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How to Find Impurities in Pharmaceutical Products

Classification of Impurities
According to the definitions of International Council for Harmonization (ICH), Food and Drug Administration (FDA) and USP, impurities are classified into DRIs, PRIs, residual solvents, and heavy metals as shown in Figure.


Two types of impurities might be API-related. 
  1. The first type of API-related impurities is generated by degradation of API itself under specific storage conditions, e.g., oxidation, dehydration, carbon dioxide removal, etc. 
  2. The other type is occurred due to the interaction between API and excipients, container, or residual impurities in excipients, reagents, or solvents. API related impurities are potentially genotoxic, mutagenic, and carcinogenic risk due to their structure activity relationship (SRA).

It is well known that excipients or the residual impurities in excipients can be very likely to cause instability of the API and drug product. A lot of impurities in excipients, such as presence of reactive peroxides or high water content in povidone or polyethylene glycols (PEGs), antioxidants in magnesium stearate, aldehydes in lactose, benzaldehyde in benzyl alcohol, formaldehyde in starch, lignin and hemicelluloses in microcrystalline cellulose were illustrated to demonstrate how reactive chemical entities are commonplace in excipients and incompatible to API. Some specific functional groups in API may be susceptible to degradation mechanisms, i.e., hydrolysis, oxidation, polymerization, etc.

Additionally, extractables and leachable such as initiators/catalysts, storage stabilizers, antioxidants, processing aids, light stabilizers, antistatic agents, colorants, lubricants associated with pharmaceutically relevant materials may also produce uncertain risks to the stability or quality of products.

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.


Regulatory Requirements for the Management of Impurity

Comparison of the application scopes in line with the impurity categories was drawn as indicated in Figure.

Comparison of the application scopes of regulatory guidelines/guidance for the management of impurities in pharmaceutical products 
* Not clearly stated in the regulation.


As said by the requirements of ICH Q3A(R2), 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 (R2) and summarized as follows:
  1. Confirm which impurities are degradation products?
  2. Monitor and/or specify the amount of all degradation products.
  3. Summarize all degradation products during manufacture and stability studies.
  4. Elucidate and justify a rational evaluation of possible degradation pathway in the drug product or interaction with excipients or container closure system.

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 (R2), and their total amount.

Specificity (selectivity) of the method applied to determine specified and unspecified degradation product shall be validated. This includes subjecting of API or drug products to stress studies of light, heat, humidity, acid and base hydrolysis, and oxidation to evaluate the HPLC separation resolution, mass balance, etc.

Although Q3B (R2) was developed by ICH to provide guidance on impurities in drug products for new drug applications (NDAs), it is also considered to be applicable to the drug products of abbreviated new drug application (ANDAs).

Regulation requirements regarding genotoxic, mutagenic, and carcinogenic impurities have been published and revised by European Medicine Agency (EMA), FDA, and ICH in 2006, 2008, and 2017, respectively, to describe how to perform assessments and controls, including prevention and reduction of impurities.


Concept of threshold of toxicological concern (TTC) has been developed to define an acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects. In general, exposure level of 1.5 μg per person per day (i.e., TTC) for each impurity can be considered as a common acceptable qualification threshold for supporting marketing application. Any impurity found at a level below this threshold generally does not need further safety qualification for genotoxicity and carcinogenicity concerns. The threshold is an estimate of daily exposure expected to result in an upper-bound lifetime risk of cancer of less than 10−6 (one in a million), a risk level that is thought to pose negligible safety concerns.

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.


How to Find Impurities in Pharmaceutical Products
The primary goal of any synthetic process is to create completely pure products, though in reality the marginal amount of impurity always has been found to be present in the final product after the complete chemical synthesis and manufacturing process. The presence of the impurities can enhance the level of toxicity and that is why an impurity analysis process has been carried out.


Understanding the nature of these impurities is important. The goal of the analysis is to check whether these impurities may bring possible hazards or not. There are some known and unknown impurities in pharmaceutical analysis.

The intention of pharmaceutical analysis should be to omit these impurities completely; if not then their intensity should be taken down to a controllable level so that no possible hazards can take place.


Overview of Workflow in Pharmaceutical Impurity Analysis:
Impurity in the pharmaceutical products has been often found as a minor component. The challenge for the analyzers is to determine the quantity of the impurities. Once the quantity has been identified, it can be ascertained that whether the impurity will increase the toxicity or not. After identifying the impurity and finding its quantity, the next big move for the analyzers is to structure the impurity.

These processes have to be carried out with high-end precision and with cutting-edge technologies so that accurate analysis results can be attained.
In case of inaccurate analysis, possible hazards are the biggest threats to the pharmaceutical industry. ICH Q3A (R2) and Q3B (R2) describes the impurities in new drug substances and impurities in new drug products respectively.

Preparing Samples:
Preparing samples of the products is an important phase of impurity analysis process. For detection as well as degradation of the impurities in a final pharmaceutical product requires a sample preparation process.

At this phase, it has to be kept in mind that the finished product or its ingredients are not the matters for carrying out analysis. The test or analysis process has been carried out to find out the minor impurities and degradants. Increase in the impurity during the stability testing is studied and any significant change is marked and investigated.


On the other hand, degradation study is a vast process and during this process, some of the common tests have been carried out. The product may undergo the process like elevated temperature tests, ultraviolet light tests, pH level test, humidity tests, etc. These tests are carried out to understand the physical properties or molecular structures of the potential impurities.

Mass Spectrometry Workflow Analysis:
Impurities are often found in the products in very low quantity, which can be typically like0.1%. This level of detection requires special technological interventions.

Chromatographic separation is the process for detecting such low presence of the impurities. For carrying out this process, mass spectrometers are required. These devices allow the detection as well as the acquisition of the fragmented data of these minor impure components.

Data Analysis Process:
After finding the presence of known and unknown impurities in pharmaceutical analysis, data analysis process has been carried out. The main objective of this process is to analyze the received data from the tests that have been carried out.
Through meticulous data analysis, the final verdict on the product has been given. The job of the data analysts is to find whether the impurity is subtle or it is highly intense as well as alarming.

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