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Regulatory Highlights

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INTRODUCTION This article seeks to examine areas of regulatory guidance and practice that can be considered as being those of highest current interest and impact on the activities of chemists and engineers in process research and development of pharmaceuticals. This is either because of ongoing evolution of new guidance or in relation to current uncertainties around practical management and/or implementation of current guidance. A current review of the CMC regulatory landscape could not start really anywhere other than with elemental impurities. This remains arguably the most complex area we, as an industry, are currently seeking to address and manage. As well as elemental impurities, the article seeks to examine the impact of regulations in the emerging market of Brazil to illustrate some of the challenges that continue to surface in a global market place. The article also looks at an area often overlooked in the concept of quality by design; that of using the principles of quality by design in the context of analytical method development. It examines how this might be used to drive continuous improvement in relation to analytical methods, making an analogy between this and established approaches for synthetic processes. It looks briefly at the topic of process descriptions and uncertainties relating to terminology, and finally the article considers ICH M71 and mutagenic impuritieswhat impact has the guideline had?

each of these would swamp industry and regulators alike, and a pragmatic solution, aligned to actual risk, is clearly needed. Certainly, from a European perspective there is a hope that the use of the Type 1A variation procedure will be commonly accepted (where no significant risk has been identified) when the limit test is removed. Concerns also exist regarding the Q3D Notice issued by Health Canada.6 There are some positives within this: implementation dates are broadly consistent with ICH Q3D and those defined by EMA and FDA. However, there is a statement within the notice that, in order to ensure any changes relating to marketed products are approved by Health Canada before the December 2017 deadline, all submissions (NDS/SNDS/ DINS) received by Health Canada after December 31, 2016 are expected to include a risk assessment for elemental impurities according to ICH Q3D. For marketed products this means that, for any CMC prior-approval change filed after Dec 31, 2016, the elemental impurities risk assessment must be included with the submission, regardless of the purpose of the change or the results of the risk assessment. Another area of concern relates to what needs to be submitted and where this should be located in the dossier. Both FDA4 and HC6 guideline helpfully clarify that a summary of the detailed risk assessment should be submitted. The HC is though prescriptive in terms of location, and this is different to that at least suggested by the FDA. What about the draft EMA guideline? This at present does not comment in detail about either point. How does this ultimately affect your risk assessment strategy? In short, in practical terms it arguably should not. If you have established and implemented a risk-based approach, one consistent with the requirements of ICH Q3D, the documents described should not affect this. These are intended to attempt to aid applicants in terms of some of the practical aspects of implementation. Whether they currently achieve this is a moot point. They are not additional guidances, and a combination of ICH Q3D, the implementation guides, industry reflection papers, and the very recent case studies provide the best source of information to guide the risk assessment process itself. The issue in relation to these implementation guidelines is not about how you do a risk assessment; it relates to how that risk assessment is represented within a regulatory filing and particularly how do you manage the transition and application for existing products. There also remain multiple practical questions surrounding areas such as analytical methodology and validation; however, it is important not to lose sight of the reality surrounding this. The reality is that to date there is simply no evidence of a substantive risk to patients regarding elemental impurities in pharmaceuticals. Assessments of both development compounds and marketed products across the industry have shown there to be virtually no risk, and specifically for established products, there has proven to be virtually no incidence where it has been

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ELEMENTAL IMPURITIES As a reminder ICH Q3D,2 Elemental Impurities, was finalized in December 2014. Given the complexity of the challenges associated with the guideline, specifically practical implementation, ICH took the unprecedented step of immediately forming an Implementation Working Group (IWG) to coincide with an implementation period of 18 months for new applications and 36 months for application to existing products. Early in 2016, the IWG published a series of training modules3 designed to assist in the practical implementation of the guideline. This has been followed by an extraordinary and, in some cases, unannounced tranche of other guidance issued to coincide with the end of the implementation period. Table 1 describes the key documents. So what is the outcome of these further guidance documents and their impact? Unfortunately, they raise the specter of a risk of introducing territorial variants, something that ICH Q3D2 was meant to specifically avoid. One particular area of concern relates to the management of withdrawal of the Heavy Metals limit test. As it currently stands, outside of the US there is no specified procedure as to how this will be handled. The FDA position4 is clearsuch changes will be managed through the annual update process when no additional requirement to introduce specific testing for individual elements of concern; but the question remains, will similar procedures be adopted and accepted in other regions? The potential impact of managing changes through formal variation procedures is massive; many companies have portfolios, accounting for different formulations, doses, and so forth, that number in the thousands. Submitting variations for © XXXX American Chemical Society

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DOI: 10.1021/acs.oprd.6b00355 Org. Process Res. Dev. XXXX, XXX, XXX−XXX


necessary to replace the outdated heavy metals limit test with specific testing.

Health Canada

USP EDQM

Q3D Notice: Health Canada recommendations for implementation of the ICH Harmonised Guideline for Elemental Impurities (Q3D) for new and marketed products6

Stimuli article “Future of Element-Specific Chapters in the USP−NF”7 Implementation of ICH Q3D in the certification procedure8

There are unfortunately dif ferences between the HC notification and the FDA and EMA guidelines. This is a concern, as such dif ferences could well drive regional variations. This seeks to address the removal of USP ⟨231⟩ (Heavy Metals limit test) and the management of other, element-specific, tests and their limits. Intended to serve as guidance on how to implement ICH Q3D in the procedure for “Certification of Suitability to the monographs of the European Pharmacopoeia” (CEP). This seeks to address expectations as they relate to the CEP procedure, specifically the need in such applications to address elemental impurity (EI) risk. It makes clear that, while the EI risk associated with API needs to be assessed, that reviewers will not themselves specifically comment on the ultimate suitability as this needs to be addressed in terms of the overall finished, packed product.

EMA Implementation strategy of ICH Q3D Guideline, draft5

Provision of specific advice to support practical implementation of ICH Q3D in USA. Addresses how risk assessments should be filed, the level of detail (a summary), and where in the CTD it should be filed. Also directly addresses how to manage the removal of USP ⟨231⟩, heavy metals limit test. Overall, this is a usef ul guideline, and the management of removal of ⟨231⟩ via the annual update procedure is extremely encouraging. This focuses heavily on the active and compares and contrasts approaches depending on the site of manufacture. It also comments on risk assessment approaches, with a clear indication of preference for approaches based on assessment of components, i.e., Option 2B (see ICH Q3D) as opposed to Option 3 (end-product testing). Another important aspect from a chemist’s perspective is the commentary relating to use of metal catalysts late in the synthesis of the active. In comparison to the FDA, no specific guidance is provided in terms of: • How to document the risk assessment in regulatory submissions, i.e., the anticipated level of detail; • Where to file the elemental impurity risk assessment within the regulatory filing and critically; • How to manage the removal of the heavy metals test from the EP. Similar to the FDA guidance, this notice seeks to define specific requirements regarding filing of the risk assessment, in terms of content, location, and management of established products. FDA Elemental Impurities in Drug Products Draft Guidance for Industry

Table 1

document title

4

issuing body

overview of purpose/key content/reflection

Organic Process Research & Development

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BRAZIL DEGRADATION PROFILE REGULATIONS Economic development in BRIC countries (Brazil, Russia, India, and China) and the ensuing growth of individual wealth has resulted in the rapid growth of the pharmaceutical industry within these countries. Such growth brings with it challenges, especially for the regulatory agencies within the countries concerned as they seek to ensure the safety and efficacy of medicines in a rapidly expanding market. The following article highlights the response of one authority, the Brazilian Authority (ANVISA, Agência Nacional de Vigilância Sanitária) to a specific challenge: that of ensuring the safety and efficacy of medicines through an assessment of stability. Late 2013, Brazilian regulations around a forced degradation testing/degradation profile were introduced. The Brazilian Health Authority (ANVISA) issued legislation, RDC53,9 and a corresponding technical guide that outlined specific requirements for forced degradation studies, including stability indicating method development. The primary purpose of the regulations was to seek to define effective identification and qualification limits in order to establish criteria for ensuring the proper basis for defining the critical quality attributes for the active and associated drug product, i.e., the key degradants. In doing so, this would then form the basis on which it is then possible to ensure that analytical methods used to monitor stability were truly “stability indicating”, i.e., capable of detecting changes in the quality of the active and/or drug product over the intended shelf life of the medicine. Stability-indicating methods are typically developed through the conduct of forced degradation studies; these identifying key degradative pathways, once identified, and then the control of the associated degradants can be ensured when the associated analytical method is developed and validated. The regulations were intended to be implemented in December 2015. Since there are no available guidances on what constitutes acceptable forced degradation studies, ANVISA endeavored to provide their expectations; however, some specific aspects of these requirements were a concern from an industry perspective. These concerns relate to areas such as: 1. Requirements to apply the regulations to both new products and existing products. 2. The extent of the degradation prescribed. The legislation advised the need for degradation of up to 20%. At such levels, very real concerns exist of the fact that rather than simply addressing primary degradative pathways that at such levels of degradation secondary degradative pathways, not relevant to product storage conditions, are seen, i.e., degradants of degradants and even reactions between degradants. 3. The scopesuch studies potentially apply to not only the active but also the formulated product and placebo. In the context of formulated product and placebo, the value of studies conducted for example at the extremes of pH were difficult to understand given the fact that there was no likelihood of exposure to such conditions under product storage, challenging the relevance of such studies. 4. The need to conduct forced degradation studies when new API or product suppliers are introduced. Degradative pathways are associated with the intrinsic nature of the molecule itself. While changes to supplier could affect the stability of the product, it is extremely unlikely that such changes can result in new degradative pathways, merely the level and extent of degradation. B




product through indication of product stability. Analytical methods are validated, like manufacturing processes, but what if the operational ranges could be established during method validation when demonstrating fitness for purpose? Would it be possible to drive method improvement, especially post validation in the same way that the concept of continuous improvement is a key driver for manufacturing processes? Despite this attractive “value proposition”, there is to date little evidence that as an industry this is being practically realized. The result is that many methods used in a QC environment lag well behind technical developments in the analytical field, often leading to the use of suboptimal procedures that impact adversely on the efficiency within the laboratory. The challenge is to create an environment whereby such changes can be made efficiently and effectively. One approach is to apply the principles of ICH Q8−10; delivering a science and risk based approach to the development and validation of analytical methods, establishing a method operable design region (MODR) within which changes can be made. Such a framework is illustrated in Figure 1.

It therefore being the view of industry that the conduct of stability studies rather than forced degradation studies were more appropriate. ANVISA responded to Industry concerns and agreed to a cross industry workshop in October 2014. The aim was to discuss with ANVISA and to seek revision of some features of the legislation. The workshop resulted in a temporary postponement of the implementation of the legislation. In December 2015, ANVISA issued new legislation to supersede the previous regulations and, soon after, an accompanying technical guide. The 2015 version of the regulation is a significant improvement over the 2013 version and reflects many of the positive outcomes of the industry/agency workshop. Despite this, several areas of concern and uncertainty remain. A specific challenge is the status of existing products. This is currently driving pharmaceutical companies to conduct a “gap analysis” preparing justifications for a number of scenarios where we are likely to have gaps opposite the Brazilian regulations. Potential areas include 1. Less than 10% forced degradation applied in the conduct of original studies; 2. No placebo or drug product forced degradation studies performed; 3. Lack of mass balance; 4. No repeated forced degradation studies with multiple suppliers of API; 5. No transition metal force degradation study. For new MAAs/new strengths/new dosage forms, the regulations are already in effect as of December 23, 2015. For marketed products, the enforcement timelines are dependent on the therapeutic classification of the product and range from December 2017 to December 2020. This means that, by the enforcement date stated, bespoke degradation product reports need to be submitted to ANVISA for their evaluation and determination of adequacy. Some organizations are currently running a pilot project to ascertain ANVISA’s receptiveness to historical data and justifications for any gaps opposite the Brazilian regulations, ahead of the 2017 implementation date. ANVISA has also recently published a Questions & Answers document10 that may be helpful to organizations; see Questions and Answers RDC53 Guideline. In addition, many Pharma companies are in consultation, sharing strategies and experiences with ANVISA’s forced degradation requirements for both initial marketing applications and post approval submissions. Despite this, the current position is an uncertain one, especially as it pertains to established products. Will ANVISA accept historical data, despite the potential gaps? Or will pharmaceutical companies be required to conduct a battery of repeat studies to address existing portfolios? Time will tell, but for all organizations, there is a need for awareness of this challenge.

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ENHANCED ANALYTICAL METHOD CONTROL STRATEGY CONCEPT The benefits of quality by design (QbD) concepts related to both product (ICH Q8)11 and drug substance (ICH Q11)12 are well-established, particularly in regards to the potential to use knowledge to affect process changes without major regulatory hurdles, i.e., revalidation/regulatory filing, etc. Less wellestablished, but potentially of significant value, is the application of the same concepts to analytical methods. Analytical methods play an obvious key role in establishing the quality of final product as they establish conformance with product acceptance criteria (i.e., specifications) and indicate the integrity of the

Figure 1.

This starts with a definition of the effective requirements of the method, an analytical target profile (ATP), this taking the specific form of acceptance criteria for method performance. Such a process can be used to not only establish effective analytical methods but is also supportive of continual improvement, specifically within the MODR. However, such a concept is potentially limited in that the expectation is that changes are restricted to within the MODR. C




The reality is that many organizations opted for early adoption of ICH M7, managing the transition from earlier guidance, specifically the EMA guideline relatively seamlessly. Areas envisaged as being potential areas of concern such as use of multiple systems for structure−activity relationship (SAR) analysis (ICH M7 predicating the need to use both rule based and statistical methods) seem to invoke little in the way of issues on practical implementation. Perhaps the most significant change associated with the introduction of ICH M7 and the end of the implementation period is the formal introduction of guidance addressing mutagenic impurities in Japan. Unlike other ICH guidelines, ICH M7 applies to both clinical phase and post approval. This presents a specific challenge in Japan as clinical trials are managed through submission of an Investigators Brochure (IB). The IB does not have a section where CMC information can be presented; hence the challenge was how information necessary to show compliance to ICH M7 should be presented during the clinical phase. This has led to the Japanese Regulatory Authority (PMDA) publishing a specific requirement for ICH M7 appendix14,15 to sit with the Clinical Trail application. There has again been no reports of significant issues since its introduction in January. Overall, therefore there are encouraging signs that guidance relating to mutagenic impurities and business practices are reaching a state of maturity.

Such restrictions may inhibit continuous improvement. A prime example is change of stationary phase or a change from HPLC to UPLC; both fall outside of the original MODR. Historically such changes have been notoriously difficult and often therefore avoided unless imperative. A recent publication13 examined this, presenting a method enhancement concept that would allow minor changes outside of the MODR. This is based on the realization that performance of any analytical method is based on the conduct of a system suitability test (SST); such tests ensure the method’s fitness for purpose. Karlsson et al. stated that changes outside of the initial MODR may be possible provided that the method principle is unchanged, failure modes are the same, and the SST is capable of detecting these, both for the original method and for any method changes that fall outside of the original MODR. Put simplychanges can be made provided the SST criteria are passed. A change from HPLC to UPLC was used to illustrate this. Revalidation of the method is still required, but critically such changes do not require regulatory interaction but can be managed through internal quality systems.

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PROCESS ACCEPTABLE RANGES (PARS) AND NORMAL OPERATING RANGES (NORS) A key aspect of any regulatory submission is the description of your manufacturing process. Unfortunately, the requirements in terms of what to include and how to document process descriptions are areas of some ambiguity, with differing regional requirements. Questions such as, do you record process acceptable ranges (PARs)? What about set points? How do either relate to normal operating ranges (NORs) and also the relationship to and need (or otherwise) to define a design space for your process (DSp)? All of these questions can be and are posed by authorities in response to submissions. Other issues including where such information should be stored in the dossier also remain unclear. Another challenge is how to relate these to change control and the level of change control, in particular the mechanism for change and requirements in terms of regulatory interactions. Uncertainties around this threaten to result in regional variance. One area in particular where this is already seen as an issue is around normal operating ranges (NORs). Requests to provide details of NORs it seems are becoming an increasingly prevalent questions from reviewers, in particular in Europe, and the absence of such information is being classified as a deficiency. The term NOR seems to have risen to prominence despite the fact that this is not an ICH term. This is an ongoing topic of discussion between industry and regulators at a regional level. Many though would argue that this needs to be discussed at an ICH level. As it stands, as an industry, this area may well remain one of uncertainty and concern until further guidance is provided, discussed, and agreed.

Andrew Teasdale*

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AstraZeneca, Macclesfield SK10 2NA, United Kingdom

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

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REFERENCES

(1) 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). (2) 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). (3) Implementation of Guidelines for Elemental Impurities. http:// www.ich.org/products/guidelines/quality/article/quality-guidelines. html. (4) FDA Elemental Impurities in Drug Products Draft Guidance for Industry. 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 / UCM509432.pdf (June 2016). (5) Implementation strategy of ICH Q3D guideline. http://www. ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/ 2016/07/WC500210121.pdf (July 1, 2016). (6) Q3D Notice: Health Canada recommendations for implementation of the ICH Harmonised Guideline for Elemental Impurities (Q3D) for new and marketed products. http://hc-sc.gc.ca/dhp-mps/ prodpharma/applic-demande/guide-ld/ich/qual/q3d-rec-eng.php (July 22, 2016). (7) Stimuli to the Revision ProcessFuture of Element-Specific Chapters in the USP−NF. http://ipecamericas.org/system/files/ GEN_STIMULI_424_-stimuli1.pdf (July 6, 2016). (8) Implementation of ICH Q3D in the Certification Procedure. https://www.edqm.eu/sites/default/files/implementation_of_ich_ q3d_in_the_certification_procedure_august_2016.pdf (Aug 2016). (9) ANVISA Brazil RDC 53 (2015) Regulation on report, identification and qualification of degradation products. http:// portal.anvisa.gov.br/documents/33836/418522/

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MUTAGENIC IMPURITIES ICH M7 Many will have no doubt seen joke wall plaques stating that “on this spot in, e.g., 1848 on January 1st, nothing happened.” ICH M71 shares many similarities with this. On January first 2016 the implementation period for ICH M7 ended. This meaning the guideline became fully implemented across all ICH regions. Reflecting on this the impact has been minimal. This is not to say that it has been ineffective, far from it; the point being made is that this has been highly effective with little or no negative associated impact, certainly in terms of confusion and uncertainty. D




Perguntas+e+Respostas+-+RDC+53+2015+e+Guia+04+2015/ 6b3dec42-546c-4953-943f-4047b8b50f87 (July 1, 2016). (10) Questions and Answers of the Resolution RDC 53/2015 and Guide no. 04/2015 http://portal.anvisa.gov.br/documents/33836/ 418522/Perguntas+e+Respostas++RDC+53+2015+e+Guia+04+2015/6b3dec42-546c-4953-943f4047b8b50f87 (July 1, 2016). (11) ICH Q8 Pharmaceutical Development. http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_ R1/Step4/Q8_R2_Guideline.pdf. (12) ICH Q11 - Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Q11. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/ Guidelines/Quality/Q11/Q11_Step_4.pdf (Aug 2009). (13) Åsberg, D.; Nilsson, M.; Karlsson, A.; et al. A quality control method enhancement conceptContinual Improvement of regulatory approved QC methods. J. Pharm. Biomed. Anal. 2016, 129, 273−281. (14) Guideline for Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk (PSEHB/ELD Notification No. 1110/3, Nov 10, 2015). (15) Revision of the Q&A on plan notifications and conduct of clinical trials of medicinal products (PFSB/ELD Notice, Dec 14, 2015).

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