1The types at a glance.
| Type | What it is | When you can implement | Review clock | Quality examples |
|---|---|---|---|---|
| IA | A change with “only a minimal impact, or no impact at all” | Before notifying | 30 days from receipt | Batch size up to 10 times the approved size, immediate-release oral form (Q.II.b.4(a)) |
| IAIN | A Type IA that must be notified straight after implementation | Before notifying, then notify at once | 30 days from receipt | New secondary packaging site (Q.II.b.1(a)) |
| IB | Neither IA, II nor an extension: the default | After acceptance, or at day 30 with no objection | 30 days, no clock stops | New finished-product manufacturing site (Q.II.b.1(e)) |
| II | A change that “may have a significant impact” on quality, safety or efficacy | After approval | 60 days, or 30 or 90, plus clock stops | Acceptance criterion moved outside the approved limits (Q.II.d.1(e)); new indication |
| Extension | A change listed in Annex I: active substance, strength, form or route | After the authorisation is amended | As for a new marketing authorisation | New strength; new route of administration |
The guidelines’ Annex classifies changes code by code. A Type IA that misses a condition may go as a Type IB under the same code, unless the Annex makes it a Type II.¹ An unclassified change is a Type IB by default; an Article 5 recommendation on it can be requested before filing, due within 60 days.²³
2When you can implement each type.
- Type IA. Make the change, then notify. For a quality change, implementation is when you make the change in your own quality system. Most Type IAs go into one annual update per authorisation, sent 9 to 12 months after the first implementation. If one is rejected, stop applying it at once.⁴
- Type IAIN. Notify immediately after implementation;¹ MHRA treats two weeks as reasonable.⁵
- Type IB. Notify, then wait. The authority checks validity within 7 days and then has 30 days; silence at day 30 means acceptance. It may instead ask for a Type II. After an unfavourable outcome you may amend once, within 30 days.¹⁶
- Type II. Wait for approval. Each request for supplementary information stops EMA’s clock, by default for one month. A centralised product implements on a favourable outcome, unless the change needs a Commission decision first, such as a new indication.⁷ In the mutual recognition procedure the Regulation allows implementation 30 days after the reference Member State accepts, once the concerned Member States have the documents to amend the authorisation; nationally, on acceptance.²¹ CMDh’s guide words it differently, allowing implementation “immediately following receipt of the finalisation letter of the reference authority” if no referral has started and the product information is unaffected.⁸ The 30-day rule is the Regulation’s; the CMDh text is a best practice guide.
3Checklist: what a Type IB or II application contains.
Every application is an eCTD submission with the elements of Annex IV to the Regulation, set out in section 2 of the guidelines.¹
| Item | What it must show | When |
|---|---|---|
| Cover letter | The authority’s request, if it asked for the change | Always |
| Application form (eAF) | Each authorisation and variation, its code or Article 5 recommendation, and that the documentation requirements are met | Always |
| Present and proposed table | Every change, and how linked variations relate | Always |
| Justification | Why an unclassified change is a Type IB | Unclassified change |
| Supporting data | Each document the Annex lists under the code | Always |
| Product information | Revised SmPC, labelling and leaflet; translations at submission for a Type IB | If affected |
| Summaries | Updated quality overall summary, or non-clinical and clinical overviews | Type II, where relevant |
4What changed in 2025 and 2026.
Delegated Regulation (EU) 2024/1701 amended the Variations Regulation from 1 January 2025.³ The Commission’s guidelines C/2025/5045, published on 22 September 2025, replaced those of 2013 from 15 January 2026.¹⁹
| Topic | Before | Now | Source |
|---|---|---|---|
| Type IA timing | Within 12 months, singly or collected | One annual update; the first implemented from 15 January 2026 started a new cycle | Arts 8(1), 14(1);³ EMA⁹ |
| Worksharing | The holder “may follow” it | The holder “shall follow” it for the same IB or II change to several of its authorisations, unless each product needs its own assessment | Art. 20(1);²³ section 3¹ |
| Biological substance | Process and site changes Type II by rule | Classified code by code; a new site is still Type II (Q.I.a.1(d)) | Annex II, 2(e)³¹ |
| Biological product site | Type II (B.II.b.1(c)) | Type IB (Q.II.b.1(e)) unless the process is complex or the site needs inspection | Guidelines¹⁰¹ |
| Chemical substance site | IAIN only within the same group (B.I.a.1(a)) | IAIN from any maker with identical route, specifications and batch size (Q.I.a.1(a)) | Guidelines¹⁰¹ |
| Codes | A, B, C, D | E (administrative), Q (quality), C, M (plasma and vaccine master files) | Guidelines¹⁰¹ |
5MRP, DCP and national filings: timetables and worksharing.
In the mutual recognition and decentralised procedures, coordinated by CMDh, a Type IB runs on the same 30 days as at EMA, with any “Notification with Grounds” by day 30.¹¹ A standard Type II runs as follows.
| Day | Step |
|---|---|
| 0 | Reference Member State starts the procedure |
| 40 | Preliminary assessment report |
| 55 | Concerned Member States comment |
| 59 | Request for supplementary information; clock stops for up to 60 days for your answer, in CMDh’s response document, and 60 for the final report |
| 60 | Final assessment report |
| 80 | Concerned Member States comment again |
| 90 | Procedure ends; endorsed product information circulated |
For worksharing without a centralised product, you choose the reference authority; CMDh recommends the reference Member State of most of the products. Send CMDh’s letter of intent at least 2 weeks before filing; the authority confirms within 7 days, or you ask your next choice.¹² With a centralised product, EMA is the reference authority¹ and wants the letter at least 2 months ahead.¹³ Super-grouping, new in 2025, puts the same Type IA change to several licences in one notification,³¹ but not yet centralised and national licences together.⁴
6Which category? Site changes in the EU and the US.
| Change | EU type and code | US route for an NDA or ANDA |
|---|---|---|
| Secondary packaging site | IAIN, Q.II.b.1(a) | Annual report (VI.D.1) |
| Primary packaging site | IAIN for a non-sterile product, Q.II.b.1(b) | CBE-30 (VI.C.1.c); prior approval if the pack controls the dose (VI.B.3) |
| Manufacturing site | IB, Q.II.b.1(e) | CBE-30 (VI.C.1.a) |
| Complex process site | II, Q.II.b.1(c) | Prior approval for modified release, inhalers, liposomes and similar (VI.B.3) |
| Site needing inspection | II, Q.II.b.1(d) | Prior approval without a satisfactory inspection for that operation (VI.B.1, VI.B.2) |
| Testing site | IA for physicochemical or microbiological tests, Q.II.b.2(a) | CBE-30 (VI.C.1.d) |
| Batch release site | IAIN without testing, Q.II.b.2(c)1 | No equivalent: QP certification is an EU step |
| Active substance site | IAIN for a non-sterile chemical substance, Q.I.a.1(a); II with a master file, Q.I.a.1(f) | CBE-30 (VI.C.1.a) |
EMA counts advanced therapies, liposomes, lipid nanoparticles, parenteral modified release, inhalers, multilayer tablets and continuous manufacturing as novel or complex, but not aseptic processing; a Type IB under these codes must justify why its process is neither.¹⁵ The US tiers follow a change’s “substantial”, “moderate” or “minimal” potential for an adverse effect,¹⁶ so they match the EU types only loosely: see PAS, CBE-30 or annual report.
7Example: one site change filed in the EU and the US.
This example is invented. Exemplol 50 mg film-coated tablets, an immediate-release chemical product, are authorised centrally in the EU and under an NDA in the US. The holder adds an Irish contract manufacturer for granulation, compression and coating; the existing site still packs, tests and releases.
| Step | EU, centralised | US, NDA |
|---|---|---|
| Classify | Type IB, Q.II.b.1(e): standard process, site inspected by the Irish authority in 2025 | CBE-30, VI.C.1.a: site found satisfactory by FDA for oral solids in 2024 |
| Validate | Batches 26-061 to 26-063, made 9 June to 21 July 2026 at production scale | The same batches |
| Submit | 1 September 2026 | 1 September 2026, received that day |
| Clock | Started 8 September; no objection by 8 October, so accepted | No objection within 30 days of receipt |
| First supply | From 9 October 2026 | From 1 October 2026 |
The EU Type IB carries these documents from the Q.II.b.1 list:¹
- Document 1. The new site’s manufacturing authorisation, by EudraGMP reference.
- Document 2. Validation batch numbers, sizes and dates for 26-061 to 26-063, with the data.
- Document 4. Batch analysis of 26-061 and 26-062 beside 26-044, 26-047 and 26-052, the current site’s last three.
- Document 6. QP declarations on active substance GMP from the release site and, as it is in the EU, the new site.
- Document 7. The updated Module 3 sections.
- Document 8. Validated transport and bulk storage to the packing site.
The CBE-30 describes the change, product, sites, studies and data, and gives the basis and date of the change.¹⁶ A site needing its first EU inspection would make the EU filing a Type II (Q.II.b.1(d)),¹ and one FDA had never inspected for this operation a prior approval supplement.¹⁴
8Fees.
EMA charges nothing for a Type IA, IAIN or IB, which the annual fee covers, and €22,000 for a Type II, or €163,200 for a new or modified indication.¹⁷⁶ National authorities set their own fees; MHRA charges none for a national Type IA or IAIN.⁵
9The UK.
The UK applies the amended Regulation from 1 January 2025 and the new EU guidelines from 15 January 2026, except that COVID-19 vaccine strain changes go as line extensions.⁵ MHRA adds:⁵
- A Type IA filed more than 12 months after implementation goes as a default Type IB.
- A new indication runs on a 120-day Type II timetable.
- A Type IB or II through the International Recognition Procedure (IRP) needs MHRA’s IRP submission checklist, and uses the new categories even where the reference regulator approved it under the old ones. A Type IA keeping an IRP dossier aligned with that regulator may be filed early, once the regulator has approved it.
10How it runs in Seal.
In Seal, a manufacturing change such as the Exemplol site addition is one change record that carries the scientific case once, while each market keeps its own filing type, clock and implementation gate, as in post-approval CMC change. The EU gate opens on acceptance of the Type IB and the US gate on its own date, from the same validation batches.
RIMS keeps the approved state of each market apart from the next submission, so a site already listed for testing is not mistaken for one approved to make or pack the product. Regulatory submissions keeps each Module 3 section tied to the batches and results it rests on. Neil drafts the market impact assessment with its sources, and your regulatory team decides the category.
References
- 1Guidelines on the details of the various categories of variation, C/2025/5045, sections 1 to 3 and the Annex, European Commission, Official Journal, 22 September 2025, applying from 15 January 2026. https:/
/ eur- lex. europa. eu/ eli/ C/ 2025/ 5045/ oj/ eng (read 8 November 2026) - 2Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations, Articles 2, 3, 5, 7, 19, 20 and 24, EUR-Lex, as published. https:/
/ eur- lex. europa. eu/ eli/ reg/ 2008/ 1234/ oj/ eng (read 8 November 2026) - 3Commission Delegated Regulation (EU) 2024/1701 of 11 March 2024 amending Regulation (EC) No 1234/2008, Article 1, EUR-Lex, applying from 1 January 2025. https:/
/ eur- lex. europa. eu/ eli/ reg_ del/ 2024/ 1701/ oj/ eng (read 8 November 2026) - 4Type-IA variations: questions and answers, questions 1, 5, 7 and 8, European Medicines Agency, updated 6 October 2026. https:/
/ www. ema. europa. eu/ en/ human- regulatory- overview/ post- authorisation/ variations- including- extensions- marketing- authorisations/ type- ia- variations- questions- answers (read 8 November 2026) - 5Medicines: apply for a variation to your marketing authorisation, Medicines and Healthcare products Regulatory Agency, GOV.UK, updated 14 October 2026. https:/
/ www. gov. uk/ guidance/ medicines- apply- for- a- variation- to- your- marketing- authorisation (read 8 November 2026) - 6Type-IB variations: questions and answers, questions 7 and 8, European Medicines Agency, updated 6 October 2026. https:/
/ www. ema. europa. eu/ en/ human- regulatory- overview/ post- authorisation/ variations- including- extensions- marketing- authorisations/ type- ib- variations- questions- answers (read 8 November 2026) - 7Type-II variations: questions and answers, questions 11 and 13, European Medicines Agency, updated 6 October 2026. https:/
/ www. ema. europa. eu/ en/ human- regulatory- overview/ post- authorisation/ variations- including- extensions- marketing- authorisations/ type- ii- variations- questions- answers (read 8 November 2026) - 8Chapter 5, CMDh Best Practice Guide for the handling of Type II variations in the Mutual Recognition Procedure, CMDh/295/2013 Rev.28, sections 7 and 8 and Annex II, Heads of Medicines Agencies, October 2025. https:/
/ www. hma. eu/ fileadmin/ dateien/ Human_ Medicines/ CMD_ h_ / procedural_ guidance/ Variations/ Amended_ Variation_ Regulation/ CMDh_ 295_ 2013_ Rev28_ 2025_ 10_ clean_ - _ Chapter_ 5_ - _ BPG_ for_ the_ Processing_ of_ Type_ II_ Variations_ in_ MRP. pdf (read 8 November 2026) - 9Guidance on the application of the revised variations framework, European Medicines Agency, updated 2 December 2025. https:/
/ www. ema. europa. eu/ en/ guidance- application- revised- variations- framework (read 8 November 2026) - 10Guidelines on the details of the various categories of variations, 2013/C 223/01, Annex, B.I.a.1, B.I.e.2 and B.II.b.1, European Commission, Official Journal, 2 August 2013. https:/
/ eur- lex. europa. eu/ legal- content/ EN/ TXT/ ?uri=oj:JOC_ 2013_ 223_ R_ NS0001 (read 8 November 2026) - 11Chapter 4, CMDh Best Practice Guide for the processing of Type IB minor variations (notifications) in the Mutual Recognition Procedure, CMDh/294/2013 Rev.29, sections 2.4 and Annex II, Heads of Medicines Agencies, October 2025. https:/
/ www. hma. eu/ fileadmin/ dateien/ Human_ Medicines/ CMD_ h_ / procedural_ guidance/ Variations/ Amended_ Variation_ Regulation/ CMDh_ 294_ 2013_ Rev29_ 2025_ 10_ clean_ - _ Chapter_ 4_ - _ BPG_ Processing_ Type_ IB_ Minor_ Variations_ _ Notifications_ _ in_ MRP. pdf (read 8 November 2026) - 12Chapter 7, CMDh Best Practice Guide on Variation Worksharing, CMDh/297/2013 Rev.37, sections 3 and 4, Heads of Medicines Agencies, July 2026. https:/
/ www. hma. eu/ fileadmin/ dateien/ Human_ Medicines/ CMD_ h_ / procedural_ guidance/ Variations/ Amended_ Variation_ Regulation/ 04_ - _ CMDh_ 297_ 2013_ Rev. 37_ 2026_ 07_ clean_ - _ Chapter_ 7_ - _ BPG_ on_ Worksharing. pdf (read 8 November 2026) - 13Worksharing: questions and answers, question 3, European Medicines Agency, updated 6 October 2026. https:/
/ www. ema. europa. eu/ en/ human- regulatory- overview/ post- authorisation/ variations- including- extensions- marketing- authorisations/ worksharing- questions- answers (read 8 November 2026) - 14Changes to an Approved NDA or ANDA, guidance for industry, Revision 1, section VI, FDA, April 2004. https:/
/ www. fda. gov/ media/ 71846/ download (read 8 November 2026) - 15Quality of medicines questions and answers: Part 1, “Novel or complex manufacturing process in Q.II.b.1 and Q.II.b.4”, European Medicines Agency, November 2025. https:/
/ www. ema. europa. eu/ en/ human- regulatory- overview/ research- development/ scientific- guidelines/ quality- medicines- questions- answers- introduction/ quality- medicines- questions- answers- part- 1 (read 8 November 2026) - 1621 CFR 314.70, Supplements and other changes to an approved NDA, eCFR. https:/
/ www. ecfr. gov/ current/ title- 21/ chapter- I/ subchapter- D/ part- 314/ subpart- B/ section- 314. 70 (read 8 November 2026) - 17Regulation (EU) 2024/568 on fees and charges payable to the European Medicines Agency, recital 16, Article 10(6) and Annex I, section 5, EUR-Lex, applying from 1 January 2025. https:/
/ eur- lex. europa. eu/ eli/ reg/ 2024/ 568/ oj/ eng (read 8 November 2026)
AQuestions and answers
Is there a template for answering a Type II request for supplementary information?
In the mutual recognition procedure, yes: download CMDh’s response document from the Templates, then Variations, section of the CMDh website. Copy each question from the reference and concerned Member States into it word for word and answer it on its own under quality, non-clinical or clinical, never combining questions; answer questions on an active substance master file separately. File it as a PDF in Module 1 and as a Word copy in the working documents folder, confirming on the cover page that they are identical, with an updated application form whenever the dossier changes.
What stability data does a Type II variation need?
It depends on the code. For many changes the classification guidelines set the minimum themselves, often 3 months on two pilot or production batches with a commitment to finish the studies. For common Type II changes EMA’s stability guideline for variations, Revision 3, in force since 15 January 2026, adds the rest: for a complex-process manufacturing site where stability could be affected, for example, 6 months of comparative long-term and accelerated data on at least two pilot-scale batches, or three for a modified-release form or an unstable substance. It covers chemical and herbal products, not biologicals, and studies continue to the end of the shelf life.
Does an accepted Type IB have to wait for the marketing authorisation to be amended?
No. Once the authority accepts it, or it is deemed accepted at day 30, you can implement it. National authorities amend the authorisation within six months of the procedure closing, and for a centralised product the Commission amends its decision within 12 months, with the accepted change carried into the annexes of the next procedure that needs a decision.
What is the difference between a Type II variation and a line extension?
An extension, often called a line extension, is one of the changes listed in Annex I of the Variations Regulation: a change to the active substance such as a new salt or isomer, or a new strength, pharmaceutical form or route of administration. It is assessed by the same procedure as the original marketing authorisation, not on a Type II timetable. A Type II is any other change that may have a significant impact, such as a new indication.
Can a Type IA be grouped with a Type IB or Type II variation?
Yes. A Type IA can leave the annual update to join an acceptable grouping with a Type IAIN, IB or II variation, and it can be grouped with a Type IB or II going through worksharing. Worksharing on its own does not apply to Type IA changes, which use super-grouping instead.