Genotoxic Impurities

Strategies for Identification and Control

Andrew Teasdale

• Publisher: Wiley
• Year: 2011
• Print ISBN:
  9780470499191
• eBook ISBN:
  9780470934753
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

This book examines genotoxic impurities and their impact on the pharmaceutical industry. Specific sections examine this from both a toxicological and analytical perspective. Within these sections, the book defines appropriate strategies to both assess and ultimately control genotoxic impurities, thus aiding the reader to develop effective control measures. An opening section covers the development of guidelines and the threshold of toxicological concern (TTC) and is followed by a section on safety aspects, including safety tests in vivo and vitro, and data interpretation. The second section addresses the risk posed by genotoxic impurities from outside sources and from mutagens within DNA. In the final section, the book deals with the quality perspective of genotoxic impurities focused on two critical aspects, the first being the analysis and the second how to practically evaluate the impurities.

Part 1: DEVELOPMENT OF GENOTOXIC IMPURITIES GUIDELINES AND THE THRESHOLD OF TOXICOLOGICAL CONCERN CONCEPT

CHAPTER 1

HISTORICAL OVERVIEW OF THE DEVELOPMENT OF GENOTOXIC IMPURITIES GUIDELINES AND THEIR IMPACT

Ron Ogilvie and Andrew Teasdale

1.1 INTRODUCTION

To enable a thorough understanding of the current regulatory position relating to genotoxic impurities (GIs), it is first important to consider the history behind the events that led up to this point and their context. Like many events, the exact point at which concerns relating to the potential presence of GIs in pharmaceuticals first emerged is difficult to determine. At the time that ICH Q3 guidelines were constructed, only passing reference was made to compounds of “unusual toxicity” and the potential need for limits tighter than those defined by the guidelines. Although the term “genotoxic” is not specifically mentioned, many have taken this to refer to impurities that are genotoxic.

The first public evidence of specific regulatory concern relating to GIs was an article published within PharmEuropa in 2000,¹ which drew attention to the potential risk of formation of sulfonate esters as a result of a combination of sulfonic acids in alcoholic solution as part of a salt formation process. At this point, this publication was merely a call for “further information”; it being part of an attempt to better understand the extent of any risk involved. The publication is now seen as a landmark event, signaling a new era of focus on genotoxic impurity risk assessment and control.

In 2002, a position paper relating to GIs was published by the Committee for Proprietary Medicinal Products (CPMP^*) on behalf of the European Medicines Evaluation Agency (EMEA) Safety Working Party (SWP) for comments in December 2002.² Outlined below is an evaluation of this first draft position paper, and an assessment of its later significance in the context of the finalized EU guideline.

1.2 CPMP—POSITION PAPER ON THE LIMITS OF GIs—2002

1.2.1 Scope/Introduction

Within the introduction to the position paper, it was made clear that the need for such guidance was due to the fact that control over levels of genotoxic residues was not adequately addressed through existing ICH guidance.

The format of the position paper was similar to that of the final guideline, it being set out in a series of sections, which addressed the issue of GIs from both a toxicological and quality perspective. The key points from those sections are described below.

1.2.2 Toxicological Background

Within the position paper, genotoxic compounds were split into two categories:

1. Genotoxic compounds, for which sufficient evidence existed to support a thresholded mechanism.

(A thresholded mechanism is one for which a clearly discernable limit exists, below which no significant toxicological effect is observed. Several examples were given within the paper of mechanisms of genotoxicity for which a thresholded mechanism may exist, including, for example, topoisomerase inhibition, inhibition of DNA synthesis, and overload of defense mechanisms.)

2. Genotoxic compounds without sufficient evidence for a thresholded mechanism.

The position paper stated that such thresholds were either unlikely to exist, or would be difficult to prove for DNA-reactive chemicals.

This categorization of GIs, on the basis of a mechanistic understanding of toxicological action, has remained in place in the finalized guideline, and the belief that DNA reactive compounds have no threshold remains widely held.

1.2.3 Pharmaceutical (Quality) Assessment

The assumption that some “in vivo” genotoxins can damage DNA at any exposure level, and therefore that any level can represent a risk, led to a conservative stance being proposed in terms of quality assessment. It was stipulated that a justification must be provided in relation to the manufacturing process that clearly explained why, for that specific process, the presence of GIs was “unavoidable.” The position paper also stated that wherever possible, alternative routes that avoid genotoxic residues should be used, and that an applicant was obliged to update the manufacturing process should a safer alternative process be available. If, after these steps had been taken, a risk remained, it was suggested that residual levels should be reduced to the level that was “as low as technically feasible.”

1.2.4 Toxicological Assessment

The position paper made it clear that only after the use of a genotoxic reagent had been justified and every effort had been made to reduce levels should a toxicological assessment be made. Different options were provided by which risk assessments could be carried out, these being through either:

1. Quantitative risk assessments: This being essentially based on the linear extrapolation of the dose-response curve from rodent cancer bioassays from a high dose to low dose region. In this case, the low dose considered acceptable being one associated with a 1 in 100,000 risk. (One excess cancer death per 100,000 people exposed to the agent concerned over a lifetime [70 years].)

2. Uncertainty factor approach: This approach, which involves the determination of a no effect level (NOEL) from preclinical studies, along with the subsequent application of uncertainty factors, is only appropriate where a threshold-mediated mechanism has been established. Such an approach is consistent with that described within ICH Q3C—residual solvents.

The position paper in this format was a cause of significant concern. The main concern perhaps related to the safety testing requirements. For many reagents, the only safety data available often relates to limited in vitro studies, for example an Ames test. Such data are generally considered unsuitable for establishing a NOEL or for performing a quantitative risk assessment. Thus, to generate data to support the determination of a NOEL, or to carry out a quantitative risk assessment as prescribed in the concept paper would require the conduct of further significant in vivo studies. This could have resulted in a significant increase in animal studies. Thus, ultimately, alternatives to this were sought. An alternative approach, previously adopted within other spheres, such as the food arena, was the concept of a “virtual safe dose.” This had been developed to deal with low-level contaminants within food. This concept itself was based on the principal of establishing a level at which any new impurity, even it was subsequently shown to be carcinogenic, would not constitute a significant risk. This paved the way ultimately for the employment within subsequent versions of the guideline of the threshold of toxicological concern (TTC for short) concept.

1.3 GUIDELINE ON THE LIMITS OF GIs—DRAFT, JUNE 2004

Significant revisions were made to the original position paper before its rerelease as a draft guideline in June 2004.³ The revised guideline struck a more balanced note. For example, the “as low as technically feasible” terminology used previously was replaced with the ALARP (“as low as reasonably practical”) principle, a small but in many ways significant shift in emphasis. Another important change was the removal of the requirement to introduce an alternative route/process should a safer one be identified. The need to provide justification of the route selected did, however, remain.

The most significant change was the tacit acceptance that the concept of elimination of risk in its entirety (zero risk) was going to be unachievable and therefore an alternative to this principle was required. This led to the adoption of the concept of an acceptable risk level. This acceptable risk was defined as a level sufficiently low that, even if the compound in question was ultimately shown to be carcinogenic, it would pose a negligible risk to human health. This took the form of the TTC. This concept obviates the need to generate extensive in vivo data to establish limits.

The most critical aspect of the TTC concept (the origin of its development and its derivation are described in detail in Chapter 2) is the derivation of a single numerical limit of 1.5 µg/day based on a lifetime (70 years) exposure resulting in a worst-case excess cancer risk of 1 in 100,000. Within other areas (e.g. food), a 1 in 1,000,000 figure had been applied; this was increased by a factor of ten in relation to pharmaceuticals to recognize the benefit derived from pharmaceutical treatment. This concept allows an adequate basis of safety and control limits to be established in the absence of any in vivo data.

The guideline, having established this TTC limit, also stated that under certain circumstances, higher limits could be established. Such circumstances included short-term exposure, treatment of a life-threatening condition for which no safer alternatives existed, where life-expectancy was less than 5 years or where the impurity was a known substance for which exposure from other sources (e.g. food) was significantly greater than that associated with exposure from pharmaceuticals. Notably, no fixed alternative limits were provided that could be applied in such instances, perhaps, as there are a myriad of potential circumstances where such considerations could apply, and thus it was considered that this topic was best left to the assessment of a specific product and a specific risk benefit analysis to agree acceptable limits. It is reasonable that product-specific risk/benefit considerations are applied, and this in many ways supports not establishing fixed acceptable limits in the guideline. This concept remains in place in the final guideline. There might, however, still be value in more specific statements in the guidance regarding necessary limits in some “extreme” circumstances (e.g. where oncology candidates are being used that themselves have known genotoxicity, it would be useful for the guidance to state that specific low-level control of potentially GIs in this instance is not required).

Since the time that the TTC concept was first introduced through this draft guideline, the TTC has come under scrutiny, principally because of its conservative nature. The guideline itself explicitly recognizes this conservatism. For this reason, the necessity of this limit has been questioned. To examine the reasons why the TTC concept was initially at least so readily accepted, it is imperative to look at it in the context of the initial concept paper. Before the TTC concept was introduced, the primary objective was elimination of risk and only where this proved impossible could limits be established. However, setting limits would, as already described, require extensive in vivo studies. Set in this context, the concept of an agreed baseline limit, even if conservative, was unsurprisingly seen as an attractive proposition.

One addition at this point was the widening of the scope to include excipients. This was perhaps surprising, although concerns do exist in relation to some excipients, for example modified cyclodextrins (concern over residues of alkylating agents used to modify the cyclodextrin). In many ways, excipients are very similar to existing products in that their safety has been well established through use over an extended period in multiple formulations. In addition, many are used in other areas, including the food industry, and thus any exposure related to intake of pharmaceuticals is likely to be small compared with other sources.

A major issue at this point in time was the lack of any guidance relating to permissible doses during short-term clinical trials. This led, in some instances, to the imposition of the 1.5 µg/day lifetime exposure limit, even for very short duration studies. This prompted the development from an industry perspective of a position paper, outlining a “staged” TTC concept. This is described below.

1.4 PHRMA (MUELLER) WHITE PAPER

A Pharmaceutical Research and Manufacturers of America (PhRMA) expert group, led by Lutz Mueller, sought to establish acceptable limits for GIs in APIs linked to duration of exposure. This was referred to as a “staged TTC” approach, and was based on the established principle that exposure risk was defined in terms of cumulative dose.⁴ Inherent to this principle is that the risk associated with an overall cumulative dose will be equivalent in terms of risk, irrespective of dose rate and duration. Thus, short-term exposure limits could be based on linear extrapolation from accepted long-term exposure limits.

The group published the outcome of their deliberations in January 2006.⁵ The key aspect of this paper, the proposed “staged TTC” limits, are displayed below in tabular form (Table 1.1).

TABLE 1.1 Proposed Allowable Daily Intakes (µg/day) for GIs during Clinical Development, a Staged TTC Approach Depending on Duration of Exposure

^a Probability of not exceeding a 10⁻⁶ risk is 93%.

^b Probability of not exceeding a 10⁻⁵ risk is 93%, which considers a 70-year exposure.

^c Other limits (higher or lower) may be appropriate and the approaches used to identify, qualify, and control ordinary impurities during developed should be applied.

A critical aspect of this is the application of a 1 in 1,000,000 risk factor when calculating limits for durations <12 months, as opposed to the 1 in 100,000 applied in relation to the standard TT...

Table of contents

• Cover
• Title page
• Copyright page
• FOREWORD
• PREFACE
• CONTRIBUTORS
• Part 1: DEVELOPMENT OF GENOTOXIC IMPURITIES GUIDELINES AND THE THRESHOLD OF TOXICOLOGICAL CONCERN CONCEPT
• Part 2: EVALUATION OF GENOTOXIC RISK FROM A PRECLINICAL PERSPECTIVE
• Part 3: PERSPECTIVE ON RISK POSED BY GENOTOXIC IMPURITIES
• Part 4: ASSESSMENT OF GENOTOXIC RISK: QUALITY PERSPECTIVE
• Index
• Color Plates