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Regulatory Highlights

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In February ICH finally published the long awaited training modules.2 These modules, produced by the ICH Q3D implementation working group, cover both safety and quality aspects, the areas covered are listed below: Module 0. This provides an overview of the modules. Included within this is a very useful flow diagram, Figure 1, highlighting the anticipated overall process from the risk assessment through to definition of control strategy. Modules 1−3 Cover Toxicology Aspects. • Module 1Different Routes of Administration • Module 2Justification of Levels Greater than Permissible Daily Exposure Limits • Module 3Non ICH Elements Modules 4−7 Cover Chemistry (Quality) Aspects. • Module 4Large Volume Parenterals • Module 5Risk Assessment • Module 6Control • Module 7Calculation Options Highlighting some key points, module 5, relating to risk assessments, discusses the key role of GMP in assessing riskthis is an important and a helpful point relating to API manufacture. It emphasizes the importance of: 1. Design and qualification; 2. Maintenance procedures. However, it also focuses on the risk arising from manufacturing equipment, making a relatively generic statement over the often more chemically aggressive nature of API manufacturing procedures compared to drug product manufacturing. It even suggests monitoring the drug substance for potential impurities arising from manufacturing equipment (e.g., stainless steelCr, Mn, Mo, V, Ni). It is a pity that this risk is highlighted without also making the point that it would be expected that such risk would be addressed as part of GMP and form part of the process accommodation procedure rather than rely on screening to verify. Rightly the module makes the point that a significant potential source of elemental impurities arises from the use of metal catalysts in the synthesis of drug substances, especially if used in the latter stages of synthesis. It also states that: “Knowledge of potential elemental impurities in synthetic steps prior to the final drug substance may provide information that can assist in the preparation of the risk assessment.” This is an interesting point and one that cuts to the heart of the uncertainties around practical implementation. While a valid point, it raises key questions such as how many steps prior to the API should be assessed? Clearly this will be process/product specific, but it is a very real question any risk assessment will have to tackle. Another interesting point made in the module is the potential for “platform” risk assessments. This is the concept of a risk

INTRODUCTION Perhaps the most significant area at present relates to the imminent implementation date for ICH Q3D, elemental impurities; finalized in December 2014, the 18 month implementation period ends at the beginning of June for new products. This review examines the remaining challenges and areas of uncertainty as well as progress made in the last couple of months. Also examined are practical aspects in the application of ICH M7, mutagenic impurities, focusing on publications in a recent special edition of OPR&D in November 2015. Finally the development of ICH Q12 is examined, seeking to provide an insight into the potential direction of the guideline.

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ICH Q3D ELEMENTAL IMPURITIES ICH Q3D1 Guideline for Elemental Impurities reached step 4 (finalization) December 2014. Included within the proposals was an implementation period of 18 months. Therefore, the guideline becomes effective in Europe and US for new marketing applications as of first of June 2016; i.e., this is imminent! Timelines for Japan, the other major ICH region, are slightly later. ICH Q3D came into force in Japan on September 30, 2015; therefore, for new products in Japan, the effective date is April 1, 2017. The reality is looming large though; any new submissions must be compliant with the requirements of ICH Q3D in little over a couple of months’ time. Hopefully most if not all readers and their organizations are prepared, but there remain real questions over what compliance will look like. Since the beginning of 2016, there has been a significant amount of activity all geared toward preparation for implementation from the perspective of industry, regulators, and other organizations, including United States Pharmacopoeia (USP) and the European Directorate for the Quality of Medicines and Healthcare (EDQM). The major developments, their possible implications, and other planned activities are discussed below.

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ICH Q3D IMPLEMENTATION WORKING GROUP (IWG)TRAINING MODULES ICH Q3D is a complex guideline. The overall requirement in terms of control is clearthere are defined limits for some 24 elements, and levels of the elements described must be controlled within these limits in the final drug product. Simple. The complexity comes when defining how this is achieved. The guideline provides a series of options to evaluate risk and effect control, ranging from control in each individual component based on a fixed dose for the product of 10 g (Option 1) to simply testing the final product (Option 3). A detailed description of the options and when/how these are applied as part of a risk assessment is beyond the scope of this review; the point is that there are significant challenges in applying the guideline practically solely using the guideline for that purpose. This was recognized by the ICH Expert Working Group responsible for the guideline, resulting in the establishment immediately after step 4 of an Implementation Working Group. A key objective of the IWG was to develop training materials to assist implementation. © XXXX American Chemical Society

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DOI: 10.1021/acs.oprd.6b00087 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development


Figure 1.

process that may affect the risk assessment, e.g., change in catalyst load, and so forth. Such changes require a re-evaluation and possibly confirmatory testing. Another point emphasized in the module is that routine testing of Class 1 metals, i.e., arsenic (As), mercury (Hg), cadmium (Cd), and lead (Pb), is NOT required unless there is an identified risk. This is a very important and helpful point clearly reiterating the core principle of ICH Q3D that any control strategy should be based on the risk assessment. This is especially important as several regulatory queries have been reported asking for data for Class 1 and also Class 2A metals for APIs.

assessment applicable across a series of products. One such platform may be for example, oligonucleotides.3 In such instances, where the manufacturing process in terms of reagent type, equipment, and process conditions are similar irrespective of the precise end product, it should be possible to conduct an assessment based on one process and for this to relevant/ transposable to comparable processes. Module 6Control of Elemental Impuritiesalso provides useful advice emphasizing the importance of control across the product lifecycle. In the context of the manufacture of the API, this requires oversight and governance over changes to the B




Several papers focused on control options, specifically ICH option 4, involving evaluation of the impact of process conditions upon the purging of mutagenic impurities. This concept was first described by Teasdale et al. in 201017 and augmented by a crossindustry evaluation published in 2013.15 The practical use of such tools is examined through two papers, that of Nevenka et al.14 and McLaughlin et al.16 This is augmented by a further publication by Welch et al.13 that describes work now being undertaken by an industry consortium to develop this tool still further as a robust in silico tool (Mirabilis). Welch et al. describe the work being undertaken to fully evaluate the potential fate of MIs under a range of common chemical transformations. A critical finding of these studies, examined through the reaction of benzyl bromide with triethylamine, was alignment between the rate constants and halflives of the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol (Figure 2). This established the proof of concept that the kinetic information obtained from the stand-alone reaction can be used to predict impurity conversion in a more complex reaction. Another area addressed in the special edition is that of sulfonate esters. This relates to the use of a sulfonic acid, used to form an API salt and the potential formation of sulfonate esters through reaction with alcoholic solvents. Snodin and Teasdale9 have reviewed the available literature information concluding that the extensive evidence supports the view that such concerns are grossly exaggerated. In parallel to this publication there have been a series of correspondences involving the EMA quality working party, the following points were released following discussion at the CVMP committee.18 “The Committee endorsed the QWP response to the EDQM request for an opinion on new information on alkyl sulfonates. The QWP reviewed the article from Snodin et al. QWP acknowledges the scientific rationale in this article and that the formation of alkyl sulfonates is very low and very much depends on the reaction conditions. This makes the presence of these mutagenic impurities at toxicologically significant levels unlikely. However, as the presence and formation of these alkyl sulfonates cannot be totally excluded, QWP proposes the following approach: marketing authorization holders should justify via Risk Assessment that alkyl sulfonates are not expected to be present for their product, which may be sufficient.” Of concern within this text is the comment that the presence and formation cannot be totally excluded; this is despite the evidence pointing clearly to fact that it can. Similarly at the end of February EDQM issued a press release relating to the Mesilates Working party.19 Included within this, as well as information relating to analytical methods, was the following revision of the production statement. “In addition to the elaboration of these methods, the Ph. Eur. Commission had also decided to revise the Production section of monographs on those active substances to further assist users: “It is considered that [XXX esters] are genotoxic and are potential impurities in [name of the API]. The manufacturing process should be developed taking into consideration the principles of quality risk management, together with considerations of the quality of starting materials, process capability and validation. The general method [2.5.XX] is available to assist manufacturers.” This also goes on to state that: “Marketing Authorisation Applicants are not obliged to perform the testing when they can justify via risk assessment that alkyl sulfonates are not expected to be present in their product.”

One area described in Module 6 is the concept of periodic testing. This is an area of potential concern and ambiguity. It states that: “Where the risk assessment indicates that routine testing is considered unnecessary but some additional assurance is needed post approval, periodic testing of the drug product or one or more individual components may be proposed by the applicant and implemented upon acceptance by the regional regulatory authority.” An example is provided relating to use of a Pt catalyst in the manufacture of the API, this being the final step used in the API synthesis. In the example detectable levels of Pt at ∼ 20% of the PDE are observed (below the 30% limit stated in ICH Q3D), based on this periodic testing being proposed. In the case study described this may seem sensible but how close to reality is such an example? In such a case would an applicant simply not specify Pt on the API specification? The worry is that the option for periodic testing may be blunt instrument and be something that is regularly requested. USP Chapter ⟨232⟩. USP very recently announced4 a series of revisions to USP Chapter ⟨232⟩, Elemental Impurities, the revisions made being intended to align the general chapter more closely to ICH Q3D. One of the most significant is the removal of the need to routinely screen for Class 1 metals as part of any analysis, the final sentence in the text outlined below being deleted. If, by process monitoring and supply chain control, manufacturers can demonstrate compliance, then further testing may not be needed. When testing is done to demonstrate compliance, proceed as directed in Elemental ImpuritiesProcedures ⟨233⟩. This is a welcome and important amendment; the previous requirement making little scientific sense, there being no actual evidence that Class 1 metals would be more prevalent, for example, where a platinum catalyst was used than in the absence of a catalyst. Such catalysts are not a source of class 1 metals. Overall. Overall there are likely to be challenges/ uncertainties associated with ICH Q3D leading up to and for some period after the effective date as the guideline beds in, but the crucial fact is that all of the evidence to date indicates it is unlikely that there will be a widespread impact caused by issues of excessive levels of any elemental impurity whereby effective control cannot be realized.

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ICH M7 Although relatively quiet in terms of any specific regulatory activities, the last 6 months have seen a plethora of publications that are associated with the ICH M7 guideline. Prominent within these was the Special Edition of Organic Process Research & Development in November 2015. This special edition focused on mutagenic impurities, examining the challenges and also opportunities faced when seeking to implement ICH M7.5 This was timely as it aligned with the effective date for ICH M7 of January 2016; the guideline when finalized in June 2014 having a defined implementation phase of 18 months. ICH M7 is, in general, a well-written guideline that provides a flexible and pragmatic framework by which the risk posed by mutagenic impurities can be effectively managed. The flexibility provided by the guideline and the opportunities this presents in terms of science and risk based thinking are examined in depth through a series of articles within the special edition. A tabulated summary of the special edition is described in Table 1. C


A Generic Industry Approach to Demonstrate Efficient Purification of Potential Mutagenic Impurities (PMIs) in the Synthesis of Drug Substances Evaluation and Control of Mutagenic Impurities in a Development Compound: Purge Factor Estimates versus Measured Amounts

A Kinetics-Based Approach for the Assignment of Reactivity Purge Factors

Boronic Acids and DerivativesProbing the Structure−Activity Relationships for Mutagenicity

Mutagenic Impurities: Precompetitive Collaborative and Data Sharing Initiatives Do Carboxylic/Sulfonic Acid Halides Really Present a Mutagenic and Carcinogenic Risk As Impurities in Final Drug Products?

Assessing the Risk of Potential Genotoxic Degradation Products in a Small Molecule Kinase Inhibitor Drug Substance and Drug Product Mutagenic Alkyl-Sulfonate Impurities in Sulfonic Acid Salts: Reviewing the Evidence and Challenging Regulatory Perceptions

Strategies To Address Mutagenic Impurities Derived from Degradation in Drug Substances and Drug Products

Based on vortioxetine and its associated PMIs predicted purge values based on the system described by Teasdale et al.15 are compared with experimental values. The results show good correlation concluding that theoretical purge values can be used to predict purging of PMIs. The purging of MIs associated with the synthesis of MK-8876 were assessed using the approach described by Teasdale et al.15 These predicted values were compared to measured values and shown to be conservative in comparison to experimental data.

highlights A survey of over 300 synthetic publications in OPR&D over a 10 year period clearly demonstrated that the synthesis of synthetic APIs was untenable without the use reactive, potentially mutagenic reagents/intermediates. That the principle of avoidance was fundamentally flawed The paper outlines a strategy for the systematic assessment of the risk posed by mutagenic degradants, describing how this relates to stress testing and long-term stability studies. Within this it seeks to define appropriate thresholds for identification directly related to the extent of degradation The degradation profile resulting from stress testing of galunisertib is described, focusing on formation of two N-oxides, examining the site of oxidation and the relevance of the pathway under typical storage conditions. Provides a comprehensive review of the existing evidence relating to sulfonate esters, examining the comprehensive mechanistic and kinetic studies and safety data. It also examines the current regulatory approaches and how this appears misaligned with the data. Examines the nature, impact, and successes of a series of cross industry initiatives covering areas such as structural evaluation (Q)SAR, data sharing−aromatic amines, boronic acids, purging and degradation. Examines evidence that indicates that in the case of both sulfonyl and acyl chlorides that Ames positive results relate to generation of a reactive species, halodimethyl sulphides (HDMSs) through reaction with DMSO and that this is the root cause of a positive response. Confirmatory negative data from other test solvents is also provided The primary purpose is to raise awareness of the potentially mutagenic nature of boronic acids and stimulate further discussion/research in the areas. It provides mutagenicity data for some 40+ examples, examining the current status of in silico predictions and postulates a potential mechanism related to oxidation of boronic acids to yield oxygen radicals Details an experimental approach that utilizes kinetic analysis to facilitate assignment of reactivity purge values.

subject

Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multistep Syntheses?

Table 1 authors

McLaughlin, M.; Dermenijan, R. K.; Jin, Y. et al.16

Betori, R. C.; Kallemeyn, J. M.; Welch, D. S.13 Lapanja N, Zupanĉiĉ B, Toplak Ĉ asar R et al 14

Hansen, M. H.; Jolly, R. A.; Linder, R. J.12

Elder, D. P.; Williams, R.; Harvey et al.10 Amberg, A.; Harvey, J.; Spirkl, H.-P. et al.11

Strege, M. A.; Osborne, L. M.; Hetrick, E. M. et al.8 Snodin, D.; Teasdale, A.9

Kleinman, M. H.; Teasdale, A.; Baertschi, S. W. et al.7

Elder, D. P.; Teasdale, A.6

Organic Process Research & Development Regulatory Highlights

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It emphasizes the importance of providing “sufficient detail” such that the performance and quality of the approved product are assured. This of course immediately begs the question What is suf f icient detail? No express guidance is given regarding this other than to highlight that this will be reviewed as part of the marketing application. Elements of a Control Strategy that May Be Considered Established Conditions. This is potentially a very useful section highlighting the relationship between established conditions/the control strategy and the overall product quality system. Within this it describes the elements that form part of control strategy that may be defined as established conditions; these include: 1. Drug Substance (DS)/Drug Product (DP) (including in-process materials) manufacturing and testing facilities. 2. Source of and specifications for starting materials for biological products. 3. Process, including in-process tests and sequence of operations, equipment, and process parameters and their ranges. 4. Specifications, including the tests, analytical procedures, and acceptance criteria including specifications for the DS, other components, in-process materials, and the DP. 5. Maintenance strategy for chemometric and/or multivariate models. This also makes the critical point that the control strategy is ultimately supported by an effective product quality system, highlighting that critical aspects of the PQS such as batch records, batch analysis, and development and validation data are not generally considered as established conditions. This point is further emphasized in the final section where the point is made that irrespective of whether or not a future change is reportable it must be addressed through a robust change management process, itself an integral part of the PQS. The draft guideline also provides detailed instruction as to where within the Common Technical Dossier (CTD) Established Conditions should be recorded. It also states that the applicant should summarize this in Module 2, section 2.3, i.e., the Quality Overall Summary. The focus of the draft guideline is to provide advice regarding what constitutes established conditions and where to record them. Through this it is possible to establish an effective framework to manage future change that allows evaluation of where such change can simply be managed through the PQS or where this requires regulatory approval. A far more considerable challenge is how to manage this for legacy products where there is no clear delineation of established conditions. A clear challenge for ICH Q12! So what of Q12 itself? What is its current status? In November 2015 ICH circulated an update in the form of a slide set, focused on progress made at a recent meeting of the EWG in Jacksonville. This focused on progress as well as a revised work plan. It is apparent that the focus of much discussion built on change is how to reduce regulatory burden for post approval change. This includes the utilization of 1. Post approval plans and protocols, when/how they are filed and what is in scope; 2. Use of “lifecycle management plans” for a product stating post approval ambitionsto set scene for plans and protocols.

Figure 2. Alignment between the reaction of benzyl bromide with triethylamine in isolation and as a low-level impurity in the TBS protection of benzyl alcohol.

Although both the QWP deliberation and the EDQM statement fall short of concluding minimal risk, they nevertheless represent for the first time at least tacit recognition that control is possible.

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ICHQ12 In 2004 the FDA instigated an ambitious plan to redefine the approach taken to cGMP, within this overall concept it sought to better regulate postapproval changes by utilizing more flexibility and risk-based principles, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century − A Risk Based Approach (September 2004).20 Unfortunately the potential benefits of this have not been realized in the context of efficient life cycle management and post approval change. Much of the reason for this lies in the challenge of defining change. Phrases such as “each condition established in an approved application” and the term “regulatory commitment” have been the subject of considerable debate and conjecture both among industry and regulators alike. In 2014 ICH issued the concept paper for a new guideline ICH Q12Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.21 Within this it articulated the current perceived barriers to effective lifecycle management. Primary within these was the need to clarify established conditions for manufacture and control based on risk, product type, development approaches, manufacturing experience, and GMP status. ICH Q12 was formally adopted in September 2014. The scope of the guideline is significant, seeking to address lifecycle management for all pharmaceutical products, including currently marketed chemical, biotechnological, and biological products. Furthermore it is seeking to address this through integration with existing guidelines, principally ICH Q9Quality Risk Management22 and ICH Q10Pharmaceutical Quality System (PQS).23 At the forefront of the guideline’s development is the desire to address the question of established conditions and what a regulatory change is. In May 2015, FDA issued a draft guidelineEstablished Conditions: Reportable CMC Changes for Approved Drug and Biologic Products.24 This reiterates the challenge and current variable interpretation of “regulatory commitments” and seeks to replace this introducing the term “established conditions”. Definition of Established Conditions. Within this section of the draft guideline it sets out the FDA definition of established conditions as: “the description of the product, manufacturing process, facilities and equipment, and elements of the associated control strategy, as defined in an application, that ensure process performance and quality of an approved product.” E




In order to continue progress made in Jacksonville, five specific workstreams have been established: 1. PQS & Assessor/Inspector Interactions 2. Legacy/Currently Marketed Products & Frequent Mfg. Changes 3. Established Conditions (Chem. & Bio.) 4. Lifecycle Management Plans 5. Post Approval Change Management Protocols In terms of timelines, these have been slightly revised; it is now anticipated that ICH Q12 will reach step 1 in June 2017.

QuestionsandAnswersonCurrentGoodManufacturingPracticescGMP forDrugs/UCM176374.pdf (Sept 2004). (21) Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. http://www.ich.org/fileadmin/Public_ Web_Site/ICH_Products/Guidelines/Quality/Q12/Q12_Final_ Concept_Paper_July_2014.pdf (July 28, 2014). (22) ICH Q9Quality Risk Management. http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q9/ Step4/Q9_Guideline.pdf (Nov 9, 2005). (23) ICH Q10Pharmaceutical Quality System. http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/ Q10/Step4/Q10_Guideline.pdf (June 4, 2008). (24) Established Conditions: Reportable CMC Changes for Approved Drug and Biologic Products, http://www.fda.gov/downloads/Drugs/ G u i d a n c e C o m p l i a n c e R e g u l a t o r y I n f o r m a t i o n / G u i d a nc e s / UCM448638.pdf?_sm_au_=iNH61FD2WjHZP02F (May 2015).

Andrew Teasdale*

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AstraZeneca, Macclesfield SK10 2NA, United Kingdom

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

REFERENCES

(1) ICH Q3D Guideline for Elemental Impurities. http://www.ich. org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/ Q3D/Q3D_Step_4.pdf (Dec 16, 2014). (2) http://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Quality/Q3D/Training_package_Module_0-7. zip (3) Analysis of Oligonucleotides and their related substances; Okafo, G., Elder, D., Webb, M., Eds.; Chapter 2, pp 22−28; ChromSoc Separation Sciences Series ISBN 9781906799144. (4) http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/ key-issues/m5192.pdf (5) ICH M7 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 (June 23, 2014). (6) Elder, D. E.; Teasdale, A. Org. Process Res. Dev. 2015, 19, 1437− 1446. (7) Kleinman, M. H.; Teasdale, A; Baertschi, S. W.; et al. Org. Process Res. Dev. 2015, 19, 1447−1457. (8) Strege, M. A.; Osborne, L. M.; Hetrick, E. M.; et al. Org. Process Res. Dev. 2015, 19, 1458−1464. (9) Snodin, D; Teasdale, A. Org. Process Res. Dev. 2015, 19, 1465− 1485. (10) Elder, D. P.; Williams, R; Harvey.; et al. Org. Process Res. Dev. 2015, 19, 1486−1494. (11) Amberg, A.; Harvey, J.; Spirkl, H.-P.; et al. Org. Process Res. Dev. 2015, 19, 1495−1506. (12) Hansen, M. H.; Jolly, R. A.; Linder, R. J. Org. Process Res. Dev. 2015, 19, 1507−1516. (13) Betori, R. C.; Kallemeyn, J. M.; Welch, D. S. Org. Process Res. Dev. 2015, 19, 1517−1523. (14) Lapanja, N.; Zupanĉiĉ, B.; Toplak Ĉ asar, R.; et al. Org. Process Res. Dev. 2015, 19, 1524−1530. (15) Teasdale, A.; Elder, D.; Chang, S.-J.; et al. Org. Process Res. Dev. 2013, 17, 221−230. (16) McLaughlin, M.; Dermenjian, R. K.; Jin, Y.; et al. Org. Process Res. Dev. 2015, 19, 1531−1535. (17) Teasdale, A.; Fenner, S.; Ray, A; et al. Org. Process Res. Dev. 2010, 14, 943−945. (18) http://www.ema.europa.eu/docs/en_GB/document_library/ Minutes/2015/12/WC500198748.pdf (Dec 8, 2015). (19) https://www.edqm.eu/sites/default/files/press_release_on_ mutagenic_impurities_february_2016.pdf (Feb 25, 2016). (20) Pharmaceutical CGMPS for the 21st CenturyA Risk-Based Approach. http://www.fda.gov/downloads/Drugs/ DevelopmentApprovalProcess/Manufacturing/ F


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