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In June 2009 the US FDA’s Office of Generic Drugs issued, “Guidance for Industry; ANDAs: Impurities in Drug Substances” which basically follows the Q3A, Q3B, Q3C ICH guidelines. These guidelines focus on Drug Substances and covers original abbreviated new drug applications (ANDAs), drug master files(DMFs), including Type II DMFs and ANDA supplements for changes in the synthesis or processing of a drug substance. The guidance provides recommendations for establishing acceptance criteria for impurities in drug substances and recommends that the specifications for a Drug Substance include a list of impurities. A rational for the inclusion or exclusion of impurities should be included. As indicated in the ICH guidelines, if an impurity cannot be identified, then the efforts made to identify the impurity should be included if present at a level greater than the identification threshold given in ICH Q3A. Organic and inorganic impurities should be considered as well as residual solvent.

Acceptable limits of impurities may be specified in the United States Pharmacopeia (USP) and may be considered in the qualification of an impurity. If the impurity does not appear in the USP monographs, you may qualify it by comparison with the observed amount of that impurity as found in the reference listed drug product (RLD). As an alternative, the impurity may be qualified by justification in the scientific literature, metabolite data, or with toxicity studies. An impurity is considered qualified when it meets one or more of the following conditions.

  • The observed level and proposed acceptance criterion for the impurity do not exceed the level observed in the referenced listed drug product.
  • The impurity is a significant metabolite of the drug substance.
  • The observed level and proposed acceptance criterion for the impurity are adequately justified by scientific literature.
  • The observed level and proposed acceptance criterion for the impurity do not exceed the level that has been adequately evaluated in toxicology studies.

Quantitative Structure Activity Relationships(QSAR) programs may be considered for predicting toxicity, but the results are not considered conclusive for the qualification process.

Qualification Thresholds

Recommended thresholds are defined as the limit above which an impurity should be qualified. These are based on the maximum daily dose of the drug substance and are described in ICH guidance Q3A(R2). When the thresholds are exceeded, impurity levels require qualification. Any prior history of adverse reactions of the impurity in patients may require a lowering of the qualification threshold. On the other hand, if concern for safety is low, the threshold may be increased. Each case is different and is addressed individually.

Qualification Procedures

Qualification of an impurity follows ICH guidelines recommended in Q3A(R2) in accordance with a decision tree contained therein. Decreasing the impurity level below the qualification threshold may be the simplest approach, but adequate data may already be available in the scientific literature to qualify the impurity. A number of factors impact on the studies required to qualify a specific impurity. Analytic studies which compare the levels in a Drug Substance covered by an ANDA to the levels measured in the RLD. If levels are similar or less, then the impurity is qualified. Scientific literature also can be used to justify specific identified impurities. Additional toxicology studies would be considered as a last resort.

Qualification of Pharmaceutical Degradants, Impurities, Solvent Residues, Leachables, and Extracts

  • In Drug Substances - Guideline ICH Q3A(R2)

Qualification is the process of acquiring and evaluating data that establish the biological safety of an individual impurity or a given impurity profile at the level or levels being considered. Definite guidelines have been established for the qualification of specific levels of degradation products, impurities, extractables/leachables, and solvent residues in drug products and drug substances. These are described in some detail in the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonised Tripartite Guidelines. These guidelines are detailed in three separate sections.

  • Impurities In New Drug Substances, Q3A(R2) dated October 25, 2006
  • Impurities In New Drug Products, Q3B(R2) dated June 2, 2006
  • Impurities: Guideline for Residual Solvents, Q3C(R4) dated February 2009

Under these guidelines impurities may include organic impurities, inorganic impurities, extractables/leachables, and residual solvents. Organic impurities can include starting materials, by-products of synthesis, intermediates, degradation products, and reagents, ligands, or catalysts. Inorganic impurities may include reagents, ligands or catalysts, heavy metals or other residual metals, inorganic salts or other incidental materials, including filter aids. Solvents are used regularly in the synthesis of a drug substance, and residues of those solvents must also be qualified.

For drug substances, any impurity level that exceeds the identification thresholds indicated in the guidelines should be identified, but those at or below the identification threshold need not be identified unless they are particularly toxic. Quantification of impurities above the identification threshold is required, and specific guidelines for qualification of that impurity is dependent on the Total Daily Intake (TDI) of the impurity and its toxicological properties. Other factors also come into play here. If the level of impurity in the drug substance has been adequately tested at similar levels in safety and clinical trials, then it could be qualified on that basis. If the impurity is also a metabolite in animal and/or human studies, it could be qualified also and if comparable amounts were present in the drug substance that was tested in animal studies, it could also be qualified in that way. If there is evidence of adverse reactions in clinical trials, then lower quantification thresholds may be applicable.

  • In Drug Products - Guideline ICH Q3B

The same basic principles that are indicated above are suggested in the guidelines for impurities in new Drug Products, but additional factors come into play. Only those impurities classified as degradation products of the Drug Substance or reaction products of the Drug Substance with excipients or packaging materials are addressed in this guideline. A listing of the degradation products observed during the manufacture and/or stability studies of the new Drug Product and an assessment of possible interactions with excipients or packaging components should be addressed. Identification thresholds are in play as described above, and the degradant should be identified when the threshold is exceeded. This is not necessary if the identification threshold is not exceeded. If a degradant is thought to be toxic or has produced some undesireable toxicological effect in animal or human studies, identification would be necessary at levels lower than the identification guideline. If the degradant cannot be identified, the analytical procedures used to attempt that identification must be described.

Analytical findings should be provided for all relevant batches of the new Drug Product used for clinical safety and stability testing as well as batches meant for commercial distribution. Quantitative results should be presented. For a new Drug Product, the following information is required for qualification of different batches of drug: batch identity, strength and size, date of manufacture, site of manufacture, immediate container closure, degradation product content (individual and total), use of batch, reference of analytical procedures used, batch number of the Drug Substance used in the new Drug Product and storage conditions for stability studies. If a degradation product cannot be identified structurally, it should be identified by the retention time or some other reproducible analytical criteria.

Qualification of a degradant obviously involves an assessment of the biological safety of that component of the new drug Product. Degradation products present at similar or higher levels in safety studies and/or clinical studies may be qualified on that basis. Higher or lower thresholds for qualification may be appropriate depending on the level of concern for possible adverse effects. Scientific justification is required for raising or lower the threshold for quantification of a degradant. Reporting thresholds, identification thresholds, and qualification thresholds are described in this guideline.

  • Residual Solvents - Guideline ICH Q3C

In the synthesis processes for producing pharmaceuticals, solvents play a critical role but residues inevitably remain in Drug Substances. This guideline addresses issues regarding excipients, Drug Substances, and Drug Products. In essence, the guideline indicates that Drug Products should contain no higher levels of residual solvents than can be supported by safety data, and it classifies solvents into the following three categories.

  • Class I: toxic solvents - should be avoided in the production of Drug Substances, excipients, or drug products unless justified on a risk-benefit basis (examples: benzene, carbon tetrachloride)
  • Class II: less toxic solvents - concentrations should be limited based on potential for adverse effects (examples: acetonitrile, methanol, toluene, ethylene glycol)
  • Class III: least toxic solvents - should be used where possible (examples: acetone, ethanol, ethyl acetate)

Concentration limits and guidelines are listed for a number of solvents in all three categories, and options are described for the calculation of concentration limits when dealing with Class II solvents with consideration being given to all components of the Drug Product including excipients. Analytical methodologies are recommended with particular emphasis on the harmonized procedures described in the US and European pharmacopeias. For the Class III solvents, loss on drying may be sufficient to satisfy the guideline for qualification.

One of the criteria for assessing potential adverse health effects of the various solvents is the length of time that the Drug Product will be taken. Short-term administration of a drug may allow a broader latitude for qualification level. For drugs that are administered chronically, questions regarding the chronic toxicity of the solvent under consideration may become critical to establishing a qualification. Methodology for establishing low-dose assessment of solvents is described in this guideline, and Permitted Daily Exposures (PDE) are calculated from whatever data is available in the published literature. Animal data is also used and no-effect levels (NOEL) and lowest-observed effect levels (LOEL) are used with appropriate uncertainty factors for translating from animals to man based on animal surface area calculations and other factors for translating the type of study to an appropriate dosing situation.

Qualifications of Dr. Richard A. Parent

Dr. Parent is board certified by the American Board of Toxicology, the Academy of Toxicological Sciences, the Regulatory Affairs Certification Board and is a recognized expert in toxicology in the European Union. He hold a PhD in organic chemistry and a minor in analytical chemistry. His credentials insure that his efforts to qualify your impurities according the ICH, FDA, and USP guidelines will be accepted by the US FDA and the international community. Furthermore, Dr. Parent’s experience in directing two toxicology laboratories provides him with the knowledge and insight necessary for designing and monitoring client-sponsored studies at outside CROs.

Initiating a Qualification Activity

For most impurities, degradant, exractables/leachables, or solvent residue qualifications, there is a flat fee. Beyond that, an hourly rate is charged. For further information or to initiate a project, you may contact Dr. Parent directly (207/563-2300;; P. O. Box 1239, Damariscotta ME 04543).


Consultox, through the services of Dr. Parent, has extensive experience in the design and placement of pre-clinical studies in the United States, Europe, and Japan. Although Dr. Parent focuses on the preclinical experimentation and technical reporting involved in the drug development process, he can provide support for the entire drug registration process from inception — experimentation, reporting, quality assurance, IND/NDA preparation, and the remainder of the registration process, including FDA interfaces.

Dr. Parent is certified in regulatory affairs by the Regulatory Affairs Professional Society. As a result of his expertise, Consultox offers a broad array of regulatory consulting services, including the strategic regulatory planning for the development, preparation, and submission of INDs and NDAs. Qualification of impurities, degradants, and solvent residues in new Drug Substances and Drug Products in accordance with Q3A(R2), Q3B(R2), or Q3C(R4) ICH guidance is provided in a timely manner. A wide range of regulatory audit activities also is available.

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