Sources of Impurities in Pharmaceutical Substances

The origin of impurities in drugs is from various sources and phases if the synthetic process and preparation of pharmaceutical dosage forms. Majority of the impurities are characteristics of the synthetic route of the manufacturing process. There are several possibilities of synthesizing a drug; it is possible that the same product of different sources may give rise to different impurities. 

According to the ICH impurities are classified as the below:

Organic Impurities, may arise from starting materials, by products, synthetic intermediates and degradation products.

Inorganic Impurities, may be derived from the manufacturing process and are normally known and identified as reagents,ligands, inorganic salts, heavy metals, catalysts, filter aids, and charcoal etc.

Residual Solvents, are the impurities introduced with solvents. 

Of the above three types, the number of inorganic impurities and residual solvents are limited. These are easily identified and their physiological effects and toxicity are well known. For this reason the limits set by the pharmacopoeias and the ICH guidalines can guarantee that the harmful effects of the these impuritis do not contribute to the toxicity or the side effects of the drug substances. 

The situation is different with the organic impurities. Drugs prepared by multi-step synthesis results in various impurities, their number and the variety if their structures are almost unlimited and highly dependent on the route and reaction conditions of the synthesis and several other factors such as the purity of the starting material, method of isolation, purification, conditions of storage etc. In addition, toxicity is unknown or not easily predictable. For this reason, the ICH guidelines set threshold limited above which the identification of the impurity is obligatory.

As said by the requirements of ICH Q3A, all types of impurities present in API at a level greater than the identification threshold must conduct studies to characterize their structures, no matter they are shown in any batch manufactured by the proposed commercial process or any degradation product observed in stability studies under recommended storage conditions. Specified identified impurities shall be included in the list of impurities along with specified unidentified impurities that are estimated to be present at a level greater than the identification threshold.

Briefly, five major steps for the management of degradation products, no matter they are degradation products of API or reaction products of API with excipient(s) or container closure system, have been requested by the ICH Q3B and summarized as follows:

Confirm which impurities are degradation products?

Monitor and/or specify the amount of all degradation products.

Summarize all degradation products during manufacture and stability studies.

Establish specifications of all degradation products, including specified identified, specified unidentified, unspecified degradation product with an acceptance criterion of not more than identification threshold described in Q3B, and their total amount.

Although Q3B was developed by ICH to provide guidance on impurities in drug products for new drug applications, it is also considered to be applicable to the drug products of abbreviated new drug application.

Currently, ICH Q3C is the major guideline related to the management of residual solvents in API, excipients, and drug products . In general, solvents that are used in the manufacturing procedures are the required parts to determine. Types of solvents are sorted according to their carcinogenic and genotoxic risks as follows:

Class 1: solvents obviously confirmed or strongly suspected to cause cancer in humans.

Class 2: nongenotoxic and possible carcinogenic risks in animals.

Class 3: low-toxic solvents.

Elemental impurities may arise from residual catalysts that were added intentionally in synthesis, or may be present as impurities, e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product. Because elemental impurities pose toxicological concerns and do not provide any therapeutic benefit to the patient, their levels in drug products should be controlled within acceptable limits. Appropriate documentation demonstrating compliance for detailed risk assessment, screenings, and validation data for release methods must be conducted.

Recommended maximum acceptable concentration limits for the residues of metal catalysts or metal reagents that may be present in pharmaceutical products were issued earlier by EMA. Another classification of impurities, i.e., elemental impurities that the pharmaceutical industry needs to comply with is defined recently in ICH Q3D. Comparison for these classifications of residues of metal or elemental impurities in pharmaceutical products defined by EMA and ICH was indicated as shown in followings. Several significant difference of elemental safety concerns between EMA and ICH, such as Cr, As, Cd, Hg, Pb, etc., can be found.

Regardless of the classes of impurities, presence of impurities may have the potential to affect the quality, safety, and efficacy of drug products. Therefore, studies of impurities are one of the most important works in the development of APIs and drug products.

Management of impurities related to APIs in pharmaceutical products must be implemented in strict compliance with the regulatory requirements of pharmaceutical industry due to their quality and safety concerns. An integrated scheme in accordance with the regulatory requirements to establish analytical methods and acceptance criteria of process-related impurities and degradation-related impurities was presented, accordingly. 

Meanwhile, procedures for the identification and validation/verification of API-related impurities were proposed. Validation or verification methods to evaluate the reliability of structure identification such as kinetic reactions, stress and stability studies, comparison of retention time(s) and ∆m/z between experimental and nominal values of targeting peaks, compatibility of MRM pairs with “real samples,” stable isotope distribution patterns, and mass balance were demonstrated. Applying of the processes proposed in this article will help to ensure the reliability and quality of the impurity analytical results.