:API assessment

Approaches and considerations

Antony Fake
WHO Medicines Prequalification Programme

API assessment: Approaches and considerations, 19 January 2011

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 Overview

 API information is assessed within the PQ programme in

two ways:
as part of the FPP assessment, or
during the APIMF assessment

 The new guidance for generic medicines emphasises that

the data requirements in either situation are the same.

 There is only one standard for the assessment of APIs.

API assessment: Approaches and considerations, 19 January 2011

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 Overview (2)

 This is a point of interest review of API assessment, it is

not a line by line review of technical requirements.

 There is a focus on the API starting material (API-SM)

and the API starting material for synthesis.

 Some requirements are scientific in nature others are

regulatory in nature.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.1 – General properties

 This section summarises information that is already

known about the API.

 Despite this applicants often do not provide complete

information.

 Particularly, information on: partition coefficients and

solubility.

 Optical rotation is sometimes performed using a different

solvent or temperature .

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.1 – General properties

An exact chemical and physical description of the API is desired.

 Different manufacturers make the same API in different

polymorphs, particle sizes, solvates, hydration states.

 It is important to understanding the molecule in question.

 Unless this information is accurately recorded it is difficult

to know in the future whether another API manufacturer is
making the exact same molecule. This could potentially
lead to bioinequivalence of the FPP.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture

Ensure the unit and block is specified and recorded.

 If it is not stated ask.

 This affects future variations for changes to the

manufacturing facility.

 It is needed for GMP inspection purposes.

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 3.2.S.2 – Manufacture (2)

A detailed description of manufacture is required.

 Detailed flow diagram of synthesis indicating chemical

structures, molecular weights, solvents, reagents.

 Detailed narrative of each synthetic step. Types and

quantities of reagents and solvents. Reaction conditions,
critical steps, in-process controls, yields.

 Alternative processes, reprocessing steps or recovery

steps should be equally detailed.

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 3.2.S.2 – Manufacture (3)

Choosing the API starting material (APl-SM)

API starting
material

API intermediate(s)

Final API intermediate

Final API

The practise of buying reaction intermediates is common. Increasingly

intermediates late in the synthesis are being purchased.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (4)

Choice of API-SM

ASSESSORS
Simpler Final API
molecules

INDUSTRY

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (5)

API manufacturers prefer to have the API-starting material

(API-SM) defined as late in the synthesis as possible
because:
 The API-SM is the point at which GMP applies to
manufacture.

 This can be advantageous when API manufacturers buy

reaction intermediates from secondary manufacturers
with limited GMP experience.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (6)

The problem for assessors is:

 Information on the preparation of a complex API from one
or two steps makes determination of impurities in the API
very difficult.
 If the SM is complex it is hard to judge the acceptability of
the SM specifications.
 The guarantee of quality API is the result of good
manufacture and control throughout all the steps.
Comprehensive testing of the final API does not replace
this. Therefore knowledge of all steps is important.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (7)

There is a clever compromise,

The API starting-material-for-synthesis.

 This defines the point in manufacture from which detailed

manufacturing information should be provided.

 This allows assessors to judge whether the controls on

the API-SM are sufficient, without obliging the preparation
of the API-SM to be in compliance with GMP regulations.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (8)
Starting material
for synthesis

Detailed
information Reaction
intermediate(s)
provided
dossier
API starting
material

GMP
API intermediate(s) compliance

Final API intermediate

Final API

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (9)

 Information on the preparation of the API commencing

from the API-SM-for-synthesis must be provided in
section 3.2.S.2.

 However, information on the steps from the API-SM-for-

synthesis to the API-SM is usually supplied as an annex.

 There is often more than one supplier of API-SM. Each

API-SM supplier must provide detailed information.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (10)

The assessor has to:

1. Judge whether the choice of API-SM is appropriate.

2. Judge whether the choice of API-SM-for-synthesis is

appropriate.

It is subjective, but there is some additional guidance.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (11)

Choice of API-SM

Poorer information
provided on the preparation
of the API-SM.
Simpler
Final API
molecules

Detailed information
provided on the
preparation of the API-SM.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (12)

The API-SM for synthesis is a synthetic precursor of one or

more synthesis steps prior to the final API intermediate.
Acids, bases, salts, esters and similar derivatives of the API,
as well as the racemate of a single enantiomer API, are not
considered final intermediates…Be incorporated as a
significant structural fragment into the structure of the API.

GUIDELINE ON SUBMISSION OF DOCUMENTATION FOR A MULTISOURCE (GENERIC) FINISHED

PHARMACEUTICAL PRODUCT (FPP): QUALITY PART

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (13)

A company submission proposes molecule 3 as the AP-SM. Can this

be accepted?

N N N

Crude Nevirapine
N CH3
O H

(2)

N N N
N NH Cl N

NH N CH3
O CH3 O H

(3) (1)
Proposed API SM Nevirapine

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (14)

First identify the final intermediate, as logically the API-SM and API-SM-
for-synthesis must occur prior to this molecule.

N N N

Crude Nevirapine
N CH3
O H

(2)

N N N
N NH Cl N

NH N CH3
O CH3 O H

(3) (1)
Proposed API-SM Nevirapine

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (15)

Conversion of the crude nevirapine (2) to nevirapine (1) is not a

synthetic step. Therefore, crude nevirapine (2) is not the final
intermediate.

N N N

Crude Nevirapine
N CH3
O H

(2)
N N N
N NH Cl N

NH N CH3
O CH3 O H

(3) (1)
Proposed SM Nevirapine

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (16)

The conversion of precursor 3 to crude nevirapine (2) is a synthetic

step. Therefore, precursor 3 is the final intermediate. Further
information on how molecule 3 is prepared is required.

N N N

N CH3
O H
(2)

N N N
N NH Cl N

NH N CH3
O CH3 O H

(3) Final intermediate (1)

Proposed SM

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (17)

The applicant states that molecule 3 is prepared from molecule 4.

Molecule 4 can be assigned as the API-SM, but as it is a complex
molecule further information on its preparation is required.
API Starting material
N Cl Cl N
N N N

NH
O CH3
N CH3
O H
(4)
(2)

N N N
N NH Cl N

NH N CH3
O CH3 O H

(3) Final intermediate (1)

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (18)

Molecules 5 and 6 can be accepted as the API-SM-for-synthesis. Each

are significant structural fragments of the final API and commercially
available.

API Starting material

N Cl Cl N
N N N
(2)
NH
O CH3
N CH3
(4) O H

N Cl Cl N
N NH Cl N N N
Cl
+ N

H2N
O CH3 NH
O CH3 N CH3
H
(5) (6) O

Starting materials for synthesis (3) Final intermediate Nevirapine

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.2 – Manufacture (19)

 Controls on the API-SM should typically include identity,

assay and impurity content.

 The controls should take into account the API-SM

preparation.

 Controls on reaction intermediates should typically

include identity, assay and impurity content, but will vary
depending on the length of synthesis and controls placed
on subsequent intermediates.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.3 Characterisation

 It would be rare that the manufacturer has synthesised a

completely different molecule. Even the wrong
enantiomer or diastereomer.

 It’s more a question of verification than being truly

worried, but you never know! And, the consequences
could be complete therapeutic failure, or worse.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.3 Characterisation (2)

 For non-pharmacopoeial substances a range of different

techniques can and should be used. UV, IR, 1H and 13C
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F, 31P NMR, elemental analysis, HRMS, MS.

 For pharmacopoeial substances comparison to the

pharmacopoeial reference standard is desirable.
Comparative IR is suggested, however, proton NMR
wouldn’t hurt either.

 Comparative IR will not address the question of

enantiomers (maybe not even diastereomers), or particle
size. It may address polymorphism.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.3 Characterisation (3)

If the molecule can exhibit stereoisomerism

 Ensure the techniques used can distinguish these.

 Optical rotation comparisons to a reference standard is

simplest.

 Through-space proton NMR (NOE, NOESY, ROESY)

experiments are increasingly used in larger organisations,
but its really just showing off.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.3 Characterisation (4)

Polymorphism

 pXRD and DSC can be used to distinguish polymorphs.

 Comparative IR is often used, but IR may not always be

able to distinguish all polymorphs, or mixtures of
polymorphs.

 The use of IR must be validated by suitable experiments.

Literature can be used for this purpose.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.3.2 Impurities

This is covered in another talk, but:

 Always look at the method of preparation.

 Pharmacopoeial monographs are not magic, they may

not control all potential impurities.

 If the test method can’t detect the impurity, you will never
see it!

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.4.1 Specifications

 Do the tests cover all the applicable physical and

chemical tests?
 Compliance with a pharmacopoeial monograph may not
be sufficient control, especially for impurities.
 If a pharmacopoeial standard is claimed then the API
specifications must meet the monograph requirements.
 A one sentence statement in the report about
compliance, or not, with a specific monograph is useful.
 Microbial quality is not an issue unless the API is sterile.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.4.1 Specifications (2)

 It is important that the manufacturer provides a signed,

dated and version-numbered specification. This is to
ensure traceability of testing requirements in case of
GMP audits and future variations.

Skip testing
 Often manufacturers will propose the elimination of
certain tests based upon batch manufacturing data.
 It is best to retain the test in specifications as a non-
routine test, with a comment that the test is to be
performed if there is a change to to manufacture, material
suppliers etc.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.4.1 Specifications (3)

 API specifications should be provided from the FPP

manufacturer and from all of the API manufacturers.

 The FPP manufacturer should have one API

specification, even if there are multiple API suppliers.

 The FPP manufacturer’s specifications may be a

compilation of all the API manufacturers‘ specifications.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.4.1 Specifications (4)

The FPP manufacturer's specifications should take into

account those of the API manufacturers. Therefore,

 if one API supplier controls the API to the EP monograph,

plus an additional impurity,

 the FPP must also control for the additional impurity.

Adoption of the EP monograph only is not acceptable.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.4.2 Analytical Procedures

 Non-pharmacopoeial test methods should be explicitly

described, and numbered.

 In an APIMF it is the API manufacturer’s procedures that

are described.

 In an FPP dossier it is the FPP manufacturer’s API test

methods that are described.

API assessment: Approaches and considerations, 19 January 2011

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3.2.S.4.3 Validation of Analytical Procedures

 The provision of validation data for pharmacopoeial

methods is not usually required.

 If an in-house method is used when claiming a

pharmacopoeial standard, equivalence of the in-house
and pharmacopoeial methods must be demonstrated.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.4.4 Batch Analyses

 Batch analysis should be provided for at least two pilot scale batches
from each API supplier.

 This should include the API batch used in the manufacture of the
biobatch.

 The size, manufacturing site and manufacturing date for each batch
should be identified.

 If testing was not to proposed specifications, a justification should be

provided.

 Certificates of Analysis from the API and FPP manufacturer should

be provided for each batch.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.5 Reference Standards

 The primary and secondary reference standards used in

the tests for assay, impurities and identification should be
stated.

 Primary reference standards obtained from the Ph.Int.,

BP, EP or USP should be used if possible.

 If a pharmacopoeial standard is claimed then the primary

reference standard of that pharmacopoeia should be
used.

API assessment: Approaches and considerations, 19 January 2011

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 3.2.S.6 Container Closure System

 Copies of the specifications for the primary packaging

should be provided.

 The materials used in the construction of the primary

packaging must be suitable for use with pharmaceuticals

 It should be verified that the proposed packaging is that

used in the stability studies.

API assessment: Approaches and considerations, 19 January 2011

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 3.S.7.1 Stability data

This will be covered in detail in a further talk, but…

 If the drug substance assessment is occurring as part of

the FPP dossier assessment the drug substance stability
data must be assessed for each API manufacturer.

 Long-term storage conditions.

API assessment: Approaches and considerations, 19 January 2011

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 3.S.7.1 Stability data (3)

Are the primary stability studies conducted at

30ºC/65%RH or 30ºC/75%RH?

 They should be unless it has been demonstrated that

the API is inherently unstable at 30ºC/65%RH or
30ºC/75%RH.

 Instability during accelerated stability trials is not

acceptable evidence of instability.

API assessment: Approaches and considerations, 19 January 2011

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 3.S.7.1 Stability data (4)

 If the API is stable at 30ºC/65%RH or 30ºC/75%RH to 24

months then a lower storage condition is not really
justified.

 If the API is unstable at 30ºC/65%RH. studies at

25ºC/60%RH should be attempted. 2ºC - 8ºC is not the
next logical storage condition.

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 3.S.7.1 Stability data (5)
If there is no data available at 30ºC/65%RH or
30ºC/75%RH then the API manufacturer should:
 commit to initiating long-term stability trials on the next
two batches (pilot scale or greater) manufactured at
either 30ºC/65%RH or 30ºC/75%RH.

 provide a signed, authorised stability protocol for the new

stability studies.

 specify a date when they will submit an APIMF

amendment or FPP variation to change the
recommended storage conditions to stored below 30ºC.

API assessment: Approaches and considerations, 19 January 2011

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 Questions

1. Does the APIMF need to be in the CTD format?

Yes, it should be. The question is why wouldn't it be?

2. If the API manufacturers have DMF in the US-DMF

format, will it be acceptable? Do they need to convert to
the CTD format, or can the applicant submit it as it is, as
annex to 3.2.S and fill the sections S.1 – S.7 in the PD
accordingly?

This course of action is not encouraged! But I would

rather have a DMF than not

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 Questions

3. If we use US-DMF or EDMF that already got reviewed by the USFDA

or European authority, will the WHO review it again?

Yes, unless the evaluation report can be provided. In which case a

peer review of the report will be conducted.

4. If the DMF is old (e.g. >5 years ago) but can still meet the current
requirements, will it be acceptable? Does the WHO have restriction
on that, or require additional data e.g. annual product review,
ongoing stability data?

No there are no specific requirements on the age of the APIMF. But

be honest, will a 5 year old APIMF really meet current requirements?
Or, accurately reflect current manufacture and control?

API assessment: Approaches and considerations, 19 January 2011

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 Questions

5. Can the WHO share the names of API manufacturers or

APIMF holders that were already passed the review by
the WHO as part of the prequalified FPP? This can help
the FPP manufacturer knows the good source of API that
can meet the WHO requirements and in turn reduce the
WHO workload in reviewing the DMF.

No. Not at this time. But, the names and details of

Prequalified APIs will be published for this very purpose.

API assessment: Approaches and considerations, 19 January 2011

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 Questions

Variations:

1. When the manufacture of an API is scaled up, a variation

needs to be introduced to the WHO. This is the
responsibility of the API manufacturer and not the FPP
manufacturer. May be the FPP manufacturer could have
a “quality agreement” with the API manufacturer asking
for this commitment. Nevertheless when an API has a
CEP is this required?

API assessment: Approaches and considerations, 19 January 2011

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 Questions

 When there is an API related change and there is an

APIMF then an APIMF amendment should first be
submitted by the APIMF holder. Once the amendment is
accepted then a variation from the FPP manufacturer
maybe required, depending on the change involved.

 If there is a CEP involved, no notification to the WHO is

required unless the CEP is reissued.

 If there is no APIMF or CEP supporting the FPP then the

FPP manufacturer should submit a variation for all API
related changes.

API assessment: Approaches and considerations, 19 January 2011

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 Questions

2. Will the reduction in number of batches for stability study

affect the variations? For example, if some changes
require stability of 3 pilot lots, will it be reduced to 2 pilot
lots as per the new guideline? It should, yes, but not for
requirements that concern production lots.

API assessment: Approaches and considerations, 19 January 2011

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 Questions

Revised stability requirements for generic FPPs were introduced to

the PQ programme as part of the new guidance document for
generic FPPs

Therefore, when stability data is required to support a variation, the

following requirements apply:

 For uncomplicated FPPs (e.g. immediate release solid oral dose

forms) the minimum number of FPP batches required to establish the
shelf-life is now two, of which one batch must be at least pilot scale.

 For complicated FPPs the minimum number of FPP batches required

to establish the shelf life is now two, both of which must be pilot scale
or larger.

API assessment: Approaches and considerations, 19 January 2011

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