- tamsinmarshall4
- Jul 11
- 11 min read
Updated: Jul 14
Peer Review Article | Open Access | Published 11th July 2025
Current Regulations For Variation Filings For Registered Products In Europe And Frequently Submitted Variations - Part 2
Arunodaya B S,1 Gaganashree T V*, Balamuralidhara V2, Chinmayee U Gowda, JSS College of Pharmacy, JSS Academy of Higher Education Research | EJPPS | 302 (2025)| https://doi.org/10.37521/ejpps30215
Abstract
This continuation of the review on European variation filing processes delves into the practical aspects of regulatory variations for medicinal products, focusing on administrative changes, excipient modifications, manufacturing process adjustments, and specification updates. Through real-world examples and case-based responses between Marketing Authorization Holders (MAHs) and regulators, this paper illustrates the categorization, evaluation, and decision-making process involved in post-approval changes. The use of a structured tabular format offers clarity on variation types (Type IA, IB, II), regulatory expectations, and outcomes. It emphasizes the importance of accurate documentation, scientific justification, and compliance with EMA guidelines. The paper also highlights common regulatory concerns, including minor vs. major change classifications, incomplete applications, and critical formulation issues. This part of the review serves as a practical guide for regulatory professionals, QPs, and dossier preparers navigating EU variation filings.
Keywords – Administrative, Extension, Timeline, EMA, Procedures.
Administrative Changes
Regulators go as far as to define “administrative” as a category in their classification guideline, whereas in other regions they fall into the lowest variation category and have significant crossover with minor variations, eg new addresses. Many agencies accept that these changes can be implemented without the need for approval. Prior approval of administrative changes is time-consuming for agencies and costly for industry. Additionally, in certain cases such as a marketing authorization holder (MAH) moving address, the change would actually need to take place prior to submission. [1]
Type of Change | Description / Reason | Regulator Comment (in italics) | Outcome |
Type IA (A.z) | Removal of reduced testing frequency footnote from finished product specifications | The variation application form should clearly outline the ‘present’ and ‘proposed’ changes as listed in section 2.5 of the application form. | Review (depends on applicant’s clarification) |
Type IA (A.z) | SmPC Section 6.5 – Harmonization of container description (PVC/aluminium foil blisters) with company’s packaging record and stability data; removal of “polyethylene ullage fillers” and replacement with “optional use of fillers”; consequential update to package leaflet and pack sizes | Individual updated SmPC fragment(s) have not been provided. Please provide these in .doc format. | Rejected (until corrected SmPC is submitted) |
Type IA (A.5.b) | Change in the name and/or address of a manufacturer/importer of the finished product (excluding batch release); update to manufacturing site | Flow chart, manufacturing and import license, and the updated present/proposed manufacturing section must be submitted. | Accepted (assuming all supporting documents provided) |
Excipients of the Finished Product
Type of Change | Description / Reason | Regulator Comment (in italics) | Outcome |
Type IB (B.II.a.3.b.1) | Adjustment of Maize Starch in intra-granular (20 kg to 32 kg) and extra-granular (20 kg to 8 kg) stages | The proposed change to the quantitative composition of the binder is not considered minor and therefore is not acceptable as a Type IA variation. The granulation process is critical and the change cannot be considered minor. | Rejected |
Type IB (B.II.a.3.b.1) | Update of standard quantity for dispensing of empty capsules in section 3.2. p.3.2 | The scope of the variation is unclear. A detailed explanation and justification reflecting the present and proposed table is required within the application form. | Review |
Type IB (B.II.a.3.b.1) | Presentation of comparative dissolution profiles for Allopurinol 100 mg tablets manufactured by the current and proposed process | Dissolution profiles presented in Module 3 Section 32p35. Rapid release observed (>85% in 15 min). | Accepted (implied) |
Type II (B.II.a.3.b.2) | Use of OPADRY II red film coating (contains Azo dye Ponceau 4R) | Use of Ponceau 4R (Azo dye) is not acceptable; substitution or omission with non-Azo dye required. However, applicant discussed with assessor and agreed to retain existing dye. Tablet images confirm no visual change affecting acceptability. | Accepted (after discussion) |
Minor change in the manufacturing process
Type IA: B.II.b.3.a - Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product. Minor change in the manufacturing process
Reason - The proposed document on Manufacturing process and controls is compared to the same document currently registered, there are differences other than that associated to the scope of the variation. Please ensure to submit the document with only the change concerned with the variation.
Response: The applicant would like to inform the agency that there is a revision for inclusion of Granulation-2 as an additional area. The impacted sections are provided in the dossier.
Stage 10.2- the updated statement ‘Inspection activity is optional and shall be conducted based on the requirement.’ is not acceptable unless thoroughly justified based on the manufacturer’s experience in manufacturing this product and supported by data. It should clearly specify what the ‘requirement’ is for inspection to be conducted
The post completion of the coating process, there is an additional control step to qualify the batch for further operations i.e. AQL (Acceptance Quality Limit) check. If the batch meets the acceptance as per AQL then the batch will be released for further manufacturing procedures. However, if batch fails to meet the AQL acceptance, “inspection operation” shall be performed. Hence the state as “based on the requirement.” incorporated in the uk-form-annex-present-proposed and 32p33 as manufacturing-process-and-controls section.
The proposed change to the quantitative composition of the binder is not considered minor and therefore is not acceptable as a Type IA variation. The granulation process is a critical step in the manufacture of the product, therefore any change to the granulation process cannot be considered minor.
Stage 8- blending and lubrication- the mixing times and speeds should be reinstated as validated; ‘suitable time and speed’ are not acceptable.
Applicant is in line to the agency opinion w.r.t criticality of the granulation/blending parameters, but it’s not batch size specific. However, when there is a change in scale/capacity of the proposed batch size there is a chance of change in parameters based on the equipment chain and capacity even though the working principle remains the same. The proposed parameters for a change in batch scale will be derived based on some scale up calculations not only but limited to tip speed or Froude numbers. And the same will be validated through process performance qualification batches to demonstrate the quality of the batches. Hence to accommodate the new scale/capacity of the equipment’s with change in batch sizes other than the submission scale during the commercialization, applicant don’t want to limit our scale specific. Furthermore, applicant assure that the parameters which were recommended by agency for reinstating in the manufacturing process will be part of the batch manufacturing records and there is no change for the specific batch size/equipment CPP’s (Critical Process Parameters). [2]
Type of Changes and Reason
Type 1A-B.II.d.1. z- Change in the specification parameters and/or limits of the finished product to more accurately describe the appearance of the drug product.
This variation has not been accepted as there is no implementation date on the application form. Therefore, this variation has been refused without review. With regards to Type IA variations, the change must be implemented before the application is submitted, as they are do-and-tell procedures. The implementation date refers to when the company makes the change in its own quality system.
Response: The applicant informs MHRA that the implementation date is updated in current application form of resubmission dossier.
Type II-B.II.d.1. e- Change in the specification parameters and/or limits of the finished product. Inclusion of know impurities which are wider than the currently approved limits.
An updated quality overall summary should be provided to justify the proposed control limits for impurities B, C and total impurities.
Response: Being an historical license, this product does not have quality overall summary as similar to other MA’s, Hence, quality overall summary would not be available for submission.
Given that the proposed control limits for impurities B, C and total impurities exceed the limits of the BP monograph for prolonged-release diclofenac tablets, full registration stability data under ICH conditions that reflect the registered packaging, shelf-life and storage conditions should be provided that justify the proposed control limits for impurities B & C and total impurities. If stability data are not available that support these limits, the controls of the BP monograph for prolonged-release diclofenac tablets should be adopted.
Response: Applicant has two aged batches which are evaluated for the impurity B & C which applicant has proposed for widening based on toxicological data. Impurity B, C & total impurity is increasing over shelf life and hence applicant is proposing for the wider limits than the BP monograph. From the toxicological data, impurity B and C results are demonstrated to be safe up to 2.0 %, however considering that over the shelf life the increase would be only up to 0.5 %, applicant is proposing for the revision of limit NMT 0.5 % at stability and NMT 0.2 % at release (as per BP) and consequently total impurity limit as above. Hence, revision is considered justified. proposed new specification.
Type IB (Category B.II.d.1.z) Change in the specification parameters and/or limits of the finished product
The currently registered shelf-life limit of NMT 0.3 % for individual impurity at shelf life is not in line with the BP monograph for domperidone tablets. The applicant should submit a variation in the near future to assure that the finished product complies fully with the BP monograph.
Response:
Applicant revised the shelf-life specification limit of individual impurity to NMT 0.25% inline to the BP monograph. Enclosed the updated specification in 32p51 as specification.
Type IB (B.II.d.2.a) - Change in test procedure for the finished product - Minor changes to an approved test procedure.
The change in dissolution method (choice of apparatus from 1 (basket) to 2 (paddle) retaining the same agitation rate of 100 rpm) gives rise to dissimilar dissolution profiles and represents a major change in dissolution methodology with potential to impact quality, safety and efficacy. This change should be removed from the scope of this type 1B variation and resubmitted as a type II variation. Suitable data, justifying the proposed dissolution conditions and demonstrating equivalent discriminatory power, should be included.
Response: Applicant would like to remove the proposed change in dissolution method and will follow the registered dissolution test method dissolution apparatus
The proposed change in dissolution method is stated to have been implemented in 2011; confirmation should be provided that the dissolution method change has been immediately disapplied for purposes of batch release and stability testing.
Response: The proposed dissolution method change is discontinued for the purposes of batch release and stability testing of batches which will be released to UK market. The updated test procedure with registered method (basket) is provided in 32p52 section.
If batches have been released to the UK market by the proposed dissolution method, the Defective Medicine Report Centre (dmrc.mhra.gov.uk) should be contacted to report that these batches do not comply with the marketing authorisation with regard to dissolution testing methodology. A list of all batches released to the UK market by this method, together with their expiry dates, should be provided.
Response: Applicant would like to inform MHRA that there are total 77 batches released with the proposed dissolution method which are within the expiry period. The applicant has retested and analysed all these batches with the registered dissolution method apparatus 1(basket) and results are found to be complying with the registered specification limit NLT 70 %. Applicant also performed dissolution testing of Azathioprine tablets 50 mg Reference product sample by Basket method. The re-tested 77 batches and Reference product sample results summary is provided for agency’s ready reference. Complete investigation and batch data has been shared
Type IB (Category B.II.d.2): Other changes to a test procedure (including replacement or addition) – Inclusion of alternative Assay method
1. Please justify proposing an alternative assay method.
Response:
The current method is with usage of internal standard and proposed method is without internal standard, we have observed that there were inconsistencies were observed between sample to sample which could be due to addition of internal standard which will lead to variation, hence proposed to adopt without internal standard as this is also one of the manual interventions during sample preparation. To rule out all possibilities with respect to error sample preparation was proposed with intact tablets and without internal standard
2. Please confirm that one assay method will not be used to circumvent failure by the other assay method and update 3.2.p.5.2 to reflect that.
Response:
Applicant has included note in the 32p52 section which will ensure & gives direction to the analyst that failure in one method will not be circumnavigated by then applying the other method.
Note: In case of any failure results in one of the methods, testing and FP release must be suspended and same shall be referred for investigation.
Please justify proposing an alternative content uniformity method.
Response:
The current method is with usage of internal standard and proposed method is without internal standard, we have observed that there were inconsistencies were observed between sample to sample which could be due to addition of internal standard which will lead to variation, hence proposed to adopt without internal standard as this is also one of the manual interventions during sample preparation. To rule out all possibilities with respect to error sample preparation was proposed with intact tablets and without
CEP update:
In the case of an addition of a manufacturing site A, the variation application form should clearly outline the ‘present’ and ‘proposed’ manufacturers as listed in section 2.5 of the application form.
The variation is proposing to remove both the active substance manufacturers registered on your license. As the addition of Site A Laboratories Ltd as an active manufacturer is being refused, the removal of both sites will mean that there will no longer be any active substance manufacturers remaining on your license.
To update different CEPs should be grouping variation not a single variation. Please update the cover letter and application form as grouping and submit
The applicant failed to provide QP declarations from Batch Release Sites A and Site B Limited who are currently registered on your license. [4]
4. Safety, Efficacy, Pharmacovigilance Changes
C.I Human And Veterinary Medicinal Products
C.I.1 Change(s) in the Summary of Product Characteristics, Labelling or Package Leaflet intended to implement the outcome of a Union referral procedure
C.I.2 Change(s) in the Summary of Product Characteristics, Labelling or Package Leaflet of a generic/hybrid/ biosimilar medicinal products following assessment of the same change for the reference product
C.I.3 Change(s) in the Summary of Product Characteristics, Labelling or Package Leaflet of human medicinal products intended to implement the outcome of a procedure concerning PSUR or PASS, or the outcome of the assessment done by the competent authority under Article 45 or 46 of Regulation (EC) No 1901/2006
C.I.4 Change(s) in the Summary of Product Characteristics, Labelling or Package Leaflet due to new quality, preclinical, clinical or pharmacovigilance data.
C.I.5 Change in the legal status of a medicinal product for centrally authorized products
o For generic/hybrid/biosimilar medicinal products following an approved legal status change of the reference medicinal product
o All other legal status changes
C.I.6 Change(s) to therapeutic indication(s)
o Addition of a new therapeutic indication or modification of an approved one
o Deletion of a therapeutic indication [5]
CONCLUSION
The examples presented in this section underscore the complexity and criticality of post-approval changes in the EU regulatory system. Each variation, whether administrative, compositional, or manufacturing-related—requires a clear justification, alignment with regulatory expectations, and robust documentation. Even minor changes can be rejected if improperly categorized or inadequately explained. The dialogue between applicants and regulatory agencies reveals that transparency, consistency, and proactive risk assessment are essential in variation management. Moreover, it is evident that granulation, dissolution testing, and excipient modifications often attract heightened scrutiny due to their potential impact on product quality and performance. Through structured tabular presentation, this chapter provides a user-friendly view into the practical realities of variation filing, helping stakeholders better prepare submissions and avoid avoidable rejections or delays.
References
01. COMMISSION REGULATION (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products (Text with EEA relevance). (n.d.)
02. EN. (n.d.).
03. EUR-Lex - 52013XC0802(04) - EN - EUR-Lex. (n.d.). Retrieved February 7, 2023, from https://eur-lex.europa.eu/legalcontent/EN/TXT/?uri=CELEX%3A52013XC0802%2804%29
04. European (EU) Variation Requirements – Pharmaceutical Updates. (n.d.). Retrieved February 7, 2023, from https://pharmaceuticalupdates.com/2020/05/29/european-eu-variation-requirements/
05. Type-IB variations: questions and answers | European Medicines Agency. (n.d.). Retrieved February 7, 2023, from https://www.ema.europa.eu/en/human-regulatory/post-authorisation/variations/type-ib-variations-questions-answers
Acknowledgements
I would like to express my special gratitude and thanks to our organization (JSS College of Pharmacy, Mysore) for giving us the opportunity of designing and drafting the manuscript of this review article.
Conflict of Interest
All authors declare that they have no conflicts of interest.
Authors
Arunodaya B S,1 Gaganashree T V*, Balamuralidhara V2, Chinmayee U Gowda
1Research scholar, Department of Pharmaceutics, Pharmaceutical Regulatory Affairs Group, JSS College of Pharmacy, JSS Academy of Higher Education Research, Mysuru, Karnataka.
2 Head of the Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education Research, Mysuru, Karnataka
Corresponding Author: Gaganashree T V
Email: Gaganashreeraju@gmail.com
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