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Multifaceted Falsified Medicines Directive Cleared in Europe; Implementation Will Pose Challenges for Industry and Regulators

Legislation adopted by the EU Council on May 27 will significantly strengthen the EU’s ability to detect falsified medicines and prevent their entry into the legitimate supply chain by adding new requirements in four main areas: ● safety features ● supply chain and good distribution practices (GDPs) ● active substances, and ● Internet sales.

The EU Council’s adoption followed on the heels of the passing of the “Falsified Medicines Directive” by the European Parliament (EP) in February. In its announcement, the Council stressed that the directive is aimed at “protecting patients against the rising threat of falsified medicines.”  The European Commission released a Q&A on the directive immediately following its passage [see link at the end of the story].

The new safety features contained in the legislation are designed to ensure the authenticity of prescription products, and will be required on the outer packaging.  The qualified person (QP) for the final dosage form manufacturer will be responsible to ensure as part of batch release that the safety features have been applied.

The supply chain security/GDP component of the directive provides increased quality management and documentation obligations for all the players involved including wholesalers, distributers and brokers. Among the key features is the requirement that wholesalers verify that their suppliers and customers comply with GDPs.

New registration requirements will also be placed on the manufacturers of active substances, and distributors of APIs will be required to register their activities.  In addition, manufacturers purchasing APIs from other firms will need to audit these suppliers.

The directive also provides a more coordinated foundation for the regulation of internet sales, which are currently being done differently within each of the member states. In addition to the member state requirements, a certification process will be put in place that will allow Internet sellers to display a logo on their website showing that they have been approved by the EU as a reputable seller.

The Falsified Medicines Directive is one of three prongs of a broad-based EU legislative effort known as the “Pharmaceutical Package.”  Also part of this package is legislation to: ● strengthen the EU’s pharmacovigilance effort, and ● better regulate the way health information is supplied to the general public.

The pharmacovigilance prong was the first to be adopted.  The directive was officially published at the end of 2010, beginning the implementation process, which will be completed July 2012. The third prong on patient information access is currently being redrafted.

Safety Feature Implementation Will Take Longer

At the PDA/EMA conference in London in early May, EMA Compliance and Inspection Principal Scientist Katrin Nodop provided an analysis of the content and significance of the falsified medicines component of the legislative effort.  She addressed the four main thrusts of the directive and the implementation pathway and challenges for both industry and regulators.  [Editor’s Note: Nodop’s full remarks are included below.]

The new directive, Nodop emphasized, “impacts all of us,” including industry and regulators, and its implementation will present a number of challenges in addition to the time constraints that are mandated. “It is a little more complex than it looks at first sight,” she stressed.

Along with implementation of the broad range of registration, authorization, auditing, and database systems required under the directive, Nodop pointed out that “there is quite a lot of new guidance to be developed – for example, the GDPs for APIs, specific provisions for brokers and certain requirements for excipients; when the excipient needs to be manufactured according to GMP.  Others will need to be amended.  For example, the GDP guideline in Chapter 5 may need a little more detail.”

The Pharmaceutical Package was proposed as an amendment to Directive 2001/83/EC and released for public consultation in early 2008.  The legislation was revised based on feedback received. The package was adopted in principle by the European Commission at the end of 2008 and transmitted to the European Parliament (EP) and Council for further refinement.  The EP formally adopted the proposed Falsified Medicines component in February.

After the late-May adoption by the EU Council, the next step is publication in the Official Journal of the EU, expected soon.  Publication in the EU Journal starts the implementation clock ticking.

Most of the legislation requirements have an 18-month transition period, at the end of which both industry and regulators need to be in compliance.  The deadline for implementing the new safety features, however, will be further in the future.

“We do not know at what time the safety features will come in,” Nodop explained.  The detailed requirements for these features will be determined by the EU Commission in the context of a “delegated act” – a procedure by which the EU commission formulates further legislation.

As part of the delegated act, the European Commission will answer the following questions, Nodop said:  ● “What are safety features? ● What are the characteristics of these safety features? ● What are the modalities for the verification – be it at the stage of the manufacturer, the wholesaler, or maybe at the very end of the chain at the pharmacy?  ● What do they actually have to do? ● Is it something that they have to follow through the entire supply chain?”

She commented that “the Commission has no deadline to produce a delegated act on safety features.  It may take two years, it may take four years – we do not know at this time.”

Major Changes for Wholesalers, Distributors and Brokers

The EMA official emphasized that new requirements for wholesalers, distributors and brokers are important for ensuring supply chain security, and that some of their activities have been overlooked or were unknown in the past.

The legislators, she said, “found that there is another group of actors out there – the brokers – which will also have requirements.  These people are completely new to us.”

A broker is an individual or firm that does not buy, receive or store products, “but they bring two parties together to say ‘this company wants to sell this at a good price.’  They probably get a margin, but they are not directly involved in the categories for which you need wholesale distribution authorization. These are now deemed to be brokers, and there is now a definition for this.”

The legislation requires brokers to have quality and documentation systems and keep records of what they sell and manage between other parties to ensure that those products are authorized for sale within the European Union.

Also newly-covered in the legislation are distributors of active substances, which will now be required to register their activities and comply with API GDPs.

Distributors who engage in parallel trade – purchasing medicinal products in one EU country to resell in another – will face major new changes to their businesses.

For parallel distribution in Europe, Nodop explained, the legislation will require that the parallel distributor remove the original safety features and replace them with “something equivalent.”

During the Q&A following her presentation, a meeting attendee asked Nodop who, in the case of parallel trade, has the burden of proof that the initial safety features are being exchanged with equivalent ones.  She clarified that “parallel distribution, due to its activities, is now deemed to be manufacturing. So this [parallel trade] organization needs to hold a manufacturing authorization.  The proof that it is equivalent will lie with the marketing authorization holder [MAH].”

Wholesalers – in addition to verifying that suppliers and customers meet GDPs – will now have a requirement to report suspected falsified medicines.

“If [wholesalers] suspect that they are being offered a medicinal product which is too good in price, too good in volume, too good in everything so that there is a suspicion that it is falsified, they are now required to inform the national competent authority about it,” Nodop stressed.  In certain cases, the MAH for the product must also be notified.

In addition, for products with safety features, wholesalers will be required to keep records of the batch numbers of the products.

Audits and Inspections Will Be Required for APIs

Under the legislation, drug product manufacturers will be required to audit their API suppliers. The QP for the finished product will need to include a certification that an audit of the API manufacturer has taken place, and when, within the QP declaration for each batch.

Nodop recognized that this API audit requirement “is a lot of work for the industry, and has been discussed in the past in great length” (see IPQ “In the News” Sept. 9, 2010 and, for a more extensive analysis, see Jan./Feb. 2008 IPQ Special Report). “The good news is that the audit can be carried out by a third party.”

For APIs that are imported into the EU, there is a new requirement that they may only be imported if they are accompanied by a written confirmation of GMP compliance by the regulatory authority in the country where they were manufactured.

The regulatory authority providing the confirmation will also need to be audited by EMA to ensure compliance with EU standards, and those deemed compliant will be placed on a list kept by the Commission.

After the agency is placed on the list, subsequent audits will be conducted to ensure ongoing compliance.  “It would be a very similar system to that we currently have in Europe, so that we will have to do repeat audits in those countries,” Nodop commented.

Pointing to already established international collaborations – for example, mutual recognition agreements –  she explained that the MRA partners “are not automatically on the list.  Having cooperated with them for so many years and knowing quite a lot about them, the audits to be carried out might be a little bit simpler. But they will also have to basically be looked at to be put on the list.”

Problematic under this program are major API producers China and India – in part because “they are not just one authority.  So we have a real challenge here to see what we will require. This is not yet sorted out.”

Implications for GDP Harmonization & Vet Products?

In the Q&A following Nodop’s talk, the differences between the EU and US requirements regarding falsified medicines and GDPs were explored. A meeting attendee asked her how these differences will be addressed.

“In the past,” the EMA regulator responded, “a lot of our focus has been on GMP, and only recently is there a shift in focus toward GDP (see IPQ “In the News” April 19). I guess that in future discussions this might become also a topic.  I know that the PIC/S has always more or less just talked about manufacturing, but they are also now in the process of thinking about whether they should expand their mandate to include GDP.”

“I am sure that EMA and FDA will exchange current practices and where there are synergies and where we can improve our guidances,” the EMA official continued. “When it came to the development of the GDP guideline, we have included and looked at WHO guidance, [Australia’s Therapeutic Goods Administration] GDPs and what was available from FDA to see that we are in line.”

Nodop was also asked about the applicability of the legislation to veterinary medicinal products.

She explained that the pharmaceutical package “was mostly aimed at amending 2001/83/EC, which is the directive for human medicinal products.”  However, in developing the legislation and refining the GDPs, EMA and the EC have been mindful of the implications in the veterinary drug context and the potential for fostering harmonization in the vet arena.

The EMA official noted that with the pending release of the revised GDP guideline, “we will be asking the veterinary industry what they would think if we were to apply this guideline also for veterinary products.”

Implementation of the directive will involve developing a harmonized format across Europe for tracking the wholesale distribution organizations. Commenting that it would “probably not” make sense to limit that effort to human medicinal products, the EMA is considering “using this format for veterinary medicinal product distributors…on a voluntary basis” to help foster European harmonization.

LINKS:

Council of Europe press release May 27, 2011

European Parliament falsified medicines text adopted February 2011

European Commission Q&A on falsified medicines

Dec 31, 2010 pharmacovigilance publication in the EU Official Journal

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EMA’S KATRIN NODOP ON THE NEW EU FALSIFIED MEDICINES DIRECTIVE

I shall give you this update on where we are with the falsified medicines legislation. And I will not go much into detail on the reasons behind it….  I will try to focus on the impact this legislation has on all of us. And when I say ‘all,’ I mean this.  Because it is not just legislation where the industry has a lot to do, but also the regulators have quite a lot of work to do.

I will give you an update of where we are in the legislative process with this amendment to our directive. I will only focus on the main changes.  I will not go through what the directive 2001/83 says, but only what will be new to the various actors.

I tried to separate it to say what the impact is that it will have on us, the regulators, and what the impact is for the various industries.  We [will need to] meet a number of challenges to implement this legislation, not only time constraints.  It is a little more complex than it looks at first sight….

In 2008, the European Commission made a proposal as part of what is known as the ‘Pharmaceutical Package.’ There were three main pieces of legislation:

● The information for the general public has been called back and is now being worked on again, but there is no more text or anything to say about it at the moment

● As you know, the pharmacovigilance legislation has already been published. The implementation is already being worked on. It has to be implemented by July of next year.

● The third part of this package is what we call “Falsified Medicines Legislation,” and this is what I am talking to you about today.

I would like to start out by repeating the definition of falsified medicines, because it goes beyond what we normally think of as a counterfeit. It is not just that the substance in a drug has been adulterated or the strength is [incorrect].  It is much, much more. It [also covers] someone in the whole chain [who] maybe falsified the records, or says it comes from Company A but it actually comes from Company B.

The definition being wider means that the implication later on is also wider. Quite simply, if you have a suspicion that the product has been falsified, it could implicate many areas and not just the active substance.

When the Commission at the time, in 2008, made a legal proposal for strengthening the legislation to avoid counterfeits from entering the legal supply chain, they based it on three pillars:

One was to ensure that for certain products there might be safety features which can follow [the product] from the point of manufacture down to the pharmacy to know where these products are. That is part of the global pillar I call ‘safety features.’

The second pillar they based the legislation on is to actually strengthen the very supply chain.  Once the product has left the manufacturer’s premises, throughout the distribution chain until it ends up in the pharmacy, it is made very secure by amending the requirements – for example, for the wholesalers and for good distribution practices.

The third pillar is strengthening the regulations for active substance manufacturers. This is quite a big change because this is very new and we have new actives in our industry which are also part of our directive.

When this was discussed back in 2008 and [went] through the discussions at the council and came up to the first reading in the European Parliament, the Parliament said, ‘no legislation is going  to be complete without tackling the illegal sales over the internet because that is a major source in Europe for patients receiving counterfeit medicinal products.’  So the Parliament requested that a fourth pillar be introduced which looks at, they call it ‘sales at distance,’ – or in laymen’s terms, internet sales of medicinal products within Europe.

I shall go now through these four pillars. I will say what is new and what the impact is on the industry.

Pillar One:  Safety Features

Let us start with the safety features. The safety feature is something new, and it applies to only certain medicinal products.

The first general rule is that the medicinal product that is subject to a prescription shall be deemed to bear safety features. There is the possibility that they might be exempt from this, because maybe the risk of falsification for the product is very, very low. There is [also] a general rule the other way around that medicinal products without the need for a prescription normally do not have to have safety features unless they are deemed to be at high risk of being falsified.

To have a good overview of which products will be deemed to have safety features, there will be a list established. This list will be hosted by the European Commission.  This list may either directly name products, or it may name product categories. The list will be established according to a number of criteria, such as the price, sales volume, the risk of falsification, and of course how high the risk is for public health if they are falsified and the patients receive them.

The impact of this is that the manufacturers have to make these safety features, and the QP of the finished product manufacturer has to ensure that the safety features are applied to the outer packaging of the product, and also that all other rules are complied with. So the QP has another additional task.

It is mainly in the chain later on for the wholesalers where those safety features have to be used to check when these products get distributed in Europe that they are really the authentic, original product. This is going to be done, in certain cases, to the individual pack. This is done to see if it is tamper-proof, and in the case of when we have parallel distribution in Europe that the original safety features have been removed and replaced with something equivalent. I know this will be very hard for the industry.  There will be a requirement for those products with safety features for the wholesalers to keep records of the batch number of the products along with all the other records they now keep.

This is a piece within the legislation which is not yet spelled out entirely, because the directive which will amend 2001/83 has come under the new treaty, and there are different ways of then formulating further legislation – we call it a ‘delegated act.’

The European Commission has to detail:  ● What are safety features? ● What are the characteristics of these safety features? ● What are the modalities for the verification – be it at the stage of the manufacturer, the wholesaler, or maybe at the very end of the chain at the pharmacy?  ● What do they actually have to do? ● Is it something that they have to follow through the entire supply chain?

So maybe [there is] a big database somewhere where the manufacturer has issued and released the product that the pharmacy then checks and hands it over to the patient. There is a lot of uncertainty in this area, and the European Commission in the next few years will work on this.

This does add a little bit of complexity to this piece of legislation, because all those new requirements are somehow interlinked. If some of those aspects are not clear yet we will not be able to, for example, in the GDP guidelines, really formulate what we expect the wholesalers to do. So this is something we will have two or three year’s time to further develop. I know that there will also be an impact assessment on this because it has a lot of impact on the wholesalers in particular.

Pillar Two:  Supply Chain and GDP

Also for the second part of the pillar – the entire supply chain, [from] finished product release to when it ends up in the last point where it is being sold to the public – there are a number of increased obligations for those wholesalers.

The first one, on the European level, is that a quality management system is now required for their activities. Some member states may have had this already, but this is now something which in general is required at the European level.

It has already been the case that wholesalers have to know from whom they are buying and to whom they are selling. The new legislation passed also requires that they have to verify that those actors – their suppliers and  their customers – do comply with GDP.  I will tell you later about how this can be done.

We know also that exportation of products can be an issue. So it has now been deemed necessary to include certain recordkeeping requirements for those distributors who export medicinal products outside the European Union.

Wholesalers already need to have procedures in place to recall a product from the market if it is deemed to have a quality defect. Now in addition to that, if they suspect that they were offered a medicinal product which is too good in price, too good in volume, too good in everything so that there is a suspicion that it is falsified, they are now required to inform the national competent authority about it, and in certain cases also the marketing authorization holder [MAH] for the product.

In previous legislation, only distributors were talked about. There was no real difference between the ones who buy, who store, who sell, or virtual wholesalers….  The falsified medicines legislation provides a definition for what a wholesale distributor is and under what activities they are called wholesalers.

They found that there is another group of actors out there – the brokers – which will also have requirements. Brokers are the people who do not themselves buy, receive, or store, but they bring two parties together to say ‘this company wants to sell this at a good price.’  They probably get a margin, but they are not directly involved in the categories for which you need wholesale distribution authorization. These are now deemed to be brokers, and there is now a definition for this.

The legislation obliges those brokers to have certain requirements – for example, a quality system as well and most importantly a documentation system. They also need to keep records of what they sold and managed between the two parties and ensure that those products that they have managed to get from Company A to Company B are actually authorized within the European Union.

These people are completely new to us and we have to learn about this exciting area of industry. We need to see what these requirements will be.

Currently, wholesale distributors are required to have an authorization, and the authorization is done by the national competent authority. What we do not currently have in Europe is a harmonized format for those authorizations. This is something that will come through the requirement – that these authorizations have to be entered into the European Union database.

Most of you are familiar with EudraGMP.  In the legislation it is just called the ‘Union Database.’ We will have to extend this database to include quite a number of things.  Among them is the authorization for wholesale distributors. We are currently working on a European format. This will make it much easier for the wholesalers if they have to verify that the wholesaler from whom they are buying or to whom they are selling is authorized and compliant with GDPs, because this will be in a publicly accessible database.

The brokers also need to be registered.  It is in the new legislation that they need to notify their activity to the national authorities. Those notifications by the brokers will not have to be entered into the European database, but they have to be made publicly available at the national competent authority level.

The requirements for GDP and for wholesale distributors mean that we have to revise quite a number of community procedures to take into account those new requirements. In particular, those will be GMP, but we are also looking at the GDP guidance.

Many of you know already that we have started to work on this, and in fact we have nearly finalized it. The European regulators themselves have agreed to a version of the GDP guideline. I hoped to be able to tell you that it is already been made public, but the European Commission is still conducting the legal review.  We think it will be published together with the falsified medicines legislation. This will probably now happen in June. The GDP guidance will include guidance for the wholesalers and specific provisions for brokers.

Pillar Three:  Active Substances

Moving on to active substances – the third pillar of this new legislation: This is the first time in Europe that active substance manufacturers have direct obligations being put upon them in the sense that they have to register their activity with the competent authorities.

The registration process, in practice, is probably like an authorization process with contents [similar to] that type of registration. They have to say who they are, where they are, what activities they undertake, and what active substances they manufacture.

One group that is new to us is the distributors of active substances. For the first time, the legislation also requires distributors of active substances to register their activity. But also – and this is another new piece of legislation and guidance that we have to formulate – they have to comply with GDP for active substances….

The requirements for the active substances pull in the manufacturers, the importers and the distributors, and require them to comply with GMP for APIs, and GDP for APIs. Again, those registrations will be entered into the European Union’s database and therefore also will be made publicly available.  If the company gets inspected, the certificate of compliance [will also be published].

The system for APIs has been made a little more complicated.  For the importation of active substances, currently, for example, somebody could ask a regulator to go in and inspect in a third country, and you always have the audits from the manufacturer of the active substance manufacturer, maybe in a third country. Now, from the new regulation onwards, active substances can be imported into the EU only if they are accompanied by a written confirmation from the authority in that third country supervising those active substance manufacturers.

This is going to be something we have to look at in detail – how we are going to do this. First we have to look at how countries will be listed. Listing these countries by the European Commission means that the country is applying the same equivalence standards that we do in Europe….

We have mandatory audits for all API manufacturers as well.  This is something that I know is a lot of work for the industry, and has been discussed in the past in great length. It has also been discussed in the past whether checking the compliance of your API manufacturer actually means auditing them, typically by going there, or not.  The new legislation details this to the extent that yes, an audit has to be carried out. The good news is that the audit can be carried out by a third party….

[I will explain more about] the written confirmation which I have been talking about that the manufacturer has to provide. You know already that you have the QP declaration and the notice to applicants. You make a statement that the API manufacturer complies with GMP. This statement has to now also include a note that an audit has taken place and when it has taken place. This is a new thing that will be part of the notice to applicants.

Now when you import an API, this written confirmation has to be included from the authorities from the exporting country. If the country, however, is on a list established by the European Commission, then you do not need this [confirmation].

So how do we get from where we are now to [the establishment] of this list?

First of all, those third countries out there need to ask to be put on this list. We will have to work hard in the international community to get them onto the list.  The next thing we have to do is to establish that their GMP supervision of their API manufacturers is equivalent to the one we have in Europe.

Europe has quite a longstanding activity in auditing other authorities – be it from the mutual recognition agreements (MRAs), where we have to establish an equivalency, or be it through the joint audit program established in Europe where we assess each other to see [if we still comply] with everything.

We are working on a module of this joint audit program checklist to include active substances. This will also be the basis for carrying out audits of those third country authorities so that we can them deem them to be equivalent.  Then they can enter onto the list established by the European Commission and you do not then need the written statement for importing active substances into Europe.

This work, at the legislative level, shall be done between the European Commission and the agency. This is not done just once.  It is actually once and then you get them on the list. But it also has to be maintained. It would be a very similar system to what we currently have in Europe, so that we will have to do repeat audits in those countries.

We have already established international collaborations – for example, MRAs. [The MRA partners] are not automatically on the list.  Having cooperated with them for so many years and knowing quite a lot about them, the audits to be carried out might be a little bit simpler. But they will also have to basically be looked at to be put on the list, the same as with the collaboration countries in PIC/S.  There are quite a number of countries which you have to put on the list.

We also know that the major countries currently producing active substances are China and India. They are big. They are not just one authority.  So we have a real challenge here to see what we will require. This is not yet sorted out. This is, again, something the European Commission, from the legislative structure, has to provide more details on by the so-called implementing measures.  It will be quite interesting to see how this will work.  There is a lot of discussion and international collaboration in this area.

Pillar Four:  Internet Sales

The last and fourth pillar is Internet sales.  Buying medicines over the internet is currently regulated differently among the European countries.  In the future there will be information available to those patients who choose to buy their medicines over the Internet.

Within the internal market, a patient in one country can buy medicine from another country over the Internet. If you do want to inform yourself whether the Internet site that you are planning to buy your medicines from is authorized and well looked after, then you can go to your competent authority and there will be a list of those Internet sites. The competent authorities will have a list on their websites of all the authorized sites, and there shall be a European logo displayed on all sites that are deemed to be safe for purchasing medicines over the Internet.

When the first falsified medicines appeared in Europe, and the risk to the public was discovered, there was a very interesting study that [showed] those people who do buy medicines over the Internet are getting a high proportion of falsified medicines.  It is the male category of around 45 years old – fully knowing the risks when they buy Viagra and everything else, for which there is a high probability of getting a counterfeit, particularly if you look at the prices.

What this means is that it is not enough just to regulate these industries.  It means that awareness campaigns have to be done for the public that will say ‘hey, look, there is a real risk if you do this.’  If you still choose it, then at least you know.  The new legislative requirements mean that there have to be awareness campaigns coordinated within Europe to make the public aware of the risks of purchasing medicines over the Internet. It is quite a new area as well, but interesting.

Implementation Challenges

The new directive has a few other bits which do not really fit into the four pillars.

In terms of the risk of falsified medicines, sometimes medicines that were not designed for the European market will end up here. It may be something that is exported, and then brought back in again, so that it is actually a released product in the European Union, or it may be something that is just transferred.

Europe’s harbors are just transfer stations for products from one country to another continent. They actually never really go into the country, but they remain in the customs area. This is something that has been looked at, and a little divergence has come out of those customs areas into the country, which should not happen.

The new legislation will look at defining what is called ‘introduction’ for products which are actually not meant to be and in the future will not go onto the European market.  They will not be able to come in.  There is a request for cooperation between GMP inspectorates and customs authorities.  Those new relationships need to be developed.

We have in the past already had the possibility of inspecting in third countries.  It is risk-based.  If you think something is non-compliant, it should be inspected.  The legislation spells this out a little more clearly – that there is the possibility of inspecting manufacturers and distributors of APIs in third countries for GMP and GDP compliance.

There is now also the possibility to do this for manufacturers of excipients.  This is a new area.  So far, we have not had any inspections in third countries of manufacturers of excipients.  This can be due to suspicion of non-compliance or at the request of a member state or the Commission.

When the European Parliament looked at the risk to the public of falsified medicines, it asked EMA if it had a recall system that goes to the patient level.  EMA replied that it does, its rapid alert system.  It contains worldwide contacts.  [Under this system], the manufacturers are obliged to withdraw those products.

But when we know that the product is already at the patient level – it has left the pharmacy and is in peoples’ hands – the way that it has been dealt with is to have big advertisements in the local newspaper announcing that the product has a quality defect and needs to be returned.  Now we need to look this again, because [we need to] look at recalling falsified medicines at the patient level, and how we would do this.  We have to look at our recall procedure being a little bit more detailed with respect to falsified medicines at the patient level….

The EMA and the Commission have to engage actively with the competent authorities in third countries.  For example, for the task for supervision to deem API manufacturers equivalent, the competent authorizes have to cooperate so we can see if they are compliant and have the supervisory framework that we do.  They need to be willing to receive us.  We have to work across all countries with respect to this requirement.

There is quite a lot of new guidance to be developed – for example, the GDPs for APIs, specific provisions for brokers and certain requirements for excipients; when the excipient needs to be manufactured according to GMP.  Others will need to be amended.  For example, the GDP guideline in Chapter 5 may need a little more detail.

We have been looking at wholesale distribution authorization.  They are already registered with the authorities and authorized, but now we want a European format, which will be the same all over Europe, because we want to put it into the database.  To define the specifications of the database, they all need to be the same.

Within Europe, we need to work on the harmonization of formats for registration authorization and notifications for brokers.  We have to work on how the certificates will look, and we will also work on how to handle non-compliance reports, which will also go into this database.

The legislation says that the manufacturer needs to ensure that excipients are compliant with GMP, following a risk assessment evaluating whether or not that particular excipient actually has an impact on the safety of the product.  We do not have that risk assessment yet.

The safety features will occupy us quite a bit over the next couple of years.  It is not only what they are and what we will allow to be safety features, but also the whole process of the verification of those safety features and who shall be doing what across the board.  This is a process we have to engage with over the next years.

The assessment of third countries, depending on how many we have, will also occupy quite a number of resources.  This is important, because if you want to import your API and you want your country to be on that list, we have to be able to assess them beforehand.  We have hear quite a big workload for the European inspectors.

For our database, which is currently the case also with EudraGMP, it will be publicly available.  It needs to be extended to quite a number of more types of authorizations, registrations and certificates.  We have quite a bit of experience doing this at the EMA, but it took us quite a long time to get there with EudraGMP.

Looking at the vast amount of data that we have to include in the future, we have to define the structure of this database.  I know that this is going to be a challenge for us.  It is also very costly.  It does not just mean that we at the agency develop a database, it means all of the countries, all of the authorities that currently issue authorizations, registrations and certificates, have to also change their systems.

For the industry, both in Europe and outside as well that have to comply, they have to be able to receive industry and regulator audits.  The MAHs have to put the QP declaration in the application.  They all have a requirement to notify the authorities if they suspect there is a falsified medicine out there.

We have our new groups of active substance importers and distributors to find, to explain to them and get them on board, and have them register and see how this interaction works.

We have the wholesale distribution authorization holders with their new requirements, waiting to see what will happen with the safety features.  They will need to develop quality system procedures for notification of falsified medicines and more intense record-keeping requirements.

We have to look at a new category of industry that we have not had any good contact with previously – these are the brokers.  We have to understand how they work, who they are, what they need to do in order to develop the notification schemes.

Pharmacies are the ones who sell medicinal products to the public.  They may be affected by the safety features at the final point of sale.  The will need to check those against the database and see that the products that they have sold to the public are actually taken out.

The big challenge is the work load.  The work load, I think, is for all of us, very difficult to manage at this time, with restricted financial possibilities and staff cuts.

We know that audits of API manufacturers are not very well-perceived, and it is a lot of work for the industry.  But I hope through the already established [third party] systems that this can be pulled together to assist the industry.

Development of our European database will take a lot of time – partly the harmonization aspects within Europe, and then the actual IT side of this, which cannot be underestimated.

For the wholesale distributors, there might be a change in the industry.  We have had quite a lot of contact with them [and they have said] that recordkeeping requirements for batch numbers down to individual products will kill them.  ‘We just cannot do it with the high volume we are spitting out and turning over.’  We will have to see how this will work in the future and hope that industry can manage that.

Implementation Timeline

Where are we at the moment?  The European Parliament adopted a version of the new directive in February.  Since then, this piece of legislation has been undergoing legal review and linguistic review.  There is still a formal process to be done.  That is the adoption by the EC that had already in December agreed in principle to the new legislation….  I can tell you that through the legal review there are a few more amendments.  What I have been telling you today is based on the publicly available version the European Parliament adopted in February.  There are still some changes to come.

We hope that this adoption by the Council takes place on May 27.  Shortly afterword it will be published in the Official Journal.  That is sort of the kick point on when it has to be implemented.

Most of the requirements of the legislation have an 18-month transition period during which both industry and regulators have to fulfill their obligations.  That takes us at the earliest to January 2013.

Some of this is delegated up to implementing measures by the European Commission.  This can take years.  We do not know at what time the safety features will come in.  The Commission has no deadline to produce a delegated act on safety features.  It may take two years, it may take four years – we do not know at this time.  We will work with the Commission very closely to see what will be done when.

We hope within our groups at the agency…to develop a work plan for the implementation of this.  We already do this at the agency.  We do this with the member states so that we have a clear plan ready on how and when with the available resources we can do what.  Once this piece of legislation is finally published and we have a final version, then we can start the consultations with industry.

We know the GDP guideline will be published as well, with a six-month public consultation.  I would guess we will have a lot of interested parties meeting to discuss this.

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