# Variation Types and Procedures for Medicinal Products
## Minor Variations of Type IA
- Submission and Review
  - Timeline: Submit within 12 months of implementation
  - Review Period: 30 days by authority
  - Grouping & Super-grouping: Allowed for multiple variations or products
- Administrative Changes (Type IA)
  - Change in ATC code: Type: IA
  - Change in name/address of non-batch release manufacturer: Type: IA
- Active Substance Quality Changes (Type IA)
  - Starting material site addition or replacement: Type: IA
  - Micronisation site addition or replacement: Type: IA
  - Physicochemical testing site addition or replacement: Type: IA
  - Cell bank storage site addition or replacement: Type: IA
  - Minor change in manufacturing process: Type: IA
  - Batch size increase for active substance: Type: IA
  - Batch size downscaling: Type: IA
  - Tightening of in-process limits: Type: IA
  - Addition of new in-process test: Type: IA
  - Deletion of non-significant in-process test: Type: IA
  - Minor change of analytical procedure for in-process test: Type: IA
  - Change within approved specification acceptance criteria: Type: IA
  - Addition of new specification attribute: Type: IA
  - Deletion of non-significant specification attribute: Type: IA
  - Minor change to analytical procedure for active substance: Type: IA
  - Deletion of active substance analytical procedure with alternative: Type: IA
  - Reduction of re-test or storage period: Type: IA
  - Extension of re-test period fully in line with protocol: Type: IA
  - Change to more restrictive storage conditions: Type: IA
  - Change to approved stability protocol: Type: IA
- Finished Product Quality Changes (Type IA)
  - Coating weight change for solid oral forms: Type: IA
  - Batch control testing site addition or replacement: Type: IA
  - Minor change in finished product manufacturing process: Type: IA
  - Batch size increase up to 10-fold: Type: IA
  - Batch size downscaling down to 10-fold: Type: IA
  - Minor changes of finished product in-process limits: Type: IA
  - Addition of new finished product in-process test: Type: IA
  - Deletion of non-significant finished product in-process test: Type: IA
  - Minor change of analytical procedure for finished product in-process test: Type: IA
  - Change within approved excipient specification acceptance criteria: Type: IA
  - Addition of new excipient specification attribute: Type: IA
  - Deletion of non-significant excipient specification attribute: Type: IA
  - Minor change to approved excipient analytical procedure: Type: IA
  - Deletion of excipient analytical procedure with alternative: Type: IA
  - Excipient source change from TSE risk to vegetable/synthetic (non-biological): Type: IA
  - Minor change in excipient synthesis, manufacture or recovery: Type: IA
  - Deletion of excipient manufacturing process: Type: IA
  - Change within finished product specification acceptance criteria: Type: IA
  - Addition of finished product specification attribute: Type: IA
  - Deletion of non-significant finished product specification attribute: Type: IA
  - Minor change to finished product analytical procedure: Type: IA
  - Update of finished product analytical procedure to Ph. Eur. monograph: Type: IA
  - Immediate packaging change for solid pharmaceutical forms: Type: IA
  - Deletion of immediate packaging container: Type: IA
  - Change in shape or dimensions of container for non-sterile products: Type: IA
  - Change in non-contact primary packaging material part: Type: IA
  - Change within immediate packaging specification acceptance criteria: Type: IA
  - Addition of immediate packaging specification attribute: Type: IA
  - Deletion of non-significant immediate packaging specification attribute: Type: IA
  - Minor change to immediate packaging analytical procedure: Type: IA
  - Deletion of immediate packaging analytical procedure with alternative: Type: IA
  - Deletion of pack size: Type: IA
  - Addition or replacement of packaging component manufacturer or supplier: Type: IA
  - Change of secondary packaging component of finished product: Type: IA
  - Change to finished product stability protocol: Type: IA
- CEP, TSE and Medical Devices (Type IA)
  - Update of approved Ph. Eur. certificate of suitability (CEP): Type: IA
  - Deletion of CEP: Type: IA
  - New TSE certificate for starting material, reagent, intermediate or excipient: Type: IA
  - Updated TSE certificate from approved manufacturer: Type: IA
  - Deletion of TSE certificate: Type: IA
  - Change to comply with Ph. Eur. for excipient, starting material or intermediate: Type: IA
  - Change to comply with Ph. Eur. update for active substance or excipient: Type: IA
  - Change in specifications from national pharmacopoeia to Ph. Eur.: Type: IA
  - Minor change for co-packaged medical device: Type: IA
  - Change of medical device material not in contact with product: Type: IA
  - Addition or replacement of device supplier or manufacturer: Type: IA
  - Other minor change to integral medical device part: Type: IA
  - Minor change to medical device dimensions: Type: IA
  - Specification change for medical device not part of final specs: Type: IA
  - Addition of specification attribute for medical device: Type: IA
  - Addition or change to analytical procedure for medical device: Type: IA
  - Deletion of medical device analytical procedure with alternative: Type: IA
## Minor Variations of Type IAIN (Immediate Notification)
- Administrative & Quality (Type IAIN)
  - Change in name/address of MA holder: Type: IAIN
  - Change in name of active substance, excipient, or device: Type: IAIN
  - Change in name/address of marketing authorisation holder: Type: IAIN
  - Change in name/address of batch release manufacturer: Type: IAIN
  - Addition or replacement of active substance manufacturing site: Type: IAIN
  - Change within approved active substance specifications for OCABR products: Type: IAIN
  - Change in imprints, bossing or markings: Type: IAIN
  - Change in shape or dimensions of immediate release oral/suppository forms: Type: IAIN
  - Addition, deletion or replacement of flavoring or coloring system: Type: IAIN
  - Addition or replacement of secondary packaging site for finished product: Type: IAIN
  - Addition or replacement of primary packaging site for finished product: Type: IAIN
  - Batch release site addition or replacement without testing: Type: IAIN
  - Batch release site addition or replacement with physicochemical testing: Type: IAIN
  - Change within finished product specifications for OCABR products: Type: IAIN
  - Update of dossier to comply with updated general monograph of Ph. Eur.: Type: IAIN
  - Change in pack size within approved range: Type: IAIN
  - Addition of or change to calendar package: Type: IAIN
  - Reduction of finished product shelf life (as packaged, after opening, dilution): Type: IAIN
  - Extension of finished product shelf life supported by real-time data: Type: IAIN
  - New CEP for active substance, starting material or excipient: Type: IAIN
  - New TSE certificate for active substance: Type: IAIN
  - Change of specification of non-Ph. pharmacopoeia active substance to Ph. Eur.: Type: IAIN
  - Addition or replacement of co-packaged medical device: Type: IAIN
  - Deletion of co-packaged medical device: Type: IAIN
  - Deletion of integral medical device part: Type: IAIN
- Safety and Pharmacovigilance (Type IAIN)
  - Implementation of Union referral procedure outcome (covered by scope): Type: IAIN
  - Implementation of agreed wording for PSUR, PASS, or PRAC signal: Type: IAIN
  - Implementation of minor changes to MA obligations/conditions/RMP: Type: IAIN
  - Inclusion or deletion of black symbol for additional monitoring: Type: IAIN
## Minor Variations of Type IB
- Procedural Rule
  - Default rule for any variation not listed as Type IA, II, or Extension (unless Article 5 recommendation applies)
- Administrative & Quality (Type IB)
  - Change in name/address of batch release site (quality aspects involved): Type IB
  - Addition or replacement of testing site for batch release, in-process, or excipient: Type IB
  - Addition or replacement of test facility for biological active substance: Type IB
  - Addition or replacement of non-batch release manufacturing site (involving quality aspects): Type IB
  - New active substance manufacturer (Type IB)
  - Change in manufacturing process of active substance (not minor): Type IB
  - Change in active substance batch size (outside 10-fold range or with quality impact): Type IB
  - Change in active substance specification (addition, tightening, or new test with minor assessment): Type IB
  - Change in active substance analytical procedure (not minor, but no major impact on quality): Type IB
  - Change in synthesis, recovery, or purification of active substance (minor): Type IB
  - Addition of new excipient (not affecting stability or bioavailability): Type IB
  - Change in excipient specification (addition, tightening, or new test with minor assessment): Type IB
  - Change in excipient analytical procedure (not minor, but no major impact on quality): Type IB
  - Change in manufacturing process of finished product (not minor): Type IB
  - Change in finished product batch size (outside 10-fold range or with quality impact): Type IB
  - Change in finished product specification (addition, tightening, or new test with minor assessment): Type IB
  - Change in finished product analytical procedure (not minor, but no major impact on quality): Type IB
  - Change in shape or dimensions of immediate release forms (affecting dissolution): Type IB
  - Change in shape or dimensions of modified release forms: Type IB
  - Change in primary packaging material (not covered by Type IA): Type IB
  - Addition or replacement of primary packaging site (involving quality aspects): Type IB
  - Addition or replacement of secondary packaging site (involving quality aspects): Type IB
  - Change in specification of primary packaging material (addition, tightening, or new test): Type IB
  - Change in analytical procedure for primary packaging material (not minor): Type IB
  - Change in pack size (outside approved range or with quality/safety impact): Type IB
  - Change in shelf life of active substance (requiring minor assessment): Type IB
  - Change in shelf life of finished product (requiring minor assessment): Type IB
  - Change in storage conditions of active substance (requiring minor assessment): Type IB
  - Change in storage conditions of finished product (requiring minor assessment): Type IB
  - Update of CEP (with minor assessment): Type IB
  - New CEP (with minor assessment): Type IB
  - Change to comply with Ph. Eur. (requiring minor assessment): Type IB
  - Change in test procedure for medical device (requiring minor assessment): Type IB
  - Addition or change to medical device specification (requiring minor assessment): Type IB
  - Replacement or addition of manufacturing site for integral medical device: Type IB
  - Change in integral medical device material (requiring minor assessment): Type IB
  - Change in dimensions of integral medical device (requiring minor assessment): Type IB
  - Deletion of non-significant test from medical device specification: Type IB
- Safety and Pharmacovigilance (Type IB)
  - Implementation of Union referral outcome (not covered by scope, no new data): Type: IB
  - Implementation of generic/hybrid/biosimilar product change from reference product (no new data): Type: IB
  - Implementation of agreed wording for PSUR, PASS, PRAC signal with minor assessment needed: Type: IB
  - Legal status change for centrally authorised generic/hybrid/biosimilar: Type: IB
  - Deletion of therapeutic indication: Type: IB
  - Deletion of pharmaceutical form: Type: IB
  - Deletion of strength: Type: IB
  - Changes to MA obligations/conditions/RMP requiring additional minor assessment: Type: IB
  - Submission of results of target patient group assessments (Article 59(3)): Type: IB
## Major Variations of Type II
- Procedural Rule
  - Requires approval by the relevant competent authority before implementation
- Active Substance Quality Changes (Type II)
  - Substantial manufacturing process change for active substance: Type: II
  - Addition or replacement of biological active substance manufacturing site: Type: II
  - Addition of active substance manufacturer supported by ASMF: Type: II
  - Batch size comparability assessment for biological active substance: Type: II
  - Widening of active substance in-process limits: Type: II
  - Deletion of active substance in-process test: Type: II
  - Replacement of active substance strain for seasonal, pre-pandemic or pandemic influenza vaccine: Type: II
  - Replacement or addition of strain/antigen/coding sequence for coronavirus or public health emergency vaccine: Type: II
  - Deletion of significant active substance specification attribute: Type: II
  - Change outside approved specification acceptance criteria for active substance: Type: II
  - Change outside approved specification acceptance criteria for starting material/intermediate with quality impact: Type: II
  - Biological analytical procedure changes for active substance: Type: II
  - Replacement of in-house reference standard without approved qualification protocol: Type: II
  - Introduction of reference standard qualification protocol: Type: II
  - Substantial change to reference standard qualification protocol: Type: II
  - Extension of re-test period based on extrapolation not in accordance with guidelines: Type: II
  - Introduction of new design space or extension of design space for active substance: Type: II
  - Introduction of post approval change management protocol for active substance: Type: II
  - Introduction of product lifecycle management document for active substance: Type: II
  - Major change to process parameter or quality attribute in active substance lifecycle document: Type: II
- Finished Product Quality Changes (Type II)
  - Addition of new test or replacement of analytical procedure with another for excipient: Type II
  - Change in shape, dimensions, or weight of solid oral forms: Type II
  - Coating weight change for modified release oral forms: Type II
  - Manufacturing process change for complex finished product/manufacturing process: Type II
  - Manufacture process change requiring new in vivo data (e.g. PK/PD): Type II
  - Substantial manufacturing process change for biological product: Type II
  - Introduction of non-standard method of sterilization: Type II
  - Introduction of new starting material for radiopharmaceutical: Type II
  - Batch size change involving equipment with different design/operating principle for sterile products: Type II
  - Addition or replacement of non-EU finished product manufacturer (not supported by MRA): Type II
  - Deletion of finished product in-process test: Type II
  - Widening of finished product in-process limits: Type II
  - Change outside approved specification acceptance criteria for excipient: Type II
  - Deletion of significant excipient specification attribute: Type II
  - Biological analytical procedure change for excipient: Type II
  - Change of source of TSE risk material to one not covered by CEP: Type II
  - Change in synthesis, manufacture or recovery of excipient affecting quality/safety/efficacy: Type II
  - Change outside approved specification acceptance criteria for finished product: Type II
  - Deletion of significant finished product specification attribute: Type II
  - Biological analytical procedure change for finished product: Type II
  - Substantial change to reference standard qualification protocol for finished product: Type II
  - Immediate packaging change for liquid/semi-solid/sterile products: Type II
  - Immediate packaging change from non-porous to semi-permeable/permeable materials: Type II
  - Addition of new immediate packaging material for sterile products: Type II
  - Change in administration device not covered by CE mark or pharmacopoeia: Type II
  - Extension of finished product shelf life based on extrapolation not in accordance with guidelines: Type II
  - Change in storage conditions of biological finished product: Type II
  - Introduction of post approval change management protocol for finished product: Type II
  - Major change to process parameter or quality attribute in finished product lifecycle document: Type II
  - Addition or replacement of non-EU biological active substance manufacturing site (not supported by MRA): Type II
  - Addition or replacement of site testing biological active substance (not supported by MRA): Type II
  - New or updated CEP/TSE certificate requiring additional data/evaluation (e.g. missing validation of generic method): Type II
  - Addition or replacement of co-packaged medical device with significant impact on safety/quality/efficacy: Type II
  - Addition or replacement of integral medical device part with significant impact on product safety/efficacy: Type II
  - Widening of device specification limits or deletion of significant parameter (affecting device performance): Type II
  - Introduction/update of Device Master File (DMF) affecting finished product properties: Type II
  - New Plasma Master File (PMF) or Vaccine Antigen Master File: Type II
- Safety, Efficacy and Pharmacovigilance (Type II)
  - Implementation of Union referral outcome requiring additional data/assessment: Type II
  - Implementation of generic/hybrid/biosimilar product change requiring additional data (e.g. comparability): Type II
  - Implementation of agreed wording for PSUR, PASS, PRAC signal requiring further substantive/clinical data: Type II
  - Changes to therapeutic indication, clinical efficacy/pharmacokinetics: Type II
  - Addition of new target species: Type II
  - Addition of new route of administration or change in route of administration: Type II
  - Changes to MA obligations/conditions/RMP requiring significant assessment/new data: Type II
  - Other variations involving substantive clinical/safety/efficacy data: Type II
## Other Procedures and Special Types
- Extensions
  - Evaluated in accordance with same procedure as initial marketing authorisation (new MA or included in initial MA)
- Annual Update for Vaccines
  - Fast-track variation procedure for annual change in active substance for seasonal influenza and coronavirus vaccines
- Urgent Safety Restrictions (USR)
  - Provisional interim changes taken by holder in event of risk to public health; notification within 24 hours
- Worksharing Procedure
  - Single application submitted for identical variations affecting multiple marketing authorisations of same holder across EU