Pharmaceutical raw material testing: how to ensure compliance with pharmacopoeial standards?

Pharmaceutical industry raw materials, such as excipients, active pharmaceutical ingredients (APIs) and their starting materials, process water, and manufacturing solvents must fulfill exceptionally stringent quality standards. In Europe, this means that each ingredient must meet the specifications outlined in the applicable European Pharmacopoeia (Ph. Eur.) monograph, if one exists.¹

The tests required to confirm that substances meet pharmacopoeial standards are typically conducted in accordance with Ph. Eur. general chapters and ICH guidelines. This article summarizes the process, covering the types of analyses conducted, performance requirements for analytical methods, and documenting compliance through the certificate of suitability (CEP) procedure.

Commonly applied Ph. Eur. methods for raw materials testing

There are over 2,500 Ph. Eur. monographs that outline detailed specifications for different pharmaceutical-grade substances.² While the number of monographs is large, the types of analyses required are similar and typically include the following:

• Confirmation of substance identity through pharmacopoeial identification tests, for example, using chromatographic or spectroscopic methods (e.g., HPLC, FTIR)

• Determination of physicochemical characteristics, such as pH, conductivity, loss on drying, viscosity, melting point, refractive index, and solubility

• Particle size distribution, particularly in cases where it impacts dissolution rates, stability, and/or bioavailability of powder- or suspension-form raw materials

• Confirmation of chemical purity through the analysis of relevant contaminants, including related substances (e.g., synthetic by-products and intermediates), elemental impurities, residual solvents, degradation products, and nitrosamine impurities

• Confirmation of microbiological quality, covering total aerobic microbial count and total yeast and mold count (TAMC & TYMC), specified microorganisms, and, in some cases, bacterial endotoxins and sterility

In addition to substance-specific monographs, testing requirements can be described in general monographs and chapters of the European Pharmacopoeia, which apply to all pharmaceutical substances within the scope of the monograph or chapter. Examples of pharmacopoeial methods often used during raw material testing are listed in Table 1.

The results of the tests are primarily evaluated against acceptance criteria specified in the Ph. Eur. monograph for the substance. In cases where the monograph does not adequately cover all relevant impurities, additional specifications and acceptance criteria may need to be determined based on ICH guidelines.⁶

Requirements for analytical methods

Analytical methods used for testing pharmaceutical raw materials must be validated to ensure their suitability for the specific purpose and sample matrix. The performance characteristics against which validation studies should be performed depend on the type of analysis. These are summarized in Table 2.⁷

When an established pharmacopoeial method is applied to a new sample matrix, or when a validated method is transferred to a new laboratory, full revalidation may not be necessary. Instead, a smaller set of verification experiments focusing on the performance characteristics most likely to be affected (e.g., precision, specificity) may be sufficient.

In addition to being validated or verified, tests must be conducted in accordance with GMP when the results are used for batch release. Non-GMP methods may be used for preliminary screening tests.

Certificate of suitability (CEP) for pharmaceutical ingredients

Conducting the required analyses to show that a raw material meets the specifications outlined in the applicable Ph. Eur. monograph makes it possible to apply for a certificate of suitability (CEP) from the European Directorate for the Quality of Medicines (EDQM). However, it may be necessary to conduct additional impurity analyses and document these in an annex to the CEP, if all relevant impurities are not accounted for in the monograph.⁸

The CEP certifies that the quality of the substance can be adequately controlled by the monograph and any additional tests. For the substance manufacturer, this provides a straightforward way to demonstrate to customers (typically the manufacturers of finished medicinal products) that the substance meets pharmacopoeial quality requirements.

There are three CEP categories applicable to different types of substances: chemical CEP for chemically well-defined organic or inorganic substances, herbal CEP for substances of herbal origin, and TSE CEP for substances with a risk of transmitting agents of animal spongiform encephalopathies (i.e., animal-derived materials from high-risk species, such as cattle, sheep, and goats). It should be noted that a TSE CEP does not certify that the quality of the substance is suitably controlled by a Ph. Eur. monograph, but rather certifies compliance with TSE risk requirements only.

Our solutions for pharmaceutical raw material testing

Measurlabs offers a wide range of analytical services for confirming that pharmaceutical raw materials meet the required quality specifications. We have experience in analyzing various APIs and excipients in accordance with the applicable Ph. Eur. monograph, as well as additional impurity analysis methods where required. The following are examples of commonly requested services:

• Microbiological quality analysis according to Ph. Eur. 2.6.12 and 2.6.13

• Elemental impurities according to ICH Q3D, Ph. Eur. 5.20, and Ph. Eur. 2.4.20

• Bacterial endotoxins according to Ph. Eur. 2.6.14

• Nitrosamine screening for both small-molecule and API-specific nitrosamine impurities

We also offer full analysis packages to check compliance with substance-specific Ph. Eur. monographs. Please contact our experts using the form below for more information or a quote.