REGULATORY CONSIDERATIONS FOR MANUFACTURING,
PACKAGING AND LABELLING OF PHARMACEUTICALS :

 GUIDELINE ON THE PACKAGING & LABELLING INFORMATION OF MEDICINAL PRODUCTS FOR
HUMAN USE AUTHORISED BY THE UNION
https://ec.europa.eu/health/system/files/2021-
04/2018_packaging_guidelines_en_0.pdf

EUDRALEX DIRECTIVES FOR HUMAN MEDICINE:

https://en.wikipedia.org/wiki/EudraLex#Volumes

VARIATIONS & EXTENSIONS:

Variations are any change to the currently approved content of a Marketing Authorisation
(MA) dossier and are essential in the lifecycle management of a medicinal product. For
human use, this mainly concerns articles 8(3), 9, 10, 10a, 10b, 10c of Directive 2001/83/EC
and Annex I thereto, as well as article 6(2) Regulation 726/2004/EC.

In accordance with Commission Regulation (EU) No 1234/2008 (the „Variations
Regulation‟), and as amended by Regulation (EC) No. 712/2012, variations to Marketing
Authorisations include Type IA, Type IAIN, Type IB, Type II and extension applications.

The following applies to medicinal products for human use approved through Mutual
Recognition Procedure (MRP), Decentralised Procedures (DCP) and Centralised Approved
Products (CAPs), and authorisations granted following a Committee for Medicinal Products
for Human Use (CHMP) full harmonisation referral.

Homeopathic and traditional medicinal products (which have no marketing authorisation but
are subject to simplified registration procedures) are not concerned by this Regulation.

Definitions of the variation types

Variations are classified according to the level of risk to public health and the impact on
quality, safety and efficacy of the medicinal product. Details regarding the classification of
variations into the various categories can be located in the “Commission Guideline on the
details of the various categories of variations”.

Type IA variations are minor variations which have minimal impact, or no impact at all, on
the quality, safety or efficacy of the medicinal product. The Variations Regulation and
Annexes list the changes that can be considered as minor Type IA variations. These minor
variations do not require prior approval but must be notified by the Marketing Authorisation
Holder (MAH) within 12 months following implementation – “Do and Tell” variations.

Type IAIN variations are also minor variations but require immediate notification to the
competent authroity on implementation. The Annexes to the Variations Regulation specifies
which minor Type IAIN variations must be notified immediately on implementation.

Generally Type IA and Type IAIN variations follow a 30 day review timetable. Type IA and
Type IAIN changes can be implemented prior to submission of the variation, however if the
variation is rejected by an authority the MAH should immediately cease applying the rejected
changes.

Type IB variations are minor variations which are not a Type IA variation nor a Type II
variation nor an extension. Approval from the competent authority is required before
implementation. Generally Type IB variations follow a 30 day assessment timetable.

Type II variations are major variations which may have a significant impact on the quality,
safety or efficacy of the medicinal product. Approval from the competent authority is
required before implementation. Generally, Type II variations follow a 60 day assessment
timetable, but can be reduced to 30 days for urgent safety issues and extended to 90 days for
extensions of the therapeutic indication.

Extension applications are detailed in the Variations Regulation Annex I and include changes
to strength, route of administration and pharmaceutical form. Approval from the competent
authority is required before implementation. Generally extension applications follow a 210
day assessment timetable.

Classification of unforseen variation. If the MAH has a variation for a MA which is not
detailed in the variations classification guideline, scientific recommendation on classification
of the submission can be requested via the Coordination Group for Mutual Recognition and
Decentralised Procedures (CMD) or the European Medicines Agency (EMA) under Article
5(1) of the Regulation.

Such a request is made using the Article 5 template form, where with justification. CMD /
EMA the proposed variation is described along with the MAH proposed classification will
consider the application and the justification and will make a recommendation on the
classification of the proposed unforeseen variation to the MAH, within 45 days.

Grouping of Variations There are certain cases where several variations can be grouped and
submitted simultaneously in one application as described in articles 7(2)(a) & (b) of the
Regulation:

-A MAH can group several Type IA and Type IAIN variations affecting one medicinal
product under a single notification to the same competent authority. For example:

Change 1 (Type IA) –deletion of

MAH MA manufacturing site

Change 2 (Type IA) –Lightening of a
specification limit

-A MAH can group one Type IA or Type IAIN variation affecting several medicinal products.
For example:

MA 1 Change 1 (Type IAIN) –change in
MAH

address of MAH

MA 2 Change 1 (Type IAIN) –Change in
address of MAH)

– A MAH can group several Type IA and Type IAIN variations affecting several medicinal
products, providing the variations are the same for all of the medicinal products and are
submitted to the same competent authority. For example:

Change 1 (Type IAIN) –Change in
MAH MA 1 address of MAH

Change 2 (Type IA) –deletion of

manufacturing site

MA 2 Change 1 (Type IAIN) –change in
address of MAH

Change 2 (Type IA) –deletion of
manufacturing site

-A MAH can group several types of variations affecting one medicinal product under
a single notification when they fall within one of the cases listed in Annex III of the
Variations Regulation, or if the proposed grouping is agreed by the competent
authority before submission. Such grouped submissions will follow the review
procedure for the highest variation in the group. For example:

Change 1 (Type IB) –Addition of new
MAH MA

drug product manufacturing site

Change 2 (Type IB) –More than 10 fold

increase in drug product batch size

Change 3 (Type II) –Widening of an

approved specification limit

– a supergrouping may be applied for purely administrative changes and other changes that do
not contain product-specific information. National, CAPs and MR/DC procedures cannot be
mixed in supergroupings. The same set of Type IA variations must be submitted for all MAs
covered by the supergrouping, such as a change of MAH address for example.

When a MAH is submitting a supergrouping variation for a group of products which are
authorised via MRP/DCP, a lead RMS must be appointed. The lead RMS must be RMS for at
least one of the MAs in the supergrouping. The lead RMS will manage the assessment and
communicate with the other member states involved. In order to request agreement for a lead
RMS the MAH submits a Letter of Intent for the supergrouping to the preferred lead RMS
authority. If the preferred lead RMS has the capacity and expertise to take on the role they
will issue the supergrouping procedure number to the MAH and the submission can proceed.

The MAH should liaise with EMA prior to the submission of a supergrouping for CAPs, and
also with relevant national competent authorities for supergrouping for national MAs.

Worksharing

As per Article 20 of the Regulation, a MAH can request a worksharing procedure where the same
Type IB, Type II or group of variations, affects several medicinal products. The change must be the
same, with no need for product specific assessment of the change.

When a group of variations only consist of Type IA or Type IAIN variations affecting several medicinal
products this is considered a group variation, not a worksharing procedure. However, Type IA and
Type IAIN variations can be included with a Type IB or Type II variation submitted for a worksharing
procedure. In such cases the review of all the variations will be performed as part of the worksharing
procedure. It should be noted that groups including an extension application are excluded from
worksharing procedures.

A reference authority takes the lead in the assessment of worksharing submissions. If one of the
medicinal products in the submission is authorised via the Centralised Procedure the EMA will be the
reference authority. If there are no CAPs in the submission the MAH selects the preferred reference
authority to lead the assessment and contacts them, using the specified email address as published
in the list of CMD contact points, at least 2 weeks before the planned submission using the template
for the letter of intent for the submission of a worksharing procedure. If none of the proposed
reference authorities are able to lead the assessment then the MAH may forward the request to the
CMD for further discussion and selection of the reference authority

Generally, worksharing procedures follow the 60 day assessment timetable of Type II variations, but
can be reduced to 30 days for urgent safety issues and extended to 90 days for extensions of the
therapeutic indication.

https://blue-reg.com/wp-content/uploads/2021/03/WP_European-variations-for-medicinal-
products-for-human-use_February2021.pdf

Extension Applications

• Definition for Extension of marketing authorisation:

Changes to a marketing authorisation listed in Annex I of Commission Regulation (EC) No
1234/2008 are regarded as “extensions” of the marketing authorisation.

Examples of extension changes:

1. Changes to the active substance(s)

– replacement of a chemical active substance by a different salt/ester complex/derivative. with
the same therapeutic moiety, where the efficacy/safety characteristics are not significantly
different;

2. Change to strength, pharmaceutical form, route of administration

• Change of bioavailability;

• Change of pharmacokinetics e.g. change in rate of release;

• Change or addition of a new strength/ potency;

• Change or addition of a new pharmaceutical form;

• Change or addition of a new route of administration.

• Such applications will be evaluated in accordance with the same procedure as for the granting
of the initial marketing authorisation to which it relates.

• The extension can either be granted as a new marketing authorisation or will be included in the
initial marketing authorisation to which it relates.

COMPLIANCE OF EUROPEAN PHARMACOPOEIA (CEP) /
CERTIFICATE OF SUITABILITY (COS):

The Certification of Suitability (CEP) is a certificate that certifies compliance of the active
pharmaceutical ingredients (API) or pharmaceutical ingredients with that of the rules laid
down in the monograph of the European Pharmacopoeia (EP).

What does compliance mean?

• Compliance with a monograph

• All mandatory parts of a monograph.

• Compliance until time of use for raw materials, ingredients.

• Compliance throughout period of validity for preparations.

• In-use compliance decided by licensing authority for each preparation.

What must comply?

• Mandatory for all substances for pharmaceutical use

• Ingredients (incl. excipients) of final formulation

• Components of solvents, buffers etc. in or used to make up final formulation

• Reagents? Not usually needed for upstream use

The Certification Procedure

• To demonstrate that the quality of a substance is controlled by the Ph. Eur. monograph and
additional tests if needed (“Chemical CEP” or “Herbal CEP”)

• To guarantee compliance with the general monograph on Products with TSE risk (“TSE
CEP”)

•CEPs are accepted in 37 Member States + EU, and beyond (e.g. Canada, Australia,
Singapore, South Africa, etc.)

•Directive 2003/63/EC: Where the active substance and/or raw and starting material or
excipient(s) are the subject of a monograph of the EP, the applicant can apply for a certificate
of suitability that, where granted by the EDQM, shall be presented in the relevant section of
the Module. Those certificates of suitability …are deemed to replace the relevant data of the
corresponding sections described in the Module…

Provides:

• Centralised assessment – saves time and resources

• Information on the need to update Ph. Eur. monographs

• Facilitates management of MAAs and variations

• Application submitted directly to EDQM by the manufacturer of the pharmaceutical
substance

• Confidentiality of data

•Governing document for the Certification procedure:

•Resolution AP-CSP (07) 1

Scope of the CEP Procedure

• Substances described in monographs in the Ph. Eur. (Active substances, excipients, herbal
drugs / herbal preparations)

•→ “Chemical” or “Herbal” CEP

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

•→ “TSE” CEP

• Open to any manufacturer regardless of geographical origin

Out of Scope of the CEP Procedure

• Substances not included in Ph. Eur.

• Biologicals (PA/PH/CEP (09) 152 rev 01)

• Human tissues derivatives, blood derivatives, vaccines

• Mixtures of API with excipients (unless justified)

• Substances which do not comply with the Definition section of the monograph

• Finished products

How to apply for a CEP

• Application form (for new application) available on the website. It contains tables to be
filled in, statements and declarations to be signed

• Quality Overall Summary (see template on the EDQM website)

• Fees:

Reference Item Fees Tick as appropriate
CEP03 Simple certificate 3000 €

(chemical or TSE or
herbal

CEP13 Certificate for 6000 €
chemical purity and
sterility

CEP01 Double certificate 6000 €
(chemical + TSE)

CEP14 Double certificate 3000 €
(chemical + TSE)

• Electronic submissions encouraged (eCTD, NeeS, pdf)

• Dossier in English (preferably) or French (see documents on the EDQM website)

What does it mean?

• A chemical CEP certifies that the quality of the substance is suitably controlled by the Ph.
Eur. monograph with addition of tests if necessary (mentioned on the CEP)

• A TSE CEP certifies that the substance complies with the EMA NfG on minimising the
TSE risk. It DOES NOT certify that the quality of the substance is suitably controlled by a
specific Ph. Eur. monograph

• It DOES NOT replace a certificate of analysis

• It IS NOT a GMP certificate

Certification – Inspection

• Integral part of the Certification Procedure

• Article 111 of Directive 2001/83/EC and Article 80 of Directive 2001/82/EC, Compilation
of Community Procedures)

• Performed before or after the CEP is granted

• Aim: to verify the compliance with

the inspection in case of major or critical deficiencies (public health issue)

https://www.ema.europa.eu/en/documents/presentation/presentation-european-directorate-
quality-medicines-healthcare-edqm-european-pharmacopoeia_en.pdf