Product-related substances

Product-related substances are molecular variants of the desired product formed during manufacture and storage, which are active and have no deleterious effect on the safety and efficacy of the drug product.2 Many recombinant protein products are inherently heterogeneous, mixtures of closely related structures or product variants. These variants possess properties comparable to the desired product and are not considered impurities. It is only when they do not have properties of the desired product that their presence is problematic. 

Drug product-Related substances (degradation products)... 

All of the monographs in the Handbook are thoroughly cross-referenced and indexed so that excipients may be identified by either a chemical, a nonproprietary, or a trade name. Most monographs list related substances to help the formulator to develop a list of possible materials for use in a new dosage form or product. Related substances are not directly substitutable for each other but, in general, they are excipients that have been used for similar purposes in various dosage forms. 

Due to the unique biosynthetic production process and molecular characteristics of biotechnological and biological products, the DS can include several molecular entities or variants. When these molecular entities are derived from anticipated post-translational modification, they are part of the desired product. When variants of the desired product are formed during the manufacturing process and/or storage and have properties comparable with the desired product, they are considered product-related substances and not impurities. 

Individual and/or collective acceptance criteria for product-related substances should be set, as appropriate. 

In addition to the evaluation of the purity of the DS and DP, which may be composed of the desired product and multiple product-related substances, the manufacturer should also assess the impurities, which may be present. Impurities may be either process- or product-related. They can be of known structure, may be partially characterized, or unidentified. When adequate quantities of impurities can be generated, these materials should be characterized to the extent possible and, where possible, their biological activities should be evaluated. 

Critical quality attributes may include items, such as potency, the nature and quantity of product-related substances, product-related impurities, and process-related impurities. Such attributes can be assessed by multiple analytical procedures, each yielding different results. In the course of product development, it is not tmusual for the analytical technology to evolve in parallel with the product. Therefore, it is important to confirm that data generated during development correlate with those generated at the time the marketing application is filed. 

The category of aggregates includes dimers and higher multiples of the desired product. These are generally resolved from the desired product and product-related substances, and quantified by appropriate analytical procedures (e.g., SEC and capillary electrophoresis). 

Drug substance (bulk material) The material that is subsequently formulated with excipients to produce the drug product. It can be composed of the desired product, product-related substances, and product- and process-related impurities. It may also contain excipients including other components, such as buffers. 

For biopharmaceuticals, the complexity of analytical test approaches is also reflected in guidelines concerning reference standards and materials (see ICH Q6B [22]). In principle, it is desirable to use the same reference material for both biophar-maceutical assays and physico-chemical testing, but in some cases a separate reference material may be necessary. It may also be necessary to establish distinct reference materials for product-related substances, product-related impurities and process-related impurities. 

Product-related variants may arise from the manufacturing, handHng, and storage of a biological drug substance. These molecular variants of the desired product include precursors, degradation products that may or may not have biochemical or biophysical properties comparable to those of the desired product with respect to biological activity, clinical efficacy, and safety. Conversely, product-related substances are molecular variants or isoforms of the desired produced form, and are not considered impurities. 

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