Exposure Based Limits for Controlling Impurities

• David P Elder Consultancy

Introduction

Whereas, the use of medicinal products is always a compromise between acceptable risks and likely benefits, the same is not true for impurities.¹ However, it is widely accepted that complex, multi-stage drug substances cannot be manufactured without the commensurate formation of impurities or degradation products.² The compromise is to develop control strategies whereby these impurities can be controlled to appropriate safety based levels.

Impurities in New Drug Substances and New Drug Products (ICH Q3A/ ICH Q3B)

The international conference on harmonization (ICH) first introduced safety based limits. ICH Q3A summarized the types of impurities found in new drug substances (or active pharmaceutical ingredients, APIs) and their controls. Impurities were assessed based on either chemistry or safety considerations.³

Impurities were additionally differentiated as “identified and unidentified impurities”, both were incorporated as separate specification tests onto API specifications.⁴ API specifications also included those unidentified impurities that were actually present at levels greater than the pre-defined reporting, identification and qualification thresholds.³

Reporting thresholds are linked to analytical capability.⁵ Identification thresholds are where unknown impurities require identification and qualification thresholds “establishes the biological safety of an individual impurity or a given impurity profile at the level(s) specified.”³

The derivation of both identification and qualification threshold limits were not disclosed; apart from linkage to the maximum daily dose of the product. For those impurities “known to be unusually potent or to produce toxic or unexpected pharmacological effects, the quantitation/detection limit of the analytical procedures should be commensurate with the level at which the impurities should be controlled”; and this is the origin for the subsequent ICH M7 guidance .⁶

Comparable guidance was also introduced for new drug product impurities.⁷ There was better delineation of the various ICH Q3B thresholds; however, it was never explained why the various ICH Q3B thresholds could not be better aligned. Therefore, there is the confusing scenario where the reporting thresholds are either above or below 1g; whereas, the identification thresholds are sub-divided into four ( >2 g, >10 mg - 2 g, 1 mg - 10 mg and <1 mg); whilst, the ICH Q3B qualification thresholds are different ( >2 g, >100 mg - 2 g, 10 mg - 100 mg and <10 mg).⁷

Additionally, the maximum daily dose (mg/day) and the maximum strength of a product (mg) are not always the same for all treatment regimens. Amitriptyline has a maximum therapeutic dose of 300mg per day for inpatient use (150mg/day for outpatient use); whereas, the highest dose strength is 150mg/tablet.⁸ However, all tablet strengths (i.e. 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg/tablet) are tested and released to the same impurity specification.

ICH Q3B reporting thresholds are reported as percentage values and aligned with method capability; whereas, ICH Q3B identification and qualification thresholds are measured in either percentage or mg/day values. Additionally, safety based impurity limits do not reflect the duration of treatment, resulting in the same limits irrespective of whether the drug is proscribed “as required” (pro ne rata (PRN)) or “throughout life time”.

ICH Q3A³ and Q3B⁷ were intended for marketed products. However, they are routinely applied during clinical development and regulatory expectations during this phase often surpass the actual requirements. For example, it isn’t unusual to see the following regulatory expectations.⁹

For Phase I expect structure (or identifier) and origin.

For Phase II expect Limit of Detection and Quantification and actual impurity levels to be established (aligned with ICH Q3A, Q3B, etc.).

Unfortunately, the final synthetic route and process of the API are rarely identified or optimized by Phase II, and the attrition rate is still high.¹⁰ The ICH M3 regulatory guidance¹¹ states that, “If specific studies are warranted to qualify an impurity or degradant, generally these studies are not warranted before Phase 3 unless there are changes that result in a significant new impurity profile (e.g., a new synthetic pathway, a new degradant formed by interactions between the components of the formulation). In these latter cases, appropriate qualification studies can be warranted to support Phase 2 or later stages of development”

Residual Solvent Impurities (ICH Q3C)

ICH Q3C¹² provides safety based guidance on permissible limits of common residual solvents within pharmaceuticals. ICH Q3C identifies three different solvent classes based on toxicity; i.e. class 1 class> 2 class> 3. ICH Q3C recommends the use of less toxic solvents (class 3) in place of toxic solvents, i.e. substitution and avoidance of highly toxic solvents (Class 1) unless their use is warranted via risk-based evaluations.¹³ Additionally, certain solvents with intermediate toxicity (Class 2) should also be restricted from a patient safety perspective. Moreover, the concept of “as low as reasonably practicable” (ALARP) was also introduced for class 2 solvents. Indeed, regulatory agencies will frequently use process capability arguments to reduce residual solvent levels below the ICH Q3C safety based limits.¹⁴

Although tolerable daily intake (TDI), acceptable intake (AI), and acceptable daily intake (ADI) were all in common usage at the time of the guidance; ICH Q3C¹² uses permitted daily exposure (PDE) to avoid confusion.

Residual Elemental Impurities (ICH Q3D)

ICH Q3D¹⁵ provides safety based guidance on allowable limits of residual elements within pharmaceuticals. ICH Q3D addresses derivation and assessment of toxicity data; establishment of a PDE for different routes of administration, i.e. oral, inhaled and parenteral; and introduction of a risk based approach¹³ for the control of elemental impurities. Unlike ICH Q3C,¹² there is no expectation to tighten limits based on process capability concerns, provided that PDE values are not exceeded. However, levels below the PDE may be justified when existing levels negatively impact on other critical quality attributes (CQAs) of the drug product, e.g. metal catalyzed drug degradation.¹⁶ Residual elements are classified into 5 different categories: class 1, 2a, 2b, 3 and others.

Although, the guidance highlights the risks inherent from both API and particularly excipients, the reality based on a multi-product assessment is that the risk is low. Li et al.¹⁷ tested 190 samples from 31 different excipients and 15 samples from 8 different APIs and they showed relatively low levels of elemental impurities, typically <PDE.

Residual Mutagenic Impurities (ICH M7)

ICH M76 is focused on mutagenic impurities (MIs) that can potentially cause cancer in man. A Threshold of Toxicological Concern (TTC) approach was introduced to describe an acceptable intake for any new MI, equating to a virtually safe dose (VSD). A default TTC value of 1.5 μg/day, which corresponds to a theoretical 10^-5 excess lifetime risk of getting cancer was introduced for MIs. The acceptable intakes for MIs are based on established risk assessment approaches.¹³ Importantly, the acceptable risk can be higher, i.e. 1 in 10⁶ for early development phases. For later stages in development and for commercial products, the risk level is reduced to 1 in 10⁵. New impurities are then categorized into five different classes in order of decreasing regulatory concern:

• Class 1, known mutagenic carcinogens. Control at or below compound specific acceptable limit, i.e. AIs¹⁸ or PDEs
• Class 2, known mutagens with unknown carcinogenic potential. Control at or below acceptable limits, i.e. Less Than Lifetime (LTL) or TTC
• Class 3, show alerting structures (un-related to drug substance) with no supporting mutagenicity data. Control at or below acceptable limits, i.e. LTL or TTC. Or conduct bacterial mutagenicity assay; If non-mutagenic = Class 5, If mutagenic = Class 2
• Class 4, show alerting structures (related to (API) which is itself non-mutagenic). Treat as non-mutagenic impurity, i.e. use default ICH Q3A/Q3B limits
• Class 5, show no alerting structures. Treat as non-mutagenic impurity, i.e. use default ICH Q3A/Q3B limits

ICH M7⁶ proposed four control options for MIs, of these only one includes control of the MI on the API specification (option 1). Options 2 and 3 identify some levels of in-process control; whereas, option 4 is focused on process understanding alone, typically termed “Purge Arguments.”¹⁹

These risk assessments are based on lifetime exposures, i.e. 70 years. LTL exposure based limits can be implemented both during development and commercial use and still maintain comparable risk levels using Haber’s law.²⁰ Thus for example, “if the compound specific acceptable intake is 15 μg/day for lifetime exposure, the less than lifetime limits can be increased to a daily intake of 100 μg ( >1-10 years treatment duration), 200 μg ( >1-12 months) or 1200 μg ( <1 month).”⁶

ICH M7 also covers changes to marketed products, including new marketing applications and post-approval submissions.²¹

Impurities in Oncology Products (ICH S9)

Oncology studies often involve cancer patients whose prognosis is poor and projected lifetime is short (<2 years).²²

Therefore, ICH S923 seeks to accelerate the development of anticancer pharmaceuticals whilst protecting patient safety. Those specific situations where requirements may diverge from other ICH guidance are described in ICH S9.²³

Historically, limits for impurities have been predicated on a negligible risk to the patient. In oncology products this consideration is not as important as patient wellbeing and higher limits for impurities may be applicable, with supporting justifications. In particular, stricter limits for mutagenic impurities⁶ are inappropriate and higher limits can be implemented.

New Considerations

Harvey et al.²⁴ demonstrated that the 1 mg/day impurity level for an unqualified impurity of unknown toxicity, proposed by ICH Q3A³ is indeed a VSD for non-mutagenic impurities. Using a modified Haber’s law approach,²⁰ they determined a VSD for shorter exposure intervals seen in early clinical studies (<6 months) of 5 mg/day (i.e. 5 times higher than existing ICH Q3A limit). The authors also introduced a percentage cut off based on 5x the ICH Q3A qualification threshold of 0.15%; i.e. 0.7%. Thus the proposed limits for drug substances are 5 mg or 0.7%, whichever is lower.

For drug products, similar LTL limits for non-mutagenic impurities can be derived. The additional constraint of 0.7% need not be applied to drug products. The authors therefore suggested a limit of 5 mg or 2%, whichever is lower, for exposure intervals of 6 months, for general drug substance impurities, i.e. non-mutagenic.²⁴

Conclusion

Safety based limits for impurities, which are predicated on daily exposure limits, rather than the more classical percentage based limits are becoming increasingly important in the effective reduction and control of toxic impurities in drug products. Historically, there has been an evolution in the approaches toward safety based impurity control. Whereas, ICH Q3A³ and Q3B⁷ mainly focused on relative levels of impurities, i.e. percentage based limits; later guidance i.e. residual solvents,¹² residual elemental impurities¹⁵ and mutagenic impurities,6 had a greater focus on daily exposure limits. This led to the introduction of various impurity specific limits, such as PDEs, AIs, TTCs and staged TTCs, all aimed at defining a virtually safe dose (VSD); which in turn led to LTL limits for MIs.⁶ Surprisingly, LTLs have not been implemented for the other specific classes of impurities or indeed general impurities. In order to address this deficiency, Harvey et al.²⁴ have assessed the underpinning data behind the current “1 mg or 1%, whichever is lower” limit in ICH Q3A³/Q3B,⁷ and they proposed an ancillary LTL for general impurities of 5 mg or 0.7% and 5 mg or 2%, whichever is lower, for API and drug product, respectively (for clinical studies with durations of less than 6 months).

From a risk based perspective an overt focus on impurity control makes little sense if the life expectancy of the affected patient is short, i.e. less than 2 years.²³ It has been reported that the LTL approach may also be appropriate “in diseases with reduced life expectancy, limited therapeutic alternatives or chronic diseases with late onset.”²¹ Interestingly, there has been little regulatory appetite for widening this entirely pragmatic approach to impurity control to other therapeutic areas, where life expectancy is equally short, i.e. rare diseases.²⁵

References

1. Jacobson-Kram D, McGovern T. (2007) Toxicological overview of impurities in pharmaceutical products. Adv. Drug Deliv. Rev., 59; 38-42.
2. Elder DP, Teasdale A. (2015) Is Avoidance of Genotoxic Intermediates/Impurities Tenable for Complex, Multi-Step Syntheses? Org. Proc. Res. Dev., 19, 1437-1446.
3. ICH Q3A(R2). (2006) Impurities in New Drug Substances. Current Step 4 version dated 25 October 2006.
4. ICH Q6A (1999) Specifications: Test procedures and acceptance criteria for new drug substances and drug products: Chemical Substances. Current Step 4 version dated 6 October 1999.
5. ICH Q2(R1). (2005) Validation of analytical procedures: Text and methodology. Current Step 4 version Parent Guideline dated 27 October 1994 (Complementary Guideline on Methodology dated 6 November 1996 incorporated in November 2005).
6. ICH M7. (2014) Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit the potential carcinogenic risk. Current step 4 version, dated 23 June 2014.
7. ICH Q3B(R2) (2006) Impurities in New Drug Products. Current Step 4 version dated 2 June 2006.
8. Amitriptyline dosage: Usual adult dose for depression. Drugs.com. https://www.drugs.com/dosage/amitriptyline.html#Usual_Adult_Dose_for_Depression. Accessed on 19 March 2017.
9. Stevens W. (2009) Expectations for data to support clinical trial drugs. APEC Advanced Workshop on Review of Drug Development in Clinical Trials, Feb 2-6 2009, Bangkok, Thailand. http://www.ich.org/fileadmin/Public_Web_Site/Training/GCG_-_Endorsed_Training_Events/Advanced_workshop__Rev_of_Drug_Dev_in_CT/Day_2/16-_Quality_Expectations_CT_Drugs.pdf. Accessed on 19 March 2017.
10. Bayliss MK, Butler J, Feldman PL, Green DV, Leeson PD, Palovich MR, Taylor AJ. (2016) Quality guidelines for oral drug candidates: dose, solubility and lipophilicity. Drug Disc. Today, 21(10), 1719-1727.
11. ICH M3(R2). (2009) Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals. Current step 4 version dated 11 June 2009.
12. ICH Q3C(R6). (2006) Impurities: Guidelines for residual solvents. Current Step 4 version dated October 20, 2006.
13. ICH Q9. (2005) Quality risk management. Current Step 4 version dated 9 November 2005.
14. Elder DP. (2016) Interpreting ICH’s evolving residual solvents guideline, Eur. Pharm. Rev., 21(5); 30-33.
15. ICH Q3D. (2014) Guideline for elemental impurities. Current Step 4 version dated 16 December 2014.
16. Waterman KC, Adami RC, Alsante KM, Hong J, Landis MS, Lombardo F, Roberts CJ. (2002) Stabilization of pharmaceuticals to oxidative degradation. Pharm. Dev. Technol. 7(1); 1-32.
17. Li G, Schoneker D, Ulman KL, Sturm JJ, Thackery LM, Kauffman JF. (2015) Elemental Impurities in Pharmaceutical Excipients. J. Pharm. Sci., 104(12); 4197-4206.
18. ICH M7(R1). (2015) Addendum to ICH M7: Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit the potential carcinogenic risk. Application of the principles of the ICH M7 guideline to calculation of compound-specific acceptable intakes. Current Step 2 version dated 9 June 2015.
19. Teasdale A, Elder D, Chang S-J, Wang S, Thompson R, Benz N, Sanchez Flores IH. (2013) Risk assessment of genotoxic impurities in new chemical entities: Strategies to demonstrate control. Org. Proc. Res. Dev., 17; 221-230.
20. Gaylor DW. (2000) The use of Haber’s Law in standard setting and risk assessment. Toxicology 149(1); 17-19.
21. Elder DP. (2014) Foreword: ICH M7: Mutagenic impurities: A critical evaluation, Eur. Pharm. Rev., 19(1), 6.
22. Jones PS, Jones D. (2012) New regulatory framework for cancer drug development. Drug Disc. Today, 17(5-6); 227-231.
23. ICH S9. (2009) Nonclinical evaluation for anticancer pharmaceuticals. Current Step 4 version dated 29 October 2009.
24. Harvey J, Fleetwood, A, Ogilvie R, Teasdale A, Wilcox P, Spanhaak S. (2017) Management of organic impurities in small molecule medicinal products: Deriving safe limits for use in early development. Regul. Toxicol. Pharmacol., 84; 116-123.
25. Department of Health. (2013) The UK strategy for rare diseases. https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/260562/UK_Strategy_for_Rare_Diseases.pdf. Accessed on 16 February 2017.