Type I Variation: Apparently Not So Simple

In response to queries from regulatory professionals, we asked one of our regulatory experts to provide an overview of a Type I variation.  In this article, we look at the common validation issues, what to look for in relation to documentation and more.

Simple?  EMA Statistics Show Otherwise

Regulatory professionals would generally perceive the Type I variation as a fairly simple regulatory procedure. New figures released by the EMA suggest differently. Statistical data released by the EMA has revealed that 44% of all Type I variation applications received for assessment by the EMA contain 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 pharmaceutical industry is always pursuing initiatives to achieve “perfection” in our processes. This 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 idea of promoting awareness.

Deficiency Areas in a Type I Variation

Three main areas stand out, the eAF, Product Information, and the Module updates. The EMA has 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 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 doing wrong with the variation eAF. The EMA have detailed what errors they are observing 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 report that missing documentation is a reoccurring theme.

• Copy of the relevant pages from the classification guideline must be 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

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. CEP 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. This is has been an overview of what the EMA is seeing with Type I variation applications. Of course some variation procedures can be more difficult than others. However, with ever increasing regulatory workloads and deadlines, successful submission of right first time Type I variations is a “must reach target” for any regulatory department. Not just to relieve workload but primarily to ensure compliance of each product as it goes through its life cycle.

We Can Help

We are acknowledged experts in regulatory affairs,  If you would like to have a chat with us about Type I variations or another topic, then get in touch.  You can contact us on 00353 52 61 76 706 or complete the form below and we will get back to you. [ninja_form id=1]

Further Reading from Acorn Regulatory

Updated for 2020: Development of the Orphan Drug Sector

Much has been written about orphan drugs in recent times.  These products, developed specifically to treat a rare disease, have become more common in the marketplace.  At the time of writing (May 2020), there are almost 770 orphan drugs commercially available and more than 5600 orphan designated drugs in the biopharmaceutical pipeline. As the sector continues to grow there has been a tendency for facts about orphan drugs to get lost in the midst of issues concerning specific patients’ needs, pricing and availability.  We look at some facts about orphan designation that companies considering entering the sector should be aware of. Read more about orphan drugs here.

Medicinal Product Labelling: What You Need To Know

Medicinal products are no exception and must be accompanied by outer and/or immediate packaging information (labelling) and a package leaflet providing information enabling the safe and effective use of the medicinal product. In fact, medicinal products are legally required to have certain information on the labels and package leaflets as defined in Title V of Directive 2001/83/EC on the ‘Community code relating to medicinal products for human use’ (as amended). Read more about medicinal product labelling here.

Outsourced eCTD Publishing Services: An Overview

More countries are implementing eCTD.  As a result, more companies are being forced to make decisions regarding how they manage their electronic submission and eCTD publishing services. We typically encounter three scenarios:

1. Companies that maintain control of electronic publishing at the corporate and head office level
2. Others that have retained the day-to-day eCTD maintenance and lifecycle at a local level
3. Companies that have outsourced eCTD entirely

In this article, we will look at the benefits and the limitations presented by the three options presented above. Find out more about outsourcing eCTD here.