API assessment: Critical issues

Isabel Ortega Diego

WHO Prequalification Team - Medicines

3.2.S.3.2 Impurities,
1 Malaysia, 29 September 2011
1 PQT Medicines Quality Assessment Training 25-28 May 2015
1|
 API quality information in a dossier

API information from the API information from the

API manufacturer: FPP manufacturer:

How the API is prepared How the API is controlled

and controlled by the API (retested) by the FPP
manufacturer. manufacturer, including
parameters that influence
the FPP performance.

PQT Medicines Quality Assessment Training 25-28 May 2015

2|
 API information in PQ dossiers

There are different options that can be used by applicants to

submit API information in a dossier to PQ.
• Use of a prequalified API (Certificate of PQ API= CPQ)
• Use of a European Certificate of Suitability (CEP)
• Use of a DMF/APIMF (open and restricted parts)
• Provision of full API information in the product dossier.

The use of these 4 options is described in our Quality Generic

Guideline
([Link]

PQT Medicines Quality Assessment Training 25-28 May 2015

3|
 API information in PQ dossiers

Regardless of the option chosen the same quality standard is

required for the API.

This is also regardless of whether the API is pharmacopoeial

or not.

The only difference is that for CEPs, the majority of the

assessment is done by EDQM.

The API information assessed within PQ is compiled in the

Common Technical Document format (CTD)

PQT Medicines Quality Assessment Training 25-28 May 2015

4|
 API Information-CTD Module 3
Section 3.2.S
3.2.S.1. General information
3.2.S.1.1. Nomenclature
3.2.S.1.2. Chemical structure
3.2.S.1.3. General properties
3.2.S.2. Manufacture
3.2.S.2.1. Manufacturer(s)
3.2.S.2.2. Description of Manufacturing Process and Process Controls
3.2.S.2.3. Control of Materials
3.2.S.2.4. Controls of Critical Steps and Intermediates
3.2.S.2.5. Process Validation and/or Evaluation
3.2.S.2.6. Manufacturing Process Development
3.2.S.3. Characterization
3.2.S.3.1. Elucidation of Structure and other Characteristics
3.2.S.3.2. Impurities
3.2.S.4. Control of the API
3.2.S.4.1. Specification
3.2.S.4.2. Analytical Procedures
3.2.S.4.3. Validation of Analytical Procedures
3.2.S.4.4. Batch Analyses
3.2.S.4.5. Justification of Specification
3.2.S.5. Reference standards or Materials
3.2.S.6. Container closure system
3.2.S.7. Stability testing
3.2.S.7.1. Stability Summary and Conclusions
3.2.S.7.2. Post-approval Stability Protocol and Stability Commitment
3.2.S.7.3. Stability Data

PQT Medicines Quality Assessment Training 25-28 May 2015

5|
 What API information do you get?

A CEP
What do these mean?

A CPQ

A complete DMF (open + restricted parts)

What are the critical
aspects?
Full API dossier

The complete open part of the DMF

Can the API be fully
assessed?
Other…

PQT Medicines Quality Assessment Training 25-28 May 2015

6|
 In this presentation

1) API critical issues: what is important for APIs?

2) Procedures to submit API information in the dossier

(CEP, CPQ, DMF)

PQT Medicines Quality Assessment Training 25-28 May 2015

7|
 What is important for APIs?

1. What is the API?

2. Who makes the API?

3. How is the API prepared?

4. How is the API controlled?

5. Can a retest period and recommended storage conditions

be established for the API?

PQT Medicines Quality Assessment Training 25-28 May 2015

8|
 What is important for APIs?

1. What is the API?

2. Who makes the API?

3. How is the API prepared?

4. How is the API controlled?

5. Can a retest period and recommended storage conditions

be established for the API?

PQT Medicines Quality Assessment Training 25-28 May 2015

9|
 What is the API?

Chemical form – simple, complex?

Origin- synthetic, semi-synthetic, fermentation, herbal
origin

Chirality - one or more chiral centres?

Acid, base, salt, hydration state

Crystalline or amorphous form

Physicochemical properties – polymorphism, particle
size, solubility

Sterile

PQT Medicines Quality Assessment Training 25-28 May 2015

10 |
 What is important for APIs?

1. What is the API?

2. Who makes the API?

3. How is the API prepared?

4. How is the API controlled?

5. Can a retest period and recommended storage conditions

be established for the API?

PQT Medicines Quality Assessment Training 25-28 May 2015

11 |
 Who makes it?
There are two aspects to this question:

What is/are the API manufacturing site(s)?

Traceability of manufacturing chain/ changes in manufacturers (if

changes tracked).

GMP compliance status of the API manufacturer

The guarantee of quality API is the result of good manufacture

and control throughout all the steps (GMP). Comprehensive
testing of the final API does not replace this.

What is the evidence – From who? For what? Issued when?

PQT Medicines Quality Assessment Training 25-28 May 2015

12 |
 Who makes it?

Sites of manufacture (incl. manufacturing, packaging, labelling,

testing and storage of the API):

What's the address?

PQ requests that the applicant declares the API manufacturing

blocks involved, since different blocks at the same site can
have varying GMP compliance.

Are there external suppliers for intermediates?

The manufacturers of intermediates should also work under
GMP.

PQT Medicines Quality Assessment Training 25-28 May 2015

13 |
 Who makes it?

How far back in the manufacturing chain to go?

If you do not have access to a DMF/full dossier then you will

probably be limited to the API site.

With a DMF/full dossier you can determine:

– If they are undertaking all the steps themselves, or if they
are buying in intermediates.
– Who are the suppliers of the starting materials.

PQT Medicines Quality Assessment Training 25-28 May 2015

14 |
 What is important for APIs?

1. What is the API?

2. Who makes the API?

3. How is the API prepared?

4. How is the API controlled?

5. Can a retest period and recommended storage conditions

be established for the API?

PQT Medicines Quality Assessment Training 25-28 May 2015

15 |
 How is the API prepared?

To assess how the API manufacturer is making the API

you are going to need access to the DMF (full DMF
including restricted part) or to full API details in the
dossier.

PQT Medicines Quality Assessment Training 25-28 May 2015

16 |
 How is the API prepared?
The assessment of the API preparation will allow you to conclude
on:

The potential impurities that may need to be controlled in the

specifications.

How the API is being controlled throughout the process (in-

process controls, critical steps, control of intermediates…).

The quality of the materials used in its production (starting

materials, reagents, solvents, catalysts), since these can have
an impact on the API impurity profile.

How well and consistently the API is being manufactured.

PQT Medicines Quality Assessment Training 25-28 May 2015
17 |
 How is the API prepared?

Is the starting point of the manufacturing process acceptable?

Z
X +Y API starting material(s) (SM)

Not under GMP +

brief information API intermediate(s)

Under GMP +
Final API intermediate detailed information

Crude API

Final API

PQT Medicines Quality Assessment Training 25-28 May 2015

18 |
 Traditional manufacturing

Raw
Final API
materials

Traditionally, the API manufacturer produced the API from

simple raw materials at their own facility.

PQT Medicines Quality Assessment Training 25-28 May 2015

19 |
 Contemporary manufacturing

Intermediate
API-SM

API-SM
Raw Material Final API

Now it is very common that intermediates late in the

synthesis are being purchased externally by the API
manufacturer.

PQT Medicines Quality Assessment Training 25-28 May 2015

20 |
 API Starting material

Choice of API-SM

ASSESSORS
Simpler Final API
molecules

INDUSTRY

PQT Medicines Quality Assessment Training 25-28 May 2015

21 |
 API Starting material

API manufacturers prefer to have the starting material defined

as late in the synthesis as possible because:

The API-SM introduction is the point at which GMP applies to

manufacture.

This can be financially advantageous when API

manufacturers buy reaction intermediates from secondary
manufacturers that do not operate under GMP.

PQT Medicines Quality Assessment Training 25-28 May 2015

22 |
 API Starting material

The problem for assessors is:

There is a concern that critical steps are not carried out under
GMP.

Information on the preparation of a complex API from only one

or two steps makes determination of impurities in the API very
difficult.

If the API-SM is complex it is hard to judge the acceptability of

the API-SM specifications.

There is a concern that impurities from the API-SM may be

carried over with the API.

PQT Medicines Quality Assessment Training 25-28 May 2015

23 |
 Potential impurities

API starting
API SM impurities
material

Reagents
Solvents
Catalysts

Reaction by-products API intermediate

Reagents
Solvents
Catalysts

Reaction by-products Crude API

Crystallisation solvent

Degradation products Final API

PQT Medicines Quality Assessment Training 25-28 May 2015

24 |
 Potential impurities

Impurities in the API-SM

Residue of the API-SM

Residue of the intermediate

Reagents

Solvents

Catalysts

Reaction by-products

Degradation products

PQT Medicines Quality Assessment Training 25-28 May 2015

25 |
 How is the API prepared?

What are the potential impurities?

Can the potential impurities be carried over into the final API?

If so, are the potential impurities detectable by the analytical

procedure?
If the absence of certain impurity in the final API cannot be
demonstrated, a test and limit needs to be included in the API
specification or in raw material or intermediate.

PQT Medicines Quality Assessment Training 25-28 May 2015

26 |
 What is important for APIs?

1. What is the API?

2. Who makes the API?

3. How is the API prepared?

4. How is the API controlled?

5. Can a retest period and recommended storage conditions

be established for the API?

PQT Medicines Quality Assessment Training 25-28 May 2015

27 |
 How is the API controlled?

Even without access to a DMF you can at least ensure the

presence of certain tests.

Unfortunately, if you do not know the preparation of the API

(DMF or full dossier), you cannot be certain on the potential
impurities and their control (i.e. toxic metals, genotoxins…).

PQT Medicines Quality Assessment Training 25-28 May 2015

28 |
 How is the API controlled?
There may be tests for:

Identification. Chiral API? – test for optical rotation

Assay

Impurities – Organic, inorganic, solvents, residue on

ignition/sulphated ash, heavy metals, chiral impurities

Water

Physical properties – Polymorphism; Particle size

Microbial quality for sterile APIs

PQT Medicines Quality Assessment Training 25-28 May 2015

29 |
 What if a monograph is available?

Monographs are developed based upon how the API was

prepared historically. A particular manufacturer's method of
preparation may lead to unexpected impurities, due to a
different route of synthesis, different reagents, etc.

Regardless of whether a pharmacopoeial standard is claimed,

a discussion should be provided of the potential and actual
impurities arising from the synthesis, manufacture or
degradation of the API.

The discussion should not be limited to the impurities specified

in the API monograph

PQT Medicines Quality Assessment Training 25-28 May 2015

30 |
 What if a monograph is available?

It is important that when you read an API monograph you also

consider the general monographs that are also applicable to
the API. These also form part of the monograph and are not
optional or nice to know.

For example any API monograph in the European

Pharmacopoeia needs to be read in conjunction with the
general monographs:
– Substances for Pharmaceutical Use (2034) and
– Control of Impurities In Substances For Pharmaceutical
Use (5.10)

PQT Medicines Quality Assessment Training 25-28 May 2015

31 |
 What if a monograph is available?

EP 2034 and 5.10 General Monographs:

The limits for impurities of the monograph only apply to the

specific impurities listed in the monograph.

If the API monograph does not provide suitable control for a

new impurity, a suitable test for control must be developed
and included in the API specification.

Residual solvents and impurities (except the ones limited in

the monograph) are limited according to the ICH principles
(see ICHQ3C and ICHQ3A).

PQT Medicines Quality Assessment Training 25-28 May 2015

32 |
 How is the API controlled?

Do not forget the test method. The limits are important but having
a validated test method is a prerequisite underlying everything.

The API methods should be able to separate/detect the

potential impurities/solvents of the manufacturing process.

All non-pharmacopoeial methods must be fully validated,

particularly assay, related substances and residual solvents
methods, as outlined in ICHQ2.

The pharmacopoeial methods should also be shown suitable for

determination of impurities related to the manufacturer's specific
route of synthesis and not covered by the monograph.

PQT Medicines Quality Assessment Training 25-28 May 2015

33 |
 What is important for APIs?

1. What is the API?

2. Who makes the API?

3. How is the API prepared?

4. How is the API controlled?

5. Can a retest period and recommended storage conditions

be established for the API?

PQT Medicines Quality Assessment Training 25-28 May 2015

34 |
 What API information do you get?

A CEP
What do these mean?
A CPQ

A complete DMF (open + restricted parts)

What are the critical
aspects?
Full API dossier

The complete open part of the DMF

Can the API be fully
assessed?
Other…

PQT Medicines Quality Assessment Training 25-28 May 2015

35 |
 European Certificate of Suitability (CEP)

The DMF has already been assessed by EDQM

PQT Medicines Quality Assessment Training 25-28 May 2015

36 |
 European Certificate of Suitability (CEP)

This means the EDQM has already assessed the applicant’s

DMF (method of preparation etc…) to determine if the API
quality is adequate and if the API can be fully controlled by the
[Link]. monograph.

There will be two possible conclusions in the CEP:

a) The API can be fully controlled by the monograph.

b) The API can be fully controlled by the monograph only if

additional tests and limits are applied.

See [Link]

PQT Medicines Quality Assessment Training 25-28 May 2015

37 |
 European Certificate of Suitability (CEP)
3.2.S.1. General information
3.2.S.1.1. Nomenclature
3.2.S.1.2. Chemical structure
3.2.S.1.3. General properties
3.2.S.2. Manufacture
3.2.S.2.1. Manufacturer(s)
3.2.S.2.2. Description of Manufacturing Process and Process Controls
3.2.S.2.3. Control of Materials
3.2.S.2.4. Controls of Critical Steps and Intermediates
3.2.S.2.5. Process Validation and/or Evaluation
3.2.S.2.6. Manufacturing Process Development
3.2.S.3. Characterization
3.2.S.3.1. Elucidation of Structure and other Characteristics
3.2.S.3.2. Impurities
3.2.S.4. Control of the API
3.2.S.4.1. Specification
3.2.S.4.2. Analytical Procedures
3.2.S.4.3. Validation of Analytical Procedures
3.2.S.4.4. Batch Analyses
3.2.S.4.5. Justification of Specification
3.2.S.5. Reference standards or Materials
3.2.S.6. Container closure system
3.2.S.7. Stability testing
3.2.S.7.1. Stability Summary and Conclusions
3.2.S.7.2. Post-approval Stability Protocol and Stability Commitment
3.2.S.7.3. Stability Data

The API quality is adequate and

the monograph (limits and test
methods) is able to control the
quality of the API

38 | API Assessment - Zazibona June 2014

 CEP WHERE ALL IMPURITIES ARE CONTROLLED BY THE MONOGRAPH
Certificate of suitabiliy
No. RX-CEP-Year-XXX-Rev XX
Name of the substance:
XXX
Name of holder:
XXX
Site of production:
XXX
we certify that the quality of the substance is suitably controlled by
After examination of the information provided on the manufacturing method and subsequent processes (including
purification) for this substance on the site of production mentioned above, XXX, we certify that the quality of the substance
monograph XXX
is suitably controlled by monograph XXX (Ph. Eur. …).
The following impurities are also detected and their limits are set at:
The following impurities are also detected and their limits are set at:
—
—
—
The submitted dossier must be updated after any significant change that may alter the quality, safety or efficacy of the
—
substance.
Manufacture of the substance shall take place in accordance with Good Manufacturing Practice and in accordance with the
dossier submitted.
Failure to comply with these provisions will render this certificate void.
This certificate is granted within the framework of the procedure established by the European Pharmacopoeia Commission
[Resolution AP-CSP (99) 4] for a period of five years starting from XXX. Moreover, it is granted according to the provisions
of Directive 75/318/EEC amended and Directive 81/852/EEC amended, and the related guidelines.
This certificate does not replace a batch analysis certificate.
(…)
 European Certificate of Suitability (CEP)
3.2.S.1. General information
3.2.S.1.1. Nomenclature
3.2.S.1.2. Chemical structure
3.2.S.1.3. General properties
3.2.S.2. Manufacture
3.2.S.2.1. Manufacturer(s)
3.2.S.2.2. Description of Manufacturing Process and Process Controls
3.2.S.2.3. Control of Materials
3.2.S.2.4. Controls of Critical Steps and Intermediates

Additional tests (e.g.

3.2.S.2.5. Process Validation and/or Evaluation
3.2.S.2.6. Manufacturing Process Development
3.2.S.3. Characterization
3.2.S.3.1. Elucidation of Structure and other Characteristics
3.2.S.3.2. Impurities
3.2.S.4. Control of the API
impurities, solvents,
3.2.S.4.1.
3.2.S.4.2.
3.2.S.4.3.
Specification
Analytical Procedures
Validation of Analytical Procedures
+ catalysts…not detected
3.2.S.4.4. Batch Analyses
3.2.S.4.5. Justification of Specification
3.2.S.5. Reference standards or Materials
3.2.S.6. Container closure system
by the methods of the
3.2.S.7. Stability testing
3.2.S.7.1.
3.2.S.7.2.
Stability Summary and Conclusions
Post-approval Stability Protocol and Stability Commitment
monograph)
3.2.S.7.3. Stability Data

The API quality is adequate and

the monograph is able to control
the quality of the API only if it is
supplemented by the limit and
test(s) given in the CEP annex.

PQT Medicines Quality Assessment Training 25-28 May 2015

40 |
 CEP WITH APPENDIX(CES) WHERE NEW IMPURITIES ARE CONTROLLED BY
ADDITIONAL METHOD(S)
Certificate of suitabiliy
No. RX-CEP-Year-XXX-Rev XX
on 0
Name of the substance:
XXX
Name of holder:
XXX
Site of production:
XXX
After examination of the information provided on the manufacturing method and subsequent processes (including
purification) for this substance on the site of production mentioned above, XXX, we certify that the quality of substance is
(…) we
suitably certify
controlled that
by the the quality
monograph XXX ([Link]…)
the substance is suitably
only if it is supplemented by thecontrolled bybased
following test(s), theon the
monograph
analytical givenonly
X (...)
procedure(s) if it is supplemented by the following test(s), based on the
in annex.
— Test for the following impurities/related substances/by liquid chromatography (annex 1)
analytical procedure(s) given in annex.
XXXnot more than XXX
XXX not more than XXX
The
− submitted
Test for dossier must be updated aftersubstances/residual
impurities/related any significant change that solvents
may alter theby
quality,
(…)safety or efficacy of the
chromatography
substance.
(annex
Manufacture X)substance shall take place in accordance with Good Manufacturing Practice and in accordance with the
of the
dossierXXXX
submitted. not more than XXX
Failure to comply with these provisions will render this certificate void.
This certificate is granted within the framework of the procedure established by the European Pharmacopoeia Commission
[Resolution AP-CSP (99) 4] for a period of five years starting from XXX. Moreover, it is granted according to the provisions
of Directive 75/318/EEC amended and Directive 81/852/EEC amended, and the related guidelines.
(…)
 European Certificate of Suitability (CEP)

Check that the CEP is valid ([Link], databases, certification
database).

RX-CEP-Year-Number-Rev XX:

 R=renewal (R0= first CEP; R1= renewal once after the first 5 years, then
unlimited validity)

 Rev= revisions (i.e. Rev 00, Rev 01, Rev 02, etc), after:

o Changes

o Revisions of the monographs (the manufacturer has to show

compliance with the new requirements)

Check that declaration of access has been filled in for the Marketing
Authorisation Applicant and that it comes with all annexes (if any).

PQT Medicines Quality Assessment Training 25-28 May 2015

42 |
 CCertificate of suitabiliy
No. RX-CEP-Year-Number-Rev XX
0
Name of the substance:
XXX
Name of holder:
XXX
Site of production:
A CEP does not indicate GMP compliance, it is not a GMP certificate.
XXX
After examination of the information provided on the manufacturing method and subsequent
processes (including purification) for this substance on the site of production mentioned above,
XXX, we certify that the quality of the substance is suitably controlled by monograph XXX
(…).
The following impurities are also detected and their limits are set at:
—
—
The submitted dossier must be updated after any significant change that may alter the quality, safety or efficacy of the
substance.
Manufacture of theof
Manufacture the substance
substance shall
shall take place take place
in accordance in accordance
with Good Manufacturingwith Good
Practice and Manufacturing
in accordance with the dossier submitted.
Practice and in accordance with the dossier submitted.
Failure to comply with these provisions will render this certificate void.
This certificate is granted within the framework of the procedure established by the European
Pharmacopoeia Commission […] for a period of five years starting from
XXX. Moreover, it is granted according to the provisions of Directive (….) and the related guidelines.
This certificate has XX lines only.
Signature
Strasbourg, XXX
 European Certificate of Suitability (CEP)
Please also note that:

Compliance with the specifications can only be shown by

certificates of analysis from the API manufacturer (the CEP
does not replace a CoA).

Applicants for a CEP can decide whether a retest period is

mentioned in the CEP or not.

If a retest period is not mentioned, stability data need to be

provided and assessed (not assessed by EDQM!) in order to
establish a retest period and storage conditions.

PQT Medicines Quality Assessment Training 25-28 May 2015

44 |
 CEP and retest period

If a retest period is mentioned, the storage conditions applied

are those of the EU guideline CPMP/QWP/609/96/Rev 2 (i.e.
those for climatic zone I/II, the relevant zone for the EU).

Therefore if you see a CEP with a retest period but no storage

statement mentioned, it should be assumed that the
temperature statement for the API is at least "store below
25°C".

PQT Medicines Quality Assessment Training 25-28 May 2015

45 |
 Prequalified APIs (CPQ)

The DMF has already been assessed by WHO PQ

PQT Medicines Quality Assessment Training 25-28 May 2015

46 |
 Prequalified APIs (CPQ)
3.2.S.1. General information
3.2.S.1.1. Nomenclature
3.2.S.1.2. Chemical structure
3.2.S.1.3. General properties
3.2.S.2. Manufacture
3.2.S.2.1. Manufacturer(s)
3.2.S.2.2. Description of Manufacturing Process and Process Controls
3.2.S.2.3. Control of Materials
3.2.S.2.4. Controls of Critical Steps and Intermediates
3.2.S.2.5. Process Validation and/or Evaluation
3.2.S.2.6. Manufacturing Process Development
3.2.S.3. Characterization
3.2.S.3.1. Elucidation of Structure and other Characteristics
3.2.S.3.2. Impurities
3.2.S.4. Control of the API
3.2.S.4.1. Specification
3.2.S.4.2. Analytical Procedures
3.2.S.4.3. Validation of Analytical Procedures
3.2.S.4.4.
3.2.S.4.5.
Batch Analyses
Justification of Specification
3.2.S.5. Reference standards or Materials
The API quality is adequate
AND
3.2.S.6. Container closure system
3.2.S.7. Stability testing
3.2.S.7.1. Stability Summary and Conclusions
3.2.S.7.2. Post-approval Stability Protocol and Stability Commitment

the API manufacturing site has

3.2.S.7.3. Stability Data

been verified GMP compliant

PQT Medicines Quality Assessment Training 25-28 May 2015

47 |
 Prequalified APIs (CPQ)

List of PQ APIs
+ WHO inspection report
Website (Public) Website (Public)

Confirmation Document (CPQ)

48 | API Assessment - Zazibona June 2014

 Prequalified APIs (CPQ)

The CPQ provides an assurance that the supplied API is of

good quality (assessment + GMP).

The API specifications, assay test method and related

substances test method accepted for the API are appended to
the CPQ.

The approved details can be verified in the list of PQ APIs

([Link]

Also, the DMF assessment report is potentially available for

National Medicine Regulatory Authorities.

PQT Medicines Quality Assessment Training 25-28 May 2015

49 |
 Drug Master File (APIMF/ASMF)

FPP
Manufacturer

AP
+
RP
WHO
API
Manufacturer
+

DMF assessment is conducted in conjunction with an FPP application.

PQT Medicines Quality Assessment Training 25-28 May 2015

50 |
 Drug Master File (APIMF/ASMF)

DMFs protect the confidentiality of the API manufacturer

information and are divided in two parts:
– The Applicant's part (AP) or open part contains the
information that the DMF holder regards as non-confidential
to the FPP applicant. It should contain sufficient information
to enable the FPP applicant to take full responsibility of the
API.

– The Restricted part (RP) or closed part contains the

information that the DMF holder regards as confidential.

PQT Medicines Quality Assessment Training 25-28 May 2015

51 |
 Drug Master File (APIMF/ASMF)
3.2.S.1. General information
3.2.S.1.1. Nomenclature
3.2.S.1.2. Chemical structure
3.2.S.1.3. General properties
3.2.S.2. Manufacture
3.2.S.2.1. Manufacturer(s)
3.2.S.2.2. Description of Manufacturing Process and Process Controls
3.2.S.2.3. Control of Materials RP
3.2.S.2.4. Controls of Critical Steps and Intermediates
3.2.S.2.5. Process Validation and/or Evaluation
3.2.S.2.6. Manufacturing Process Development
3.2.S.3. Characterization
3.2.S.3.1. Elucidation of Structure and other Characteristics
3.2.S.3.2. Impurities
3.2.S.4. Control of the API
3.2.S.4.1. Specification
3.2.S.4.2. Analytical Procedures
3.2.S.4.3. Validation of Analytical Procedures
3.2.S.4.4. Batch Analyses
3.2.S.4.5. Justification of Specification
3.2.S.5. Reference standards or Materials
3.2.S.6. Container closure system
3.2.S.7. Stability testing
3.2.S.7.1. Stability Summary and Conclusions
3.2.S.7.2. Post-approval Stability Protocol and Stability Commitment
3.2.S.7.3. Stability Data

PQT Medicines Quality Assessment Training 25-28 May 2015

52 |
 Drug Master File (APIMF/ASMF)

Our APIMF procedure is described in

[Link]
[Link]

A DMF procedure serves to bring the API manufacturer under

closer regulatory examination. It creates a direct link between
the regulator and the API manufacturer.

It is of little use if there is no communication between the FPP

manufacturer and the API manufacturer, especially if changes
to the DMF are not communicated to the FPP manufacturer.

PQT Medicines Quality Assessment Training 25-28 May 2015

53 |
 What API information do you get?

A CEP Full API assessment

has been already done
A CPQ

A complete DMF (open + restricted parts)

Full API assessment can
be done
Full API dossier

The complete open part of the DMF

Full API assessment
Other… cannot be done

PQT Medicines Quality Assessment Training 25-28 May 2015

54 |
 Conclusion

There are critical issues to be assessed in the API information

provided by the API manufacturer.

These critical issues can only be assessed if full information on

the API is provided.

The assessment work does not need to repeated in the case

of CEPs and WHO Prequalified APIs.

PQT Medicines Quality Assessment Training 25-28 May 2015

55 |
 Thank you
Please feel free to email me at: Kaushalv717@[Link]

PQT Medicines Quality Assessment Training 25-28 May 2015

56 |
 Questions?

PQT Medicines Quality Assessment Training 25-28 May 2015

57 |
 Abbreviations
AP: Applicant's part of a DMF (or Open part)

API: Active Pharmaceutical Ingredient

CEP: Certificate of suitability to the monographs of the European Pharmacopoeia

CoA: Certificate of Analysis

CPQ: Confirmation of API Prequalification document

CTD: Common Technical Document

DMF: Drug Master File (in PQ APIMFs= API Master Files, in the EU ASMFs=Active Substance Master Files)

EDQM: European Directorate for the Quality of Medicines & Healthcare

EU: European Union

FPP: Finished Pharmaceutical Product

GMP: Good Manufacturing Practice

Ph. Eur.: European Pharmacopoeia

RP: Restricted part of a DMF or closed part

SM: API Starting Material

WHOPIR: WHO Public Inspection Report

PQT Medicines Quality Assessment Training 25-28 May 2015

58 |