The European Union’s pharmaceutical industry and competent authorities complained that the new variations regulations may create a heavy workload in submitting – and processing – minor manufacturing changes, and urged the European Commission to exempt these changes from the annual reporting requirements. There were also complaints that pre-notification requirements on upcoming manufacturing changes are unworkable.
There were also concerns that the variations regulation may accord a higher level of regulatory scrutiny than is necessary for biological product changes, and that these changes should be treated the same way as changes for small-molecule products.
Yet others said that the Jan. 1, 2010, implementation date does not give industry and competent authorities enough time to comply with the new requirements.
These comments were issued in response to two draft guidelines explaining how the new procedures on variations to marketing authorizations and how the new classification structure for variations will work.
The first draft document “Guidelines on the Operation of the Procedures Laid Down in the New Variations Regulations” known as the “procedures” guidance, elicited 29 comments.
The second document “Guidelines on the Operations of the Details of the Various Categories of Variations in the New Variations Regulations,” known as the “classification” guidance, garnered 46 comments. The deadline for comment on both was May 18.
Overall Variations Initiative Welcomed by Industry
Generally speaking, contributors welcomed the initiative taken by the commission in making the framework on variations simpler, clearer and more flexible.
The European Generic Medicines Association echoed the sentiments of many respondents. The trade group said that it “welcomes the newly drafted guideline on the classification of variations as a tool to make the variations regulation simpler, clearer and more flexible and also as a means to reducing the overall number of variation procedures while focusing on those changes having a genuine impact on quality, safety and efficacy.”
Nicolas Rossignol of the commission’s Directorate General for Enterprise Warsaw , Poland
Rossignol further noted that the overwhelming majority of marketing authorizations approved, about 90 percent, are for marketing at a national level by a member state competent authority, while only nine percent are approved via the mutual recognition procedure and only one percent through the centralized procedure.
Because the national rules vary from one country to another, this leads to disharmonized requirements and an administrative burden on manufacturers. There was a consensus, noted Rossignol, that “there needed to be a common set of rules for all variations, regardless of the authorization status of the product.”
The variations directive would create a “do and tell” procedure for certain minor variations that mirrors FDA’s annual reporting requirements for the least significant changes. Currently in the EU there are two types of minor variations: Type IA Type IA
The new variations regulation defines the following types of variations:
Type IA
Type IB variations and Type II changes will still require prior approval by competent authorities with tacit acceptance after 30 days in the case of a Type IB change.
Under the proposal, a number of changes now classified as Type IB would shift to Type IA. Type IA
The classification guidance contains a list of variations which should be classified as Type IA
Comments were invited on all sections of the classification guideline. However, specific comment was sought on the following:
· Classification of Type IA
· Identification of further changes which could be Type IA
· To include changes that could be subject to regulatory flexibility other than the introduction/extension of a design space under ICH Q9, Q9 and Q10.
Minor Changes Require Too Much Work
Some commenters said that the conditions to be fulfilled for Type IA
The German Pharmaceutical Industry Association (BPI) noted that even the minor Type IA
Notifications of Type IA
BPI noted that “the aim should be to regulate on a lower level and to delete variations whenever possible. … Also the lowest level of regulation, e.g., a Type IA variation, triggers at least the following workflow in competent authorities and industry: initiation, decision making, change of documentation and archive. Please note that in every year many thousands of variations are processed. If the variation is not really required to ensure the safety of a product, it should consequently not be processed. Such variations could be classified as a Type IA without the need to submit a documentation/variation.”
There was also a concern that the number of variations listed in the classification guide which lists the type of changes and what category it falls into has increased.
BPI noted that “instead of reducing the amount of variations defined, they were increased from 43 to 64. Additionally, in this draft many variations are more detailed then in the currently valid regulations. … It seems that in fact the bureaucratic burden has increased in this draft. This is contrary to what was intended by the commission.”
F. Hoffmann La Roche concurred that “there is an ambivalent perception of the current and proposed concept. On one side people are used to and appreciate the clear guidance with regard to classification. But on the other side the administrative burden for regulatory handling of minor changes, especially Type IA
Biologics Changes Should Not be Treated Differently
Some commenters contended that the proposal should treat biologics license changes no differently than manufacturing changes for small molecule products.
EuropaBio writes that “our major concerns are related to the continued handling of variations to biologicals as different from handling of variations to chemical entities.”
EuropaBio wrote that for minor variations to the finished product, a distinction should be made between minor and major variations for the biological finished product. “If the [marketing authorization holder] can justify that there is no impact on the quality, safety and efficacy, it should be handled as a chemical entity and not as Type II.”
The European Federation of Pharmaceutical Industries and Associations concurred that “the current draft guideline reflects a conservative approach to the classification of biological/immunological medicinal products. It is disappointing that the continued classification of the majority of changes for biological/immunological products is Type II. We consider that there is an opportunity to reduce the reporting category of a number of these variations.”
And BfArM, Germany’s drug regulator, contended that “we think that there may be a possibility for some simplification in the field of biological medicinal products…as not all active substances in this area are of similar complexity (e.g. small peptides, snake venoms, erythropoietin). However, as in the moment this is a scientific case-by-case decision, we see some difficulties to address this in a more differentiated way in this categorization guideline. Having said this, we support the idea of the European Commission for further discussions between the experts of the marketing authorization holders and the regulatory agencies and fully support the idea of a specific workshop on this theme.”
Concerns Expressed About Timeframe
There were concerns that the Jan. 1, 2010, deadline to comply with the regulations do not give industry nor competent authorities sufficient time to prepare.
EFPIA wrote that “companies will require appropriate timeframe to introduce critical changes to internal procedures to comply with the new EU variations system. … It is our understanding that the final guidelines will not be issued until November/December 2009. We would like to explore possible avenues to make the text available earlier to allow sufficient time to prepare for implementation.”
Pre-Notification Impractical
There were other concerns that the pre-notification requirement in the procedures guidance is impractical.
In the “procedures” guidance, there is a requirement that marketing authorization holders inform the reference member state, the European Medicines Agency, and the co-Rapporteur of all upcoming post-authorization change requests – both major and minor – for the next 6-12 months, “in order to allow optimal planning, availability of resources and identification of potential procedural issues.”
EGA wrote that “due to the significant number of applications for variations per year (from 6,000 for a medium sized generics company to 19,000 for a large sized company) it will be very difficult (almost impossible) to inform the competent authorities about planned submissions for the following six to 12 months.”
EGA further noted that “the management of such a large amount of information by the authorities seems to be a very time and resource consuming process itself. We believe that this advice should be seen as a possibility/opportunity for the applicant in case of more complex variations rather than as a routine requirement.”
Seven Day Notification Impractical
There was also some opposition expressed in the “procedures” guidance regarding Type IB variations. The procedures guidance requires that the reference member state where the variation is filed will check within seven calendar days whether the notification is correct and to complete validation before the start of the evaluation procedure.
The Irish Medicines Board wrote that a longer time for making such a determination was necessary.
“We believe that requiring this decision to be made within such short timelines is not appropriate. In some cases the applicant may provide an appropriate justification in the variation documentation as to why the variation should be classified as a Type IB based on the particular nature of the product and/or of the proposed change. However, because of the tight timelines proposed and the resources needed, it may not be possible for competent authorities to consider this justification.”
More Flexibility Using Risk Management
Several industry commentors requested greater flexibility using a risk based approach for the classification of variations.
Wyeth wrote that “we believe that the final guidelines should leverage the use of quality risk assessments. The draft guidelines only propose their use in a limited set of changes (namely, deletion of non-significant parameters from specifications). However, an appropriate science and risk based approach could be extended to other changes which are presently categorized as Type II in the draft guidelines. For example, any change in a specification outside the approved specification limits for an active ingredient (variation category 14 d) is collectively classified as a Type II variation in the draft guidelines. However, a scientific risk-based assessment of a change in a physicochemical parameter concluding that it is not likely to impact the quality, safety or efficacy of the product could support its assessment as a Type 1B variation.”
Lack of Drug Master File Criticized
The International Pharmaceutical Excipients Council Europe, in its response to the classification guidance, said that the proposed variation regulation omits a drug master file system for excipients, which it contend is a mistake.
“It is clear from this draft guideline that significant levels of detail are required to support many changes to excipients, especially if these are used in the medicinal product in a novel way or in relation to a biological active substance or concern a genotoxic impurity. … IPEC Europe considers that it is not possible to provide the required level of detailed information without being able to use the master file system as significant amounts of this information are confidential to the excipient manufacturer. Therefore we would argue that it will not be possible for the marketing authorization holder to comply with the new variation regulations without an EMF system in place.”
IPEC Europe further notes that in other major world regions, including the U.S., Japan, Canada, Australia, and New Zealand, master files are used for chemical and biological pharmaceutical components such as active substances, excipients, and packaging components while in the EU, the master file system is restricted to non-biological active substances.
IPEC contended that “we believe that the use of excipient master files would certainly improve and simplify the variations regulations system, for both industry and regulators.”
The European drug master file procedure is used when the active substance manufacturer is not the applicant for a product marketing authorization with the intent of protecting valuable information on the manufacture of the active substance. The DMF is a document containing the information required to demonstrate that the quality of the active substance is adequately controlled by the specification proposed by the applicant.
– Joanne S. Eglovitch (j.eglovitch@elsevier.com)
