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Regulatory Highlights

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INTRODUCTION 2014 was perhaps one of the most significant ever in terms of regulatory activity within the CMC area (Chemistry Manufacturing and Controls). It saw the finalisation (step 4) of two entirely new guidelines Elemental Impurities (ICH Q3D)1 and Mutagenic Impurities (ICH M7),2 as well as the instigation of a new topic ICH Q12 addressing post approval changes. It also saw the somewhat surprising publication of the finalized EMA guideline relating to shared facilities3 (it had been anticipated that there would be a further opportunity for industry to review) as well as considerable activity relating to GMP (ICH Q7) and quality by design (ICH Q11). As ever though the issuance of new guidelines is only part of the equation, however well thought out and well written the guideline, there is the inevitable period immediately following publication where the specifics of their practical implementation are established. As a consequence in many ways, 2015 will be as challenging, if not more so, as we enter a phase of reflection and evaluation, industry and regulators alike seeking to establish practical frameworks within each of the areas described. This article will therefore seek to look across these areas and provide at least some thought as to what the specific challenges will be, as well as possible solutions.

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critical to ensure that any proposed starting material is wellcharacterized, and the associated MI risk is well-understood and controlled. Another area of interest relates to probable impurities formed during the process. One area more than any other relates to situations where sulfonic acids are present in the synthesis as either a reagent or used to form a salt of the active. There remains heightened concern over the potential formation of sulfonate esters as a result of reaction with alcoholic solvents. This is unfortunate as this relates to a perceived risk rather than an actual one. Extensive mechanistic and kinetic studies6,7 have demonstrated that such a reaction can only occur under highly acidic, anhydrous conditions at high temperature. Even under such conditions conversion rates are poor; for methanesulfonic acid (MSA)/ethanol, the conversion after 24 h at 70 °C is 0.4 mol %. Critically, under the conditions prevalent within a salt formation process no such reaction can occur. Despite this, it remains an area of high concern often leading to requests to provide analytical data. Two other areas that are very likely to draw scrutiny are those of structural evaluation of impurities and reporting requirements. Although both are technically out of scope during the 18 month implementation phase applicable to ICH M7, there remains little doubt that they will become important factors in the future. In relation to structural evaluation, ICH M7 specifically defines the need to assess mutagenicity using two different methodologies, one rule based, and the other statistical. The challenge is likely to come where there are conflicting positions between predictions made by the different methodologies and the role of expert opinion in such circumstances. An in-depth evaluation of such challenges is outside the scope of this regulatory review, but it is important to reflect the fact that this is a difficult area, one where the implications for the chemist and the overall control strategy are significant. Imagine for one moment a situation where an impurity has been classified as nonmutagenic and the control strategy is predicated on this fact, that on submission this status is challenged by a regulator. Closely related to this is where an impurity possessing an alert is structurally similar to another structure which has been proven to be nonmutagenic. ICH M7 contains a five class classification system for defining impurities: Class 1: Carcinogen Class 2: Mutagen (carcinogenicity status undetermined) Class 3: Alerting Class 4: Alerting but API (or other relevant structures) demonstrated to be nonalerting Class 5: No alert It is unlikely that it will ever be possible to succinctly define similarity, models do exist, e.g., Tannimoto scores, but these are subjective. This is again an area where the chemist’s knowledge of reactivity and the steric and electronic environment of the related molecules can be critical.

DNA REACTIVE (MUTAGENIC) IMPURITIES ICH M7

ICH M7,2 Assessment and Control of DNA Reactive (Mutagenic) Impurities In Pharmaceuticals to Limit Potential Carcinogenic Risk, was approved (Step 4) in June 2014. In the previous regulatory review,4 I focused on some of the key areas within the guideline and their impact on the risk assessment process from a chemist’s perspective. In this I highlighted the principle challenges faced by the chemist, these being where to start a risk assessment and what to include in the assessment in terms of actual and potential impurities. This was of course a reflection on an interpretation of the requirements from ostensibly an industry/applicant’s perspective. How will the guideline be interpreted from the perspective of a regulator? It is of course a dangerous game to attempt to second guess this, and I will not be as presumptuous to do so; however, it would appear that the certain areas are already currently attracting specific interest. One such area relates to starting materials and a desire to understand the potential risk posed by mutagenic impurities within the material. Specific concerns over MIs arising from starting materials are a key topic discussed within the EMA Starting Materials Reflection Paper5 (this is discussed in more detail later in the article). Indeed the EMA paper makes clear consideration of such a risk is an integral part of the assessment of suitability of a proposed starting material. Such scrutiny is understandable given the concern that lesser control of the process preceding the starting material could lead to variable levels of impurities, including mutagenic impurities and that this could result in unacceptably high levels of a mutagenic impurity within the final active substance (API). Whether such a risk is real or apparent is somewhat academic, the onus is clearly there to prove this is not a concern, and hence it is © XXXX American Chemical Society

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DOI: 10.1021/acs.oprd.5b00085 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Jan 1, 2018 No centralized position Refer to local schedules

EP 2.4.8 will remain, but cross references will be removed from monographs Jan 1, 2017.

USPJan 1, 2018

Implementation deadline (existing marketed products) products) Withdrawal of “heavy metals” test

Implementation deadline (new products)

Risk assessment process

No centralized position Refer to local schedules

EMA guidance on metal catalysts has been effective since Sep 2008 (new products only) ICH Q3D effective for new marketing applications in June 2016. ICH Q3D guidance will become effective for existing marketed products in Dec 2017. ICH Q3D implementation deadline not defined for new products. Expected 2015−2016

N/A (See ICH Q3D) N/A (See ICH Q3D)

See ⟨233⟩. PDG will harmonize USP/EP/JP method chapters.

Not defined (reference to pharmacopoeial methods) Yes, Q3D includes detailed process No centralized position Refer to local schedules Analytical methods defined

USP/FDA

EMEA/Ph Eur B

USP ⟨232⟩ will be updated to align limits with ICH Q3D.

ICH Q3D1 was finalized in December 2014. Critically finalisation brought with it commitments to harmonize key aspects, including permissible limits, within the United States Pharmacopoeia (USP) general chapters ⟨232⟩8 and ⟨233⟩.9 2015 has already seen considerable regulatory activity as ICH and pharmacopoeias seek to clarify timelines for implementation. The current position is outlined in Table 1. Similar to ICH M7, ICH has proposed an 18 month timeline for implementation for new products, although to date only the EMA have formally adopted this. Timelines for existing products are also under review with the EMA publishing an effective date of December 2017 and USP January first 2018. It is important to note, however, that currently neither the FDA or PMDA (Japan) have confirmed the deadline for either new or current products. Reflecting on this the timelines for USP in particular are a marked contrast to the original proposed date of May 2014 and clearly show that the complexity and extent of work required has been now recognized. ICH have also taken the unprecedented step of immediately establishing an implementation working group (IWG) to support the roll out of the finalized guideline. The primary purpose of the IWG is to produce training material to support the process. It is anticipated that training will cover both safety and quality aspects, looking at specific aspects such as

ICH Q3D

ELEMENTAL IMPURITIES

Finalized December 2014

Table 1. Summary of ICH, US, and European Elemental Impurities Alignment

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Permitted limits

ICH M7 also includes specific guidance relating to reporting requirements. This is phase-dependent; at the time of marketing application the requirements are extensive. One area likely to be of contention relates to the need to include details of all structures that have been evaluated. What is meant by all impurities? This might seem a strange question until one considers the iterative process involved in the risk assessment as it is conducted during the phases of development. Such an assessment will most likely change extensively, driven by changes to route/process and increased knowledge and understanding. Would all impurities include the inclusion, for example, of a theoretical impurity assessed during phase I relating to a route no longer used to manufacture the active? This would seem unrealistic and excessive as it may never have been proven to be present and would never form in the future. Another area that remains a challenge is that associated with establishing compound specific limits for mutagenic carcinogens. Many common reagents sit within this category, e.g., acrylonitrile or hydrazine; these have associated safety data, including carcinogenicity study data. It is, though, a significant challenge to evaluate this as data quality is often variable, especially for historical studies; also there may be multiple endpoints, and finally there is the need to also assess the relevance of these to humans. To address this and provide a common framework, a working group was established to develop an addendum table to ICH M7. This addendum table, analogous to limits in Q3C for solvents will provide a common standard for some 25 reagents. This is still under review but will be released as a step 2 document during the early part of 2015. Despite these challenges, ICH M7 remains in the minds of many a pragmatic and well-defined guideline, and hence the challenges should be surmountable as practical implementation evolves and experience is gained.

Metal catalyst limits defined in EMA guideline and EP chapter 5.20. EP 5.20 will be updated to align limits with ICH Q3D. Chapter 2.4.20. PDG will harmonize USP/EP/JP method chapters.





• SafetyDetermination of PDEs for non-ICH Q3D elements/limits for other routes of administration/ justification of higher limits; • QualityRisk assessment processes/Control strategy; • Case studies. Critically no further substantive changes were made to the guideline before finalisation, and therefore the risk assessment principles described in previous regulatory reviews remain germane.4

Active Pharmaceutical Ingredients (APIs) are not discussed in Chapters 3 and 5 of the GMP guideline; the general principles outlined in this guideline to derive a threshold value for risk identification could be applied, where required.” Does this infer that limits calculated for a drug product should be applied directly to API manufacturing facilities? To do so may fail to take into account the clearly enhanced capacity that exists in a solution based process to purge any cleaning residue from a previous product manufacture. In order to address the issues described, there is clearly an immediate need for greater dialogue between industry and regulators. Without this the implementation of this new guideline may have a significant adverse impact both in terms of resource and also potential risks to the supply chain.

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DEDICATED FACILITIES The classification of certain drug categories, e.g., antibiotics, hormones, and cytotoxics, and uncertainties as to when/where dedicated facilities are required for their manufacture have for some time posed significant challenges for industry and regulators alike. To address this, the EMA sought to develop a specific guideline: a guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. This guideline was unexpectedly published in Nov 2014.3 In parallel the European Commission (EC) also amended General GMP chapters 310 and 511 to include new specific sections focused on prevention of cross contamination. The publication in November was somewhat of a surprise especially given that many felt there were a number of unresolved issues that needed further discussion. Of even greater concern are the effective dates: • Revisions to GMP chapters 3 and 5 become effective March 1, 2015. • The EMA guideline 01 June 2015 (new products), November 20, 2015 (existing products). What is unclear is the basis for the implementation timelines, these certainly appear aggressive when contrasted with the 18 month implementation time lines applied to ICH M7 and ICH Q3D. The guideline indicates the need for each product to calculate an acceptable daily exposure (ADE) and advocates the use of preclinical data and the use of the calculation defined within ICH Q3C.12 Fundamentally, there is little challenge to the concept of basing limits on such principles; however, what is unclear and of significant concern is how this aligns with current approaches. A survey of current practice conducted by EFPIA showed that in terms of limits many (over 50%) of current limits are based on fraction of the clinical dose, and that this was largely consistent across all therapeutic classes. The guideline does allow for alternative approaches to be taken “The use of other approaches to determine health based exposure limits could be considered acceptable if adequately and scientifically justified”. Critically, though no guidance is provided as to what other approaches may be taken nor is any guidance given as to what would be required to demonstrate such an approach was “scientifically justified.” So what does this mean in practice? Many organisations are certainly faced with an extensive re-evaluation of limits. How should this be approached? Do organisations calculate revised limits for all products? Is there an effective process whereby high risk products can be identified and prioritized (i.e., a risk based approach)? Certainly it would be useful to somehow bracket products such that risk assessments concentrate only on those products where current procedures and limits are deemed inadequate. Another key question is how should the guideline be applied to API manufacture? The guideline simply states that “While

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REGISTERED STARTING MATERIALS The previous regulatory review4 highlighted specific challenges the industry and regulators alike have faced relating to interpretation and practical implementation of ICH Q11. A particular concern from a regulatory perspective has been a perception of an increasing tendency for applicants to define complex, custom synthesized starting materials, often in close proximity, one or two stages from the final API, as starting materials. These concerns led the EMA in Sept 2014 to publish a reflection paperReflection on the requirements for selection and justification of starting materials for the manufacture of chemical active substances.5 This paper specifically seeks to outline the expectations of authorities as they relate to the selection of starting materials and applies to both synthetic and semisynthetic drugs. This is achieved within the paper via a combination of text (extracted directly from the guideline) accompanied by explanatory notes. The paper starts by laying out a problem statement, the specific problems identified include: 1. The high level nature of the guideline allows for variable interpretation that leads to differences in opinion between applicant and reviewer. 2. The increasing registration of short syntheses that employ complex custom-made starting materials. 3. The provision by applicants of insufficient details to allow authorities to be able to assess the suitability or otherwise, of the proposed registered process and its accompanying control strategy. Through the explanatory notes the following points are emphasized: 1. Full details of the synthesis must be provided; this should take the form of a flow diagram highlighting all reagents/ solvents and associated process conditions. That this should cover all steps critical to the quality of the final API. It emphasizes that criticality must be assessed before proposed starting materials are selected; the document providing examples of steps that should be considered critical. 2. There is a clear emphasis on steps and that a step specifically involves the formation of one or more covalent bonds. While within the paper, it is recognized that recystallisations/salt formations play a role in the reduction of impurities in later stages of the synthesis, there are still very likely to be concerns that there is a potential overemphasis within the paper on bond-forming steps and that this at least partially ignores or downplays the role of other processing actions in the effective control of impurities. The paper also places considerable weight on the correlation between criticality C




key aspects of QbD such as design space/control strategy and others.

and distance between a step and the API. While generally this would seem a reasonable correlation, it is nevertheless empirical and not necessarily true of all processes, again highlighting concerns over the limited perspective of the paper. 3. The term “significant structural fragment” is frequently misinterpreted by applicants as meaning structural proximity to the active substance. In this context, however, the phrase applies to materials which contribute to the final molecular structure of the active substance, as opposed to reagents, catalysts, or solvents. Justification of a late intermediate as a starting material by claiming it is a significant structural fragment is not considered a valid argument as this could apply to any intermediate in the manufacturing process. 4. In a direct attempt to address concerns over the level of information provided in submissions the paper makes clear the need for an applicant to provide a clear and comprehensive overview of the identity/fate and overall control of impurities. 5. Specific concerns over the potential introduction of nonrelated impurities (cleaning residues) arising from nonGMP steps are outlined. Again this is an argument against the registration of short syntheses. It is also made clear that proposals to implement “GMP like” controls for starting materials to support a late starting material will not be accepted as this would not fall under the EMA GMP guideline framework and nor would sites concerned be inspectable under the associated inspection framework. Also the paper makes clear that a proposed starting material cannot be supported on the basis of a closed DMF provided by the material manufacturer to the authority concerned. 6. Another key consideration is change control. Again there are specific concerns that the absence of a formal change control process for non-GMP steps could adversely impact the impurity profile. Such changes need to be fully evaluated in order to assess the potential impact on impurity profile and levels. Conversely there is a view held by many in the industry that effective change control, combined with strong vendor agreements, can support the selection of later stage intermediates as starting materials. 7. The reflection paper makes it clear that is not acceptable to look to simply address some of the points described above or to look to address each one in isolation. There is a clear emphasis on the need for a holistic approach to defining appropriate starting materials, one that addresses all of the points outlined. Overall there is a very clear message that, although not impossible to register a short synthesis, this is not the general expectation and that it is likely that any such proposal will face a substantive challenge. Overall this provides a clear perspective of at least the EMA’s interpretation of ICH Q11 and requirements for starting material selection. It is therefore hoped that it provides a solid foundation for further discussion between industry and the EMA.

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ICH Q7 QUESTION AND ANSWERSOUTPUT FROM IMPLEMENTATION WORKING GROUP Again this was discussed in detail within the last update.4 Work on the questions (69 in total) is reported to be complete, and the step 4 document is now due for publication. This Q&A document will seek to provide clarity around the following key aspects of ICH Q7: • Definition of a starting material. • Scope of GMP at manufacturing steps before the registered API starting material. • Dedicated equipment. Clearly there are very close relationships between many of these areas and discussions surrounding other key guidelines, starting materials (Q11), dedicated equipment (EMA shared facilities guideline3), and therefore it will be very interesting to see how the responses align with the guidelines described and indeed agency positions (EMA starting material reflection paper5). These are obvious topics for consideration in future reviews. To finish though, finally it is also important to note that the Expert working group for ICH Q12 met for the first time in November 2014. Obviously it is too early to comment on status/progress and certainly likely content, but again the development of this and the principles upon which it will be predicated will be closely followed. Andrew Teasdale* AstraZeneca, Macclesfield SK10 2NA, United Kingdom

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Corresponding Author

*E-mail: [email protected]. Notes

The views represented here are the views of the author and do not necessarily represent the views of AstraZeneca.

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REFERENCES

(1) ICH Q3D Step 4 16th December - Guideline For Elemental Impurities. http://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Quality/Q3D/Q3D_Step_4.pdf. (2) ICH M7 Step 4 June 2014- Assessment and Control of DNA Reactive (Mutagenic) Impurities In Pharmaceuticals To Limit Potential Carcinogenic Risk. http://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_ Step_4.pdf. (3) Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. http://www.ema.europa.eu/docs/en_GB/document_ library/Scientific_guideline/2014/11/WC500177735.pdf. (4) Regulatory highlights. Org. Process Res. Dev., 2014, 18, 468−472. (5) Reflection paper on the requirements for selection and justification of starting materials for the manufacture of chemical active substances http://www.ema.europa.eu/docs/en_GB/ document_library/Scientific_guideline/2014/10/WC500175228.pdf. (6) Teasdale, A.; Eyley, S.; Delaney, E.; et al. Mechanism and Processing Parameters Affecting the Formation of Methyl Methanesulfonate from Methanol and Methanesulfonic Acid: An Illustrative Example for Sulfonate Ester Impurity Formation. Org. Process Res. Dev. 2009, 13, 429−433. (7) Teasdale, A.; Delaney, E. J.; Eyley, S. C.; et al. A Detailed Study of Sulfonate Ester Formation and Solvolysis Reaction Rates and Application toward Establishing Sulfonate Ester Control in Pharma-

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OTHER AREAS There are several areas where the publication of documents is eagerly anticipated, these include the following.

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AUTHOR INFORMATION

QUALITY BY DESIGN

The output from the EFPIA/QWP QbD workshop described in detail in the previous review is due very soon. This should provide an important overview of areas where industry and regulators, in Europe at least, have reached a consensus around D




ceutical Manufacturing Processes. Org. Process Res. Dev. 2010, 14, 999−1007. (8) Elemental Impurities − Limits, Revision Bulletin Official February 1, 2013. (9) Elemental Impurities − Methods, Revision Bulletin Official February 1, 2013. (10) http://ec.europa.eu/health/files/eudralex/vol-4/chapter_3.pdf. (11) http://ec.europa.eu/health/files/eudralex/vol-4/chapter_5.pdf. (12) ICH Q3C (R5) GUIDELINE FOR RESIDUAL SOLVENTS, Step 4 version 4 February 2011 http://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines/Quality/Q3C/Step4/Q3C_ R5_Step4.pdf.

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