,
protected from light and kept in a cool place

Discussion of the suitability of the container

closure system with respect to:
Protection from light

f.ex. types/colour of inner and outer bags/drums

Protection from oxygen and moisture (well-closed)

f.ex. type of inner/outer container

f.ex. use of seals, joints, gaskets

Guilin, January, 9 13, 2006

Dr. Birgit Schmauser, BfArM, Bonn