EDQM ON IMPLEMENTING ICH Q3D IN PH. EUR. AND CEP IMPACT

To help explain the impact of ICH Q3D implementation on the European Pharmacopoeia and CEP assessments, EDQM held a webinar in late January 2017 hosted by two of its key scientific officers – Bruno Spieldenner from Ph. Eur. and Lennart Seidler from EDQM’s substance certification division. Spieldenner led off the webinar with an overview of the evolution of EIs in Ph. Eur., and then focused on the impact of ICH Q3D implementation on the general test, general methods, general monograph, and individual monograph sections. In focusing on the impact on the CEP process, Seidler discussed: ● EDQM’s 2016 policy document ● the two options for addressing EIs – with and without a risk management summary ● specifications ● limits ● CEP content and assessment, and ● CEP revision/renewal.

BRUNO SPIELDENNER ON IMPLEMENTATION IN PH. EUR.

Background and Ph. Eur. Structure

It is my pleasure this morning to give you the presentation on the implementation of the ICH Q3D in the European Pharmacopoeia.

Background

To start off with a little bit of background on the elemental impurities in the European Pharmacopoeia: Before 2008 we had no guidelines for safety limits. The EMA guideline on specifications limits for residues of metal catalysts or metal reagents was introduced in 2008, and this one lasted until 2013 when the work on the ICH Q3D development and implementation started.

On the methods side, we of course had this non-specific heavy metals test with a limit of 10 or 20 ppm lead in the monographs since the very early years. That moved to a more flexible method that was introduced together with the EMA guideline in 2008. That was method 2.4.20 which allowed a little bit more flexibility – just giving out validation parameters for any method to be used for testing of elemental impurities. And this moved again with the implementation of ICH Q3D towards a risk management approach for testing or for controlling of elemental impurities.

Here is an outline of the different press releases and the communication we have published over the years since discussion started on the ICH Q3D guideline…. The final bullet point you will see is a very new press release we just issued a few days ago, which summarizes actually the discussion we had at the last commission session and the decisions that were taken there (link provided above).

Ph. Eur. Structure

Before going into detail of what we did to implement ICH Q3D in the European Pharmacopoeia, this slide gives an overview of the structure of the European Pharmacopoeia.

The first text you read whenever you would open the European Pharmacopoeia is the general notices. They provide basic and general information that is valid for all texts. They help to understand aspects of wording, the structure of monographs and general chapters, and also the requirements of the European Pharmacopoeia.

The sublevel will be the general chapters. They are subdivided into general methods, which give general recommendations for analytical procedures, and general texts, which are more or less informative texts – sometimes reproduction of guidelines. They only become mandatory when they are cited in a monograph – be it a general monograph or an individual monograph.

The next layer is the general monographs. Those also are subdivided into dosage form monographs, which are applied during licensing, and then there are specific general monographs for some groups of products that may be defined by production methods, risk factors or the intended use. Those general monographs summarize mandatory aspects that are common to the given group they are directed to.

And then the final layer is the individual monographs. Of course, whenever you go to the center of those circles, you increase the specificity of the text.

Implementation in the General Texts

To start off with the implementation, I will go layer by layer, and start with the general text [of chapter 5.20]. It currently refers to the EMA guideline on metal catalysts and metal reagents. That is a verbatim reproduction of it. We replaced the EMA guideline by the principles of the ICH Q3D guideline.

We decided there not to do a verbatim reproduction to avoid introducing a European Pharmacopoeia copy of the guideline, because the enforceable text is the version as published by the ICH and there are no changes there to be done. This allows also that the guideline stays with the very useful modules that were developed by the ICH implementation working group that are also available on the ICH website.

The publication for the modified 5.20 chapter is in Supplement 9.3, so the implementation date is January 2018. So it aligns with the timeline decided by EMA, which was December 2017.

We, as I said, decided not to do a verbatim reproduction, but we reproduced only the introduction and the scope of the ICH Q3D, with a little bit of information specific to the guideline, in the European Pharmacopoeia.

The new version of the chapter [explains] that ‘the European Pharmacopoeia applies this guideline to medicinal products except products for veterinary use, unlicensed preparations and products excluded from the scope of the guideline…. The PDE’s established in the guideline are considered to be protective of public health for all patient populations. In some cases, lower levels of elemental impurities may be warranted when levels below toxicity thresholds have been shown to have an impact on other quality attributes of the medicinal product or one of its ingredients (e.g., element catalysed degradation of a substance for pharmaceutical use.)’

So these are examples of what you will find in the new version of chapter 5.20, which will be available by July 2017, so you will have to wait a few more months to see the full version of it.

Implementation in General Methods

The next step of the implementation was in general methods. The major implementation was in the general method 2.4.20. This was the method that allowed a bit of flexibility in the determination of elemental impurities.

Here we will go with a two-step approach: The first one is an editorial revision to align the wording with the ICH Q3D guideline, because as I said this general method was introduced with the EMA guidelines. So the wording there was really dedicated to the EMA guideline, and we have to go now to the ICH Q3D guideline. That means replacing metal catalyst and metal reagent residues by elemental impurities.

Then as the second step, this general method had been put on the agenda of the PDG which is responsible for international harmonization. The coordinating pharmacopeia here is USP, and the work to harmonize all the chapters of the European Pharmacopoeia, the USP and the Japanese Pharmacopeia is ongoing with high priority within the PDG.

As far as other general methods are concerned, for example the old heavy metals test 2.4.8 and arsenic 2.4.2, there is no deletion foreseen at the moment, because some of these methods are still referred to in other monographs or general texts, and especially in monographs and products for veterinary use.

Implementation in General Monographs

Implementation in general monographs: We had two main monographs where we had to implement the ICD Q3D.

The first one is the one on substances for pharmaceutical use, 2034. And here also we had two layers of implementation. The first one concerned the elements intentionally added. Those should be controlled during the production. Therefore we introduced the sentence, which says: ‘the identity of the elemental impurities derived from intentionally added catalysts and reagents is known and strategies for controlling them should be established by using the principles of risk management.’

The second part would be to clarify the deletion of specifications for substances. That is said with the following sentences: ‘Elemental impurities. Permitted daily exposures for elemental impurities (e.g., as included in the ICH Q3D guideline, the principles of which are reproduced in General Chapter 5.20 Elemental impurities) apply to the medicinal product. Individual monographs on substances for pharmaceutical use therefore do not contain specifications for elemental impurities unless otherwise prescribed.’ And the publication of that is in Ph. Eur. supplement 9.3 – so again, the implementation date is January 2018.

The second step of implementation in general monographs was for the general monograph on pharmaceutical preparations. The approach here was to add a cross reference to general text 5.20 – which is the principles of ICH Q3D – and that reference will render the text so ICH Q3D is legally binding for medicinal products in the scope of ICH Q3D.

Second part was to clarify that for medicinal products outside of the scope of ICH Q3D, elemental impurities should at least be considered in a risk management strategy. And that is made in the following reference that:

●‘General chapter 5.20 Elemental impurities applies to medicinal products except products for veterinary use, unlicensed preparations and other products excluded from the scope of general chapter 5.20.’

● ‘For pharmaceutical preparations outside the scope of general chapter 5.20, manufactures of these products remain responsible for controlling the levels of elemental impurities using the principles of risk management.’

● ‘If appropriate, testing is preformed using suitable analytical procedures according to general chapter 2.4.20 Determination of elemental impurities.’

When we published both of those monographs in public consultation, [which] ended on August 31 [2016], there was some concern, especially for products out of scope of ICH Q3D, that additional requirements would be introduced with the sentences we added in the monograph on pharmaceutical preparations.

However, we think that there is absolutely no extension of the scope of the ICH Q3D guideline, because we clearly said that Q3D sets human toxicology limits. That is clear – the PDEs are made for humans, and therefore especially veterinary products are out of scope. And the term ‘control’ that we use in those sentences is to be understood as a comprehensive approach using risk management, not ‘control’ in the analytical sense.

Where we say that, we have to highlight as well that elemental impurities are an important quality attribute of substances and products, just as any other type of impurities. Therefore, in the absence of specifications for elemental impurities in substances, this should be covered by a risk management strategy in line also with good manufacturing practices.

Implementation in Individual Monographs – Heavy Metal Tests

The final layer of implementation is in individual monographs. The first step was the suppression of heavy metal tests 2.4.8 from individual monographs, except those for veterinary use only. You will have noticed that monographs without the heavy metal test was published in the 9th edition.

There was a total number of texts of 754 monographs, which represents 43% of all the monographs that are published in the European Pharmacopoeia. So for obvious practical reasons, this had to be combined with a new edition of the European Pharmacopoeia, and therefore the timelines there could not be completely aligned to the ones decided by EMA. However, there was no anticipated entry into force expected for already marketed products. From a regulatory point of view, manufacturers are expected to comply with ICH Q3D by December 2017 at the latest.

This idea was also communicated in the press release from April 2015: ‘The absence of the heavy metal test from an individual monograph does not preclude substance manufacturers from controlling the levels of elemental impurities in their products. Control of heavy metals according to method 2.4.8 is still acceptable until ICH Q3D comes into force for a given finished product.’ So basically until ICH Q3D becomes fully applicable…you still can use heavy metals tests if you want to.

For other monographs: For individual monographs on finished products…there no additional requirements for elemental impurities will be added in the specific individual monographs because they are covered by the general monograph on pharmaceutical preparations.

For the monograph on ‘water, purified,’ the public consultation just ended, and the comments are under consideration by the relevant group….

And the final point is on monographs, materials and containers: The discussion here is ongoing in the relevant group of experts to decide what should be done with respect to elemental impurities.

Implementation in Individual Monographs – Specific Metal Tests

The final point of the implementation is the specific metal tests. In the European Pharmacopoeia there are approximately 300 monographs that describe more than 450 specific metal tests. Those are the dedicated tests for arsenic, copper, iron, for instance. There the discussions started in 2015 in the group of experts, basically on the ICH Q3D Classes 1, 2a, 2b and 3.

The concerns on those tests is that there is often a historical reason for the presence of the test in the monographs and the exact rational for each is not known because the monographs date from a long time ago and some of these monographs were taken over from national pharmacopeias.

The second concern was for some of these metals, especially those that are intentionally added, there is no change control whenever, for example, the production pathway is updated. So we would not be allowed at the level of the European Pharmacopoeia to follow those changes.

The final concern was on the substances of natural origin – for example, the mined excipients, or other substances where elemental impurities are potentially present but not intentionally added.

Ferrous Fumarate Monograph Example

For that last category I have a small example to show: Here you have seen extract of the monograph for ferrous fumarate. It is not exactly an excipient here as this is an API, but it is a mined API so it shows problems we will face here.

You will see in this monograph that there is, for instance, tests for arsenic, cadmium, lead, mercury. There are several metals here – nickel and zinc as well. So basically, there are nine tests in this test section of the monograph. If we would now go for a complete deletion of that, we would end up with a monograph on ferrous fumarate having just a sulfate test, a ferric iron test, the zinc test, and a loss on drying test.

So the question we asked ourselves is what is the meaning of an EP compliance of ferrous fumarate with only those tests? It is pretty much meaningless, so therefore we had to refine our strategy of what we do with those specific metal tests.

One of the easy decisions was that for an elemental impurity without a PDE, so those that are categorized as ‘others elements’ in the ICH Q3D Guideline – examples are iron, calcium or aluminum – the tests should remain because there are no PDEs given by ICH Q3D, so the only limits, if there is one, is in the monograph.

Four Classes of Specific Metal Tests

For other elemental impurities that have a PDE in ICH Q3D, we said that there should be no systematic deletion of individual tests in monographs, and we had to run a risk analysis for elemental impurities contamination. We identified four classes based on the ICH Q3D:

● The first one is ‘the residues from elements intentionally added.’ Those are covered by general monograph 2034, the one on substances for pharmaceutical use. That was a sentence I was relating to in one of my previous slides that has been added in the production section of the monograph.

● The second class was the ‘not intentionally added but potentially present.’ Those should be kept in the monograph.

● The third category was the ones ‘potentially introduced from manufacturing equipment.’ This risk could be mitigated by applying GMP.

● The final category is ‘potentially leached from container closure system.’ Again, the risk would be mitigated, at least identified, with container closure system compatibility studies.

So the categories1, 3, and 4 would not be covered in individual monographs.

Next Steps

What are the next steps for specific metal tests?

The first phase is that each group of experts involved will assess, case by case, whether the specific test can be suppressed in cases 1, 3, and 4 or maintained for the specific case 2. The main focus of course will be on substances of natural origin, and this is mainly mined excipients.

The second phase would be on the longer run actually to obtain batch data and revise these tests that would stay in the monographs, or maybe add new ones, if necessary, based on the batch data. For that, of course, we will need more expertise and support, especially from manufacturers of the substances, to revise and maintain these tests in the future.

This leads me to the end of the presentation. So, here are a few people I want to thank for putting that strategy together and helping over the years in trying to implement the ICH Q3D in the European Pharmacopoeia.

And with that I thank you for your attention, and I will now hand you over to Lennart, who will give you insights on the certification procedure in the implementation of ICH Q3D.

LENNART SEIDLER ON IMPACT ON THE CEP PROCESS

Welcome to everyone from my site. My name is Lennart Seidler, and today I will lead you through our presentation, ‘Implementation of ICH Q3D,’ which is based on the policy document with the same name.

In the run up to this webinar, we offered the possibility to send us questions to this second presentation on issues that you would like to have addressed. We will try to consider all questions which are of general interest and which are related to the certification procedure and our policy document. However, several questions were related to the ICH Q3D guideline itself or otherwise out of the scope of this presentation. Please understand that we cannot address these questions in this session.

As already mentioned, you can also contact us now during the presentation. With me are my colleagues Annick Degardin, Cécile Thouvenel and Ciaran Feeney, who.are ready to answer all of your questions at the end of the presentation.

Now to the content of my presentation: ● I will start with a few general words about the policy document. ● Then we will have a look at the two scenarios that are offered to you as an applicant. ● Specifications ● Analytical methods ● Limits ● An important topic is the question of what will be reported on the CEP,’ and here mainly the tests and limits. Afterward, I will show you some case studies. ● And the last topic of the presentation is revision/renewal.

Policy Document

The new policy document was published last August and has been in place since September 1, 2016. The policy document is applicable to new, renewed, and revised CEP’s, but of course only for substances that are used in products within the scope of Q3D. So, for example, it is not applicable to substances that are restricted to veterinary use only.

And just a remark: For now, we will not implement ICH Q3D when evaluating gaseous substances. As a result, we will not have statements relating to elemental impurities on a certificate for a gas.

Applicants and CEP holders have two possibilities to address elemental impurities:

● They can provide a risk management summary performed at the level of the drug substance or excipient. This is also known as the component approach, and should be, with regards to the centralized assessment, the preferred scenario.

● Our second scenario, an applicant does not provide the risk management summary, and the information on elemental impurities has to be provided at the stage of the drug product.

Including a risk management summary in the CEP dossier is an option, not an obligation. The benefit for substance manufacturers of including a risk management summary is that EDQM assesses once the carryover of elemental impurities.

The result of this assessment is annexed to the CEP. This saves resources on the side of the regulators and the industry. Further repeated assessments by national competent authorities can be avoided, including further requests for additional information. And you could also reduce the time and work for completing loads of questionnaires for finished product manufacturers and other data exchange with them.

The CEP and the Annex will provide the users of your CEPs with all necessary information.

Scenario 1: Risk Management Summary Provided

If scenario 1 is chosen, it should be apparent that the component approach is followed. We will not issue a long list of questions to raise the non-risk management summary dossier to the level of a risk management summary submission.

You should indicate the route of administration. In the guideline Q3D, permitted daily exposures are established only for the oral, parental, or inhalation route. Consequently, you will have to choose one of these routes so that we can conclude on absence of impurities based on these PDEs. I will say some words about substances used by other routes of administration when we come to the case studies.

The indicted route of application should be realistic. If it is known that a substance is only used parenterally, no proposal for oral use will be accepted. And finally, of course, the risk management summary should be provided.

How detailed should this summary be? We have seen examples where companies just stated it may come from the equipment or water – and on the other hand, a company that investigated the elemental impurity level after each process step, so addition of hydrochloric acid, sodium hydroxide, and so on.

Both are extreme examples. In general, we expect that the company explains why certain impurities are addressed and others not, and that applicants explain their control strategy. This summary might be succinct, but the screening alone is not considered as a risk management summary.

This table is a possible way to present your risk management summary. However, this is only an example, and this slide should not restrict your creativity. If you are used to presenting the results in another format, please feel free to do so.

In this mock up, the risk for carryover of the catalyst introduced in the last step has been classified as high. The specification in the final substance has been established accordingly. Even though catalysts are used in the manufacture of a solvent and the packaging material, significant carryover has been excluded. No further action has been taken. For contaminants potentially originated from reagents and equipment, the risk has been classified as moderate. It has been decided to verify the actual levels by a screening study.

This is an example of a risk management summary, which can be used to explain your control strategy. It is important to notice that this summary does not replace the table in the annex of our policy document.

The Annex 1 table has to be provided in addition, as it will be annexed to the CEP. We will come back to the Annex 1 table on the next slides.

As shown in the risk management summary mock up, it is not necessary to perform a systematic screening for all 24 elements of the guideline. The screening can be restricted to those elements for which a risk has been identified – that they might be at or above the control threshold, which is 30% of the acceptable limit.

This could be the case for: ● impurities introduced late in the process ● impurities which are potentially originated by multiple sources ● and also for those impurities with a low PDE. ● Furthermore, it might deemed necessary to obtain analytical data for contaminants present at highly variable levels. ● Migration studies can be necessary for the packaging material, and especially for non-solid substances, as described in the EMA guideline ‘Plastic Immediate Packaging Materials.’

Analytical Methods

What information is necessary in regard to the analytical methods? Risk management includes in general some screening results, at least to demonstrate absence of some contaminants.

For these methods, we do not expect a full method description. It is enough if you indicate that ICP-MS or atomic absorption spectrometry, for example, has been used. Limited validation data is expected. Specificity and sensitivity should be shown, so that it is demonstrated that the method is suitable and to exclude metrics effects.

For methods used to control elemental impurities in the final substance, full validation data should be presented. ICH Q2A and the European Pharmacopoeia General Chapter 2-4-20 provide information on the validation requirements.

A detailed method description should be provided, which should be suitable to be annexed to the CEP if needed.

What the CEP Will Look Like

Now we have received everything that we need. What will the CEP look like when the proper risk management summary has been provided? We are mentioning this on the CEP with the following sentence: ‘The risk management summary for elemental impurities has been provided.’

If applicable, we will also mention the test on the CEP. Here the standard sentence has changed from ‘test for residual catalysts’ to ‘test for elemental impurities.’

The table, which we will annex to the CEP, represents the outcome of the risk management summary. The table shown here is the example from the Annex 1 of our policy document. You do not need to use the one from the policy document, like for the risk management summary. You can use your own version. However, the information requested in our template needs to be in your version too. Especially, the proposed route of administration has to be mentioned.

For the route of administration, please mention only the most critical one, so that it is clear to which permitted daily exposure your statement ‘absent’ refers.

If this approach is followed, selenium is the only element for which potentially further explanation is necessary, as the parenteral PDE for selenium is lower than the one for inhalation. If this rare case affects you, please use an annotation to explain which PDE you are referring to for selenium.

The proposed route of administration does not restrict the use of the CEP. If you have, for example, a CEP for salbutamol and you have proposed the parenteral route as shown here, you are of course free to use this CEP in support of an oral formulation. But you are also free to use it in support of an inhalation powder. In the latter case, it is only necessary to adapt the risk management summary at the stage of the drug product. As in this case, all Class 3 elemental impurities have to be considered.

Other parts of the CEP dossier need no reassessment. Of course, absent means below 30% of the Option 1 limit. You should make a relevant annotation on the same page on which the table is printed, as this is the case on our template in the Annex 1.

Now to the fourth column: You should write “yes” if you have considered this element in your risk management summary. In our mock up, antimony has been identified as a potential impurity in the packaging material, polyethylene terephthalate. As no contamination is expected, no analytical testing has been performed. Nevertheless, in such a case you should indicate ‘yes,’ as a rationale has been provided why no contamination is expected.

In addition, ICH Q3D requests that antimony is considered for parenterally applied products. First if ‘no’ would be indicated in the respective field, the risk management summary could not be considered as complete.

The table has to be provided by the applicant and will not be prepared by the assessors. Therefore, please pay special attention when completing the table. It can easily happen that a mistake occurs in one of the 72 fields that you have to complete. As the table is annexed to the CEP, we cannot ignore an even obviously clerical error, even if the correct information is provided in another part of the dossier.

In such a case, you would receive a request for dossier update, and the whole procedure could be delayed by one or two months, if this is the only outstanding issue.

For most elemental impurities, ‘absent’ will be mentioned in the table. If an elemental impurity is actually present, you should not put actual batch data in the table, which will be annexed to the CEP. Otherwise the table is probably no longer valid with the next produced batch. Instead you should define a threshold for which you are confident that it covers all future produced batches, as this is shown on the right side.

The thresholds will not be commanded, except if they are totally unrealistic with regard to batch data. But this is not what we expect to see, as a high threshold is no advertisement for this source of API.

Scenario 2: No Risk Management Summary

Now we come to scenario 2. This covers the case that no risk management summary is provided.

In this case you should identify all intentionally introduced elemental impurities, namely catalysts and reagents. The carryover should be investigated. And for analytical methods, the same requirements as for scenario 1 apply.

On the CEP, we are mentioning the elemental impurities that are intentionally introduced in the process, following the addition of the starting material, all be confirmed that no elemental impurities are used in the process.

We have restricted the statement to those elemental impurities covered by ICH Q3D. So the less toxic elements like magnesium or iron are not listed here. Again, we might mention a test. In that case, we use the same sentence as for scenario 1.

And in case of scenario 2, we do not take a position on the absence of elemental impurities on the CEP. So even if it has been demonstrated that no impurities are present in the final substance, this information will not be mentioned on the CEP. If an applicant wishes to have this information on the CEP, a risk management summary should be provided.

Specifications

Now what specifications do we mention on the CEP? For both scenarios, if an elemental impurity is intentionally introduced prior to the last synthesis step, and the applicant has proposed a specification, we will include this on the CEP regardless if absence has been shown or not. If no specification is proposed, no question will be raised.

This slide is again true for both scenarios, and addresses the case when an elemental impurity is introduced in the last step of the synthesis. No specification is expected if the elemental impurity is purged to below 30% of the Option 1 limit. If this is not assured, a specification in the final substance is expected. This policy is in line with the draft EMA document implementation strategy of the ICH Q3D guideline.

This draft document has been published for consultation last year and is applicable to CEPs and ASMFs. The final document may offer more flexibility as testing could also done at the stage of the final drug product. If the EMA document will be modified in this sense, we will align our policy with the one of the EMA.

And to the second bullet point, if the applicant proposes a specification, we will include it on the CEP regardless of the levels found.

On the previous slides I have explained which specifications will be mentioned on the CEP. However, there are also specifications which we will not mention. We have seen that some companies introduced routine screening for all 24 elemental impurities mentioned in Q3D – either because the requirements of the ICH Q3D were not clear to these companies, or just because it is not much more of burden than testing only for one element.

However, CEPs should not be overloaded with unnecessary tests. Therefore, in case a risk management summary has been provided, we will specify only those elemental impurities on the CEP which are actually present at all of the control threshold, or which are intentionally introduced. In case no risk management summary has been provided, we will not add specifications for contaminants, as we do not have information about the relevance of the specifications. This means we will only mention specifications for intentionally introduced elemental impurities.

We have been asked by CEP holders if the tests for heavy metals according to the general method 2.4.8 could be used to control impurities after a risk management summary has been prepared, and in order to comply with the component approach described in ICH Q3D. The original purpose of establishing ICH Q3D was the intention to get rid of the more-than-100-years-old non-specific pharmacopeial precipitation tests. These tests are considered as deficient and should therefore be replaced by specific tests. It is therefore expected that applicants or CEP holders implement specific tests.

Limits

Now to the limits. The limits proposed by applicants will be accepted by the EDQM as proposed. Even through the limits might be above the Option 1, they can be toxicologically fully acceptable.

In this example, palladium is used in the last step of the synthesis of adrenaline tartrate, and this might lead to the high residues in the final substance. However, based on Option 2B, or the short-term use (it is actually a one-time use for adrenaline), this level might be totally acceptable as described in the ICH training module 2. But this has to be addressed at the stage of the drug product. So EDQM will report the proposed limit on the CEP.

There are a few exemptions to this rule, and they are mentioned in Q3D. This is, for example, if the test for sulfated ash would no longer be met due to a limit of 2000 pbm for tin, or if element catalyzed degradation is an issue. For this reason, we have low limits for the last toxic elements: copper, iron and ascorbic acid. But nickel could be used in the synthesis and act in a similar way. So for the cases where we have information about element catalyzed degradation, the proposed limit could be questioned.

In any case, limits will be questioned when they are unrealistic with regard to batch data. In the case of acitretin, it is known for years that it can be produced with a palladium content of not more than 10 ppm. When this test gets removed from the monograph, we can also accept higher limits, but they should be in accordance with the batch data. So if 15 ppm of palladium are found, a limit of 1300 ppm is not considered acceptable. Again, we do not expect that applicants will propose such limits as this is no advertisement for their substance.

Assessment

We have already mentioned that intentionally introduced elemental impurities will be reported on the CEP. ‘Intentionally introduced’ means introduced during the API synthesis. Consequently, catalysts used in the starting material are considered as contaminants and not mentioned on the CEP.

In this case, platinum is used in the synthesis of 2,3-dichloroanaline. As dichloroanaline is the starting material, the use of platinum will not be mentioned on the CEP. If a risk management summary is provided, platinum should not be marked as intentionally introduced on the Annex 1 table.

According to our policy document, ‘Content of the Dossier,’ manufacturing alternatives can be described in a single application if the impurity profile of the final substance manufactured by each alternative is the same. Based on this policy, we have accepted in the past process alternatives with different elemental impurities, if they have been purged in the synthesis.

In this example, you could obtain phloroglucinol starting from TNT by using chromium or starting from 3,5 dichloroanaline using copper. There is even a third alternative, which starts from trinitrobenzene and makes use of nickel. For now, we continue to accept these alternatives in one dossier as long as both elemental impurities are purged.

Since this approach is not excluded according to the policy documents ‘Content of the Dossier’ and ‘Implementation of Q3D.’ In this case, we mention all elemental impurities – so chromium and copper – on the CEP as intentionally introduced. However, this is not our preferred solution. This means we might revise the policy document with regard to process alternatives. So if you intend to file an application which falls into this category, please consult again the policy document prior to submission to check if there has been a change in policy.

The next example is related to substances, used at very low dose. Salmeterol is used by inhalation only and at very low daily doses. For the inhalation route, we have in general the lowest PDEs. This can become analytically challenging. An applicant might therefore decide to use a more realistic approach, and not the Option 1 limit based on 10 gram drug product per day.

If there is a sufficient safety margin, we can still conclude on the absence of elemental impurities, even though the limit of detection might be higher than the 30% threshold, or elemental impurities are actually found at or above this threshold. This means we are applying a reasonable approach and not putting unnecessary burden on the applicant.

From time to time, we receive applications in which reference to other CEPs is made. There were enough cases to trigger the publication of a specific policy document that explains how these cases will be treated. In such a case, the applicant should identify all elemental impurities introduced after the starting material. Especially also the ones used by the CEP holders for the intermediates.

All elemental impurities will be mentioned on the CEP for the final substance. In this example, selenium, which is used in the last step of dexamethasone, will be mentioned on both CEPs – the one for dexamethasone and the one for dexamethasone isonicotinate.

A range of substances are not generally administered by one of the routes for which an ICH Q3D permitted concentrations are established – namely the oral route, parenteral and inhalation.

The calculation of the appropriate PDE is based on bioavailability, local or systemic effects, local toxic effects, and is dependent on the drug product. This is described in the ICH Training Module 1. So at the stage of the CEP procedure, it is not possible to conclude an unacceptable PDE for these substances

However, the applicant can propose to apply the oral or even parental PDE in the assumption that this will not be a safety factor. In this case, the risk management summary approach can be used. The suitability of the oral PDE for the dermal product has then to be assessed at the stage of the drug product.

Few substances and consequently, of course also the drug products, are used at daily doses above 10 g. This makes it difficult to conclude an absence if a risk management summary is provided. In these cases, applicants should mention in the table, which will be annexed to the CEP, levels as described on slide 11 for all elemental impurities – so for example, ‘cobalt below XY ppm and not absent.’

Revision/Renewal

Now we are close to the end. The last topic is revision/renewal. We apply the policy documents systematically at the stage of renewal. The renewed CEPs will then mention the intentionally introduced elemental impurities and all other information as described before.

For revisions, we apply the guideline only if the revision leads to higher levels of an elemental impurity, if a new elemental impurity is introduced, or if changes to the analytical control are requested – and this means changes beside the deletion of the test for heavy metals. And of course, we apply the guideline also when a risk management summary is provided.

A hot topic for a number of CEP holders in the deletion of reference to the General Method 2.4.8 from individual monographs. Our approach is described in the policy document, and therefore CEP holders have not been contacted individually, as this is normally done in case of monograph revisions.

It is the responsibility of the CEP holders to assess the consequences of deleting the heavy metals test. The test can be simply removed from the specification of the substance, if it is concluded that this does not result in a lack of control.

It is not necessary to perform a full risk management before the tests can be omitted. Chromium or cobalt, for example, are in any case not detectable by the heavy metals test. So there is no need to perform a risk management for these two elemental impurities before a decision on the heavy metals test is taken. However, it should be assessed which elemental impurities have been controlled by this test and if it is necessary to further control these impurities with a specific method.

In case the heavy metals test can be omitted without establishing an analytical control, CEP holders should not submit a revision only for the deletion of the heavy metals test. You should include the change in the next revision that is filed for any other reason. The deletion of the test will not be further assessed by the EDQM. And the deletion of the test does not impact the classification of the next revision.

If it has been concluded that elemental impurities are not sufficiently controlled following the deletion of the heavy metals test, any change in the control strategy should be submitted as a revision. The classification should be done according to the EDQM guideline on requirements for revision and renewal.

CEPs will only be revised following a request for revision or renewal. There are no plans to systematically revise all CEPs. Only a very limited number of CEPs that have a reference to Chapter 5.20 will be revised by simply deleting the reference. This is necessary as Chapter 5.20 is for the moment still a reproduction of the EMA catalyst metals guideline. With the pharmacopeia supplement line three, this chapter will refer to ICH Q3D. This was already explained in the first presentation.

Conclusion

Now you have heard a lot about the details of implementing Q3D at the stage of the CEP procedure. I hope this information will help you to revise your control strategy for elemental impurities.

Companies have already submitted applications with a risk management summary, as they have seen a benefit of having elemental impurities centrally assessed. CEPs with a risk management summary as an annex have been granted.

And with this slide, I want to close my presentation. ICH Q3D is a new policy for all of us – regulators and industry. We expect to see more specific cases in the next month that are not covered by the more general, high-level policy document. With more experience, we will review the policy document in 2017 and revise it as far as is necessary. Of course, we will keep you informed.