THE EUROPEAN

DIRECTORATE FOR THE

QUALITY OF MEDICINES
& HEALTHCARE
(EDQM)
 General overview of the
CEP procedure

Anaïs Bouisseau
Certification of Substances Department, EDQM

Module 5: Fundamentals of the CEP Procedure (Live Webinar)

9th December 2024

2 © EDQM, Council of Europe, 2024. All rights reserved.

Summary

• Background & legal framework

• The CEP procedure
• Comparison between CEP and ASMF procedures
• How to apply for a CEP
• Evaluation of applications and granting of CEPs
• Key figures and information available on EDQM
website

3 © EDQM, Council of Europe, 2024. All rights reserved.

Summary

• Background & legal framework

• The CEP procedure
• Comparison between CEP and ASMF procedures
• How to apply for a CEP
• Evaluation of applications and granting of CEPs
• Key figures and information available on EDQM
website

4 © EDQM, Council of Europe, 2024. All rights reserved.

Certification – Background
• CEP = Certificate of Suitability to the monographs of the European
Pharmacopoeia
• The procedure for the CEPs was established in 1994 and was initially
only applicable to pharmaceutical substances
• In 1999, the procedure was extended to include products with a risk of
transmissible spongiform encephalopathy (TSE)
• The procedure was further revised to allow for the control of herbal
drugs and herbal drug preparations

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EU legislation and Certificates of Suitability (CEP)
• EU Directive 2001/83/EC (human) and amendment
2003/63/EC state that active substances should comply
with the Ph. Eur monograph if there is one

…“where the active substance is the subject of a monograph of the Ph. Eur, the applicant can apply for a
certificate of suitability that, where granted by the EDQM, shall be presented in the relevant section of the
CTD Module. Those certificates of suitability …are deemed to replace the relevant data of the corresponding
• sections described in the Module…”

… “i n cases where a specification contained in a European Pharmacopeia monograph might be

insufficient to ensure the quality of the substance (new impurities), the competent authorities may request
more appropriate specifications from the marketing authorisation holder.”

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Summary

• Background & legal framework

• The CEP procedure
• Comparison between CEP and ASMF procedures
• How to apply for a CEP
• Evaluation of applications and granting of CEPs
• Key figures and information available on EDQM
website

7 © EDQM, Council of Europe, 2024. All rights reserved.

 Governing document for the Certification procedure
• Resolution AP-CSP(07) 1 on the "Certification of Suitability to the
Monographs of the European Pharmacopoeia” and adopted by the
Public Health Committee of the Council of Europe

• Describes the process for the procedure

• Available on the EDQM website ([Link])

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 Scope of the procedure
• Substances described in monographs in the Ph. Eur. (active substances,
excipients, herbal drugs)
→ “Chemical” or “Herbal” CEP

• Products with risk of TSE (SM, intermediates, reagents,..)

→ “TSE” CEP

A CEP does not replace a certificate of analysis.

A CEP does not replace the QP declaration.

A CEP is not a GMP certificate.

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 Scope of the procedure
• Substances described in monographs in the Ph. Eur. (active substances,
excipients, herbal drugs)
→ “Chemical” or “Herbal” CEP

• Products with risk of TSE (SM, intermediates, reagents,..)

→ “TSE” CEP

• Open to any manufacturer of pharmaceutical

substances regardless of geographical origin

• CEPs are recognised by all member states of the

Council of Europe and the European Union. They are
also recognised by other countries such as Canada and
Australia.
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Out of Scope of the CEP Procedure
• Substances not included in Ph. Eur. (except TSE CEP)
• Substances which do not comply with the Definition section of the
monograph, if applicable
• Biologicals and products extracted from animal tissues
• Human tissues derivatives, blood derivatives, vaccines
• Finished products

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The CEP procedure
• A CEP is intended to demonstrate that the quality of a given substance can be
suitably controlled by the relevant Ph. Eur. monograph(s), with additional tests if
necessary

• An international platform for:

➢ Assessment of the quality of substances for pharmaceutical use (mainly
APIs), with reference to monographs of the Ph. Eur.
➢ Source of information to update Ph. Eur. monographs
➢ Centralised assessment
➢ Facilitates management of MAAs and variations
➢ Coordination and conduct of GMP inspections of API manufacturers

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Summary

• Background & legal framework

• The CEP procedure
• Comparison between CEP and ASMF procedures
• How to apply for a CEP
• Evaluation of applications and granting of CEPs
• Key figures and information available on EDQM
website

13 © EDQM, Council of Europe, 2024. All rights reserved.

CEP and ASMF procedures
• Drug substance documentation is an integral part of a marketing authorisation
application
• Based on EU NfG « Summary of requirements for active substances in
the quality part of the dossier », the applicant can choose the way to provide
data on the quality of an active substance:
➢ Certificate of suitability

➢ Active substance Master File (ASMF)

➢ Full details of manufacture in marketing authorisation application

• The data to be submitted are the same, regardless of the option selected

CEPs are not mandatory, but generally avoid any

subsequent reassessment
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Comparison between CEP & ASMF procedures

CEP procedure ASMF procedure

Purpose ➢ The CEP is independent from MAA The ASMF is submitted in the context of a
➢ It confirms that the active substance specific MAA for medicinal products
complies with European Pharmacopoeia
requirements

Scope of material Pharmacopoeial substances only Active substances only

➢ Active substances or excipients ➢ New chemical entities
➢ Any substance for TSE CEP ➢ Existing substances

Dossier ➢ Content identical (CTD 3.2.S) ➢ Content identical (CTD 3.2.S)

➢ Full dossier sent directly by the ➢ AP sent to the marketing authorisation
manufacturer to EDQM (will generally be holder of medicinal product and the full
the holder of the CEP) dossier is submitted to the competent
authorities (NCA / EMA)

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Comparison between CEP & ASMF procedures

CEP procedure ASMF procedure

Evaluation ➢ Single evaluation centralised at EDQM ➢ Multiple evaluations
➢ Assessment is performed by assessors from ➢ Assessment of ASMF by each competent
Competent Authorities appointed by the authority in the context of assessing a
Certification Steering Committee specific marketing authorisation
➢ The pool of assessors is a mix of EDQM and application or variation for medicinal
assessors from NCA products

Evaluation Assessment against: Assessment against:

references and ➢ ICH/EU guidelines for quality ➢ ICH/EU guidelines for quality
principles ➢ Ph. Eur monographs ➢ Ph. Eur monographs (if applicable)
➢ EDQM specific guidance

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Comparison between CEP & ASMF procedures

CEP procedure ASMF procedure

Deliverable ➢ The Certificate is granted to the CEP holder A Marketing Authorisation for the
(usually API manufacturer) medicinal product using this particular
➢ CEP holder can provide a copy to their API
customers (users of the substance)

Variations ➢ Changes to the CEP dossier centralised at Submission of changes to marketing

EDQM authorisation applications, according
➢ Submission of revised CEPs according to to EU Variations regulation
EU Variations regulation
Use ➢ Ph. Eur member states (including the UK) ➢ EU/EEA member states
➢ others (Australia, Canada, New Zealand, ➢ UK
Tunisia, Morocco, Singapore, South ➢ Australia and Canada
Africa, Saudi Arabia, etc)

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Worksharing and cooperation accross Europe
• Holder’s commitment / Annex 7 of the CEP application form foresees
sharing EDQM assessment reports with:
₋ National Competent Authorities of the Ph. Eur. member states
₋ EMA including all CHMP and CVMP Members and their experts

₋ Competent Authorities of countries with whom EDQM has a Memorandum of

Understanding and/or Confidentiality Agreement in place (list on the EDQM
website)

• ASMF reports may also be made available for EDQM

(see NfG ASMF procedure CHMP/QWP/227/02 Rev 3 corr).

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Summary

• Background & legal framework

• The CEP procedure
• Comparison between CEP and ASMF procedures
• How to apply for a CEP
• Evaluation of applications and granting of CEPs
• Key figures and information available on EDQM
website

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How to apply for a (new) CEP
• Application form (for new applications) available on the EDQM
website. It contains tables to be filled in, statements and
declarations to be signed.
• Last version of this application form (June 2023) should be used.
• Fees:

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How to apply for a CEP
• When the product is already covered by an ASMF this information should be shared
as it can speed up the evaluation :

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 How to apply for a CEP
• Quality Overall Summary : new template available from January 2024
- Mandatory component of the CEP application
- Gives a concise overview of the technical dossier
- Highlights the control strategy applied

Template for Quality Overall Summary to be submitted for Certification applications (PA/PH/CEP (15) 26
1R, January 2024)
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How to apply for a CEP
• Dossier in English (preferably) or French

• Content in compliance with:

- EDQM guideline « Content of the Dossier for Chemical CEP": comparable to ASMF or 3.2.S of
CTD
- For TSE risk CEP: requirements from Ph. Eur. general text, 5.2.8 and "Content of the dossier for
TSE risk"
- "Content of the dossier for herbal drugs/herbal drug preparations"
- "Content of the dossier for sterile substances"

• Electronic submissions for any applications (NDOS/Rev/Renewal): in eCTD only

- via CESP, register for a CESP account on the Heads of Medicines Agencies website

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Summary

• Background & legal framework

• The CEP procedure
• Comparison between CEP and ASMF procedures
• How to apply for a CEP
• Evaluation of applications and granting of CEPs
• Key figures and information available on EDQM
website

24 © EDQM, Council of Europe, 2024. All rights reserved.

How it works

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How it works
Submission of responses in additional rounds of assessment

After an assessment, the EDQM may send to a company a request for additional information, for clarification or for
dossier update.

According to the EDQM policy document PA/PH/CEP (10) 85 “Changes to Submitted Documentation No Longer
Accepted During the Assessment Phase” the company’s response to such EDQM letters:
- should contain only information requested by EDQM
- should not contain any additional changes introduced within the responses not related to the questions asked
by EDQM and omitted to be submitted in the initial round

Exceptions can be accepted only in cases of:

- administrative changes of company names/addresses
- dossier update after a revision of the monograph
- submission of stability data which would support longer re-test periods

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 How long it takes
For a new CEP application:

Management of applications for new Certificates of Suitability, Requests for Revision or Renewal
of Certificates of Suitability and applications using the ‘sister files’ procedure (PA/PH/CEP (13)
110, 3 R, November 2021)
We are still experiencing some delays

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 Who performs the evaluation?
✓ Assessors are proposed by National Competent Authorities and appointed by the CEP
Steering Committee; EDQM assessors, also appointed by the Steering Committee

✓ New applications areassessed by 2 assessors: most commonly one from EDQM and
one from NCA from Ph. Eur. member states and beyond

✓ About 100 assessors from authorities from 25 countries, including Canada

• Skilled in the relevant domain (chemical evaluation, TSE risk, herbal products,
toxicologists)

• Come regularly to EDQM premises for the evaluation of dossiers

• Procedure for remote evaluations introduced in 2020 (due to Covid-19 pandemic)

A great and successful example
of international cooperation!

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 Sister files
• A company holding a CEP may wish to apply for another CEP for the
same substance  sister file

• Documents available on the EDQM website :

❖ Management of applications for new Certificates of Suitability, Requests for
Revision or Renewal of Certificates of Suitability and applications using the
‘sister files’ procedure
❖ Guidance on applications for «sister files»

Fast track procedure

Harmonised assessments

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Summary

• Background & legal framework

• The CEP procedure
• Comparison between CEP and ASMF procedures
• How to apply for a CEP
• Evaluation of applications and granting of CEPs
• Key figures and information available on EDQM
website

30 © EDQM, Council of Europe, 2024. All rights reserved.

Key figures
• Since 1994, close to 9000 CEP
applications received for nearly 1500
different substances

• Currently more more than 6500

valid CEPs

• About 1500 manufacturers from >50

different countries (50% in India and
China)

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 Keep up-to-date with CEP activities
• EDQM Website ([Link]) > Medicines > Certification of Suitability

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Communication with EDQM

• General questions on CEPs: Look at the FAQs and if necessary

use EDQM Helpdesk

• For queries specific to applications : via the email address

included in EDQM communication

• Technical Advice: to meet the EDQM staff and get advice about
applications (fee applicable)

33 © EDQM, Council of Europe, 2024. All rights reserved.

 - Use of a CEP -
Ekaterina Nagdiyev
EDQM, Certification of Substances Department

2024 EDQM virtual training program:

Module 5: Fundamentals of the CEP Procedure
9th December 2024

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Content
1. Aim and scope of EDQM public document PA/PH/CEP (15) 31
“How to read a CEP” (April 2018, currently under revision)
2. How to interpret the information laid down on chemical CEPs -
Practical examples
3. Highlight of the most important changes following the
implementation of “CEP 2.0”
4. How to use the CEP in marketing authorisation applications

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 How to read a CEP
EDQM public document PA/PH/CEP (15) 31 How to read a CEP describes the information stated on a
Certificate of suitability to the monographs of the European Pharmacopoeia (CEP) and clarifies how it should
be interpreted by industry and competent authorities.

It does not cover the use of a CEP in the context of a Marketing Authorisation Application (MAA),
where a CEP is used to replace the quality part of the CTD dossier related to that given source of
the substance, or in any variation. QWP Q&A How to use a CEP in the MAA and MAV: Link
Link

It does not contain new information or new instructions, but it is rather a compilation of
information currently spread in other EDQM guidelines/policy documents.

It should be read in conjunction with other applicable EDQM Certification Policy Documents and
Guidelines.

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Types of CEP
• A chemical or an herbal CEP certifies that the quality of the substance is suitably
controlled by the Ph. Eur. monograph and any supplementary tests deemed
necessary in line with ICH and EMA guidelines (mentioned on the CEP).

• A TSE CEP certifies that the substance complies with the Ph. Eur. General Chapter
5.2.8 on minimising the TSE risk. It does not certify that the quality of the
substance is suitably controlled by a specific Ph. Eur. Monograph.

• A CEP does not replace a certificate of analysis.

• A CEP does not replace the QP declaration.
• A CEP is not a GMP certificate

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 How to interpret the information laid down on
each type of CEP

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Formats of CEPs (all types of CEP):
In September 2023, major changes were introduced to CEP document, which resulted in 3 different formats:
“CEP 2.0”, “old CEP” and “hybrid CEP”:

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CEP declaration of access / LoA (all types of CEP):
• The CEP holder authorises its customers to use the CEP in support of a
MAA for a particular product(s):
➢by filling in a letter of access (for CEP 2.0 and hybrid CEP, template is available on
EDQM website), which is provided together with a copy of CEP received from the
EDQM
➢ by filling in a CEP declaration of access or “box of access” (for old CEP) on a copy of
CEP in old format received from the EDQM

• CEP is accepted in all Ph. Eur. Convention member states + other countries
(e.g. Canada, Australia, Singapore, South Africa, etc.)

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Communication CEP holder / MAH
• Communication between CEP holder and drug product manufacturer /
MAH is key:
➢MAHs are ultimately responsible for the quality of APIs used in their finished
product and are legally obliged to get information they need to take this
responsibility.
➢API manufacturers should be supportive to their customers and share
information.
• EDQM Policy document PA/PH/CEP (21) 57 “CEP holders' responsibilities towards
their customer” (January 2022)
• EDQM continues working with stakeholders to promote better sharing of
information

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 Information on a
CHEMICAL CEP

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Subtitle (optional)
• A CEP can cover specific physico-chemical characteristics of a substance (e.g.
specific polymorphic form or particle size distribution) or its sterility. These are
mentioned on a CEP as subtitle.
• A subtitle can also be used to differentiate CEP applications for the same substance
from the same holder (e.g. “process B” or “produced in site X”).
• In addition, a subtitle is also used to reflect on the CEP the requirements of the
“labelling” section of the monograph, where applicable (e.g. presence of
antioxidant for an API-mix)
• A grade (e.g. micronised, polymorphic form) is mentioned on the CEP as subtitle,
only if:

1. requested* by the CEP holder (application form)

2. accepted* during the CEP evaluation procedure

* in line with EDQM policy document PA/PH/CEP (04) 1 « Content of the Dossier for Chemical
Purity and Microbiological Quality »

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 Subtitle (examples)
- If a subtitle is requested and accepted by the EDQM, the corresponding quality
attribute(s) are included in the specification appended to CEP (CEP 2.0) or mentioned
on CEP (hybrid and old CEP) + analytical method(s) are annexed to CEP
- A CEP may mention more than one grade provided that they have the same impurity
profile; otherwise, separate CEPs will be issued
Examples:
Micronised, non-micronised: data related to determination of particle size (e.g. microscopy, laser
diffraction spectroscopy) are assessed by EDQM
Polymorphic form: Data concerning elucidation of the polymorphic form (e.g. XRPD, DSC, IR) are
assessed by EDQM

What does it mean if a CEP has NO subtitle ?

Data relative to a particular grade are not included in the CEP dossier OR the CEP holder has not
applied for a subtitle.

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Manufacturing sites

Sites (name + address) are mentioned according to their roles:

• CEP holder
• Intermediates manufacturer(s)
• Substance manufacturer(s)
starting material manufacturers are NOT mentioned on a CEP
Additional sites, when applicable (subtitle), even if already listed as manufacturers
(CEP 2.0 change):
• Site(s) of physical treatment
• Site(s) of micronisation
• Site(s) of sterilisation

SPOR/OMS Loc and Org IDs are mandatory for all sites in all CEP
applications

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Production sites are mentioned in Annex 1 of the CEP:

Name of the intermediate(s) is

not specified on the annex

The CEP does not distinguish

which manufacturer produces
which intermediate
(if more than one intermediate
is involved)

CEP user should communicate with CEP holder to obtain more

details on intermediates and manufacturers

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Contents of CEPs: Specification (CEP 2.0)
• Specification of the substance is appended to the CEP
• Specification should be based on the corresponding Ph. Eur. monograph, ICH and
EMA guidelines. Compliance of these tests is checked and approved during CEP
evaluation procedure
• Specification includes limits for related substances as foreseen by Ph. Eur. monograph
+ additional process-related impurities (not mentioned Ph. Eur.), if needed
• Quality attributes, acceptance criteria and reference to test procedures (e.g. Ph. Eur.
or in-house) are included in the specification table
• Specification may include information on skip testing if it is foreseen by the
corresponding ICH or EMA guidelines (e.g. elemental impurities in line with ICH Q3D,
mutagenic impurities in line with ICH M7, nitrosamine impurities in line with
EMA/425645/2020)

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Contents of CEPs: Test Procedures (CEP 2.0, hybrid and old CEP)
• Alternative test procedures to those described in Ph. Eur. monograph (e.g.
developed in-house or taken from another pharmacopoeia) may be used
provided that these are at least equivalent to those of Ph. Eur. monograph
➢ The in-house method should be cross-validated against the Ph. Eur. method
➢ This is assessed by EDQM

• When Ph. Eur. monograph is demonstrated to be suitable to control the quality

attribute, the in-house test procedures are not appended to CEP
• For quality attributes not covered by Ph. Eur. monograph but which are needed
to control the quality of the substance, company’s in-house test procedures are
appended to the CEP (e.g. GC for residual solvents, ICP-MS for elemental
impurities)
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Impurities statements (old and hybrid CEPs)
For hybrid and old CEPs, full substance specification is not annexed to the CEP.
Tests required in addition to the corresponding Ph. Eur. monograph are reported on the CEP.
Limits for “additional related substances” to those already listed in the Ph. Eur.
monograph); 2 cases possible:
a) If present in the substance above Identification threshold set by Ph. Eur. general
monograph (2034), these impurities are stated on the CEP with specified limits. N.B.: if
they can be controlled by Ph. Eur. test for related substances, no test procedure is
appended to CEP

b) If present in the substance above Reporting threshold set by Ph. Eur. general monograph
(2034), and Ph. Eur. monograph method is not suitable to control them, they are controlled
by a validated in-house method. The limits for these impurities are stated on the CEP and
the in-house method is appended to the CEP
Impurity X not more than 0.10%

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Impurities statements (CEP 2.0, old and hybrid CEPs)
Limits for “unspecified impurities”
➢ When the current Ph. Eur. monograph does not include a limit for unspecified
impurities (this is still the case in some old monographs; they are progressively revised).
➢ Such a limit has to be introduced in the specification and included on the CEP (limit to be
set in line with Ph. Eur. general monograph (2034).

➢ For CEP 2.0, the limit for unspecified impurities is transparent from the specification
appended to the CEP.

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Impurities statements (old and hybrid CEPs)
What does it mean when the method for related substances is “replaced”?
➢ If Ph. Eur. monograph describes a non-quantitative method (e.g. TLC) for
related substances => the manufacturer should replace it by a quantitative
validated in-house method, which is appended to CEP

NOTE: a TLC method is nevertheless acceptable for the control of one specified impurity, but not as
control method for all related substances.

The statement on the CEP will read as follows :

Impurity XXX

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Mutagenic impurities on the CEP

• A mutagenic impurity is limited on the CEP (or in its specification appended to the
CEP) when it is present or potentially present in the substance.
• The limit proposed by the applicant is assessed and accepted at EDQM in line with
the ICH M7 requirements.
• If the Ph. Eur. method is not suitable to control this impurity, the in-house method is
annexed to the CEP.

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Mutagenic impurities on the CEP

What does it mean if no mutagenic impurities are limited on the

CEP?
- There are NO potential mutagenic impurities formed/introduced in the route of
synthesis proposed by the API manufacturer.
OR
- There are potential mutagenic impurities, and the control strategy put in place by the
manufacturer enables NOT including a limit in the final substance specification (in
line with ICH M7).
OR
- They are controlled by the monograph.

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Residual solvents (old and hybrid CEPs)
Solvent used in the last step
of the substance YES
manufacturing process?

Which solvents are mentioned on a CEP? NO

those likely to be present in the substance

Residual levels in the
AND substance above 10% of ICH Solvent
limit* (or 30% for class 1 YES limited on
those used in the last step solvents) the CEP
*ICH Q3C
NO Option 1 limit

Solvent is considered
absent in the substance and
it is NOT limited on CEP

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Residual solvents (old and hybrid CEPs)
What are the limits mentioned on the CEP for solvents?
Limits proposed by the manufacturer, as assessed and accepted by the EDQM.

a) Limits on a CEP are mostly those of ICH Q3C Option 1:

b) Sometimes limits are tighter than ICH Q3C Option 1:

c) Exceptionally, higher limits than ICH Q3C Option 1 are acceptable if suitably justified (e.g. Option 2,
this is made transparent on CEP).

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Residual solvents (old and hybrid CEPs)
When is a Loss on drying test mentioned on the CEP?

a) When LOD test is included in the Ph. Eur. monograph (limit: NMT 0.5%) and class 3 solvents
are likely to be present in the substance:

b) When LOD test is NOT included the Ph. Eur. monograph and manufacturer uses LOD test of
Ph. Eur. 2.2.32 (limit: NMT 0.5%) to control water and class 3 solvents:

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Residual solvents (old and hybrid CEPs) - Example:
Applicant’s specification:

However, the CEP mentions only this:

Why? Acetone and methanol are used in the last purification step. All other solvents are used ealier
in the process and found < 10% of ICH Q3C Option 1 limit in the substance. In addition Acetone is a
class 3 solvent and there is a test for LOD in Ph. Eur. monograph.

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Residual solvents (CEP 2.0)

• Limits for residual solvents stated in the specification and the corresponding test
procedures appended to the CEP are those proposed by the CEP holder (as
accepted by the EDQM)

Note: If all solvents used in the process are limited in the specification, these controls are appended
to the CEP as part of the specification

• If class 3 solvents used in the last steps of the process are controlled by LOD test
of Ph. Eur. monograph or by Ph. Eur. General chapter 2.2.32 (if LOD test is NOT
included the Ph. Eur. monograph Ph. Eur.), a corresponding statement is
mentioned on CEP

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Residual solvents
When is water mentioned on the CEP?

Water is mentioned on the CEP if used in the last process step(s) → likely to be
present in the substance.

The quality of water (in line with the EMA “Guideline on the quality of water for
pharmaceutical use” EMA/CHMP/CVMP/QWP/496873/2018, i.e. potable water,
purified water, water for injections) is specified on the CEP 2.0

59 © EDQM, Council of Europe, 2024. All rights reserved.

Elemental impurities
• ICH Q3D on elemental impurities has been applied to medicinal products for human use from
September 2016;
• Since January 2021 risk assessment regarding elemental impurities in veterinary medicinal
products should also be performed;
• EDQM public document PA/PH/CEP (16) 23, 2R Implementation of policy on elemental
impurities in the Certification Procedure was published in April 2021;
• EDQM does not make a decision on compliance with ICH Q3D.
• The CEP provides transparency, to be considered by the manufacturer of medicinal product in the
context of a MAA.

60 © EDQM, Council of Europe, 2024. All rights reserved.

Elemental impurities

What is the meaning of the following CEP statements?

a) A RMS is provided by the CEP holder, and its summary is annexed to the CEP with the necessary
information on the level of elemental impurities of the substance
b) RMS reflects the presence/absence of elemental impurities in the final substance

For CEP 2.0:

61 © EDQM, Council of Europe, 2024. All rights reserved.

Elemental impurities

• When a RMS is not provided, the CEP is transparent on the introduction of elemental impurities,
not on their absence/presence.

Note: The applicant might have set a limit in the specification => in this case, test procedure is
annexed.

62 © EDQM, Council of Europe, 2024. All rights reserved.

 Route of
Intentional
administration
introduction

See document
“Implementation of
policy on elemental
impurities in the
Certification
Procedure”
(PA/PH/CEP (16) 23, 2R)

All 24
elemental
impurities as
mentioned Should mention
in ICH Q3D the basis on
which “absence”
of elemental
impurities has
been determined

63 © EDQM, Council of Europe, 2024. All rights reserved.

Omission of Ph. Eur. tests
When it is demonstrated that a test specified in the Ph. Eur. monograph is not
necessary for a named compound because the impurity/solvent/compound cannot
be present with the applied route of synthesis or is not used, the absence of control
may be accepted (when justified).

Note: Omission is acceptable for specific tests to control one or few impurities; however, it does not
apply to the test for related substances.

For CEP 2.0, the omission is transparent from the specification appended to the CEP.

64 © EDQM, Council of Europe, 2024. All rights reserved.

Microbiological quality

Microbiological control generally should not be part of the specification

proposed in a CEP dossier

Microbiological quality is covered by Ph. Eur. general monograph 2034

Substances for pharmaceutical use

Microbiological quality is to be addressed considering the final use of

the substance in the finished medicinal product, and it is for each
national competent authority which receives the CEP in a marketing
authorization application to evaluate this aspect.

65 © EDQM, Council of Europe, 2024. All rights reserved.

Container closure system
The full packaging material (immediate and outer) is described on the CEP even when
no re-test period is requested by the CEP holder.

Examples:

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Retest period (optional but highly recommended)
The CEP statement reflects the fact that the substance is stable
• during XX months mentioned on the CEP
• in the packaging material mentioned on the CEP
• in long term conditions: 25°C ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH
(short term excursions are covered by additional testing at accelerated test conditions)

Different re-test periods and storage conditions can be proposed within one CEP application
(e.g. different re-test period depending on the container closure system or climatic zone).

67 © EDQM, Council of Europe, 2024. All rights reserved.

Retest period
What does it mean if a CEP does NOT indicate a retest period?
• Not requested by the CEP applicant (thus stability data not assessed).

OR

• Requested by the CEP applicant, however stability data presented did not allow
granting a retest period (e.g. insufficient data, invalid data obtained under non-
regulatory storage conditions or under unjustified restrictive storage conditions, OOS
observed, etc.).

Stability data should be evaluated during the assessment of the

MA dossier; alternatively, the finished product manufacturer should
demonstrate that the substance complies with the Ph. Eur.
monograph (and any additional tests in the specification)
immediately before its use.

68 © EDQM, Council of Europe, 2024. All rights reserved.

Storage conditions

• The absence of any specific storage conditions (e.g. temperature) on the CEP means that
the substance is stable under climatic conditions for zone I/II (combination of long-term
and accelerated conditions)
• Why some CEPs indicate specific storage conditions?
➢ either that they are needed to ensure the stability of the substance in the described
container closure system.
➢ or that the CEP holder/applicant is applying stricter storage conditions than those
recommended by EU/ICH guidelines.

Example:

In any case, the re-test period is supported by stability data obtained in the appropriate
conditions.
69 © EDQM, Council of Europe, 2024. All rights reserved.
Material of human/animal origin
CEP applicants have to declare whether any material of human or animal origin is
introduced in the manufacture of the substance

70 © EDQM, Council of Europe, 2024. All rights reserved.

Production section in monographs
Instructions to manufacturers about particular aspects of the manufacturing
process (e.g. source materials, in-process testing or testing to be carried out by
the manufacturer on the product prior to release).

Not all statements of the Production Section can be verified during the CEP
procedure:
No further action needed
during the assessment of
• If assessed: nothing mentioned on the CEP the MA dossier

Information in the
• If not assessed: statement on the CEP Production section is to
be addressed during the
assessment of the MAA

71 © EDQM, Council of Europe, 2024. All rights reserved.

Statements on CEP for a sterile substance

• A “sterility CEP” does not exist on its own.

• Always combined with a Chemical CEP or with a Double CEP (chemical + TSE).

• The CEP includes the typical statements of each type of CEP (as applicable).

The European system requires that sterilisation data should be included in

the MAA even if a CEP for a sterile substance is submitted

72 © EDQM, Council of Europe, 2024. All rights reserved.

Typical sterility related statements
• Subtitle “Sterile”

• Sterilisation method
• Statement regarding compliance with the test for sterility (2.6.1) of the Ph. Eur. (old
CEPs)
• Statement that the sterilisation process has been assessed and accepted (old CEPs)

or

73 © EDQM, Council of Europe, 2024. All rights reserved.

Statements on a TSE CEP
Additional information, as applicable:

• Subtitle (e.g. manufacturing process for gelatin)

• Country(ies) of origin of source materials
• Nature of animal tissues used in manufacture
• Manufacturing process applied (if relevant for the safety of the product e.g.
gelatin)

A TSE CEP does not certify that a particular source of a substance

complies with the corresponding Ph. Eur. monograph for that
substance.
A TSE CEP certifies that the substance is compliant with Ph. Eur.
Monograph 1483 => it is “TSE safe”

74 © EDQM, Council of Europe, 2024. All rights reserved.

Statements on a herbal CEP

For extracts:
• Drug extract ratio (DER) calculated on genuine extract (without excipients)
• Residual solvents with acceptance criteria and control methods if used in last steps
• Extraction solvent(s) used
• Information on excipients used: name and percentage (or statement of non-use of
excipient)

For all:
• Packaging material
• Re-test period if requested by the applicant
• Use/non-use of material of animal or human origin

75 © EDQM, Council of Europe, 2024. All rights reserved.

CEP in a Marketing Authorisation Application in the EU

76 © EDQM, Council of Europe, 2024. All rights reserved.

CEP in a Marketing Authorisation Application outside the EU
• CEPs are accepted in countries outside Europe
• At the discretion of the authorities of those countries
• These authorities decide on the scope of the acceptance of CEPs and the conditions
that may apply, e.g. in addition to the CEP there may be a requirement for provision of
a DMF (open part or full content) or other documents
• Applicants to verify the acceptability and conditions associated with the use of a CEP
in such countries prior to submission

77 © EDQM, Council of Europe, 2024. All rights reserved.

 Thank you for your attention

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