Regulatory Highlights - American Chemical Society

Regulatory Highlights Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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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 because of either ongoing evolution of new guidance or, in the case of one of the specific areas examined in detail in this review, Question and Answer documents drafted with the intent, at least, to improve the applicability and understanding of current guidelines. 2017 has seen the finalization of one such Q&A document, that being the Q&A document relating to ICH Q11,1 which deals specifically with the vexed issue of regulatory starting materials and was examined in some detail in the earlier review from 2017;2 a brief commentary on its final status is included below. The other, relating to Normal Operating ranges (NORS) and Process Acceptable ranges (PARS),3 is examined in more detail below. As well as examining these two Q&A documents this article looks at the issue of mutagenic impurities, specifically what next after the issuance of the revised guideline.4 It also briefly looks at another hot topic − Extractables and Leachables (E&Ls), long felt the specific concern of devices, e.g. inhalation devices and of parenterals; more and more this has become an area of importance from a processing point of view, particularly for Biologics. Other topics considered are setting specifications, the balance between preclinical cover (qualification), and process capability and the somewhat esoteric issue of iron oxides. The latter provides an example of the fact that pharmaceuticals are not insulated and separate from other industries and hence awareness across areas such as food is key.

in draft form in 2015, this has been revised based on feedback and consultation with industry. The document focuses on five questions, which are summarized below along with a reflection on the answer provided and its implications.

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WHAT IS AN NOR AND HOW SHOULD NORs BE PRESENTED IN THE MARKETING AUTHORIZATION DOSSIER? Requests to provide details of NORs have become an increasingly prevalent request from reviewers, predominantly in Europe, the absence of such information being classified as a deficiency. It was noted that the term NOR seemed to have risen to prominence even though this it is not an ICH term. Interestingly the answer draws specific attention to this and concedes this is not a formal ICH term. The framing of this question is interesting and already indicates the EMA thinking by posing the questionhow should NORs be presented? the subsequent answer makes very clear NORs should be presented. Is this an issue? Arguably not as many organizations have presented NORs within section S2.2 without challenge. But it makes abundantly clear that this is unlikely to be optional. So what is an NOR? The document provides the following definition: An NOR describes a region around the target operating conditions that contain common operational variability (variability that cannot always be precisely controlled to a single and specific value). This is consistent with the thinking of many and should allow the definition of a range which reflects equipment capability. For example, a range of 35 °C ± 5 C° may reasonably be considered an NOR given the variability of the temperature control and calibration systems. Overall while effectively introducing a “new” term this is an established concept already widely used and thus this is not considered as a significant concern.

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ICH Q11 Q AND A DOCUMENT The key aspects of this were examined in depth in the previous review article;2 since that point, the document has been finalized, with little change. The finalization of the document essentially closes the door on the debate relating to quality agreements for preregistered stages. For many this is a concern, as it seems to do little to differentiate from those with robust agreements in place and those organisations who simply purchase to specification. One important addition to the final document is an appendix within which is a decision tree. This is intended to be a graphical representation of the selection process and augments the text within the document. There are two parts: part I focuses on chemical evaluation based on structure (Figure 1), and part II, on which steps impact the impurity profile of the drug substance (Figure 2).

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WHAT IS A PROVEN ACCEPTABLE RANGE (PAR) AND HOW SHOULD PARs BE JUSTIFIED AND PRESENTED IN THE MARKETING AUTHORIZATION DOSSIER? Again a specific definition is provided: The PAR is defined as a characterized range of a process parameter for which operation within this range, while keeping other parameters within set points or NORs, will result in producing a material meeting relevant quality criteria (ICH Q8 R2).5 A key phrase within this seems to be the statement that other parameters must be kept constant. Is this ever the reality, and what is constant? Later in the document in the answer pertaining to DSp, there is effective recognition that some form of interrelationship will generally exist. What is perhaps more important is establishing the criticality of this relationship not that one simply exists. Later within the answer it is also stated

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MA QUESTION AND ANSWERS: IMPROVING THE UNDERSTANDING OF NORMAL OPERATING RANGES (NORs), PROCESS ACCEPTABLE RANGES (PARs), DESIGN SPACE (DSp), AND NORMAL VARIABILITY OF PROCESS PARAMETERS In June of this year, the EMA issued a revision of their earlier Q&A document focused on NORs, PARs, and DSp.3 First issued © XXXX American Chemical Society

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DOI: 10.1021/acs.oprd.7b00372 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development


Figure 1. ICH Q11 Decision tree (reproduced from ICH Q11 Q&A document1): Part 1.

above statement relating to interactions it may be thought that an applicant will inexorably be driven to submit a DSp even though the Q&A document in question 5 makes the statement that a DSp is optional. It is critical to understand more about when an interaction is significant, how is this defined? One can imagine this to mean no impact of the quality of the drug substance. If there are no significant interactions across the ranges proposed, i.e. no impact on drug substance quality is demonstrated through multivariate experiments, then surely a design space is not required. The other questions relate to postapproval changes to an approved DSp and process flexibility; both provide useful, if not total, clarity. In the case of postapproval changes, the relationship to ICH Q124 will still need to be clarified to avoid conflicting viewpoints. Another interesting point relating to question 5 is the following statement A flexible manufacturing process (ranges) can be registered when justified, or alternatively fixed process parameters. However, when a flexible manufacturing process is requested (i.e., ranges of process parameters that are wider than what would be accepted as an NOR; ranges of input material attributes that can affect the quality of the process output), then the process should be established within the framework of a DSp This again reflects concerns already expressed in terms of what is an acceptable NOR and also the apparently almost unavoidable need to define a DSp. Like all guidance the devil is in the detail, and this while providing a very useful perspective on the subject will need further very careful consideration.

that where an interaction exists between different parameters, the parameters should be included in a Design Space. One might be forgiven for believing that this may penalize the more diligent applicant who seeks to properly study possible interactions. Missing at present is clarity around what happens if you explore multiple parameters and find no interactions or more likely no “significant” interactions. In such circumstances where the interactions have no impact, it should be possible to justify multiple ranges (or at least a range wider than the NOR). There is also a need to understand more about when an interaction is significant. If there are no interactions across the ranges proposed and no impact on drug substance quality is demonstrated with multivariate experiments, then surely we do not need a design spaceit adds no value and makes no sense.

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WHAT IS A DESIGN SPACE (DSp) AND HOW SHOULD DESIGN SPACES BE JUSTIFIED AND PRESENTED IN THE MARKETING AUTHORIZATION DOSSIER? Overall this seems helpful, including the definition provided: The design space is defined by the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. It goes on to make clear that changes within a design space are not subject to formal change and can be made within an organization’s own quality system. It however also states that critical processes should always be part of a formal DSp even if controlled. Combined with the B




Figure 2. ICH Q11 Decision tree (reproduced from ICH Q11 Q&A document1): Part 2.

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ICH M7 ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK In May of this year the first revision of ICH M7 (R1)3 was published. This update reflected the completion of the longawaited addendum table. The purpose of this table is to provide specific agreed limits for a series of some 16 common reagents, with the primary focus being on mutagenic carcinogens. In each case outlining the permitted limit as well as the method of calculation. Another important aspect of the addendum is that it also sets out a series of criteria aimed at establishing a common set of principles upon which other compound specific limits may be established. These include the following: Studies. • Number of animals, ideally >50 animals per dose per sex, • Number of doses studied, >3 dose levels, • Concurrent controls, • 7-day dosing • Lifetime duration. It also examines other issues including selection of tumor type and site. Data associated with a particular chemical are often complex. In the case of carcinogenicity studies this may well involve multiple studies, often of varying quality, and also multiple

tumor types and sites. Another factor is human relevance. How, for example, to assess the formation of tumors within a rodent fore-stomach when humans obviously do not have a fore-stomach? As already stated this focuses, in line with the guideline itself, on mutagenic carcinogens, but what about other common reagents that are not mutagenic, how should they be assessed? During the initial development of the addendum a significant number of other reagents were assessed. Many of these had over time become victims of extrapolated suspicion, considered mutagenic based often on little more than supposition. Examples include mesityl oxide (self-condensation by product of acetone) and acetamide. Such reagents often draw requests from regulatory authorities for control to threshold of toxicological concern (TTC) levels. Examination of the associated safety data has allowed for the correct classification of such reagents, but at present there is a lack of visibility of this given that the specific focus of the ICH M7 addendum meant their exclusion at this stage from the addendum. While the addendum provides a clear framework upon which risk assessments can be determined, there is still a desire to do this as consistently as possible, and hence, the industry group initially responsible for the development of the addendum plans to now publish risk assessments and proposed limits for some 25+ additional reagents. Another important reason for doing so is that the “extrapolated suspicion” continues to drive the development of highly specific, C




highly sensitive methods for reagents such as formaldehyde,6 even though formaldehyde exposure occurs in air, water, and food, and formaldehyde is a byproduct of endogenous metabolism. It is a common endogenous component of biological materials and is a naturally occurring component of many foods such as meat, dairy products, fruit, and vegetables. Levels of daily exposure to formaldehyde via the dietary route have been estimated in the range 1.5−14 mg/day.7 Formaldehyde is also a product of normal human metabolism and is essential for the biosynthesis of certain amino acids. The human body produces and uses approximately 50 g of formaldehyde a day which is rapidly metabolized and cleared from blood.7 Control to ppm levels based on the TTC makes no sense.

requirements. The uncertainty creates undue delays in the review and approval of marketing applications and, ultimately, delays delivery of safe medicines to patients. An ICH harmonized guideline addressing qualification thresholds for E&L could remove much of the uncertainty, enhancing drug product safety and quality. One illustration of the current problems relates to the question as to whether or not a leachable study is always required, even if the extractives study demonstrates no materials of toxicological concern are present within the material in question. A recent presentation given by a representative of the FDA highlighted a series of examples where it was clearly demonstrated that the risk had not been adequately assessed through the extractive study. The question is whether this is a general issue? or a specific flaw in the design of the extractive studies examined? Whatever the reality, one consequence of this is a rise in postapproval commitments being made requesting conduct of long-term leachable studies aligned to long-term product stability studies. What is missing is a clear framework defining when/where this is appropriate. The result of this at presence is real uncertainty, in one instance acceptance of risk assessments based on extractive studies, perhaps combined with a simulation study, followed by rejection and commitment to conduct a leachable study for the next product. This uncertainty applies to both product and manufacturing processes.

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EXTRACTABLES AND LEACHABLES: THE REGULATORY EQUIVALENT OF A MAZE Every year around this time proposals are made in terms of potential ICH topics, with each topic vying to make their compelling case. There are major advantages to having an ICH guideline in place for a specific area. This is especially true of impurities, where an effective framework of ICH guidelines has been established for management of impurities both product and process related. These include general impurity management, ICH Q3A8 and ICH Q3B,9 updated guidelines on residual solvents, ICH Q3C,10 and new guidelines covering elemental impurities, ICH Q3D,11 and mutagenic impurities, ICH M7.3 Mindful of this, it is perhaps timely to reflect on the one area pertaining to impurities for which no ICH guidance currently exists, a potential major source of impurities: extractable and leachable compounds (E&Ls). E&Ls are derived from materials, including the container closure system and the drug manufacturing process. Leachables may ultimately have a significant impact on both the quality and safety of a drug substance and associated drug product, and hence, their evaluation and ultimate control to appropriate levels is required. Some guidelines on packaging exist, e.g., European Medicines Agency (EMA),12 US Food and Drug Administration (FDA) guidance,13 and some groups have produced recommendations for specific dosage forms, e.g., Product Quality Research Institute (PQRI).14 In addition, other recommendations exist as pharmacopeial standards. Indeed the United States Pharmacopoeia (USP) is revising some packaging-related chapters ⟨381⟩,15 ⟨661⟩16 as well as creating several new ones, including a draft chapter ⟨665⟩17 relating to process materials, the latter emphasizing that the risk posed by E&Ls also needs to be actively considered in the context of manufacturing procedures as well as container closure systems. The European Pharmacopoeia also contains a chapter on quality of packaging materials.18 Separately, reference is made to E&Ls within ICH M73 (specifically the threshold of toxicological concern (TTC) potentially used to define a threshold for leachables) and ICH Q3D11 (elemental impurities from processing equipment or container/ closure systems), as well as ISO standards (e.g., ISO 10993 series). The issue is that the variety of documents either directly or indirectly related to E&L issues are limited to specific regions and/or specific drug or manufacturing applications. No harmonized guidance and international agreement on the reporting, identification, and qualification thresholds for E&Ls exists, which would apply across multiple dose forms and align to the principles of a science led risk based approach and quality by design. This gap generates high uncertainty with a lack of clarity and alignment in how best to meet regulatory

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SETTING APPROPRIATE SPECIFICATION LIMITS The process of establishing an appropriate control strategy (specification) for Impurities can, as many will no doubt recognize, be challenging. Breakthrough medicines such sa Tagrisso present particular challenges, as there is often only limited batch data upon which to base control. So what if any guidance exists to help in this process? ICH Q3A9 includes the following statement: Acceptance criteria should be set no higher than the level that can be justified by safety data, and should be consistent with the level achievable by the manufacturing process and the analytical capability. Where there is no safety concern, impurity acceptance criteria should be based on data generated on batches of the new drug substance manufactured by the proposed commercial process, allowing sufficient latitude to deal with normal manufacturing and analytical variation and the stability characteristics of the new drug substance. Is this helpful? In many ways, sadly not. It does recognize the key relationship between levels of impurities observed in relevant batches and the level of the impurities qualified in preclinical studies, that the primary requirement is that limits should be no higher than those supported by safety data. However, it contentiously states that levels should be consistent with manufacturing data, i.e. levels observed within material produced using the commercial process. Within this subsection it is stated that this can take into consideration variation of both the manufacturing process and analytical control methods. Despite this caveat, this “requirement” is often a point of tension, leading to approaches to setting limits based on, for example, mean ±3 SD. It is critical to first understand the intermediate precision of the analytical method before attempting to establish any limits based on process variability, as much of the variability may be related to the method rather than the actual process. Even then, and particularly in cases where there is limited batch data, setting overly restrictive presentations can severely impact the viability of the commercial process. D



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It can lead to a considerable tightening of limits that serves to achieve little in terms of patient safety and yet can lead to substantive numbers of failed batches that provides no additional assurance to patients. Ultimately it is vitally important that a sensible balance between safety and quality factors is achieved when establishing an impurity specification for the active. Outlined are expectations a patient should have of any medicine:

REFERENCES

(1) ICH Q11 Guideline: Development and Manufacture of Drug Substances (Chemical Entities and Biotechnological/Biological Entities) Questions and Answers, Version: 23 August 2017. (2) Teasdale, A. Regulatory Highlights. Org. Process Res. Dev. 2017, 21, 1209−121. (3) Questions and answers: Improving the understanding of NORs, PARs, DSp and normal variability of process parameters, EMA/ CHMP/CVMP/QWP/354895/2017. (4) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk M7(R1) March 2017 http://www.ich.org/fileadmin/Public_Web_ Site/ICH_Products/Guidelines/Multidisciplinary/M7/M7_R1_ Addendum_Step_4_31Mar2017.pdf. (5) ICH Q8 Pharmaceutical Development http://www.ich.org/ fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_ R1/Step4/Q8_R2_Guideline.pdf. (6) ICH Q12 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. (7) Teasdale, A.; Elder, D. Analytical Control Strategies for Mutagenic Impurities: Current Challenges and Future Opportunities? TrAC, Trends Anal. Chem. DOI: 201710.1016/j.trac.2017.10.027. (8) Dhareshwar, S. S.; Stella, V. J. Your prodrug releases formaldehyde: Should you be concerned? J. Pharm. Sci. 2008, 97 (10), 4184−93. (9) ICH Q3A Impurities in New Drug Substances http://www.ich. org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/ Q3A_R2/Step4/Q3A_R2__Guideline.pdf. (10) ICH Q3B Impurities in New Drug Products http://www.ich. org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/ Q3B_R2/Step4/Q3B_R2__Guideline.pdf. (11) ICH Q3D Guideline for Elemental Impurities http://www.ich. org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/ Q3D/Q3D_Step_4.pdf. (12) Guideline on Plastic Immediate Packaging Materials http:// www.ema.europa.eu/docs/en_GB/document_library/Scientific_ guideline/2009/09/WC500003448.pdf. (13) Container Closure Systems for Packaging Human Drugs and Biologics https://www.fda.gov/downloads/drugs/guidances/ ucm070551.pdf. (14) Norwood, D. et al. Best Practices for Extractables and Leachables in Orally Inhaled and Nasal Drug Products: An Overview of the PQRI Recommendations, Pharm. Res., Vol. 25, 4, April 2008.72710.1007/s11095-007-9521-z (15) https://www.usp.org/sites/default/files/usp/document/ workshops/381_elastomeric_components_used_in_injectable_ pharmaceutical_packaging_delivery_systemspf_43_3.pdf. (16) http://www.uspnf.com/sites/default/files/usp_pdf/EN/ USPNF/revisions/661_rb_notice.pdf. (17) USP ⟨665⟩, ⟨1665⟩ USP Draft General Chapters on Plastic Components and Systems Used in the Manufacturing of Drug Products. (18) Guideline on the Pharmaceutical Quality of Inhalation and Nasal Products http://www.ema.europa.eu/docs/en_GB/document_ library/Scientific_guideline/2009/09/WC500003568.pdf.

• Safe and Efficacious • Delivers the performance defined on the label • Performs consistently over the product shelf life • Is manufactured to standards that ensure quality • Available when required. Several of the points made here are germane to this discussion. These requirements cannot be achieved based on safety qualification alone, as there are often examples where intrinsic safety would permit levels of an impurity at several %. At such levels, there could be a clear, negative impact on the quality of the medicine, effects ranging from coloration due to an impurity to impact on product performance and hence efficacy. High levels of impurities with different physicochemical properties could also affect critical quality attributes of the API and ultimately the drug product. These and other factors need to be considered during evaluation of the final specification (control strategy). What is ultimately needed is a balance, a balance based on a clear understanding of not only the safety profile of an impurity but also the effect the impurity/impurities have on quality and performance.

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IRON OXIDES Every once in a while, the pharmaceutical industry is confronted by a potential regulatory issue that originates from another area. One such issue, with the potential for significant impact on the industry, relates to iron oxides. Iron oxides are widely used in solid oral dosage forms as colorants, used to distinguish between different doses (red, 5 mg; blue, 10 mg; etc.). Iron oxides are also used as food additives and hence governed by regulations pertaining to food. The European Food Standards Agency (EFSA), as required by regulation, have asked for additional safety data relating to various iron oxides; without this there is a real threat they will be delisted. Why does this matter to the pharmaceutical industry? In the absence of specific pharmacopoeial standards in Europe most products are registered using the food safety standard E172. Delisting could therefore require reregistering products or worse still replacement of iron oxides and reformulation, which is unfeasible given the impact and cost. This is a reminder that organizations need to be constantly vigilant to risks/issues associated with other regulated industries and that the pharmaceutical industry does not exist in its own bubble. Andrew Teasdale* AstraZeneca, Macclesfield SK10 2NA, United Kingdom

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The author declares no competing financial interest. E


Regulatory Highlights - American Chemical Society

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