Container Closure Changes Under the EU Variations Regulation: Type IA, IB and II Classification and EMA Data Expectations

Container closure changes under the EU Variations Regulation: Type IA, IB and II classification and EMA data expectations

Changes to the container closure system (CCS) of an EU-authorised medicinal product are handled as variations under Commission Regulation (EC) No 1234/2008. The detailed categories sit in the Commission's classification guidelines, which were rewritten in 2025 following Commission Delegated Regulation (EU) 2024/1701 ¹⁹²²²⁴. The classification mostly depends on three things: the dosage form (solid, semi-solid or non-sterile liquid, sterile), whether the product or active substance is biological, and whether the new pack protects the product as well as the approved one. The data EMA expects comes from three places: the conditions and documentation set out in each variation category, EMA's guideline on plastic immediate packaging materials, and EMA's stability guidance for variations.

1. The legal framework: what Type IA, IB and II mean

Regulation 1234/2008 defines the three variation types as follows ¹¹⁰:

• Type IA (minor): the change has only a minimal impact, or none, on quality, safety or efficacy.
• Type IB (minor): the change is not Type IA, not Type II and not an extension.
• Type II (major): the change is not an extension and may have a significant impact on quality, safety or efficacy.

Annex II of the Regulation gives two examples that bear directly on packaging. A change to packaging material not in contact with the finished product is Type IA. (The condition that the change must not affect delivery, use, safety or stability comes from the classification guidelines, not Annex II itself.) A change to an integral or exclusively used medical device is also Type IA if it has no impact on quality, safety or efficacy ¹¹¹. On the other side, changes outside approved specifications, limits or acceptance criteria are Type II, and so are device changes that may significantly affect quality, safety or efficacy ¹¹².

Procedural consequences

• Type IA: the marketing authorisation holder (MAH) can implement the change first. It notifies the authorities within 12 months of implementation, for example in an annual update. Changes flagged for immediate notification (IAIN) must be notified straight after implementation ^113114115.
• Type IB: this is a notify-and-wait route. The MAH can implement the change only after the authority accepts the notification, or the notification is deemed accepted. For centrally authorised products, implementation follows a favourable (or deemed favourable) EMA opinion ¹²⁰.
• Type II: this is an application-and-assessment route. Implementation needs acceptance or a favourable opinion. For mutual recognition and decentralised procedures, the MAH can implement 30 days after the reference Member State informs it of acceptance, if the required documents have been provided ¹²¹. For centrally authorised products, Type II changes that require the Commission decision to be amended are generally implemented only once that decision is updated.

Default rules

• Unclassified changes: if a change is not an extension and its category cannot be determined from the Regulation and guidance, it defaults to Type IB ¹²³. It becomes Type II instead if the MAH requests Type II at submission, or if the authority concludes the change may significantly affect quality, safety or efficacy ¹²³.
• Unmet Type IA conditions: under the 2025 guidelines, if a Type IA condition is not met, the change can generally be submitted under the same code as a Type IB ²⁹⁶. This does not apply if the change is specifically classified as Type II, or if the MAH considers it may have a significant impact. The authority can also require a default Type IB to be upgraded to Type II ²⁹⁶.

2. Which classification guideline applies: 2013 B.II.e versus 2025 Q.II.e

The Commission's 2025 guidelines on variation categories (OJ C/2025/5045, published 22 September 2025) replace the 2013 guidelines ¹⁷⁹²²⁴. The 2025 guidelines apply from 15 January 2026. Submissions made before that date follow the 2013 guidelines ²²⁵.

The 2025 annex reorganises the quality section:

• Q.I covers the active substance. Its container closure system section is Q.I.c ⁹⁰²⁸⁷.
• Q.II covers the finished product. Its container closure system section is Q.II.e ¹⁴⁸.

Some item numbers have moved. In the older table, a change in container shape or dimensions was B.II.e.4 ²⁵⁰. In the 2025 guidelines it is Q.II.e.2 ²⁷¹. Dossier teams should check that internal change-control templates use the current codes.

The revision also introduces more flexible grouping across marketing authorisations and wider use of worksharing. For biologicals, including ATMPs, it moves to a risk-based approach instead of classifying some quality changes as major by default ^226227228.

3. Finished product: Q.II.e.1 change in immediate packaging

Q.II.e.1 is the central category for primary packaging changes ¹⁴⁸.

All classifications in this table are from the Q.II.e.1 table ¹⁴⁸.

Conditions to be fulfilled

Not every condition or documentation item applies to every row of the table. For example, condition 4 and documentation item 6 relate to deleting a container under (c), while the material-equivalence and stability items relate to composition changes. Check the official table for which numbered items gate each row.

1. The change involves the same packaging or container type only, for example blister to blister ³⁰³.
2. The proposed material is at least equivalent to the approved material in its relevant properties ³⁰⁴.
3. Stability studies under ICH conditions:
   • Relevant stability studies have started under ICH conditions, with relevant parameters assessed on at least two pilot- or industrial-scale batches ³⁰⁵.
   • At least three months of satisfactory data are available at implementation ³⁰⁵.
   • If the new pack is more resistant than the current one (for example, a thicker blister), the three-month data need not be available yet ³⁰⁵.
   • The MAH must complete the studies and report immediately any results that are, or may be, out of specification at the end of the approved shelf life, with proposed action ³⁰⁵.
4. The remaining presentations are adequate for the SmPC dosing instructions and treatment duration ³⁰⁶.
5. The product is not biological ³⁰⁷.
6. The product is not sterile ³⁰⁸.

Documentation to be supplied

1. Amended EU-CTD sections, with revised product information where appropriate ³⁰⁸.
2. Comparative data on the new packaging, such as permeability to oxygen, carbon dioxide or moisture. Where appropriate, include evidence that there is no adverse interaction between content and packaging, such as migration into the product or loss of product components into the pack. Confirm compliance with relevant pharmacopoeial requirements or Union legislation on plastics in contact with food ³⁰⁹.
3. A declaration that the ICH stability studies have started, with batch numbers. The declaration confirms that any required minimum data were available and satisfactory at implementation, and commits the MAH to completing the studies and reporting out-of-specification results ³¹⁰.
4. Stability results on at least two pilot- or industrial-scale batches covering at least three months ³¹¹.
5. A comparative table of current and proposed immediate packaging specifications, if applicable ³¹².
6. A declaration that the remaining pack sizes are consistent with the approved posology and treatment duration ³¹³.

In practice, conditions 5 and 6 limit the Type IA route under (a)(1) to non-biological, non-sterile solid forms. Any composition change for a sterile liquid is Type II ¹⁴⁸. Sterile solid forms (for example, lyophilisates) are not listed under (a)(3) but are excluded from the Type IA route by condition 6, so confirm their route in the current table before filing.

4. Other finished product container closure categories (Q.II.e.2 to Q.II.e.7)

A name or address change for a supplier of a packaging component or device part is an administrative Type IA. Deleting such a supplier site is also Type IA ²⁷⁰.

5. Active substance container closure (Q.I.c)

The 2025 guidelines classify changes to the immediate packaging of the active substance under Q.I.c.1 ⁹⁰:

The Type IA conditions mirror those for the finished product ⁹¹⁶⁴:

• The new material is at least equivalent in relevant properties.
• ICH stability studies are in place, with the stated batch and three-month data requirements. As for the finished product, there is an exception where the new packaging is more resistant.
• The active substance is neither sterile nor biological.

6. Devices that form part of the container closure system

The 2025 guidelines distinguish between co-packaged devices and integral devices ²⁵⁷.

Integral devices ²⁶³:

• Type II: adding or replacing an integral device, or a major change to its material, design or performance that may significantly affect the medicinal product.
• Type IB: adding or replacing an integral device without significant impact on performance, delivery, quality, safety or efficacy. The Type IB route also covers qualifying changes to material in contact with the medicinal product.
• For Type IB, the MAH provides a risk-based justification if there is no Notified Body opinion, EU certificate or EU declaration of conformity. Where applicable, it also provides stability results and evidence on drug-device interaction and material compliance ²⁶⁴.
• Changing an integral device supplier or manufacturer is Type IA. Changing the sterilisation site or process is Type IB ²⁶⁵.

Co-packaged devices fall under Q.IV.1. The dossier should include ²⁶²:

• device description, drawings and material composition
• compatibility and usability studies as appropriate
• evidence of conformity for an added or replacement device, such as an EU declaration of conformity, EU certificate or other evidence of compliance with the General Safety and Performance Requirements

7. What supporting data EMA expects

Stability

EMA's stability guidance for variations covers changes to immediate packaging:

• Less protective packs, or packs with a risk of interaction: where the new packaging is less protective or there is a risk of interaction, particularly for semi-solid or liquid products, provide six months of comparative stability data under long-term and accelerated conditions. Use at least three primary batches, two of them at least pilot scale; the third can be smaller ²⁵. The same approach applies to sterile products with a relevant packaging change ²⁵.
• Test container and comparator: testing must use the container closure system proposed for marketing. Results for the varied product should be compared with those for the unchanged product, and earlier studies can supply the comparator data ²⁹³⁰.
• Follow-up batches: where finished product stability data are required, commitment batches should be followed up for Type IA and IB variations. For Type II, at least the first production-scale batch after the variation should go on long-term testing through the shelf life ³¹.
• Shape or dimension changes: the veterinary counterpart guideline adds case-specific batch numbers where stability may be affected. Use two pilot-scale batches for conventional dosage forms with a stable active substance, and three primary batches for critical dosage forms or an unstable active substance ²⁸.

Plastic materials: extractables, leachables and toxicology

EMA's guideline on plastic immediate packaging materials covers any plastic in direct contact with the active substance or product, including plastic parts of containers, closures and seals ¹⁶⁹¹⁷⁰. The guideline is not applied retrospectively to products already authorised in their current pack. However, a variation that introduces a new plastic immediate pack must meet the guideline's requirements, whether or not the material has been used for pharmaceutical packaging before ¹⁷⁶. The core data package is:

• Material description and control: identify every plastic component, with the chemical name and monomers of each material. Depending on the route and dosage form, also provide the supplier and the full qualitative composition, including additives. Provide specifications against a pharmacopoeial monograph or an in-house monograph, with a certificate of analysis for a representative batch ¹⁵³¹⁷¹.
• Extraction studies: these use suitable solvents under stress conditions to identify extractables ¹⁷². For non-compendial plastics used with non-solid inhalation, parenteral or ophthalmic products, extraction studies are required even if the material is approved for food contact ¹⁷².
• Interaction and migration studies:
  • Solids are generally low risk. Solid inhalation or parenteral products may still need studies.
  • Non-solid substances and liquid products need comprehensive, product-specific studies ¹⁷³.
  • Migration studies should use the product itself under representative conditions, on at least one batch, with validated methods and proposed leachable limits where needed. They can be omitted only if the calculated maximum leachable levels are justified as toxicologically safe.
  • Leachables can instead be monitored in formal stability studies if developmental migration studies were not done.
  • Consider outer layers, inks and adhesives ¹⁷⁴. Sorption studies may also be needed ¹⁷⁴.
• Toxicological assessment: assess extractables and leachables based on their levels and structures. Non-compendial plastics and additives for inhalation, parenteral or ophthalmic products need toxicological data even when food-approved ¹⁷⁵.

The draft ICH Q3E guidance says that changes in contacting materials can alter the leachables profile, including changes in composition, supplier, manufacturing, geometry or pretreatment. Such changes should be assessed scientifically using existing information and/or new studies ¹⁷⁷¹⁷⁸.

Container closure integrity and sterility assurance

For a changed CCS, EMA guidance expects the dossier to re-establish that the system is suitable for storage, transport and use. This covers compatibility, sorption and leaching, safety, and dose-delivery performance ⁵⁵. Container closure integrity studies should be described. For sterile products, they should show that the system prevents microbial contamination ⁵⁶. Sterility assurance rests on a designed, validated and controlled process that includes bioburden control, sterilisation and container closure integrity. The sterilisation method must be explained and justified ⁵⁷⁵⁸⁵⁹. For device components, the dossier should provide QC specifications, critical dimensions and functional tests linked to attributes that matter for quality, safety or efficacy ⁶⁰⁶¹.

8. Practical classification checklist

• Dosage form and sterility: for a non-biological, non-sterile solid with the same container type and an equivalent material, Type IA under Q.II.e.1(a)(1) is usually available ^148303304. Semi-solids and non-sterile liquids generally move to Type IB, and sterile liquids or a new sterile container type move to Type II ¹⁴⁸.
• Protection level: a less protective pack that leads to tighter storage conditions or a shorter shelf life is Type II ¹⁴⁸. It also triggers the six-month, three-batch comparative stability expectation ²⁵.
• Container type: switching container type (for example, bottle to blister) or adding a new container is at least Type IB ¹⁴⁸.
• Biologicals: biological finished products and biological active substances are excluded from the Type IA immediate packaging routes ³⁰⁷⁹¹.
• New plastic contacting material: expect an extractables, leachables and toxicology package under the plastic packaging guideline. The size of the package scales with the route of administration ^172175176.
• Device components: check whether the device is integral or co-packaged, and whether there is Notified Body or conformity evidence. Without it, a risk-based justification is required ²⁶³²⁶⁴.
• Submission date: use the Q-codes for submissions from 15 January 2026, and the 2013 B-codes before that date ²²⁵.