New EU variation classification guidelines

Good afternoon and welcome to the webinar on the new variation regulation guidelines for specifically address for marketing authoration holders. So my

name is Alberto Gyan Himenez and together with Susan Vintter side we'll be co-chairing this uh this webinar that is organized by the European medicine

agency in together with the CMDH.

So if we go to the next slide please the next so the aim of this webinar it's uh to support marketing author and other

stakeholders on the upcoming changes that are resulting to the to the publication and enter into force of the European Commission version guidelines

that will apply from the 15th of January 2026. So this weeks and uh we really

2026. So this weeks and uh we really want to present to you what are the main changes of the Barison guideline and also updates of relevant Q&As I guide

and guidance from the European Medicine Agency and the CMDH that will be relevant for applicants when preparing their their submissions.

This uh webinar is uh presented by by WebEx and we have more than 1,000 participants through WebEx and it's also broadcasted due to the high interest and

we also have many many other interested person following through through our broadcast. Erh, we I I need to inform that the recording of this

webinar will be available in the Emma event web page dedicated to this to this webinar and also it will be also posted in the Emma YouTube channel and uh you

can also find the presentations available after this webinar in the Emma event web page that will be posted shortly. Just moving to some

shortly. Just moving to some housekeeping rules. uh you can find uh

housekeeping rules. uh you can find uh this link to a slide a slido where you can post any question that you may have

on the on the webinar at any time. So

you can please take a picture of this uh of this QR code that you can also find in the Emma event web page in case you you miss this uh this slide. So the

questions will be addressed uh either in writing through the webinar or we will also select some questions for the uh Q&A session that we have at the end of

of the webinar and also we will collect all the main points where applicants need support in order to uh later analyze and see whether further guidance

need to be required of any specific aspect. We have a two-hour webinar and

aspect. We have a two-hour webinar and if we go to the next slide, the agenda will be first started by my co-chair Susan who will provide some information

an overview of what has been the revision process of the European variations guidelines. Later we will

variations guidelines. Later we will move on to provide uh an overview of the specific changes of the different sections of the barition classification guideline and we will follow afterwards

with a presentation of the relevant updates of MCMDH question and answers and guidance. Finally we will end the

and guidance. Finally we will end the session with a Q&A sessions taking some questions that are posted for all attendance. Having said that I hand over

attendance. Having said that I hand over to my co-chair Susan.

Yes, thank you very much Alberto and good afternoon and a warm welcome also from my side. I would like uh to start with a short overview of the v revision

of the uh EC variations guidelines. We

can go to the next slide please. So um

the background was as you all know the uh pharmaceutical strategy that was uh published from the European Commission

in 2020 and the variations framework was part of this uh pharmaceutical strategy.

Um it started all with a call for evidence then for the variations and the amended variation regulation was then

published on the 17th of June in 2024 and it became applicable on the 1st of January in 2025. So we are working for a

year now with a new regulation and part of this new regulation were of course also the new permission variation guidelines and these were published on

the 22nd of September in 2025 and uh we are still working with the older guidelines from 2013 but the new

ones will apply from the 15th of January uh 2026. So we will start in two days

uh 2026. So we will start in two days with the new guidelines. There's also a second revision announced of the variations uh framework and this is

expected once the revision of the basic acts of the new farmer legislation. So

the regulation and the directive uh is complete. So there will be another

complete. So there will be another review in the future. Next slide please.

Yeah. uh why have we done this variation framework revision at the moment? The

aim was of course to improve the existing variation system by incorporating experience that has been gained in the last years and make the

life cycle management of medicines more efficient for regulators as well as uh for marketing authorization holders.

And it uh the a the other aim was to make it future proof with regard to scientific and technological progress.

Um um of course um overall it was intended to simplify it and enable an agile review of the classification guideline and operational procedures.

And you will hear um in detail what uh is meant by that in the later um presentations.

And there were also uh several short-term measures um included in the revised framework which can be done independently from the review of the basic legislation and therefore this was

done in the first step. Next slide

please.

So the revision of the variation guidelines um there were several principles for this revision um that have been considered. Uh the first is

that all categories of the variations were reviewed based on the experience acquired u with the former variation regulation and its underlying guidelines

as well as the scientific and technical progress.

Um there's of course the aim to improve the efficiency ensuring the protection of public health in the EU

and uh where appropriate it was intended to streamline the variation framework for example by decreasing or downgrading

and simplifying the various categories of variations.

And um it was of course the the um the will where possible to future proof the variations framework for the upcoming

changes. So also to adapt or prepare for

changes. So also to adapt or prepare for innovation in the future and also the changes made are compatible with the

revised regulation.

Yes. and um only with the regulation and uh the guidelines um it is not possible to work with the variations you know

that very well. So EMA and CMDH prepared a lot of new and revised guidances and question and answers to support the implementation of the revised variation

guidelines. I just want to show you

guidelines. I just want to show you which guidances and um question and answers um you will see today and which have been published in the last months

and weeks. And you can also see that

and weeks. And you can also see that additional guidances uh are upcoming um in the near future. And I will hand over

to Alex um for starting to invite you to the new guidelines guidances and question answers. Thank you very much.

question answers. Thank you very much.

>> Thank you Suzanne. Good afternoon

everyone. I will now present the main changes to the procedural aspects of the new EC variations guidelines. If you can move to the next slide please. So in

terms of administrative changes references to legislative frameworks were updated including the deletion of references to the veterinary legislation.

In addition, the guidelines have been streamlined by removing repetitive information and moving practical information to the EMA and CMDH guidance

where appropriate. Also, some

where appropriate. Also, some information was reorganized across the document. If we can move to the next

document. If we can move to the next slide please.

So in terms of additional information, I would like to highlight the cutoff date for the new variations guidelines that was set by the commission on 15th

January 2026, next Thursday.

There is uh an expanded list of definitions in the introduction section.

Also, we have new sections with guidance on grouping, super grouping and the annual update of type 1A variations.

In addition, there is guidance namely on the annual update of the EC variations guidelines on update of influenza and corona virus vaccines as well as on

public health emergency.

Of note, there is a change in the coding system from chapter A to D to chapter EQ and M. And finally, there is some

and M. And finally, there is some specific guidance on the need to review the quality documentation in case of clinical variations, namely changes on

the therapeutic indication, pausology or maximum daily dose. If we can move to the next slide, please.

So the guidelines lists the current super grouping cases that that are currently possible and those scenarios are for administrative or quality type

1A variations in the mutal recognition procedure, the centralized procedure or purely national procedure in more than one member states or when agreed with

the concerned member states for the remaining scopes. An additional case for

remaining scopes. An additional case for super grouping that is foreseen is for type 1A variations in the MRP or DCP if

the reference member state is the same.

And finally, it's also possible to have a super grouping for type one variations in the centralized procedure.

This additional of note additional cases may be identified in the in the future.

If we can move to the next slide, we will now review the K changes to DNX of the new EC variations guidelines. On

the right, you can see the table of content uh of DNX with the new coding system. I will start with the

system. I will start with the administrative changes chapter E and the other presents will cover the remaining uh chapters. If we can move to the next

uh chapters. If we can move to the next slide and the next. So starting with the administrative changes, the current eight scopes have been

reduced to five scopes including the previous article 5 recommendations.

Of note, there was no changes to the conditions or documentations for two variations, the new E1 and E2 on changes

to the name of the finished product and changes in the ATC codes. If we can move to the next slide

for two scopes E2 and E5, the scope of the variation have been extended. Of

note, scope E2 now also covers changes in name of medical device or packaging component. And under scope E5,

component. And under scope E5, there is an extension to the manufacturing activities that can be deleted including a reference to the medical device.

If you can move to the next slide.

Finally, three scopes have been merged into one. the new scope

into one. the new scope E4 and the list of explicit referenced manufacturing activities have been

expanded. This new scope now covers

expanded. This new scope now covers changes to the name and or address of the marketing authorization holder, the SMF holder or any of the suppliers

manufacturing sites. I will now hand

manufacturing sites. I will now hand over to Alisa who will cover the main quality changes applicable to chemicals and biological products. Thank you.

>> Good afternoon. I will try to give an overview over the last next 20 minutes of the major changes that apply to uh

section uh Q1, Q2 and uh Q3 uh with regards to biologicals and chemicals and then other colleagues will complete with the with the remaining section. Uh next

slide please. So I'll start with the section Q1A1 on the for the additional new manufacturing site. In this slide I just want to flag what are the main uh

categories that should be used uh for additional sites for biological active substances or uh biological starting material reagents raw material

intermediates used in the manufacturing of the biological active substance. And

amongst this uh second bullet point some examples are uh for will fall under a type two for example sites for

manufacturing cell banks uh regulation reagents cytotoxic payload of antibbody drug conjugates cytoines used in ATMP manufacturing. Uh this is not an

manufacturing. Uh this is not an exhaustive list. Another scope in the

exhaustive list. Another scope in the remaining cases uh where D uh does not apply could be scope C. Uh and this scope is for starting materials. All the

starting materials used in the manufacturer of the active substance.

All reagents were uh required to be mentioned in the dossia. Uh scope K has been downgraded from a type 1 B uh to a type 1 A. So now additional storage

sites for master cell banks and working cell banks can be added via type 1 A. Uh

next slide please. With regards to chemicals uh these are the main scopes to should be used. Um some type 2s uh are now being merged into a single

scope. for example, uh uh and this is

scope. for example, uh uh and this is scope B that now uh can be used to add new sites for active substance or

intermediates that require a significant update of the uh active substance uh section in the dosia or uh where the

site manufactures the active substance via a substantially different route of synthesis. uh scope A also has been

synthesis. uh scope A also has been rewarded to uh uh remove the

same pharmaceutical group as this is not does not bear any additional risk and the entire category has been expen to

include not only active substance but also intermediates and the remaining scope uh remain the same. Next I next

slide please. So uh this is for the QC

slide please. So uh this is for the QC testing site and uh uh the most uh important changes is been uh is the

downgrading of the category uh covering a new site performing a biological monological monochemical analytical procedure which currently is a type two

and and in the new guideline is a type 1 B and similarly uh a new site performing a physicochemical or microbiological an

analytical procedure uh is now a type 1 A uh so downgraded from a type 1 B uh also for bio. Um

uh all the conditions and documentation requirements were rewarded to add clarity or to strengthen the the requirements.

Next slide please. Uh with regards to changes in the an active substance manufacturing process, um the entire category now applies not only

to active substance but also to intermediates starting materials and or starting materials for biological active

substance. uh for minor change. Uh now

substance. uh for minor change. Uh now

the condition excluding uh um biologicals or ASMS from submitting type 1A when the changes are uh very minor is

been removed and but condition two and four still ensure that these are minor changes and this these should be minor changes and the MAH has a full

visibility of the change. Um category B now is a single uh category uh encompassing biologicals and chemicals and should be used when the major ch

there are major changes to the manufacturing process which might have a significant impact on the quality safety and efficacy. So there is no more

and efficacy. So there is no more specific type two applying to uh biologicals but now is a uh a a scope

that uh can be used for uh for for both uh uh bio and chemicals. Another new

scope under this category uh is a scope B for deletion of a manufacturing process and this comes from an article five. And here as well uh many uh

five. And here as well uh many uh documentation and condition uh have been uh updated to uh uh provide more clarity

or strengthen the requirements. Uh next

slide please. With regards to changes in bush size uh scope A and B for chemicals uh in this um in this scope the uh

threshold of 10fold uh is not has been removed uh since it's not relevant for active substance it remains for finished product um and the

upscaling of more than 10fold compared to the originally approved batch side now can be submitted as a type 1 A the entire category now applies not only to active substance but also to

intermediate to make it uh clearer for bio there are not uh uh big changes it's just some uh tweaking of the

documentation uh requirements um next slide please uh with regards to Q1 A4 that applies to improcess controls

um the scope has been broadened to uh include intermediates and starting material for biol ologicals. Um in scope

A uh now we use the term minor changes instead of tightening uh to allow more flexibility. Addition of a new improcess

flexibility. Addition of a new improcess control uh is being considered a low risk so can be done via a type 1A. Uh so

the biological condition method condition here has been removed while the replacement of an improcess control is higher risk and remains a type 1 B.

uh conditions for deletions of improcess control uh have been strengthened to avoid uh revision of the control strategy uh and because this is not the

category that should be used for this uh purpose. Uh minor change under F uh of

purpose. Uh minor change under F uh of analytical minor change of analytical procedure uh for an IPC now can be a type 1A except if it's a biological

method. Uh next slide please. uh for uh

method. Uh next slide please. uh for uh changes in specification attributes here there's some changing terminology to align with CH and also uh we use change

within instead of tightening or uh change outside instead of widening to allow more flexibility and uh a proportional riskbased approach has been

applied. Um

applied. Um again here as for APC additional new spec is low risk type 1 A replacement of

a spec is uh type 1 B higher risk uh for widening uh of a specification active substance uh this is a high risk type

two h and should be a type two also if the widening applies to critical certain material intermediates or reagents but is a lower risk for others

Um I know this is just if it's a certain material immediate intermediate and reagent uh has an impact on the quality of the active substance in other cases

can be a type 1B and there is a new scope okay K as well uh resulting from article uh five and this for changes in

testing from routine testing to skip or periodic testing and vice versa and for this I refer to a Q&A which will be illust illustrated later. Uh next slide

please. Uh for changes in analytical

please. Uh for changes in analytical procedure here the section has been split in two. Higher risk for active substance lower risk for uh starting

material reagents intermediates and uh proportionally lower categories apply.

For example, uh the introduction or a substantial change to a biological method would be a type two for active substance and a type one but a type 1 B

for uh starting material reagents of intermediates. Other changes type 1 B uh

intermediates. Other changes type 1 B uh for active substance uh and proportionally lower type 1 A for uh starting material reagent intermediates

and so on and so forth. Um next slide please. uh we section Q1 B3 is a new one

please. uh we section Q1 B3 is a new one uh in the new annex uh there was no corresponding section in the previous uh uh

variation guideline h but we had a Q&A to uh help applicants to classify those changes. So now we have a section uh

changes. So now we have a section uh that categorize introduction of a qualification protocol or replacement of an inhouse reference standard and

preparation that is not covered by an approved protocol and other changes. Um

same category can be used also if the reference uh standard is is used to test finished product and not only active sub

substance. So there is no corresponding

substance. So there is no corresponding section under a finished product. Uh

next slide please.

With regards to the change in immediate packaging of the active substance also here a proportional risk based approach has been applied. The risk uh in this

category is mainly related to the extractable leechables and therefore will be higher for semiolids liquid

active substance or container closure.

integrity and therefore higher for sterile active substance. Therefore, for

non-liquid active substance, low risk, a type 1A can be used unless the active substance is sterile or biological. And

here there will be a condition that default to a type 1 B. If the active substance is sterile, type two. If the

active substance is nonsterile but liquid, medium risk, type 1 B. Um, next

slide, please. uh for changes in the retest or storage period of the active substance. Uh here um

substance. Uh here um uh we added a documentation requirement to uh for a reduction of the retest period to justify the change. There is a

new scope for an introduction of a retest period and um for extensions based on extrapolation modeling not in

accordance uh with a guideline. This is

still a type two uh when the extension is based on extrapolation or modeling in accordance with the stability guideline uh medium risk at time point B and this

is a downgrade for biologicals and the most important one here the extension based on realtime data uh in

line with the protocol uh is now being downgraded for all active substances uh to a type 1A uh variation if the all

conditions are fulfilled. This means

that if um the stability studies um are being conducted in accordance with the stability protocol, all uh batches met

the predified criteria and no trends have been observed. It can be a type 1A variation. Um irrespective of the nature

variation. Um irrespective of the nature of the active substance. um

changes to more restrictive storage condition is still a type 1A uh but there is a new condition uh provided that uh there is no change in physical

state uh while a change for storage condition uh of biological now is downgraded to a type 1B also.

Uh next slide please. Um then there are new uh the there are the sections with regards to the uh additional regulatory tools uh for design space uh a new

design space for an analytical procedure is downgraded to a type 1B uh and for changes or extensions of the design space this is a new category and is a

type 1 B and you will notice that also the implementation of the post approval change management protocol for biologicals there is been a downgrade

Now it can be a type 1 A, a type 1 A immediate notification or a type 1 B depending on what has been agreed at the time of the approval of the post approval change management protocol. And

for this I will refer also for the question to the question and answer that is been updated and you will hear uh this update later on in this

presentation. Um and the similar similar

presentation. Um and the similar similar changes apply to the corresponding uh finished product uh sections. Next slide

please. And this section on the PLCM is a new one. Uh so there are new scopes for uh to allow the use of the PLCM. So

the uh product life cycle management document uh in the active substance or finished product uh uh sections uh to

introduce the PLCM to change uh uh for changes to active substance and finished product in line with the PLCM or for changes to the PLCM itself. And also for

this I will refer to further details in the uh Q&A which will be illustrated uh uh a little later on today.

Next slide please. So moving on to the finished product part um with regards to

the uh composition uh particularly related to the exipients in Q2 uh A3. Um

there has been a removal of the biological product type two and the scope has been modified to focus uh rather on the exipient uh that might

have impact on the quality, safety and efficacy and for example uh biological exient or exipient with viral viral

safety or TSC risk. Also in Q2 uh A4 there has been a downgrade for the gastro resistant pharmaceutical forms to

a type 1 B. Uh others remain type two.

Uh next slide please. Uh for changes to the manufacturing sites of the finished product. uh this can be applied uh uh

product. uh this can be applied uh uh via type 1 B uh which is scope E unless uh um it's the site requires an

inspection or uh so that's scope B D or if this the finished product is been manufactured by novel or complex manufacturing processes and those those

terms are uh are clarified uh in a a newly updated Q&A and which will be

illustrated later as well. Um for QC uh testing sites a similar approach to the uh corresponding section in the active substance uh apply. So I will not go

through this again. Um next slide please.

for changes in uh to finish product manufacturer also here uh for minor changes um the bio condition has been removed but there's still a condition

that uh upgrades this to a type 1 B if the finished product is sterile um the specific type two for biologicals also is not there but this there is a single

uh type two for major changes similarly as for the active uh substance um and then there is a new category for

a change in all time uh or storage condition for the intermediate. Um in

Q2B4 uh for changes to the batch size, we also find uh a type two uh that refers to uh the term of novel and complex

manufacturing process uh which which will require uh yeah uh the submission of type two and this is also explained in the same Q&A I referred to earlier uh

for IPC. I'm not going to repeat because

for IPC. I'm not going to repeat because it's the same approach as uh used for the active substance. Uh next slide

please. Uh for control of exipients uh I

please. Uh for control of exipients uh I would just flag uh two main changes in Q2C3

the categories been rewarded according to TSC risk rather than the if the exhib if the exhibion is being used to

manufacture a biological product. that's

um and in Q to uh C4. Uh for category B uh this um there is an overarching type two for all critical exipients and not

just biolog not just if the product is biological. Uh next slide. Uh for

biological. Uh next slide. Uh for

control of finished product also here uh the se the categories been brought in line with the changes have been made in the corresponding active substance

section and also here we find the new scope for the changes from routine to skip and periodic testing uh resulting

from article five. Um next slide please.

for container closure system of the finished product. Similar approach as

finished product. Similar approach as for the active substance risk related to extractable and leechables uh or container closure ident

integrity and therefore higher risk for semiolids, liquid or sterile finish products and the categories uh are

following this logic. Um next slide please. uh here I will not go through

please. uh here I will not go through these details but you will have the slides so you can uh check uh the changes that have been made in this uh

sections. Uh next slide please. uh for

sections. Uh next slide please. uh for

uh changes to shelf life and storage conditions. Apart from bringing in line

conditions. Apart from bringing in line with the similar changes made in an active substance, the only difference here I would like to flag is that uh when the the finished product is uh

packaged for sale, an extension of the shelf life supported by realtime data and fully line with the stability protocol is not a type 1 A for all type

of products but only for immediate release film content tablets for all the others remain a type 1B. B uh and uh and

the condition has been uh uh updated accordingly. Um and uh uh and also here

accordingly. Um and uh uh and also here uh as for the active substance we find that downgrading for biological in case the extension is based on

extrapolational model in accordance with the uh stability guidelines. You will

note that the uh note which used to block the use of strapolation for biologicals is now uh not there anymore.

Um next slide please. Uh moving on to Q3 uh one uh about the C here uh there is no there hasn't been any upgrading there

are still type 1A but uh some of the scopes have been merged to simplify and improve readability and the note has been included to explain situation in which the additional variations are

required. This is to improve the quality

required. This is to improve the quality of the submissions and similarly conditions and documentation requ uh uh requirements have been revised to help

applicants to classify uh changes accordingly.

Um next slide please. uh for TSC certificates uh not not major changes just some conditions have been uh

revised or deleted uh uh in the for condition six the previous condition six has been deleted for scope for a certain

scope as indicated in the slide to allow type one a variation. Um and finally uh next slide. Yeah, this is my last slide

next slide. Yeah, this is my last slide and uh to cover changes to comply uh with the European Pharmacopia or with the National Pharmacopia of Amendment

States. Here the category uh has been

States. Here the category uh has been revised to include references to reagents intermediates exants immediate packaging materials and active

substance starting materials in addition to the active substance. uh to make clear um also that changes that apply to the

finished product should not be submitted under this category but Q2D should be used instead and I finish here and hand

over to Carmen for the changes specific to herbal medicinal products. Thank you.

>> Thank you very much. So as you mentioned indeed I will continue with also the quality changes but linked with this narrow domain of the herbal medicinal

product and I will start saying that all the time when we have any any vibration linked with the her medicinal product we should take into account that the herbal

active substances are not chemicals because they are this multicomponent mixture. So they have their own

mixture. So they have their own complexity and variability which actually supposed to be reflected in how the variation are notified and assessed.

And I also would like to highlight the fact that for traditional registered medicinal product the regulation and also the guideline variation are not

applicable. Indeed, we have the CMDH

applicable. Indeed, we have the CMDH recommendation that says at least for the MRP and DC procedure, we should follow the same variation regulation.

But we also have to keep in mind all the time when you have a national application, it's a national decision if the variation regulation and also the

guideline it's applicable.

Saying this, I will be brief and highlight which are the new herbal scopes or if the previous scopes they were included in the previous guideline

were downgraded using the same uh risk based approach that was used also of the chemicals and biologicals.

So may I have the next slide?

So let's start with the active substance manufacturing site. Indeed, if you're

manufacturing site. Indeed, if you're going to check the scope A and C are also applicable for the herbal medicinal products, but if you fulfill the condition one that says you have to take

the same geographical source for the herbal substance and the same manufacturing process for the herbal substance and this is also highlighted in the documentation too that should be

provided. So if you are not going to

provided. So if you are not going to fulfill the criteria then definitely for the herbal medicinal product will be a type 1B variation.

May I have the next slide please?

And indeed we also have a new herboscope. So it's the E saying

herboscope. So it's the E saying addition or replacement of a new herbal starting material supplier or of a new herbal active substance manufacturing

site. In this case is type 1B and indeed

site. In this case is type 1B and indeed if you are going to to check also the terms they are used to define the scope you are going to see that it's covering

different plant production so also cultivated and wild collection and on the documentation requirements there are two new documentation requirements so

seven and eight and I think now I hope it's very clear what kind of documentation should be submitted when you have a new herbal substance supplier or when you have a new herbal active

substance manufacturer and here maybe just to highlight what is really important especially for preparation this comparability between the

preparation so you need to have this comparison regarding the specification but also the critical quality attributes and here I mean the DR extraction

solvent strength of section solvent but also the manufacturing process steps And may I have the next slide?

And then moving on to the changes on the active substance manufacturing process here on the first scope. So a indeed the the minor change the manufacturing

process is not changed for the herbal medicine product. Maybe the wording in

medicine product. Maybe the wording in the condition two was a little bit updated for more clarity but was really changed actually was downgraded is the

Cisco. So the change in the geographical

Cisco. So the change in the geographical source of the herbal starting material or production of herbal substance previously was type two now is

downgraded to type 1B and indeed if you are going to check the new documentation requirements especially four and five you will see what kind of documentation

should be provided. So also the declaration that the change is not having an impact on the quality, safety and efficacy. Then you need this

and efficacy. Then you need this detailed comparison regarding the quality determining process characteristics. And of course when you

characteristics. And of course when you are talking about a new supplier then the update JCP declaration or when you are talking about the herbal active substance then the declaration of the

market authorization holder. the fact

that actually the manufacturing process is unchanged and may I have the next slide please and

then let's move also on the control of the active substance here we have a new herboscope J that it's applicable only

for the other extracts because it's referring to analytical marker so indeed change in the analytical mark or widening of the acceptance criteria of the analytical marker marker for the

herbal active substance is type 1B variation and the documentation that should be provided it's really comparable with the documentation that

it's also provided for similar changes in the specification for the active substance and may I have the next slide

and then we also can say a few words about the finished product actually you heard that biological the extension of the shelf life of the finished product

was not changed and also for the herbals we considered that indeed uh their complex behavior during the stability should be assessed so it just can be

downgraded to type 1 A that's why in the new guideline it's type 1B and in the condition for not just biological but

also herbal finish products are included and may I have the next slide Right. And

then the last but new scopes they including in the guideline variation.

The first one is referring to SEPs.

Indeed, it's a separate variation and I think it's really good to have a separate scope only herbals for so the new or updated certificate of

suitability for herbal active substance.

Now it's classified 1B and indeed if you are going to check the documentation requirement especially 61 you are going to see that you need this detailed

comparison regarding the specification but also KY quality attributes of the per preparation

and the next slide and also a new peroscope that is included in the variation guideline uh it's the one linked with the change to

complying to European pharmacopia or with national pharmacopas it's the D once again it's separated from the chemicals and indeed it's still 1B

comparable with the steps and the documentation requirements are also comparable with a previous herbal scope that I just mentioned more or less these

are the main changes referring the herbals in the new guideline on variation Thank you and I will give the floor to the next presenter.

>> Thank you Carmen. So I'm going to continue with the changes for medical devices and plasma master files.

Changes for medical devices are now classified under Q4 one 2 and three. All

the scopes are new and they've been drafted taking into account the requirements of the medical device regulation.

Q41 is to be used for addition, replacement, deletion or changes to compact or reference devices. So in

terms of changes, we have Q41B for major changes, those that may have significant impact and Q41D for minor changes that do not impact the delivery, quality,

safety or efficacy of the medicinal product or the usability of the device.

And if conditions are not met or if the change does have a potential impact, then it should be submitted as a 1B. No

specific 1B scope has been listed, but the default Z scope can always be used.

And uh maybe to highlight that documentation too, evidence that the relevant standards have been met only applies to Copak devices, not to reference devices. And you can find more

reference devices. And you can find more information about these on the questions and answers document for combination products.

Next slide.

So Q42 is for changes to an integral medical device to be used for addition, replacement, deletion or any other change excluding the ones that are

listed in Q43.

Um maybe to remember that the addition of a site responsible for the assembly of the device should be done under Q2B1F. There is a specific scope for

Q2B1F. There is a specific scope for that since this activity is considered part of the manufacturing process. So

should be described in section 3 to P3.

The addition or replacement of a supplier when there is no change to the device can be submitted as 1A.

And just note that the deletion should be classified as E5 as administrative change.

Um there is now a specific scope for the addition or replacement of a site responsible for sterilization and or change to the sterilization process of the device when supplied as a sterile.

So if you're adding a new site with a new sterilization process, this scope can cover both changes. You don't need a separate one. But this is only when the

separate one. But this is only when the manufacturer is buying the device as a sterile ready to use. So when the sterilization is done by the manufacturer of the medicinal product as

part of the manufacturing process described in P3 and then you need to choose a scope under Q2B.

Next slide.

Here I just would like to flag documentation two. Uh in case of minor

documentation two. Uh in case of minor changes to the device with no significant impact on the medicinal known product, then a justification for the absence of a notified body or use

certificate that is based on the impact assessment performed by the marketing authorization holder can be acceptable.

And uh you can also find more information about these justifications in the Q&A and combination products.

Next slide.

Q43 is listing changes in dimensions, specifications, acceptance criteria and analytical procedures for integral

devices, integral only. And u maybe to note that Q43A is for really minor changes in dimensions. So this is typically an adjustments of a few

millimeters that do not impact the performance of the device. When you have major changes in dimensions, then it would be considered a change in design.

And this is a major change to be submitted under Q42A.

Also to highlight that Q43 is only applicable to specifications and analytical procedures for the medical device. So those listed in 32P7

device. So those listed in 32P7 analytical procedures and specifications that are part of the final product specification and control strategy. So

those that are listed in 3 to B5 should be classified under the appropriate Q2 uh D category not Q4.

Next slide. Um here are some general principles. So changes to medical

principles. So changes to medical devices should be submitted under the appropriate Q4 classification even if the medical device also acts as

container closure system. So you should not use the packaging ones. Medical

devices have additional requirements under the MDR. So you need to use the Q4 classification and not the ones for packaging materials.

And for clarification on when a new certificate or a notified body opinion is needed. Um we have included here the

is needed. Um we have included here the link to the Q&A. Uh so you can check all the instructions and for dos your requirements for combination products

please review the questions and answer under this link and just remember that any information that is not a requirement should not be included in the dossier but if you do include it

then it would need to be maintained through the corresponding variation. So

it's better to ensure that only the necessary information is registered.

Next slide.

So the questions and answers document for combination product has been updated to include the reference to the new classification guideline in a new section called life cycle management and

you can find clarifications here in which cases a notified body opinion is expected and in which cases a justification can be acceptable. So in

general for minor changes a justification can be accepted but always based on the risk assessment performed by the marketing authorization holder.

And also keep in mind that in case of groupings of multiple changes impacting the device, the assessment should be done on the entire group of changes since they may have a greater impact as

a whole rather than separate individual ones.

Uh next slide. Um this is an extract of the Q&A. So as a general rule, a new or

the Q&A. So as a general rule, a new or revised notified body opinion is required when a new device is introduced or in case of major changes such as a

change to the design, the addition or replacement of an integral device, change to the performance characteristics of the device or to its intended purpose. and is also expected

intended purpose. and is also expected for changes to the medicinal product that may impact the performance or safety of the device. So for example, if you have a new formulation for the

finished product that results in a different viscosity that significantly impacts the performance of the device, then a notified body opinion will also be expected.

Next slide.

Um, moving now to plasma master files.

So I'm going to focus only on the main updates for section uh Q5 and section M.

So the old B5 and D. Uh Q5 A1D the PMF second step procedure has been downgraded from uh 1A immediate notification to 1A when the changes do

not affect the properties of the finished product and the new documentation 5 has been added.

Uh the old classification D is now M and it's been reduced from 23 categories to 16. No changes to the vital antigen

16. No changes to the vital antigen master file scopes.

And on the M classification uh for M4, the relocation of blood plasma collection centers within a blood establishment that's already included in the plasma master file has been

downgraded from 1B to 1A. as long as it remains the same legal entity, it's been inspected and has the same quality system.

In M5, a new scope 1B has been created for a change from nonoperational to operational when epidemiological data has not been annually submitted or that

have been other than administrative changes in blood centers.

In M7 and in M9, the relocation has been downgraded to 1A. In the same case as the previously described for M4,

the previous categories D14 to D16 have now been combined into M10 where uh new scopes for miniipools nucleic acid

testing have been created. So for those if the test kit is C marked then it can be submitted as type 1 A but if it's non C marked then it's a type two.

Previous categories D17 and D18 have been combined into M11 and the removal of inventory hold period or reduction in its length has been downgraded from 1B

to 1A.

uh in M12 a new 1B scope has been created for noncm marked blood containers when there is no impact on quality with new documentation requirements. So proof of equivalent

requirements. So proof of equivalent quality and confirmation than the anti-coagulant solution complies with European pharmacopia.

So that's my quick update. Now I hand over to Suzanne for the cyscopes.

>> Yes, thank you very much Roina. Um yes I would like to introduce to you to you the changes in the sea scope. So on

safety efficacy and phriligence changes we can go to the next slide please. So uh first of all you can see

please. So uh first of all you can see here in this comparison table that there have only been uh very few categories been revised and there's one new

category. Um these are mainly minor

category. Um these are mainly minor revisions and I will introduce them to you um soon. um they contain clarifications and incorporate article 5

recommendations that have been given in the past. Some redundant categories have

the past. Some redundant categories have been deleted. Um the section C2 for

been deleted. Um the section C2 for veterary products has been completely removed and as you can also see in the

table um the Roman numeral one was removed for human products resulting in new classification codes for all variation categories. So that this Roman

variation categories. So that this Roman one has now been completely deleted.

Next slide please.

So the first revision was made in category C3 and here clarification um was made that this category also covers PR recommendations and other joint

recommendations of the EU competent authorities and the type 1B classification 3DB uh has been added for implementation of

changes that require minor assessment and uh this was formally um included in the article. five recommendation table

the article. five recommendation table and was widely used as a set classification.

Next slide please. Then we have a revision in C.9.

Uh here was a type 1A classification. It

it was clarified there um uh to emphasize that the scope is to implement a previously conduct conducted assessment and the previous guideline it

only read agreed wording and now it says the outcome of previous assessment and there's also type B classification added for various changes that require minor

assessment. This was also uh previously

assessment. This was also uh previously uh covered uh via the uh article 5 recommendation table. Next slide please.

recommendation table. Next slide please.

There there's a new type 1B category C11 for package leaflet user test. This is

also based on a former article 5 recommendation and there is a revision in C12

um where it uh now um states that by equivalent studies are explicitly mentioned in the scope for the clarification and there's also further

clarification made in the note below that this category is intended for variations where no product information

revision is proposed. um by the M mah uh when submitting the variation. And this

uh already uh finishes the changes in the C chapter and we can go to the next slide. And um now I would like to

slide. And um now I would like to introduce into the uh updates of the EMA and CMDH question and answers and

guidances together with my colleagues. I

will start on the next slide um again with this slide that you already know where you can see all the new and

revised guidance here. It is included um in a historical order. So um the first one that was um published was the

uh EMAN CMDH guidance on the application of the revised variations framework which was already published for the first time in June 25 and updated in

September. Um then already in October

September. Um then already in October you can see that um the CMDH guidance documents um have been um published so

that you can um prepare adequately several months in advance of the new guideline. Uh and there were other

guideline. Uh and there were other question answers and guidance documents um that will be introduced by my

colleagues um in the upcoming slides.

Next slide please. So just some general remarks uh on the revised variations framework for type 1 B and type two variations. This is also published on

variations. This is also published on the EMA and CMDH websites. And um for type 1 A and type two variations, if

they are submitted before the 15th of January 2026, then the current E application form should be used and the procedure will

follow also the current uh variation guidelines that have been published since 2013 uh until its conclusion.

And for those applications that are submitted submitted as of the 15th of January 26, the updated e application form should be used and the new

variation guideline published in September 2025 should be followed.

And on the next side um the guidance is given for type 1 A variation which is a bit more complex because for type 1 A variations not the submission

date is relevant but the date of implementation of the type 1 A variation should be taken as the point of reference for the

application of the current and the new uh variation guidelines. which means

that all type 1A variations implemented before the 15th of January should be submitted before the 15th of January

2026. So at the latest today or tomorrow

2026. So at the latest today or tomorrow and if no annual update is due before this date um marketing authorization holders

should then submit an earlier annual update or individual notifications outside the annual update um in order to um meet

between old and new guideline. and then

15th of January 26. This will then start a new cycle for the annual update which will then have to be submitted according to the general rules. I don't see it actually but uh

>> yes Susan we can we are in the next slide. I think the connection is a

slide. I think the connection is a little bit incorrect but uh we can hear you now. Perfect. So go on. Is the next

you now. Perfect. So go on. Is the next slide on on the on the >> Okay. Yeah, the next slide is then also

>> Okay. Yeah, the next slide is then also my my last slide. Um here you can see two screenshots where we have uh just mentioned um how many guidance documents

we have been updated in the past. Um

actually um on the left side you can see a screenshot uh where the revised variation framework from the CMDH is published and um as mentioned before um

these guidances and there are more so this is not the full picture um will be transferred to the current guidances that are published on the website um

starting from Thursday the 15th of January. And on the other uh side you

January. And on the other uh side you can see where you can find all the updated guidances from the email. Um

they have new and old guidance coexisting sometimes um in the same document.

>> Good afternoon everyone. Uh Alberto just checking you can hear me. Okay.

>> Yes. Perfect. Brian, thanks.

>> Yeah, perfect. Uh maybe we could go back one slide and I'll just just summarize what Suzanne was saying there. So the

message really to the stakeholders is uh you saw on the previous slide a long list of uh EMA and CMDH guidance documents which we've published and then

here uh additional lists uh which are available on the CMDH website and on the EMA website. So the main message we want

EMA website. So the main message we want to convey is that there's a huge amount of supporting information available uh through our websites uh that will support you in the implementation and

the interpretation uh of the variation guidelines and we'd encourage everyone um before they submit variations to consult these documents. So next slide please. So over the next few slides, I'm

please. So over the next few slides, I'm going to uh go through some of the highlights uh of the content of those EMA question and answer documents and additional guidance. Uh as I've

additional guidance. Uh as I've mentioned, they're they're quite detailed. So I obviously won't be going

detailed. So I obviously won't be going into huge detail, but we've picked out the main uh changes and things that we think are important to highlight, but I would again say to the stakeholders,

please do take the time for you and your teams, those involved in submitting variations to read through these applicable Q&As's in parallel to the new variation guidelines.

So the first one to talk about is this Q&A. Uh no, you can stay where it was,

Q&A. Uh no, you can stay where it was, please. The first one um to talk about

please. The first one um to talk about is this EMA Q&A on the classification of changes. So in November we published an

changes. So in November we published an updated uh version of the guidance on classification of changes and these uh should apply to changes submitted and and implemented from the 15th of

January. There were a number of new

January. There were a number of new Q&As's developed as well as updates to the existing Q&As and those updates were to align with the updated classification

guideline and classification codes and where uh necessary to add some clarifications or or modify the wording.

There were a number of Q&As's removed and those were uh the ones which were no longer relevant.

Next slide please.

So the the the new Q&A is to highlight.

So under the E scopes and the administrative changes, there's there's a new question about uh applying for a change in a name or address of an MA holder of a manufacturing site. With

respect to quality changes under the Q scopes, there's a new uh Q&A relating to the variation category that should be used to remove or replace the rabbit

pyrogen test from uh the dossier.

Uh with respect to clinical and nonclinical changes, there are a couple of Q&As's um added. This one is particularly important. The the question

particularly important. The the question about what uh quality documentation should be um considered where there's a change in the clinical use of a product.

So that means where there's a change in the therapeutic indication physology or maximum daily dose. uh what we were seeing were cases where uh maybe a a

change in the indication resulted in a change to the maximum daily dose and a knock-on effect on impurity limits for example uh which needed to be addressed in the quality documentation. So there's

a a detailed answer given to that question and some examples which I think should be considered by applicants before they uh submit such variations.

There's also a new Q&A relating to uh submission of user testing results.

Um, next slide please.

So, one of the Q&As's that we mentioned was the the QWP's Q&A on uh, skip testing. So, um, there are two new

testing. So, um, there are two new variation scopes added to the guidelines uh, that Alisa highlighted earlier. Q1

under Q1 B1 and Q2D2 which um, are a change in uh, the testing frequency from routine to skip or periodic testing and vice

versa. These variations now are

versa. These variations now are classified as type 1B variations. Um

they have um documentation requirements uh defined uh which are clearly laid out in the classification guideline. On the

next slide, so why do we need a Q&A on skip testing?

Well, QWP noticed um over the last years that there is sometimes misunderstanding and confusion between the term skip testing and reduce testing both for

assessors and also for from applicants.

uh we requested clarification from the inspector's working group on the responsibilities of assessors and inspectors with respect to this and it was clarified that the decisions on skip

testing are under the remit of assessors and should be made during the assessment of uh applications or variations.

Following that feedback we decided to initiate work on a Q&A on skip testing.

uh we prepared six questions and uh five of which were prepared by uh the QWP from the assessment side and one uh from the inspectors question six the text was

adopted by the QWP and inspectors working group earlier this year and it was published in October uh 2025

there will be a a re a revised uh version of the existing Q&A on reduced testing of starting materials and we expect that we will publish that amended version in 2026. So it's important I

think uh for stakeholders if you're submitting variations which uh fall under those scopes uh those new scopes relating to the frequency of testing but either for active substance or finished

product that you refer to this uh EMA Q&A.

Next slide please.

So uh we have published a a new Q&A uh on the interpretation of the term novel or complex manufacturing processes as it is used in the context of the categories

B2B1 C and B2B4. So these are uh the variations for uh addition of a manufacturing site for the finished product or changes in scale or batch

size for a finished product. Um within

these two uh these two categories there are type two variations uh for required when uh the product is manufactured by

novel or complex manufacturing process.

This um complex manufacturing process wording was already there in the previous version of the classification guideline and there were two existing uh

Q&As from QWP on the EMA website. So now

we've revised those two existing Q&As's into a single Q&A and we've broadened the applicability. Previously it was QWP

the applicability. Previously it was QWP only relating to chemical active substances. Now this Q&A relates to any

substances. Now this Q&A relates to any active uh any uh finished products containing any type of active substance.

Next slide please.

So what's challenging here is we we want to um be risk proportionate in terms of the uh the categorization of variations to add finished product manufacturing

sites and changes to batch size.

Um it's noted that we have the guideline on process validation and that clearly defines within its annex what are considered to be uh standard manufacturing processes and non-standard

manufacturing processes. It's not the

manufacturing processes. It's not the case that uh all non-standard processes should be considered complex. Those uh

complex manufacturing processes are generally a subset of what are considered to be non-standard. And what

the Q&A tries to do is to uh highlight the or explain uh regulators thinking in terms of why we consider certain uh manufacturing processes to be uh novel

or complex and when we consider that a change to such processes would potentially be a high impact on quality safety or efficacy and that would therefore require a type two variation.

So within the Q&A, you'll see examples of products manufactured by processes that could be considered complex. And

these are processes and and product types where we consider that there could be challenges during site transfer or scaleup activities and potentially an impact on the quality of the finished

product. Therefore requiring review

product. Therefore requiring review under a type two variation procedure. So

you'll see the list of of products there. Um typically ATMPS, liposomaal uh

there. Um typically ATMPS, liposomaal uh preparations, etc. Uh next slide.

There are also particular manufacturing processes themselves which uh would fall into this category. Um you can see the list of examples here. Product finished

products manufactured by continuous manufacturing or using decentralized manufacturing. Additive manufacturing

manufacturing. Additive manufacturing also known as 3D printing where process models are used in the control strategy where um personalized medicines are

being manufactured. As a general rule of

being manufactured. As a general rule of thumb, if your manufacturing process um has required an interaction with the quality innovation group of EMA, uh you

could consider that it it is an innovative manufacturing process. Um and

I think in that case we would uh consider that a type two variation to add a new cider to scale up such complex processes uh would be required. There

are um outside of these uh cases then a type 1B variation would be uh the applicable variation category for addition of a finished product manufacturing site or a scaleup uh of a

finished product manufacturing process where um applicants consider that their process and product is not novel or complex. They can provide a

complex. They can provide a justification within a type 1B um as as to why they don't consider to be novel or complex. If that justification is not

or complex. If that justification is not accepted however though the competent authority can upgrade the variation to a type two. Um we also encourage where um

type two. Um we also encourage where um possible tools like the post approval change management protocol can be used by applicants in order to um have some relief in ter in terms of the reporting

category for the variation. Uh but we would always encourage applicants to um to consult the relevant authority whether that's the national compet

authority or EMA. Um, next slide please.

So the other side of the coin then I suppose are what are finished products that are are not considered complex um by by default. So um these if you look

in the in the NX2 process validation guideline uh these type of uh dosage forms or manufacturing processes are generally considered to be non-standard

manufacturing processes uh but they're not necessarily considered complex uh in in the frame of this variation category.

So for example, aseptic processing is always considered a non-standard manufacturing process. But in uh when

manufacturing process. But in uh when you read the Q&A on on uh uh novel or complex manufacturing processes, it's not considered to be novel uh or

complex. Therefore, a change to add a

complex. Therefore, a change to add a manufacturing site for a aseptic finished product manufacturer could be a type 1B or a scaleup could be a type 1B.

Um and the same principle um applies to all of those that are that are listed there. So it's important when submitting

there. So it's important when submitting finished product variations uh for new sites and scale up that uh this Q&A on complex manufacturing is is referred to.

Next slide please.

Uh I'd like to say a few words now on the plan Q&A on uh the use of the product life cycle management document.

Uh next slide. So um in the revised variation regulation which entered into force this year a new article 6A was inserted which uh gave the legal basis to what are called the additional

regulatory tools. That was article 6A.

regulatory tools. That was article 6A.

Uh the this article 6A of the regulation was then uh implemented within chapters Q1 and Q2G of the revised variation guidelines. So we we already had uh

guidelines. So we we already had uh tools here um which are considered additional regulatory tools. So we know the design space tool for example uh its technical and scientific requirements

are defined in ICQ8114 and it had um it has uh variation categories for seen under Q&A and Q2G.

Similarly, the post approval change management protocol um details around that are are defined 12 and it's been part of our um of our EU variations

framework for uh over a decade now. But

uh the new one that we're adding is the PLCM document. So the PLCM similar to

PLCM document. So the PLCM similar to the design space and post approval change management protocol. It's a an ICH defined tool which now has um its legal basis in the variation regulation

and the details for the variations relating to the use of that tool have been elaborated uh under chapters Q1E and Q2G.

Uh next slide please. So for those um not familiar with the PLCM, it's a tool that's defined in the CHQ12 guideline on life cycle management specifically under chapter 5. It's a global tool for

chapter 5. It's a global tool for harmonized life cycle management. when

it's used, it should be submitted in in the EU uh under the regional part of uh the CTD under 32R and it serves as a central repository of of the legally

binding elements that are necessary for product quality. So that would be a

product quality. So that would be a combination of quality attributes, manufacturing process parameters, analytical parameters, acceptance criteria, etc. Um the the purpose of the

PLCM is to enable planning and implementing future changes in a predictable uh manner and it it aims to provide transparency and facilitate uh continual improvement. Next slide

continual improvement. Next slide please. You'll see the new categories

please. You'll see the new categories that have been added to the variation classification guideline annex. Uh so

for example here this is the the finished product uh section uh Q2G6 introduction of a PLCM and then there's additional variation categories for implementing changes and for making

changes to a PLCM.

So next slide please.

We've prepared a Q&A on the use of uh PLCM. We expect to publish it in the

PLCM. We expect to publish it in the coming weeks. Um key points to note from

coming weeks. Um key points to note from uh this Q&A is uh we recognize the PLCM as as a tool to facilitate a global harmonization of life cycle management.

Um from from an EU point of view, we don't consider it necessary. So it's

it's an optional tool. Um we we already have very effective life cycle management of EU authorized products but we do recognize that having a globally harmonized tool to facilitate life cycle

management activities can be beneficial for for applicants where where a PLCM is to be submitted um it needs to come via

a type two variation procedure. Um it uh the PLCM uh should be very specific in terms of uh which manufacturing process

steps or analytical procedures uh are in scope. uh it should apply to specific

scope. uh it should apply to specific manufacturing uh or testing sites and they should be clearly uh clearly defined and any future variation types

or categories uh to to change uh the information of PLCM need to follow the EU variation guidelines. In order to um have approval of a the use of a PLCM

document, GMP compliance and PQS effectiveness of the site uh will need to be confirmed. And um I just want to note in parallel that uh the inspector's

working group have agreed to uh run a pilot on uh PQS effectiveness and how PQS effectiveness for change management

uh can be demonstrated uh for those sites where PLCM is intended to be to be used. Um we're in planning the

used. Um we're in planning the practicalities. uh the inspector's

practicalities. uh the inspector's working group will be reaching out to their interested parties and announcing this uh pilot on PQS effectiveness. The

important thing is um where an applicant intends to submit a PLCM document by a type two variation, we very much encourage them to uh have a presubmission interaction with EMA or

the national competent authority and with the supervisory authority of the um uh the manufacturing site concerned and that we have a clear understanding of

when the PLCM variation is planned for submission. uh so we can uh plan our uh

submission. uh so we can uh plan our uh review uh accordingly.

Uh next slide please.

So there are some references some examples and training materials. with

the ICH Q12 guideline. Uh the step five annex is available on the EMA website and also on the CH uh website under the quality guidelines page. There is uh

quite a lot of training material relating to CH12 and also to the PLCM specifically and that can be accessed through the links uh that are here and

these slides will be made available after the um webinar. Next slide please.

practically speaking on this Q&A. So,

we've uh prepared a draft Q&A which was presented to the QWP and PWP in December. It was then uh through a round

December. It was then uh through a round of uh review by the the network member state comments were made on the draft.

The drafting group has reviewed the comments and revised the Q&A text. Uh

the next steps are for the QWP and B2B to adopt the um Q&A text and then for it to be adopted by CHMP and published. Our

target is to publish this as soon as possible after those steps uh are taken.

So I would imagine in the next week week or two um exact date to be confirmed, but we expect to publish this final Q&A uh on the use of PLCM on the EMA website. So you can keep keep an eye out

website. So you can keep keep an eye out for that one. Um I'm going to pass now to Garnet Hearn uh from the Austrian Agency to talk about the revised Q&A on

change management protocols. Got

>> many thanks Brian. Good afternoon to everybody. Um last topic of today uh the

everybody. Um last topic of today uh the revised question and answer on post approval change management protocol protocols. Next slide please.

protocols. Next slide please.

So let's dive directly into the topic.

What is a post approval change management protocol? It's a protocol for

management protocol? It's a protocol for specific planned quality changes. So

each of those words is relevant. It

cannot be used if nonclinical or clinical data are required or if the change results in the line extension.

There have to be concrete plans to implement the change in the foreseeable future otherwise it would be discouraged to do so. For example, a PACMP in a

marketing authorization application for not yet identified new manufacturing site is discouraged.

Ultimately, it should be sufficiently detailed and specific enough otherwise it will be refused.

Such a protocol unequivocally defines changes, studies, supporting data and acceptance criteria.

Adequate knowledge to manage the implementation of the changes which are planned should be demonstrated and all the relevant information should

be included in the post approval change management protocol itself. References

to other sections are not sufficient as those sections could be changed after approval of the PACMP and accordingly the PAMP would need to

be re-evaluated with every such change.

Next slide please.

Well, how can a PACMP be submitted, updated, or deleted?

Preferably, it is submitted via type two variation. In principle, it could also

variation. In principle, it could also be included in a marketing authorization application, but this is not recommended.

Over the course of such a procedure, dossier sections change a lot and the PACMP would need to be revised and reassessed every time such changes in

the dossier occur. So this is not an efficient way to proceed.

It may be updated prior to implementation of changes described in the PACMP. So if we are talking about a

the PACMP. So if we are talking about a minor change which does not change the overall strategy then this should be submitted as a type 1B variation. An example would be

1B variation. An example would be replacement of analytical proc of analytical procedure with an orthogonal method.

In contrast uh if it's a major change we are talking about this should be submitted as a type two variation. An

example would be removal or addition of tests or studies.

PSMP of course can also be deleted prior to implementation. So this would be uh

to implementation. So this would be uh type 1A on the conditions that the deletion is not a result of unexpected events or out of specification results during the

implementation and also there should be no effect on the already approved information in the dossier. Next slide please.

dossier. Next slide please.

How will the changes in a post-approval change management protocol be implemented?

So the implementing variation has to comply with the PACMP approved. All

studies should have been performed as described. The results should comply

described. The results should comply with predefined acceptance criteria.

Minor deviations which do not change the overall strategy of the protocol could be acceptable if they are sufficiently justified. In such a case though it is

justified. In such a case though it is not possible to submit the implementing variation as a type 1 A or 1 A in typically the implementing variation

would be one type lower than described in the classification guideline. So it

would be type 1 A, type 1 A in or type 1 B type has to be proposed as part of the PACMP and is subject to approval of the

authorities.

In exceptional cases, however, type two implementing variations could be required. Examples are given um like

required. Examples are given um like certain complex changes for example complete redesign of drug substance manufacturing processes or

multi-use post approver change management protocols that require products or sight specific adaptations.

We'll come to that with the next slide.

Please continue.

So, can a PSMP apply for multiple changes? Can a PAMP applied multiple times and for multiple

products? The answer to all of those

products? The answer to all of those three questions is yes. A PACMP can cover more than one change provided that those changes are interrelated

and that those changes can and will be implemented together via a single type 1 A type 1 A in or 1B variation. A

respective justification has to be provided in the protocol itself.

A PSMP can also be designed to be used repeatedly applying the same principles meaning multi-use of a PSMP.

The conditions and acceptance criteria described in the PSMP need to be sufficiently specific and the strategy and acceptance criteria should be relevant over the planned time frame.

product or sight specific adaptations are in principle not acceptable and if such adaptations are needed, the respective protocol may not be

accepted unless as mentioned before the implementing variation is chosen as a type two variation.

Although um marketing authorization holders will not um benefit from lower type of variation, at least the

predictability of outcome of the variation procedure will be increased.

Finally, the feasibility of the proposed multi-use approach has to be demonstrated.

Such a protocol can also cover multiple products.

on the condition that the protocol and the changes have to are applicable to all products in scope.

Such a protocol can only be submitted via type two worksheet. So not at the time of the marketing authorization application because those procedures are

for individual products only.

And finally, all products which are addressed in the PACMP should also be in the scope of the variation

that is submitted to introduced the PACMP.

Next slide, please.

How is oversight of PACMPS maintained?

There should be a listing of PACMPS provided and maintained in module 32R.

A unique identifier or name should be included along with procedure number in which the PACMP was submitted. A brief

description of changes covered by the PACMP. The proposed reporting category

PACMP. The proposed reporting category of implementing variation.

an overview of module 3 sections expected to be impacted and the status of the PSMP. So whether the implementation is pending or it already

has been implemented.

The implementing variation then should reference to the approved PACMP and the precise scope of the changes in the electronic application form and there

should be an overview with highle description of the proposed change and supporting data. Overall

supporting data. Overall module 3 documents should be self-standing.

Next slide please.

And what will the impact of the revision of the U variation guideline on already approved PACMPS be? So if your PACMP was

approved before but the submission of the implementing variation is after the 15th January of 2026

then the implementing variation should be submitted according to the agreed variation type in the post approval change management protocol. So if a type

1B was agreed then the implementing variation should be submitted as type 1B variation irrespective of the type according to the new variations

guideline. However, the corresponding

guideline. However, the corresponding change category of the new variations guideline is to be used if the PACMP was approved after the 15th

January 20, please refer to the new variations guideline. And uh with that we've come

guideline. And uh with that we've come to the end of this part and I hand over to Alberto for the final question and answer

session. Thank you very much Hernot and

session. Thank you very much Hernot and I will really like to thank to all presenters Alex, Susan, Elisa, Bhinia,

Brian, Carmen and her not for their very comprehensive presentations and uh driving us through all the changes of the V classification guideline and the

related guidance Q&As and and guidance.

So we have now uh half an hour for question and answers and I really encourage participants to continue providing questions through the QR code

that that you can find in in the slides.

We have already received uh a large number of questions more than 125 questions and we have tried to address some of them already in writing but u I

think now we are going to just take some orally and uh and uh reply them uh in the in the webinar and I would like to start with the first one which uh I

think has been one of the most popular and not unexpected questions which is linked to implementation aspect. So we

already both CMDH and the agency already encourage applicants to submit all type 1A variations implemented before the 15th of January 2026

uh to sub to to submit them by this date. But of course we are now two days

date. But of course we are now two days uh two days before this deadline. And um

one of the main questions and more repeated questions that we receive is even if marketing authorization holders despite all their efforts are not able to submit a type 1A change be already

implemented before this date before Thursday. Uh how would should these type

Thursday. Uh how would should these type 1A be submitted and hand them practically after the the cut off date?

So I would propose um Alex or Susan to to take this question. So I don't know who wants to start. Alex please.

>> Thank Albert I can perhaps start. So

indeed it's correct that EMA and CMDH guidance and CMH have published some guidance last summer once we knew the final date the cut off date for the

implementation of the new variations guidelines and we expect Mahes to adhere to this guidance. Of course, we understand that there might be some

exceptional cases where it's not possible to to fulfill this guidance and we would encourage you to discuss this with the competent authority. Thank you.

>> Thank you, Alex. I wonder if uh I mean Susan you want to complement but I mean this I think applies both for centrally authorized products but also MRPDCP but

I don't know Susan if you have any additional remark you wanted to add.

Thank you very much, Alberto. No, I

think uh I fully agree with Alex and I have nothing to add. Thank you.

>> Another question I think maybe this one will be also for you Susan or or Alex is one of the questions that is mentioned is whether I mean the application of the

unforeseen Z category is still applicable in the same way as was previously applied in in the varian classification guidelines. So don't know

classification guidelines. So don't know who wants to to take it.

>> I can take this one Alberta as well. So

indeed it's correct that unforeseen zeta variations are still available on the e application form and PLM portal for submission. Thank you.

submission. Thank you.

>> Thanks uh Al Alex and um another of the of questions that we received and this one it's mainly for

Susan. what can we do when a com uh what

Susan. what can we do when a com uh what can we do as a company when Emma and NCA do not follow the new regulation guideline the same way? So maybe I mean

it's a question of how we can ensure the consistency across the network and the activities. So I think Susan I mean you

activities. So I think Susan I mean you would be best pleased to address this one.

>> Yes, thank you very much. I hope my connection is stable now. Um yes I I can assure you that uh we are aligning between CMDH and EMA for all the

guidances and we really try to interpret it in completely the same way and uh in cases where uh we have a maybe a slight

different interpretation we are looking for a solution we are discussing this um in order to harmonize our uh ways of interpreting it in the same way I know

that there are questions concerning the grouping of type 1 A and type 1 A immediate notifications uh where we have different um interpretations and this is on the

discussion at CFDH.

Thank you.

>> Thank you Susan. So in indeed I would like also like to complement that I mean in addition of all the work that CDH is doing to harmonize among member states

also the agencies closely collaborating and in fact I mean we also did a joint session recently for training and uh the

whole network as RNC to ensure that this harmonized implementation took place. So

thanks. Um we have another question.

This one is more linked to quality. So

maybe it will be for for Lisa to address. So it's related to varation

address. So it's related to varation category Q2 F1 B1 to extend save life of drug products who now I mean the new guideline request they down three

batches whereas two batches were previously needed. So I mean industry is

previously needed. So I mean industry is claiming that of course completing a stability study of one additional batch means delaying variations sometimes uh

could take some time. So the the question is is there any flexibility or what the flexibility in BC? So

>> yes, so this answer applies also for the same categories under the active substance and since it's been there has been some downgrading uh so certain

extensions can be filed now as type 1A uh we had to uh um uh kind of uh put a higher a little bit stronger condition

and requiring uh three batches also uh to bring the requirements in line with the um CH guideline it has been uh

revised at the moment. But so if uh if the category is a type 1 A and you uh have only two batches, you could upgrade

the type 1 A to a type 1 B and justify why two batches are sufficient. So this

is going to be assessed. So if it's a type 1 B anyway, you can uh justify uh why you only have two batches instead of three. So there is a flexibility there.

three. So there is a flexibility there.

I'm also taking the opportunity to clarify that these sections for active substance and finished product related to stability has been uh revised to try

to take to try to future proof these these categories. Uh as as I said

these categories. Uh as as I said guideline has been revised. So also what I said about the extrapolation

uh being possible for biotech products this today is still not possible because the currently uh valid guideline uh still mentioned that is not possible but

the uh the the draft one uh it's opening up uh uh towards that. So uh when that is finalized then it will be possible to

use extrapolation for biologicals and stability modeling and for stability modeling in particular we always encourage applicants to come for scientific advice as this can be tricky.

>> Okay thank you very much Elisa and also for this clarifications.

Um we also have uh one question linked also to herbal medicine product. So this

one will be more for for carmen. So the

question is for changes Q31 and Q32 it is not clear why herbal medicines are type 1B and hence have a different classification than chemicals. There

have not been any issues with herbal medicinal products in the past and the rational remains unclear. So I think more carmen this is more a static question just to a little bit understand

the background reasoning behind. So

>> yeah thank you. So we should keep in mind all the time that the herbal and chemical active substances are completely different. So when you have a

completely different. So when you have a certificate of suitability, it's only going to say that the active substance is compliant with that monograph in

European Pharmacopia. But this is so

European Pharmacopia. But this is so easy for a chemical API. But for a herbal API, just check different monographs European

Pharmacopia and you you will see that the monograph is covering several different extracts with really significant differences because the

monograph can cover I just double check the European phmicopia for example for Savali serata extractum. So the one monograph is covering CO2 supercritical

extract but also hexane extract and ethanolic extract. You don't have DR in

ethanolic extract. You don't have DR in the monographs. So actually they are

the monographs. So actually they are completely different extract. So at the end you have to assess and really to justify to demonstrate

that these are comparable. That's why I mentioned from the beginning herbals are not chemicals and that's why can't it just can't fit in type 1 A should be

assessed. So it's type 1 B.

assessed. So it's type 1 B.

Thank you. Thank you very much Carmen.

It's always good to understand I mean the reason behind also to to better interpret the classification guideline.

I would like to now to move to to the medical device section which I think here there is a big improvement in the classification guideline because we have many more scopes and uh there is here

one question for Binia is there any update planned to the device question and answer other communication following the initial experience with the new scopes. So

scopes. So >> so uh yes I mean the answer is yes we keep updating this document on a regular basis. uh I think that last year it was

basis. uh I think that last year it was updated twice. uh so we always collect

updated twice. uh so we always collect all the cases and all the questions that uh we receive uh from industry or notified bodies from any channels

conferences questions all sorts uh and uh we will keep this document updated.

So most likely this year there will be another update. But uh for now we are

another update. But uh for now we are just gaining experience with the new scopes and if we see that there is any issue that there is a particular trend

that is not fully understood or that we have problems for any reason then we will include uh a clarification on the questions and answers. So uh yes the answer is absolutely.

>> Okay.

Thank you. So yes, it's it's good that I mean we have a a varian classification guideline that really details I mean establish the framework but also that we complement with guidance which is much

easier to update and uh we can provide the the further interpretation that the sector really needs. Um I think um we

move to to another question. So we are going to move to to to a question on uh PLCM. So this is for Brian and uh there

PLCM. So this is for Brian and uh there is one question that where do you see PLCM would have a value in the EU for a marketing authoration holder or for a

competent authority. So I don't know

competent authority. So I don't know Brian if you have any views on the on on what will be the value of the of this

new tool both for for us regulators and and national competities but also for for industry.

>> Yeah thanks Alberto. So yeah, as I as I outlined, I mean, we see this tool as having value as a global harmonizing harmonization tool. Um, and that really

harmonization tool. Um, and that really the benefit there is is for the industry uh that if they want to have a a common uh global dossier that they can um submit in multiple regions and and have

a harmonized dossier and harmonized submission, that's that's um the advantage in terms of um specific advantage for EU. I mean we don't need

this tool. We have a very well

this tool. We have a very well functioning and and highly detailed life cycle management uh system which works uh which works fine at the moment. So

the PLCM is an optional tool uh that the applicants can use to help facilitate global life cycle management. Um it's

probably more it's more work to assess uh a PLCM for for EU regulators. Um but

we're we're happy to do it if it if it facilitates um a more efficient uh global life cycle management.

>> Thanks uh Bryant. And um another question, this one is for Got uh for approval change management protocol. Can the overview of the

protocol. Can the overview of the supportive data with tables referring to an approved acceptance criteria be placed in module one? is more like a like a link to to the dosier

requirements. So G

requirements. So G >> thanks. I think that's a short answer.

>> thanks. I think that's a short answer.

So based on the current dosier structure information should be in 32R not in module one.

>> So very careful >> with with with new M4Q this then will change but for the time being it's 32R.

Yeah, very clear, very clear and straightforward. I have another question

straightforward. I have another question also for for you and uh I mean of course we have the the concept of PLCM and

PACMP. So and uh often with all these

PACMP. So and uh often with all these acronyms often many people confuse themselves. So what is the main

themselves. So what is the main difference or can you explain the difference between both concepts because I think it will be good especially for for some of of person that are starting to to work with the classification

guideline and with the EU system to get a clarification what is the main difference because of those concepts >> in the in the meaning of our classification guideline the PLCM

document as mentioned by Brian is a tool which facilitates global harmonization of post approval CMC changes

While a PACMP is a stepwise approach in the assessment of such changes which allows an early evaluation of the strategy for the change and a later

separate evaluation of the data produced based on the grid strategy.

So as as Brian mentioned before, based on our very comprehensive EU variations

framework, we do not need to um to define every

possible variation in the PLCM.

But if applicants um want to do that for the sake of a global harmonized dossier, we accept that. But there is no um

benefit in the EU. While on the other hand for the post-approved change management protocol, if you have a specific change you plan to implement in

the foreseeable future, you can delineate your plans, get an approval up front before implementing and so you

have an quicker implementation and and a more um foreseeable outcome of this variation procedure. So there's

clearly um different relevance in between those two types of documents.

>> Thank you very much Henot. I think it's very clear. So we have many more

very clear. So we have many more questions. So I will pick this one. So

questions. So I will pick this one. So

um it's related to CNN's uh article 5 recommendation. And uh here the question

recommendation. And uh here the question is uh will there be >> do we expect >> okay do we expect no is do we expect article five unforeseen changes to be

updated?

>> So maybe this one is for for Susan.

>> Yes thank you very much Alberto. So uh

currently we have uh checked the article 5 uh recommendations that were already tabled in the past and these have been included in the new um variations

guideline where applicable. Um and so um the the list will be empty starting from the 15th of January. But of course we still have the article 5 procedure

covered in the variation regulation and um so um you can raise article 5 requests as in the past. The time frame has been a bit shorter now but of course

if new recommendations uh will um be issued they will be included in the table and um they will then also be considered in the future

updates of the guideline.

Thank you.

Thank you Sus Susan and um I would like to take uh just uh one additional question. I mean it it's all linked to

question. I mean it it's all linked to to also global development and uh I think the question relates more about submission of type 1A outside uh outside

the annual update and the question was if it would be possible to have submission outside the annual update in order to support the regulatory submission from other country. So I

don't know who who could take this one whether it I think yeah >> yeah that's fine. Um so yes this is one

of the exceptions included in the guidon uh for the annual update. So if uh you need the change for reliance purposes because it needs to be implemented in a

third country and you need a CPP or an authorization letter you can include the justification in the application form.

uh and uh yeah it will be checked and review. It's one of the exceptions that

review. It's one of the exceptions that we agreed as part of the guidance and is listed. So uh it's a mechanism that you

listed. So uh it's a mechanism that you can use if you need that variation to be approved in a third country.

>> Okay.

Thank you very much Binia and uh I will really like to thank all participants for the number of questions that uh we have received. As mentioned before, we

have received. As mentioned before, we have addressed some of them h already in writing in the in in already in slido

and uh we took I think the most relevant and the most voted ones here in in in in the session and definitely we will review the rest that remain unanswered to ensure that I mean they are part of

our guidance or whether our guidance will require any kind of of of the update. uh we still have uh 10 more

update. uh we still have uh 10 more minutes and I would like to end up in the final part which is just uh the conclusion some final remarks. So here I

would like to to give the floor to to Susan just for some concluding remarks.

>> Yes, thank you very much Alberto. First

of all I have to apologize for the connection problems. I hope it is stable for now. Um I would like to thank the

for now. Um I would like to thank the the EMA team and all presenters for um having this training today. I think the webinar was perfectly organized and

processed and we heard excellent presentations showing the details uh on the classification guideline update as well as the procedural amendments. Um,

we have been introduced to the new and updated guidances as well as question and answers in relation to the new variation framework. And we hope that

variation framework. And we hope that most of the questions raised via slido could be resolved in the question and answer part so that you are now able to

work well with the revised variation framework. And um I can inform you this

framework. And um I can inform you this was also raised several times in slido that the presentation and video video recording will be available on the

events web page um after the webinar. So

I hope that uh the objectives of this um training have been achieved and you will now look forward to work uh with a revised framework and the updated classification guideline starting on the

15th of January. So thank you for joining the training today and now I would like to hand over for to Alberta again for some final remarks. Thank you.

>> Thank you very much Susan. So yes the the final remarks as it has already already been said and uh I think you are all aware I mean the new varian specification guidelines will take

effect on Thursday on the 15th of January 2026. I mean uh both uh the

January 2026. I mean uh both uh the agency and uh CMDH will continue uh monitoring the implementation of these new varian classification guidelines. I

mean there will be more opportunities for engagement especially with industry.

It will we will have I mean interested parties meetings that CND regularly does and also the agency through the MI industry platform on the centralized procedure with the main industry

associations. So we will be monitoring

associations. So we will be monitoring and and uh reviewing how the implementation will take place. I also

want to pass a message for all applicants if they have any doubts do not hesitate to after you have reviewed the the guidance that we have already available to contact I mean your NCA

your reference member state in case of the centralized or mutual recognition procedures and the agency specifically the procedures office or your quality

specialist or your PL in in terms of uh of of the centralized procedure. I

really want to pass also a final slide where you can have the main MCMDH question answer and guidelines links that we can have that we have in the in

the next slide and where you will you will be able to find the most updated relevant guidance and we really encourage you that this will be your

first uh point in order to prepare your your submissions and uh we just really hoped to have a a smooth transition and

we hope that this webinar uh had been useful in order to to support this transition from the new vision guideline to the to from the old one to the to the

new one. I really want to thank uh as

new one. I really want to thank uh as echo in Susant all presenters from Emma staff CMDH and QWP representatives and

all participants for your active engagement even if we don't hear you we it has been notorious the number of questions that we have received and uh

we could only host 10,000 people in our web link but there has been a very wide also audience in the our uh broadcast.

So, thank you very much. Good afternoon

and looking forward to continue collaborating with all of you in the implementation of the new varian guidelines. Thank you.

guidelines. Thank you.