As part of the development of any new drug substance and its conversion into an elegant commercially viable dosage form, it is necessary to have some understanding of its safety profile prior to it being administered in clinical studies to patients in therapeutic doses.
To accomplish this, a series of pre-clinical studies are generally performed. Such studies are done in one or more animal species at doses and likely with impurity levels in higher amounts than to be administered human subjects in the clinical studies.
While the intent of the non-clinical studies is to qualify impurities in the drug substance and drug product at higher levels than present in the non-clinical studies, there are circumstances, due to a variety of developmental reasons, that result in what may be considered non-qualified impurities in either or both drug substance and/or drug product.
Some questions one may consider when such a situation occurs are as follows:
- What is the Health Authority’s perspective on non-qualified Impurities in the drug substance and/or drug product?
- What happens when a new non-qualified Impurity is identified in the drug substance lot to be used in Phase 1, 2, or 3?
- What happens when a new non-qualified Impurity is identified in drug product lot to be used in Phase 1, 2, or 3?
- What happens when a new non-qualified Impurity is identified in the drug substance due to a change in the route of synthesis?
- What happens when a new non-qualified Impurity is identified in the drug product due to a change in the formulation and/or Interaction with packaging component(s)
- What would be an acceptable level of risk, risk mitigation, and best practices for any of the aforementioned situations?
Impurities are undesired chemical substances found in pharmaceutical drug substances or drug products with no therapeutic benefits and, in some cases, can pose a risk to patient safety if their levels exceed a certain limit.
Impurities may be identifiable or unknown, volatile or nonvolatile, organic or inorganic. Impurities present in the drug substance can affect quality, safety and efficacy of pharmaceutical products causing serious health hazards. Impurities can arise during the manufacturing of any drug substance or drug product. Drug substance impurities can result from an incompatibility with the excipients, or can result from an interaction with the packaging materials.
Organic impurities mainly arise during the process of manufacturing and storage of a new drug substance. Organic impurities can result from the starting materials, manufacturing by-products, intermediates, degradation products, enantiomers, reagents, solvents, ligands and catalysts.
Inorganic Impurities can result from the manufacturing process. They may come from reagents or solvents, ligands, catalysts, heavy metals or other residual metals, inorganic salts or other materials such as filter aids or charcoal.
Ideally, the drug substance batch used in the safety/toxicity studies has higher impurities levels than the drug substance batches to be used in Clinical Trials. Such toxicity/safety batches are usually non-GMP manufactured, specifically and intentionally tailored with possibly added impurities to investigate their impact on safety and/or toxicity. Two possible approaches that are usually undertaken are:
- One (1) batch approach – Same lot of drug substance; the clinical sub-lot has higher purity.
- Two (2) batch approach – Different lots of drug substance with different impurity levels; the toxicity lot may have spiked impurity levels.
In dealing with impurity levels in the drug substance, emphasis is put on the importance of three key guidelines: ICH Q3A, Q3C, and M7. ICH Q3A focuses on the classification of impurities and establishes thresholds for control of impurities in the drug substance. The ICH Q3C guideline addresses the control of residual solvents in drug substances and provides a list of solvents with their acceptable limits classified according to their toxicological properties. The ICH M7 guideline focuses on the identification and control of mutagenic impurities in drug substances.
Per ICH Q3B, impurities in the drug product can be a combination of those from the drug substance (both process and degradation), the degradation of the drug substance in contact with the excipient in the formulation, degradation of the excipients, and interaction of the container/closure system (including label/label adhesive and the printing ink on the label) with the drug substance and/or components in the drug product formulation.
ICH Q3A (Drug Substance) and Q3B (Drug Product) with ICH M3 (Non-Clinical Safety Studies) are intended for Marketed Products, but generally and routinely applied to clinical development. It would not be unreasonable as a regulatory expectation that for Phase 1, the origin and structure of identified impurities be included in the submission. For Phase 2, it may further be expected that impurities LOD and LOQ are noted, and actual impurities levels are established.
The final synthetic route and process for the drug substance are generally not identified nor optimized by Phase 2. ICH M3 states that if specific studies are warranted to qualify an impurity or degradant, these studies are not required before Phase 3 unless there are changes that result in a significant new impurity profile (e.g., new synthetic pathway, a new degradant formed by interaction between the components of the formulation). In these later cases, appropriate qualification studies can be warranted to support Phase 2 or later stages of development.
Reporting and Identification thresholds for impurities serve as practical limits for identifying and monitoring impurities. When the concentration of an impurity exceeds the identification threshold, efforts should be made to characterize and identify the impurity through various analytical techniques. Identification may involve comparing the impurity’s characteristics with known standards or reference materials to determine its identity. The identification threshold is typically higher than the reporting threshold and helps to establish a limit for analytical methods sensitivity. Any impurity above this threshold must be identified and included in the impurity profile. If the impurity is below this threshold, no further action is required.
The reporting threshold is typically set at a level that ensures the ability to detect impurities accurately and assess their potential risks. Identifying and reporting of drug substance impurities at a level of 0.05 % is recommended. For drug product the limit is 0.1 %.
The qualification threshold is the concentration limit at which an impurity requires further assessment for its potential impact on patient safety. Impurities exceeding the qualification threshold are subjected to a comprehensive evaluation of their toxicological properties and potential risks. This evaluation helps to determine the need for additional control measures, such as establishing specific limits or implementing appropriate manufacturing process modifications to minimize the impurity levels. If the impurity level is below this threshold, no further action is required.
Once the structure of the impurity is identified, an evaluation should be conducted to determine whether the impurity poses a known human relevant risk. If there is evidence of a potential risk, efforts should be made to reduce the impurity level to minimize its presence in the drug substance. When the impurity cannot be reduced to a level below the qualification threshold, toxicity studies should be conducted to assess its potential adverse effects on patients. These studies help to determine if the impurity poses a clinically relevant risk. If no adverse effects are observed, the impurity can be considered qualified.
Haber’s Law of Toxicity states that the incidence and/or severity of a toxic effect depends on the total exposure, i.e. exposure concentration rate times the duration time of exposure (c x t). This rule, within constraints, is often used in setting exposure guidelines for toxic substances. Establishing reference doses (acceptable daily intakes) for long-term exposures when only the results of short-term studies are available requires the use of an uncertainty (safety) factor. The value of this uncertainty factor often approximates a value comparable to Haber’s Law for extrapolation from short-term to long-term exposure durations.
As a default procedure, cancer risk estimates are generally based on the average lifetime daily dose which is derived from the total cumulative exposure, i.e. Haber’s (c x t). This has been shown both theoretically and empirically to be valid within a factor of 20 for carcinogenesis. This provides some credence for the use of an additional safety factor of 10, in some instances, for exposures of children to carcinogens.
For the majority of drug substances can usually justify non-mutagenic impurity levels based on limited exposure. Thus, a 1 mg/day impurity level for an unqualified non-mutagenic impurity of unknown toxicity in drug substance for a clinical study of no more than 6 months could be considered acceptable. For a non-mutagenic drug product, a limit of 5 mg/day or 2 % for an exposure interval of 6 months is also reasonable.
If the impurity is unidentified and below the limit of about 0.15% (about 1.0 mg/day) no additional action should be necessary. If the structure is known, a risk assessment should be conducted based on limited exposure during Phase 1 and the initial safety evaluation.
According to the FDA ANDA Guidance on Impurities in drug products, a specified identified degradation product is considered qualified when it meets one or more of the following conditions:
- When the observed level and proposed acceptance criterion for the degradation product do not exceed the level observed in the RLD.
- When the degradation product is a significant metabolite of the drug substance.
- When the observed level and the proposed acceptance criterion for the degradation product are adequately justified by the scientific literature.
- When the observed level and proposed acceptance criterion for the degradation product do not exceed the level that has been adequately evaluated in toxicology studies.
Further, according to an EMA Reflection Paper on the qualification of non-mutagenic impurities, “in case impurities have not already been qualified in previous safety studies (i.e. novel impurities) or when higher levels of impurities need to be qualified (that were previously qualified at a lower level), it is recommended to use alternative methodologies. Only in rare cases where a remaining concern cannot be resolved otherwise, should the conduct of an animal study be considered. In those cases, only a study with the neat impurity might provide relevant information on the safety profile of the impurity.”
It is not unusual to change, update, and/or optimize analytical methods for both drug substance and drug product as development progress through pre-clinical studies, through Phase 1 and up to the end of Phase 2 studies. These changes are generally intended to improve the method(s) LOD & LOQ. These changes may uncover impurities previously not detected, and/or result in impurity level different from previously detected.
Forced degradation studies (e.g. heat, light, moisture, etc.) are generally performed as part of the studies to optimize and validate the analytical methods and are not required until Phase 3.
Retained Sample Evaluation
Samples of all toxicity and clinical lots of drug substance should be retained until after NDA approval. Samples of drug product lots used in stability and clinical studies including, PK studies, should also be retained until after NDA approval. Retained Samples can be analyzed by updated methods to verify presences of previously undetected impurities, and/or changing impurity levels. These data can be used to ‘justify’ the ‘undetected’ impurity and/or possibly differing concentrations.
Summary
There is no single correct answer. Each situation must be evaluated on its merits taking into account, the level of the impurity, its structure (if known) and the potential to cause harm. A risk evaluation is a critical part of this determination. It is not unusual to have unidentified, and potentially unqualified drug substance and/or drug product Impurities in Phase 1 studies Drug substance synthetic route changes generally occur in Phases 1 and 2 developments and sometimes (rarely) in Phase 3. Drug substance Phase 3 changes are usually optimization in nature and involve process modifications (e.g. time, temperature, etc.) and solvent changes which can affect the formation of impurities and their amounts. Drug product Phase 3 changes may be due to instability and/or interaction with the container/closure system; drug product reformulations have occurred as a result.
The End-of-Phase 2 (EOP2) Meeting, and other CMC Type C Written Communications depending on the topic, are options to address CMC development topics with FDA. Such discussions with FDA are recommended when making ‘significant” changes to the drug substance synthetic route, identification of new impurities, changes in starting materials, etc. Key to a successful development program is to have an understanding of the drug substance and drug product issue(s), how they are to be addressed, and the potential impact on the drug substance and drug product quality.
References
- ICH Q3A (R2): Impurities in New Drug Substances, October 2006
- ICH Q3B (R2): Impurities in New Drug Products, June 2006
- ICH Q3C: Impurities: Guidelines for Residual Solvents, April 2021
- ICH M7: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, July 2023
- FDA Guidance for Industry: ANDAs: Impurities in Drug Products, November 2010
- FDA Guidance for Industry: CGMPS for Phase 1 Investigational Drugs, July 2008
- FDA Guidance for Industry: Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well Characterized, Therapeutic, Biotechnology-derived Products, November 1995
- FDA Guidance for Industry: INDs for Phase 2 and Phase 3 Studies Chemistry, Manufacturing, and Controls Information, May 2003
- ICH M3: Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorizations for Pharmaceuticals, January 2010
- S J Dsouza, et al., “Impurities in Drug Substance – An Overview of ICH Q3A, Q3C and M7 Guidelines,” Pharmaceutical Investigations, Vol 14, Issue 2, April 2 2024 Updated April 10 2024.
- D P Elder, “Exposure Based Limits for Controlling Impurities,” American Pharmaceutical Review, June 20 2017
- J Harvey, et al., “Management of Organic Impurities in Small Molecule Medicinal Products: Derving Safe Limits for Use in Early Development,” Regul. Toxicol. Pharmacol. 84, pp 116-123
- Reflection paper on the qualification of non-mutagenic impurities, 02 December 2024. EMA/CHMP/543397/2024. Committee for Medicinal Products for Human Use (CHMP)