How To Complete A Type I Variation

Type I Variations to a Marketing Authorisation are surprisingly difficult.  The procedure that many people perceive to be a simple process can prove to be otherwise.  This article looks at how to complete a type 1 variation and we will consider:

  • common deficiencies
  • common validation issues
  • the challenges posed by the eAF
  • what to do when documentation is missing
  • how to handle GMP variations
  • what happens when a CEP is presented for an active substance instead of a GMP certificate

After reading this article you will be better placed to complete a Type I Variation to a Marketing Authorisation while avoiding the common pitfalls outlined below.

Firstly, what is a variation?

The European Medicines Agency states that a variations is ‘a change to the terms of a marketing authorisation. This section provides guidance for marketing authorisation holders on the regulatory requirements and procedures for the different types of variations’.

Statistical data released by the EMA in 2017 revealed that 44% of all Type I variation applications received for assessment by the EMA contained errors. It is reasonable to assume that these figures are mirrored for National and MRP variations. The figure of 44% is quite high when you consider that the variations classification guideline for Type I variations is quite detailed.

The Quest for Perfection

The pharmaceutical industry is always pursuing initiatives to achieve “perfection” in our processes. The lean approach increases efficiency, improves quality and achieves what the pharmaceutical industry is primarily focused on, providing safe and effective medicinal products to the public. The function of Regulatory Affairs is no different. Identifying areas of improvement and increasing “Right First Time” is a goal of all regulatory personnel.

This article details the common deficiency areas with the aim of enabling you to complete an error free Type I Variation.

Deficiency Areas

Three main areas stand out, the eAF, Product Information and the Module updates. The EMA have published the checklist that is used when validating an application and is a useful document for any regulatory professional. Common validation issues are observed around the eAF, classification deficiencies and missing documentation.

Common Validation Issues

eAF:

  • Scope: No precise scope is provided
  • Annexes: impacted annexes are incorrectly selected
  • Present/Proposed table: not provided
  • Editorial Changes: not listed

Classification Deficiencies include:

  • Incorrect scope applied for
  • Incorrect number of scopes applied for
  • Not all amendments are detailed

Missing Documentation

  • Justification for changes being applied for
  • Associated GMP documentation
  • Discrepancies between provided documentation

So what’s going wrong?

eAF

The introduction of the eAF (electronic application form) has posed challenges for us all. Regular revision updates, bugs, workarounds and fixes have become part and parcel of completing any of the eAFs. So what are we doing wrong with the variation eAF. The EMA has detailed the errors they have observed, and these include:

  • Incorrect MAH and contact details are being provided. The contact person must be the person that the relevant agency has on record as being able to communicate on behalf of the applicant.
  • Details regarding the products concerned. Only products and presentations affected by the change should be listed
  • Incorrect Scope Selection. In the case of grouped variations it is important to select the correct number of scopes
  • Information regarding the change not being clear or concise
  • Validation of the form itself. Make sure that that boxes 2 & 3 are ticked for Type IAs and that the last box is ticked for IGs or WS variations.

Documentation Missing

The EMA reported that missing documentation is a re-occurring theme.

Therefore, it is in your best interest to ensure that:

  • A copy of the relevant pages from the classification guideline is supplied.
  • Documentation and amended sections of the dossier must be presented in accordance with CTD formatting guidelines
  • Product Information: National translations are regularly omitted. Editorial changes have been included in the Product Information but not reflected in the eAF. The EMA quote that 24% of issues with national product information relate to the incorrect implementation of wording in alignment with the reference product in the EEA
  • RMP: Clean version not presented in eCTD sequence. Tracked versions not included in a working docs folder outside of the eCTD sequence
  • RMP: A summary of change document must be included for larger updates but also when the RMP is being updated into a new template

The Problems With GMP Variations

GMP or Quality related variations seem to pose additional areas where errors routinely occur. Deficiencies are observed in a number of areas.

eAF

  • Incorrect scope applied. The actual change in not in-line with the proposed scope e.g. change of address is physical and not administrative
  • Discrepancies in the activity terminology performed by the manufacturer (i.e. term used is “packaging” which implies primary and secondary, whereas the manufacturer is authorised to perform secondary packaging only
  • Missing paper or Eudra GMDP reference
  • Invalid or incorrect MIAs and or GMP certificates
  • Lack of justification for omission of a QP declaration
  • QP declarations can either be not complete and do not cover all the relevant API sites

Guideline Conditions

  • The proposed variation is on a sterile product and one the variation conditions excludes sterile products
  • Missing implementation dates and conditions of transport and bulk storage.

Official Documentation

  • Submission of company letters instead of official documentation
  • Omission of official documentation entirely

Present and Proposed Table

  • Present and Proposed table is missing
  • Table doesn’t reflect the change being applied for

Discrepancies

Discrepancies within the content of the various documents within the dossier. Examples of which would be inconsistencies in the name of the proposed manufacturer and sites addresses etc.

The CEP Issue

A common deficiency is that a CEP is provided for an active substance instead of the GMP certificate for the manufacturer of the API.  A CEP does not replace or confirm the GMP status of a manufacturer.

The Type I Variation, as you can read above, has many aspects that might prove to be pitfalls.  However, with ever increasing regulatory workloads and deadlines, first time successful submission  of Type I variations is a “must reach target” for any regulatory department.

We can assist you with Type I Variations.  Our large team of regulatory professionals has considerable expertise in this area.  If you would like us to assist your company with Type I Variations then please do get in touch by calling us on 00353 52 61 76706 or completing the web form below.

 

About the Author
Gemma Robinson, PhD
Managing Director
As Managing Director of Acorn Regulatory, Gemma Robinson is actively involved on client projects on a day to day basis and she leads a team of respected pharmaceutical, medical device, pharmacovigilance and clinical trial experts.  Gemma is also an active contributor to developing and promoting standards in the regulatory affairs profession and she has worked with a number of academic and not for profit organisations to encourage individuals to pursue a career in regulatory affairs and the broader STEM subjects. You can read more articles by Gemma by clicking the link below.
Other articles by Gemma Robinson PhD