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Regulatory Highlights

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INTRODUCTION The last 6 months has seen an intense period of regulatory activity within areas germane to chemists within the pharmaceutical industry. Activities relate to areas such as impurities (elemental impurities and genotoxic impurities), manufacturing (dedicated facilities, GMP), and registration (ICH Q11). The following article seeks to describe the key aspects within each area and their possible implications.

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DNA REACTIVE (MUTAGENIC) IMPURITIES ICH M7 ICH M7,1 currently at step 2, reached another key stage at the end of 2013 when, during the most recent ICH meeting (Japan, November 2013), the ICH M7 Expert working group (EWG) confirmed their intention that the guideline progress to stage 4 (Implementation) in June 2014. Reflecting on the guideline from a chemist’s perspective, substantive progress has been made in terms of a number of critical areas since its inception as an ICH topic at the end of 2010. Key areas include: • The specific focus on DNA reactive (mutagenic) impurities. While at first it might be supposed that this is more the concern of toxicologists, this is nevertheless an important point from a chemist’s perspective. The reason is that it removes the uncertainty surrounding a number of common synthetic agents that are nonmutagenic carcinogens. Examples include acetamide, which until now, despite it being nonmutagenic, has been controlled to levels associated with DNA reactive species i.e. TTC levels. The implications of this are discussed later in the review. • The scope of the guideline is not only clearer in terms of the specific focus on mutagenic impurities, it is also clearer in terms of the scope in relation to established products. The focus is now firmly on changes to the product concerned, e.g. introduction of a new synthetic route and/or process change. Another important fact is that, even in instances where changes to the route/process have been made, the applicant is simply required to assess the impact on the specific stages in question as opposed to a full-scale retrospective evaluation of the route. Similarly for any change to the formulated product any review should focus on specific degradants associated with the revised formulation. There is no requirement for a retrospective assessment of the synthesis of the active pharmaceutical ingredient (API), provided no changes have been made to this. This represents a significant shift; previously, minor changes to the synthesis and even to the formulated product have triggered requests for a review of the risk associated with mutagenic impurities. • One area to be aware of is the potential change in status of a material, i.e. demonstration of its mutagenicity. Although a structural alert itself does not automatically trigger a re-evaluation, new safety data may well do. This was exemplified by the recent example of the coupling reagent EDAC (N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride). Testing performed to comply © 2014 American Chemical Society

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with REACH2 requirements led to a positive finding in an Ames test. The guideline remains essentially unchanged from the earlier EMA guideline3 in terms of impurities that need to be considered within the overall risk assessment. This includes materials used within the synthesis, reagents, solvents, processing agents etc., as well as probable impurities formed during the process. Critically, the framework for impurity identification remains ICH Q3A.4 There is therefore no requirement to attempt to address every theoretical, potentially mutagenic impurity, that may form at a level of parts per million. Unlike the earlier EMA guideline 3 the guideline specifically describes the need to assess the risk posed by degradants. Often seen as the domain of the analyst/pharmacist, this is an area where intrinsic knowledge of the chemistry of the associated synthetic process can play a key role in identifying primary degradation pathways. Structure Activity Relationship (SAR) assessments. The use of in silico tools to predict the potential mutagenicity of impurities has been an integral part of the risk assessment process essentially from the inception of guidance within the genotoxic impurities arena. The draft ICH M7 guideline1 endorses the use of such tools, advocating the use of both rule-based systems (e.g., DEREK) and statistical/quantitative methodologies (e.g., MultiCASE/Leadscope). A specific challenge brought with such systems is the management of conflicting predictions, i.e. positive in one system/negative in another. In such circumstances the role of expert evaluation is key; not just of the toxicologist but also the chemist. This is particularly true in the context of an understanding of the nature of the reagent, e.g. is it an alkylating agent? The control section within the draft ICH M7 guideline has the most significant impact from a chemist’s perspective. ICH M7 offers multiple options to demonstrate control, ranging from Option 1 (Test for the impurity in the drug substance) to Option 4 (So reactive that no testing is required). Of these, Option 4 presents the best opportunity to avoid excess testing. Until recently, there has been little or no option other than to test for the mutagenic impurity of concern, even when there was compelling scientific understanding to challenge the notion that there was a substantive risk of carryover to the API at even ppm levels. Option 4 permits the assessment of risk on the basis of an understanding of the physical/chemical properties of the impurity and the process conditions it is exposed to, i.e. its reactivity, solubility, etc. These principles are encapsulated in the purge factor approach described by Teasdale et al.5−7 Returning to an earlier point, at the most recent ICH meeting a proposal to include an addendum table to the guideline was discussed. The purpose of the table will be to provide, in a manner analogous to that for solvents

Published: March 6, 2014 468

dx.doi.org/10.1021/op500061a | Org. Process Res. Dev. 2014, 18, 468−472

Organic Process Research & Development


Figure 1.

chapters ⟨232⟩11 and ⟨233⟩.12 Differences relate to both the elements considered and their proposed limits. A major step forward in terms of harmonization was agreed at the midpoint of 2013, when the USP agreed to delay implementation of USP chapters ⟨232⟩ and ⟨233⟩13 and to align their implementation with that of the ICH guideline.9 Similarly EMA14 also agreed to align their guideline to the ICH guideline. Despite this, there still remain considerable hurdles to harmonization and ultimately implementation. Challenges include alignment between ICH Q3D and pharmacopoeias. ICH Q3D does not specify how testing should be performed; the guideline states that “Pharmacopoeial procedures or suitable validated alternative procedures for determining levels of elemental impurities should be used, where feasible.” The USP of course provides this through chapter ⟨233⟩; however, at present there is no clear understanding as to how this will be addressed in other major pharmacopoeias. In addition USP has stated the intent to remove the existing limit test ⟨231⟩. Similar tests are also present in other pharmacopoeias. At present there is no clarification as to whether these will be similarly removed, either at a general level or from individual monographs. Challenges also exist in the practical use of techniques such as ICP and in sample preparation. In the majority of cases this will involve acid digestion; this then leads to the question which acid? The choice of acid is potentially both material- and/or element-dependent. Another challenge is the scope of the assessment in terms of how far back in the process should the assessment look? For example, in relation to the API, would a registered starting material require evaluation of the stages preceding this, particularly if these were likely to involve the use of metals in their synthesis, e.g. catalyst? The fish bone diagram, Figure 1 also requires the consideration of other potential sources e.g. manufacturing equipment, water, etc. Clearly the synthesis of the API is likely to involve the use of equipment, reagents (solvents), and water that could be a source of metals. However many of these are tightly controlled through GMP. Minimum standards such as the use of WHO drinking water standards and plant compatibility assessments should mitigate against such risks, but what is not clear at present is the burden of evidence required to eliminate them as a source of risk. This concept extends still further to excipients and packaging materials. It would seem somewhat ironic that, although the risk assessment ultimately focuses on the formulated product, it

(ICH Q3C8) and metals (ICH Q3D9), definitive limits for a series of common reagents. While it is likely that this will not be added to the guideline until after finalisation, this will ultimately be of significant benefit, providing not only clarity in terms of defined limits but also addressing the status of a series of common reagents which to date have been incorrectly identified as being mutagenic, acetamide serving as a specific example. Overall it might reasonably be concluded that ICH M7 draft guideline1 provides a clear and effective framework for control that will allow chemists to develop effective synthetic routes and processes while still utilizing reagents of mutagenic potential. It is hoped that this will clarify that control is the key element in the risk assessment process, not avoidance.

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ELEMENTAL IMPURITIES The need for adequate control over potentially toxic metals is unquestioned. Over time however the approach taken to ensure this control has evolved. For nearly 100 years testing typically took the form of a wet chemistry test involving the use of hydrogen sulphide, the test working through the formation of an insoluble salt (sulphide) via reaction in solution with any metal present. The inadequacies of the test are well-known. Indeed concerns began around 15 years ago and sparked a revision process by the USP. Due to the identified shortcomings, combined with the development of new, more specific tests (based on approaches such as ICP-OES/ICP-MS and XRF), the need to introduce new control methods was compelling. The advent of such specific tests also drove the desire for specific control over individual impurities and the need for individual safety limits. This was initially led through the development of the EMA guideline10 which focused specifically on residues arising from metal catalysts. Additionally and effectively in parallel, the USP, through the development of chapters ⟨232⟩11 and ⟨233⟩,12 and the ICH (through the development of ICH Q3D - Elemental Impurities9) have sought to adopt an holistic approach to the assessment of the risk posed by elemental impurities by developing guidelines focused on the final drug product, taking into consideration all potential sources of metals. Such sources are described in Figure 1. The major concern to date from an industry perspective, both the pharmaceutical industry and excipient suppliers, has been the lack of alignment between the ICH guideline and USP 469



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still seems likely that the primary risk would emanate from the deliberate use of metal catalysts in the synthesis of the API. To further emphasize the fluid nature of this area, USP announced on their web site on 27th December 201315 approval of their General Notices section 5.60.30, Elemental Impurities in USP Drug Products and Dietary Supplements, establishing an official date of December 1, 2015. In doing so this established the formal date of application of General Chapter ⟨232⟩, Elemental Impurities, USP commenting that the delay (original date May 2014) was to allow industry more time to implement the standard. This also confirmed the intent (subject to ballot) to remove all references to General Chapter ⟨231⟩, Heavy Metals, from monographs and general chapters in the USP-NF. The same note also included proposed revisions to General Chapters ⟨232⟩ and ⟨233⟩, Elemental Impurities - Procedures. Within this same update USP also provided a link to its comments pertaining to ICH Q3D, step 2b.9 The link included detailed and specific comments relating to several elemental impurities; these include a proposed lowering of the oral PDE for mercury, revision of the parenteral limit for molybdenum, as well as several other proposed modifications to the limits currently defined in ICH Q3D. A series of other changes were proposed, perhaps the most significant being a proposal to simplify limits: the USP suggesting rounding the PDEs down to the nearest number ending in 5 or 0 per the examples in Table 1 below.

class

oral pde, μg/day

parenteral pde, μg/day

inhalation pde, μg/day

As Cd Hg Pb Co Mo Se V Ag Au Ir3 Os3 Pd Pt Rh3 Ru3 Tl Ba Cr Cu Li Ni Sb Sn

1 1 1 1 2A 2A 2A 2A 2B 2B 2B 2B 2B 2B 2B 2B 2B 3 3 3 3 3 3 3

15 5.0 40 5.0 50 150 (180) 150 (170) 100 (120) 15 (170) 100 (130) 1000 1000 100 1000 1000 1000 5 (8.0) 13000 11000 1000 (1300) 750 (780) 600 1200 6000 (6400)

15 6.0 4.0 5.0 5.0 150 (180) 85 10 (12) 35 100 (130) 10 10 10 10 10 10 5 (8.0) 1300 1100 100 (130) 350 (390) 60 600 600 (640)

1.5 (1.9) 3.0 (3.4) 1.0 (1.2) 5.0 2.5 (2.9) 7.5 (7.6) 100 (140) 1.0 (1.2) 5 (6.9) 1.0 (1.3) 1.0 (1.4) 1.0 (1.4) 1.0 1.0 (1.4) 1.0 (1.4) 1.0 (1.4) 65 (69) 300 (340) 2.5 (2.9) 10 (13) 25 6.0 20 (22) 60 (64)

DEDICATED FACILITIES

In December 2013 the EMA published a guideline16 relating to dedicated facilities. Prior to this the manufacture of certain classes of active substances had required the use of dedicated or segregated self-contained facilities. Examples include antibiotics, hormones, and cytotoxics. Due to a lack of clarity regarding classification, however, this had proved difficult to implement and led to disparate interpretations of categories affected, particularly during inspections. The intent of the guideline was to provide clearer guidance around classification and to address and to facilitate uniform practice in relation to calculation of limits. Since the draft guideline was issued, discussions have been held between interested parties, including a formal workshop, to seek to determine how the guideline will be implemented practically. The central tenant of the guideline is the use of toxicological data to generate a permissible daily exposure (PDE) limit, used to define cleaning limits. Such an approach is intended to replace the often used current practice of the use of 10 ppm or 1/1000th clinical dose, approaches viewed by many as somewhat empirical. There are, though, significant implications of adoption of this revised approach. These include: • Will this PDE approach be adopted retrospectively? Doing so would have major implications given the volume of products that would be affected. Certainly it would be hoped that before such a decision was taken the level of risk associated with current practice would be properly assessed. While there are concerns over the perceived empirical nature of current approaches, it should be noted that the 1/1000th of the clinical dose is related to toxicological data, as clearly such data are taken into consideration in establishing the clinical dose. Moreover, in many cases the current limits are likely to be lower than limits based on calculation of a PDE. • Other challenges include calculation of a PDE during the clinical development of the product. The absence of key critical data, e.g. reproductive toxicity, is likely to prove a challenge to such approaches. • Will the guideline apply to the API as well as the product? From a cleaning perspective the two are quite different. In the case of API manufacture the preceding process will be a solution-based process, often involving a chemical transformation, both providing further opportunities for removal of any residual active remaining. It is likely that significant further discussions between interested parties will be required before finalization. Certainly there are real concerns over the potential retrospective application of the guideline in terms of the scale of the task involved were this to be required. Would the effort required be balanced by a noticeable benefit to the safety of patients? This question remains unanswered.

Table 1. Permitted daily exposures (μg/day) for elemental impurities: suggested rounding to simplify analytical procedures (current limits defined within ICH Q3D step 2b document in brackets - where different) element


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ICH Q7 IMPLEMENTATION WORKING GROUP (IWG) An Implementation working group (IWG) was established at the end of 2012 to produce a Q&A document focused on provision of further clarification concerning ICH Q7. ICH Q7 was introduced in 2000. Since this point, the industry has seen significant changes, changes including types of activities, with the increasing prevalence of biotech APIs, as well as new guidelines (ICH Q8/Q9/Q10/Q11), and also changes in

This continues to illustrate the fluid state of guidance in the area of elemental impurities. There seems little doubt elemental impurities will be hot topic for this review for some time to come! 470




analysis of data derived from Design of Experiments (DoE) has undoubtedly led to greater process understanding, there are concerns that this has led applicants to propose complex, custom-synthesized starting materials often in close proximity, one or two stages from the final API. Regulatory Authorities have expressed concerns over such an approach, focusing on a view that the provision of limited information pertaining to the synthesis of the API makes it very difficult to determine whether the proposed controls satisfactorily address and ensure the required API quality. There are also concerns over the risks relating to the complexity of the associated supply chain, manufacture often taking place at multiple sites. A recent Gold sheet article20 provides a detailed summary of recent meetings relating to ICH Q11 and the specific views of key regulatory agencies. One particularly telling comment was a statement from EDQM that some 40% of applications in 2013 were rejected due to deficiencies pertaining to starting materials. Another specific concern is the inability of analytical methodology to detect issues such as residues associated with other processes present in a vessel as a result of poor cleaning practices. It is self-evident that the smaller the number of synthetic steps between a starting material and the API, the greater the risk of this nature. The requirements for starting materials are outlined in section 5 of ICH Q11. These describe the critical relationship between risk and the number of steps separating a starting material (start of GMP control) and the final API. Risk centers on both impurities (their generation, fate, and rejection) and physical properties. Another key factor in defining starting materials is a clear understanding of critical steps. ICH Q11 states that any critical step must be carried out under GMP control. This emphasizes the need for specific control of steps critical to the impurity profile of the API (either steps associated with impurity formation or steps critical to the removal of an impurity, without which the impurity would be expected to be present in the API). There is, though, an understandable reluctance on the part of the ICH Q11 EWG to provide prescriptive guidance in the form of definitive guidance in terms of number of steps. At present there is a lack of clarity around a number of the areas described; hence, recently a workshop was held between EFPIA and the Quality Working Party of the EMA to develop key guiding principles which address the areas described. This is not intended to replace ICH Q11 but to augment it. Clearly, this is again an area where understanding and practice are evolving.

manufacturing strategyspecifically the increased complexity of manufacturing supply chains. The IWG has been charged with addressing the following specific areas: 1. Review of existing Q&A processes, specifically a questionnaire under development by Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (jointly referred to as PIC/S). 2. Technical issues, including supply chain management and the management of GMP within contract manufacturing facilities. Key within this is which activities can be delegated and which cannot, seeking to clarify the accountabilities within the quality assurance units within the customer organisation. 3. The alignment of ICH Q7 to new guidelines (ICH Q8/ Q9/Q10/Q11), a specific concern being the variable interpretation of starting materials, i.e. the point of introduction of GMP controls. 4. Process validation. 5. Cleaning validation. Another major factor is the recently published Falsified Medicines directive,17 the directive requiring marketing authorization holders to ensure compliance with ICH Q7 for any imported API. It is thought likely that the Q&A document in question will be released for comment during 2014.

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ICH Q11 DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES (CHEMICAL ENTITIES AND BIOTECHNOLOGICAL/BIOLOGICAL ENTITIES) Since its inception ICH Q1118 has faced significant challenges in its practical implementation. One of the key concepts introduced in ICH Q819 and reinforced in ICH Q1118 is the concept of a design space, this being defined as ‘The multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality’. Unfortunately it is apparent that at present there is considerable variance in terms of the practical interpretation as to what this actually means. Organizations have reported extensive scrutiny of submissions made under Q11 accompanied by requests for the inclusion of additional critical control parameters even where it was felt that the data provided justified as noncritical the definition of the parameter concerned. One of the benefits of proposing a design space is that movements within the design space are not considered a change; hence changes within the design space should, in principle, not require regulatory approval. Again, practical experience has been mixed, with changes proposed within the defined design space still being subject to regulatory scrutiny. A workshop has been initiated between EMA and EFPIA, involving the generation of industry cases studies to learn from previously approved MAAs. These are being subjected to further review with, in each case, an aligned assessor with whom the outcome of the submission will be discussed. The intended outcome of this exercise is a clearer understanding of the interpretation of ICH Q8, Q9, Q10, and Q11 from the perspective of both an applicant and the reviewer. There is intended to be a particular emphasis on the development of a common understanding of the concept of a design space and also the construct of the submission requirements to support a given control strategy for a product including design space, if submitted. A further important aspect of Q11 is the relationship to registered starting materials. While the comprehensive understanding gained through approaches based on the multivariate

Andrew Teasdale

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AstraZeneca, Macclesfield, United Kingdom

AUTHOR INFORMATION

Corresponding Author

E-mail: [email protected] Note

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 M7 Step 2 February 2013 - Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (2) Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 Concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

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(3) Guideline on the Limits of Genotoxic Impurities, CPMP/SWP/ 5199/02, EMEA/CHMP/QWP/251344/2006; Committee for Medicinal Products (CHMP), European Medicines Agency (EMEA): London, 28 June 2006 (4) International Conference on Harmonisation (ICH). Guideline Q3A (R2): Impurities in New Drug Substances; October 2006. (5) Teasdale, A.; Fenner, S.; Ray, A.; Ford, A.; Phillips, A. A Tool for the Semi-quantitative Assessment of Potentially Genotoxic Impurity (PGI) Carryover into API Using Physicochemical Parameters and Process Conditions. Org. Process Res. Dev. 2010, 14, 943−945. (6) Teasdale, A. Genotoxic Impurities - Strategies for Identification and Control; John Wiley & Sons, Inc: NJ; 2011; Chapter 9, Section 9.3.4.8, pp 236−237. (7) Teasdale, A.; Elder, D.; Chang, S.-J.; Wang, S.; Thompson, R.; Benz, N.; et al. Risk Assessment of Genotoxic Impurities in New Chemical Entities: Strategies To Demonstrate Control. Org. Process Res. Dev. 2013, 17, 221−230. (8) International Conference on Harmonisation (ICH), Guideline Q3C (R5): Impurities: Guidelines for Residual Solvents; February 2011. (9) Guidance for Industry - Impurities - Guideline for Elemental Impurities, Step 2b, July 2013. (10) Guideline on the Specification Limits for Residues of Metal Catalysts, EMEA/CHMP/SWP/4446/2000; http://www.gmpcompliance.org/eca_guideline_3495.html. (11) Elemental Impurities - Limits, Revision Bulletin Official February 1, 2013; http://www.usp.org/usp-nf/official-text/ accelerated-revision-process/accelerated-revision-history/elementalimpurities-limits-and-elemental. (12) Elemental Impurities - Methods, Revision Bulletin Official February 1, 2013; http://www.usp.org/usp-nf/official-text/ revision-bulletins/elemental-impurities-limits-and-elementalimpurities-procedures. (13) USP Compendial notice, 24 - May 2013, http://www.usp.org/ usp-nf/notices/implementation-deferred-general-chapters-elementalimpurities-limits-and-elemental-impurities-procedures. (14) EDQM notice 30 - August 2013, http://www.edqm.eu/en/TheEuropean-Pharmacopoeia-revises-its-strategy-regardingimplementation-of-chapter-520-Metal-catalysts-or-Metal-reagentresidues-1587.html?mbID=128. (15) Key Issue - Elemental Impurities, http://www.usp.org/usp-nf/ key-issues/elemental-impurities. (16) Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. EMA/CHMP/ CVMP/ SWP/169430/2012. (17) Falsified Medicines Directive - Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011; http://ec. europa.eu/health/human-use/falsified_medicines/index_en.htm. (18) ICH Q11 Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities); U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Rockville, MD, 2012. (19) ICH Harmonised Tripartite Guideline: Pharmaceutical Development Q8, (R2); U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER): Rockville, MD, Aug, 2009. (20) Eglovitch J. S. Conflicts over API Starting Materials Persist Despite ICH Q11 Guide. The Gold Sheet; December 2013, Article # 08131219004.

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Regulatory Highlights - American Chemical Society

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