1-3 API common deficiencies

Helena Martin-Ballestero
WHO Prequalification Team - Medicines

3.2.S.3.2 Impurities,
1 Malaysia, 29 September 2011

WHO PREQUALIFICATION TEAM – MEDICINES

 Abbreviations & acronyms
API – Active Pharmaceutical Ingredient

APIMF – Active Pharmaceutical Ingredient Master File, also referred to as a DMF (USA) or ASMF (EU)

BP – British Pharmacopoeia.

CEP – Certificate of suitability of Monographs of the European Pharmacopoeia, or more commonly known as a Certificate of
Suitability.

CPQ – Confirmation of Prequalification Document for a Prequalified API.

CTD – Common Technical Document.

DMF – Drug Master File.

EDQM – European Directorate for the Quality of Medicines & Healthcare.

FPP – Finished Pharmaceutical Product.

GMP – Good Manufacturing Practice.

JP – Japanese Pharmacopoeia.

OP – Open part, the non-confidential portion of the APIMF, also referred to as the applicant part.

Ph.Eur. – European Pharmacopoeia.

Ph.Int. – International Pharmacopoeia.

RP – Restricted part, the confidential portion of the APIMF, also referred to as the closed part.

SM – Starting Material

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 Overview

1. API information

2. Submission of an APIMF

3. Most common deficiencies found in APIMFs

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 API INFORMATION
Full Data

EDQM CEP Drug Master File

S&E FPP API (APIMF)
GMP (CRO, FPP, API) APIMF
Prequalified FPP Procedure

PQ API API GMP

Prequalified API

WHO List of Prequalified Medicinal Products WHO List of Prequalified APIs

The use of these 4 options is described in guideline: TRS no. 970 – Annex 4
http://apps.who.int/iris/bitstream/handle/10665/75168/WHO_TRS_970.pdf?sequence=1&isAllowed=y#page=135

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 API INFORMATION
1. Full dossier
3.2.S – Full details of the chemistry, manufacturing process,
in-process controls and process validation of the API
are included in the FPP dossier.

2. CEP
Only for APIs with a Ph.Eur. substance monograph.
EDQM has already assessed the DMF.
A copy of the currently valid CEP is provided in the FPP dossier.
+ declaration of access
+ commitment that applicant will inform WHO if the CEP is withdrawn
Stability data should be submitted in the FPP:
- if no retest period/storage conditions stated in CEP
- if storage conditions are not zone IV

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 API INFORMATION

3. APIMF Procedure
The API manufacturer submits RP and OP along with a letter of
access to WHO for assessment.
The OP needs to be included in the Product Dossier.

4. PQ API
The APIMF has already been assessed by WHO PQ.
A copy of the Confirmation of API Prequalification document (CPQ)
should be provided. (quality assessment + GMP)

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 API INFORMATION

• Regardless of the option chosen, the same quality

review standards are applied during the assessment.

• The API information submitted for assessment should be

compiled in the Common Technical Document format
(CTD).

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 API INFORMATION: CTD – Module 3 Quality
3.2.S Drug Substance

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 SUBMISSION OF AN APIMF

There are 2 uses of APIMFs in PQ:

- APIMF Procedure
- API Prequalification

The use of APIMFs in the PQ programme is described in

Technical Report Series 948, Annex 4 (TRS948).
https://cdn.who.int/media/docs/default-source/medicines/norms-and-
standards/guidelines/regulatory-standards/trs948-annex5-
guidelinesactivepharmaceuticalingredient.pdf?sfvrsn=c64a180f_2

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 APIMF Procedure

• It is only used to support a FPP application for PQ.

• PQ will contact the APIMF holder directly if there are any

questions arising during the assessment or requires
further information.

• The API manufacturer should commit to inform WHO of

any changes to the APIMF (RP or OP).

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 APIMF Procedure

Letter
APIMF holder of FPP applicant
access
APIMF FPP
submission submission

APIMF
assessment

APIMF FPP
acceptance assessment

FPP
Prequalification

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 API Prequalification

• It is a standalone procedure.

• It seeks to verify, identify and recognise APIs that are of

good quality and manufactured in compliance with
GMP.

• It seeks to facilitate sourcing of quality APIs by FPP

manufacturers of essential medicines leading to the
greater availability.

• It offers National Regulatory Agencies information on the

quality of these APIs for consideration during their
assessment decision making.

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 API Prequalification

BENEFITS to API manufacturers:

• APIs can be prequalified independent of an FPP

application

• Opportunity to verify GMP compliance

• Public recognition: list of Prequalified APIs

https://extranet.who.int/pqweb/medicines/active-pharmaceutical-
ingredients

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 API Prequalification

Invitation

Application for
API PQ

Assessment Assessment
Quality GMP

Decision

Publishing

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 DIFFERENCIES
APIMF Procedure API Prequalification
WHOAPI-XXX &
File numbers APIMFXXX
APIMFXXX
Use in FPP PQ applications Yes Yes
Only once the associated FPP Once the API application
Evaluation commences has been accepted for has been accepted for
assessment assessment
Follows ICH and PQT
Quality evaluation Follows ICH and PQT guidance
guidance
As part of the PQ decision of
GMP evaluation Yes
the FPP
Fee No (part of the FPP PQ fee) Yes
Pubic listing No Yes
APIMF amendments APIMF amendments
API Post-approval changes
FPP variations FPP variations (limited)

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 SUBMISSION

Applicant WHO

API information

What do we expect?

An API of acceptable and consistent quality

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 An API of acceptable and consistent quality
1. WHAT ? Chemical form, origin, chirality, physicochemical properties.

2. WHO ? Name and address of API manufacturer. Specify the blocks

3. WHERE? All sites involved should be mentioned: SM manufacturer,

Intermediate manufacturer, testing, packaging etc

4. HOW? Manufacture: synthetic scheme, flow chart and description of the

manufacturing process.
Control: API specifications, description and validations of
Analytical methods.

5. HOW LONG ? Stability of the API.

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 COMMON DEFICIENCIES
by CTD section:

- General Properties (3.2.S.1.3)

- Description of the manufacturing process (3.2.S.2.2)
- Control of materials (3.2.S.2.3)
- In-process controls and control of intermediates
(3.2.S.2.4)
- Characterization (3.2.S.3.1)
- Control of impurities (3.2.S.3.2)
- Specifications and control of the API (3.2.S.4)
- Stability (3.2.S.7)

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 General properties (3.2.S.1.3)

 The grade claimed for the API is not clearly stated.

It should be clearly indicated in the APIMF if the micronized

grade is claimed for the API.

This is important because micronization can affect

chemical stability of the API.

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 General properties (3.2.S.1.3)

If the micronized grade is claimed:

- The micronization process should be described in section

3.2.S.2.2

- The manufacturing site where micronization takes place

should be indicated – GMP compliance

- Particle size distribution criteria should be stated

- Determination of polymorphism should be post-micronization

- Batch release and stability data from micronized batches

should be provided

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 General properties (3.2.S.1.3)

- Different grades of the same API can be included in the

same APIMF.

- If the APIMF supports a prequalified API, then separate

entries will be made on the WHO List of Prequalified APIs
and separate CPQs will be issued. Ex: WHOAPI-995a
WHOAPI-995b
- We prefer that separate API specifications, clearly
labelled, are provided for the different grades of the API.

- The retest period of a micronized API starts from the date

of production of the non-micronized API.

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 General properties (3.2.S.1.3)

Detailed information on the requirements for micronized

APIS:

FAQ : Active Pharmaceutical Ingredient micronization

(15 April 2019)

https://extranet.who.int/pqweb/sites/default/files/documents/160%20FAQ_Micro
nization_Sept2019_newtempl.pdf

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 Manufacturing process (3.2.S.2.2)

 The manufacturing process of the API is not well

described.

- The description of the manufacturing process should

include the chemical names of all the materials used and
the corresponding quantities.

- The operating conditions and yield ranges should be

indicated.

- Same level of details is requested for outsourced

intermediates.

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 Manufacturing process (3.2.S.2.2)

 Use of recovered solvents not stated/not well

justified.

- If recovery of solvents occurs, recovery process should

be properly described

- The ratio of fresh/recovered solvent should be indicated.

- Supporting batch data of API batches should be

provided.

- Specifications for recovered solvents should be

provided.

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 Manufacturing process (3.2.S.2.2)

 Information on reprocessing/reworking.

- Reprocessing as a repetition of a process step to

enhance purity is acceptable.

- The steps where reprocessing may occur should be

identified.

- Reworking implies the use of a different process or

different reagents that are not defined in the main
process and should not be included in the APIMF.

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 Control of materials (3.2.S.2.3)

 The selection of the SM is not acceptable/not justified.

- Introduction of the starting material is the starting point for

GMP.

- The starting material must be selected correctly in order to

ensure the quality of the API.

- A proper justification based on ICHQ11 should be

provided.

- The justification should include each of the general

principles from ICHQ11
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 Control of materials (3.2.S.2.3)

 The selection of the SM is not acceptable/not justified.

A corrected selected SM will:

- ensure a sufficient amount of the synthesis is provided in

the APIMF to judge the acceptability and controls of the
API (impurities may carried over to the final API)

- ensure a sufficient number of manufacturing steps are

undertaken under GMP

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 Control of materials (3.2.S.2.3)
 The selection of the SM is not acceptable/not justified.

Consequences:

If the proposed SM is not acceptable, redefinition of the SM

is requested.

The manufacturer of a non-accepted SM becomes an

intermediate manufacturer (external) and that means that:
- The site should be GMP compliant
- Sections of the APIMF need to be revised and the
information in the restricted part of the APIMF needs to be
reorganised.

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 Control of materials (3.2.S.2.3)

Guidance documents for the selection of SM:

ICHQ11: Development and manufacture of drug substances

(May 2012)

Q&A document for ICHQ11 (August 2017)

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 Control of intermediates (3.2.S.2.4)

 Complexity of the process

We have noticed an escalation in complexity in the

manufacturing processes…

Traditionally, the API manufacturers produced the API from

raw materials from their own facility

RAW MATERIALS FINAL API

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 Control of intermediates (3.2.S.2.4)

2 suppliers for SM A
Final API 4 suppliers for SM B
2 suppliers for intermediate

Intermediate

Intermediate Supplier 1 Intermediate Supplier 2

Starting material A Starting material B Starting material A Starting material B

SM Supplier 1 SM Supplier 1 SM Supplier 2 SM Supplier 1 SM Supplier 1 SM Supplier 2

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 Control of intermediates (3.2.S.2.4)

 Complexity of the process

- We do not accept different SMs selections for

intermediate manufacturers in the same APIMF.

- In the same APIMF the preparation of the intermediate

should be essentially the same, irrespective of the
source.

- For each intermediate manufacturer, detailed information

about the preparation, materials and controls should be
included in the APIMF.

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 Characterization (3.2.S.3.1)

 No information on the potential formation of

polymorphic forms is provided.

Polymorphic forms may have different chemical and

physical properties that can have a direct impact in the
properties of the FPP, such as stability, dissolution and
bioavailability.

It should be indicated if the API exhibits or not

polymorphism.

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 Characterization (3.2.S.3.1)

API manufacturers are expected to have adequate

knowledge about the polymorphism of the API.

You should provide information on the potential for forming

other polymorphs, if applicable.

- Information in literature
- Experimental investigations

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 Characterization (3.2.S.3.1)
If the API exhibits polymorphism:
Highly soluble API Non-highly soluble API

- The polymorphic form should be - The polymorphic form should be

stated and characterized sated and characterized
- Consistency of production of the - Consistency of production of the
polymorphic form should be polymorphic form should be
demonstrated demonstrated
- Stability of the polymorph should
be demonstrated
- Test for polymorphism to be
included in the API specification

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 Control of impurities (3.2.S.3.2)
 Insufficient discussion on potential impurities
Impurities from Reagents
API starting material
the SM Solvents
Catalysts

Residue of Reagents
API intermediate Solvents
intermediate;
By-products Catalysts

By-products Crude API

Crystallization solvent
Degradation
products FINAL API

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 Control of impurities (3.2.S.3.2)

 Insufficient discussion on potential impurities

The discussion should include all the potential impurities:
organic impurities, inorganic impurities, residual solvents,
genotoxins.

The carry-over of the potential impurities into the final API

should be discussed.

 Levels of the impurity in the final API

 A control strategy should be proposed

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 Control of impurities (3.2.S.3.2)

If absence of the impurity is not demonstrated a limit

should be included in the API specification. The limits
should be justified.

- Limits in a recognised monograph – If it is a specified

impurity
- ICHQ3A for organic impurities
- ICHQ3C for residual solvents
- ICHQ3D for elemental impurities
- ICHM7 for genotoxic impurities

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 Control of impurities (3.2.S.3.2)

Compendial API

The discussion of a pharmacopoeial API should not be

limited to the impurities specified in the monograph.

- Monographs are developed based upon how the API was

prepared historically.

- A particular manufacturing method may lead to

unexpected impurities, due to the use of a different route
of synthesis or different reagents or may justify excluding
some of the impurities listed in the monograph.

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 Control of impurities (3.2.S.3.2)

 Information on elemental impurities

ICHQ3D guideline was implemented in Europe in June 2016.

It presents a process to assess and control elemental impurities
using the principles of risk assessment. The scope of the
guideline is the drug product.

PQT adopted in May 2018 the ICHQ3D guideline for the

assessment of the elemental impurities information in APIMFs.
https://extranet.who.int/pqweb/sites/default/files/documents/161
%20ICHQ3D_Guideline_Oct2019_newtempl_0.pdf

It is not a mandatory requirement for APIMFs.

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 Control of impurities (3.2.S.3.2)
 Information on elemental impurities
New application: 2 options of API manufacturers:
- Option 1: do not provide a risk management summary (RMS) on
elemental impurities

- Option 2: provide a risk management summary (RMS) on elemental

impurities
The selected option should be indicated in the application form

Accepted APIMFs: amendment application to submit RMS

https://extranet.who.int/pqweb/sites/default/files/documents/30_AmendmentGuidance_Oct2019_newt
empl_0.pdf

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 Control of impurities (3.2.S.3.2)
 Information on elemental impurities

OPTION 1: No RMS is provided

- Carry-over discussion on the elemental impurities used in the

manufacturing process.
Batch data should be provided.
- Control strategy should be justified.
- Limits justified.

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 Control of impurities (3.2.S.3.2)
 Information on elemental impurities

OPTION 2: RMS is provided

- Screening of impurities is not sufficient. A proper discussion about
the elemental impurities including all the potential sources of
elemental impurities should be provided (i.e. materials used, water,
equipment, packaging etc)

Batch data should be provided

- Control strategy should be justified.

- Limits justified based on the route of administration.

Worst case scenario to be considered.

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 Control of impurities (3.2.S.3.2)

 Information on elemental impurities

Regardless the option:

If an elemental impurity is above 30% the acceptable limit in the

final API: ROUTINE TEST

If it is below 30% of the acceptable limit: NO TEST REQUIRED,

unless the elemental impurity is used in the last step: Skip test

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 Control of impurities (3.2.S.3.2)

 Information on potential genotoxic impurities (GI)

The applicant should perform an investigation on the

potential genotoxic impurities.

- Known mutagenic impurities

- Impurities containing a structural alert should be

identified and classified in line with ICHM7 (class 1 to 5)

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 Control of impurities (3.2.S.3.2)

 Information on GI: control strategy for genotoxic

impurities not well justified
As stated in ICHM7 there are 4 options approaches to
develop a control strategy for genotoxic impurities:
Option 1: control of the GI in the API specification at the acceptable limit
Option 2: control of the GI in SM /intermediate or as in-process control at or
below the acceptable limit
Option 3: control of the GI in the SM/ intermediate or as in-process control
above the acceptable limit.
Option 4: no control of the GI.

The control strategy should be well justified and supported

by batch data.

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 Control of impurities (3.2.S.3.2)

 Information on GI: limits not well justified

The limit for GI has to be calculated as follows:

Limit (ppm) =

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 Control of impurities (3.2.S.3.2)

Acceptable intakes based on LTL (“less than lifetime”)

concept.

 The duration of the treatment

 The maximum daily dose (MDD) of the API

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 Control of impurities (3.2.S.3.2)
 Nitrosamines

- Medicines Regulatory Authorities first became aware of

the presence of nitrosamine impurity, N-
nitrosodimethylamine (NDMA), in products containing
valsartan in July 2018.

- Nitrosamines refer to any molecule containing the

nitroso functional group bonded to an amine and belong
to the so-called “cohort of concern” (ICHM7), which is a
group of highly potent mutagenic carcinogens.

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 Control of impurities (3.2.S.3.2)
 Nitrosamines

- Can be formed during production:

Presence of 2ary/3ary/4ary amines and NaNO2 under

acidic conditions

* source: https://www.fda.gov/media/141720/download

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 Control of impurities (3.2.S.3.2)
 Nitrosamines

- Nitrosamines can also be carried over during the manufacturing

process when using already-contaminated equipment or
contaminated solvents and reagents.

- They can also be formed as degradation products.

- Medicines regulatory authorities have described possible root

causes for nitrosamines (EMA and US FDA guidelines)

- Discussions are ongoing (new root causes; acceptable intakes)

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 Control of impurities (3.2.S.3.2)
 Nitrosamines
- In PQ, since April 2020, we request the APIMF holders to
conduct a risk assessment to determine the likelihood of the
presence of nitrosamines.

- If a risk is identified, the presence of the nitrosamine has to be

confirmed through confirmatory testing using sensitive and
appropriately validated methods.

- If the impurity is confirmed to be present, the root cause

needs to be investigated and the manufacturers need to
implement changes to reduce or prevent it.

- For APIMFs submitted after 31 Dec 2020 the risk assessment

should be provided with the submission.

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 Control of impurities (3.2.S.3.2)
 Nitrosamines
The following acceptable intakes have been adopted by
regulators for some specific nitrosamines:

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 Control of impurities (3.2.S.3.2)
 Nitrosamines
Challenges:

• Method sensitivity (specially for high daily dose medicines).

• Acceptable long-term exposure when they cannot be kept

below the limits (i.e. impact on benefit/risk balance).

• Other nitrosamines are possible!

Applicants should assess their own manufacturing processes
(see root-causes in EMA CHMP assessment report dated
June 2020 and also USFDA guidance dated Sep 2020).

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 Control of impurities (3.2.S.3.2)

Guidance on root causes, control and mitigation measures

in EMA and US FDA websites:

https://www.ema.europa.eu/en/human-regulatory/post-
authorisation/referral-procedures/nitrosamine-impurities

https://www.fda.gov/drugs/drug-safety-and-availability/information-
about-nitrosamine-impurities-medications

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 Control of impurities (3.2.S.3.2)
 Nitrosamines
Within PQT nitrosamines risk has been confirmed in APIs:

- Rifapentine
- Rifampicin
https://extranet.who.int/pqweb/sites/default/files/documents/FAQ_Nitrosamine_18Dec2020.pdf

https://extranet.who.int/pqweb/news/nitrosamine-concerns-rifampicin-products-update

https://extranet.who.int/pqweb/news/nitrosamine-concerns-rifapentine-products-update

PQT continues to assess the information on nitrosamine impurities in

APIs, following root-causes identified in EMA and US FDA guidance.

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 Control of impurities (3.2.S.3.2)
 Nitrosamines
As Ph.Int monographs get updated, information regarding
nitrosamines is going to be added, where relevant.

Rifampicin monograph: a method to test impurity MeNP is under

development and once finalized, reference to this method will be put
in the monograph.

General monographs regarding control of nitrosamine impurities have

been published:
- Ph.Eur.: 2.5.42. N-nitrosamines in Active Substances
- USP: <1469> Nitrosamine impurities

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 Specifications and control of the API (3.2.S.4.1)
 API specifications are not acceptable

- The version number of the API specification is missing

There has to be a version number in the API specification
to ensure traceability of testing requirements in case of
GMP inspections and future variations.

- The API specification should include reference to the analytical

procedures and whether they are compendial or not.

PQ only recognise Ph.Int.; USP; Ph.Eur; BP; JP

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 Specifications and control of the API (3.2.S.4.1)

Limits for “specified impurities”, “any unspecified impurity” and

“total impurities” should be included in the API specifications.

ICHQ3A limits, based on the MDD are generally required:

Specified impurities: known impurities qualified or ≤ ICH qualification threshold

Unspecified impurities: unknown impurities ≤ ICH identification threshold
Total impurities: sum of impurities > ICH reporting threshold

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 Specifications and control of the API (3.2.S.4.1)

EXAMPLE

Darunavir MDD = 1200 mg/day

Identification threshold? Qualification threshold?

0.10 % of 1200 mg = 1.2 mg > 1.0 mg 0.15 % of 1200 mg = 1.8 mg > 1.0 mg
1.2 mg 0.10% 1.8 mg 0.15%
1.0 mg 0.08% 1.0 mg 0.08%

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 Specifications and control of the API (3.2.S.4.3)

 The validation of analytical procedures is not sufficient.

- All non-pharmacopoeial methods must be fully

validated, particularly assay, related substances and
residual solvents methods.

- Validation of analytical procedures should be performed

in line with ICHQ2.

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 Specifications and control of the API (3.2.S.4.3)
 The validation of analytical procedures is not
sufficient.

- For the pharmacopoeial methods for related

substances, it should be verified if the method can detect
specific impurities related to the process and not
covered in the monograph, if applicable.

- If the applicant claims an officially compendial standard

for the API (e.g. Ph.Int, USP, Ph.Eur) but uses an in-
house method instead of the compendial method, cross
validation data should be provided to show that the in-
house method and the compendial method are
equivalent.

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 Stability (3.2.S.7)

 Long term stability studies have not been conducted

at 30°C

PQ requirement is that long-term stability studies should be

conducted at either 30ºC/65%RH or 30ºC/75%RH.

If such data is not available then a commitment to

commence stability trials at these conditions is required.

Once the stability data at 30°C are available the applicant

should submit an amendment application to change the
storage conditions to store below 30°C.

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 Stability (3.2.S.7)
 No storage conditions are proposed or the storage
conditions are not acceptable.
A storage temperature must be specified.

WHO storage conditions are:

- Do not store above 30°C
- Do not store above 25°C
- Store between 2°- 8°C
The ancillary statements “protect from moisture” ; “protect from
light” should also be considered.
Some variation in expression is permitted for labelling, but the WHO
statement will be used for publishing purposes.

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 Stability (3.2.S.7)

 No storage conditions are proposed or the storage

conditions are not acceptable.
“Protect from moisture”
Humidity conditions of long term stability studies
If the long term studies have been conducted at 75% RH,
not required.
If not, this statement should be included in the storage
conditions.
The hygroscopicity of the API should also be considered.
"Store in a tight container” is considered equivalent and it
is acceptable for labelling
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 Stability (3.2.S.7)

 No storage conditions are proposed or the storage

conditions are not acceptable.

“Protect from light”

The results of the photostability studies and/or the
statements included in a recognised monograph should be
considered.

Whether it is stated or not in a recognised monograph,

“protect from light” does not substitute for photostability
studies or light protective packaging.

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 CONCLUSIONS

• This is a summary of the most frequent technical

deficiencies found in the API assessment.

• The quality of the APIs is evolving, and new

requirements and guidance may come up.

• Our goal: to ensure that the API is of the required

quality.

• The process of assessment is affected by the

completeness of data.

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 Thank you for your attention

Any questions?

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for Manufacturers 26-29 September 2022 68
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