The Importance of Testing Bulk Substances

Kathy Heatherly, MSFS, ARL Technical Sales

A bulk substance, also known as an active pharmaceutical ingredient (API), is often the starting point of a compounded preparation.   Prior to use, compounding pharmacies and outsourcing facilities should confirm the quality of an active pharmaceutical ingredient to ensure consistency of the material as received from the supplier and suitability for use in a compounded preparation.  At a minimum, identity testing is recommended for each lot, but more rigorous testing should be evaluated. 

The United States Pharmacopeia, Food and Drug Administration, and International Council on Harmonization have published guidelines for testing APIs.  Per USP General Notices, 4.10.10. Applicability of Test Procedures,A single monograph may include more than one test, procedure, and/or acceptance criterion for the same attribute.  Unless otherwise specified in the monograph, all tests are requirements.  In some cases, monograph instructions allow the selection of tests that reflect attributes of different manufacturers' articles, such as different polymorphic forms, impurities, hydrates, and dissolution.” 

Per the cGMP Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act Guidance for Industry, published Dec 2018, “Components that are not approved finished drug products must be tested to verify identity and evaluated for conformity with appropriate specifications.”  An objective of the ICH Good Manufacturing Practice for Active Pharmaceutical Ingredients Q7 is to provide guidance for assuring API’s meet the quality and purity requirements that the manufacturer says they possess.  Sections 7.30 and 7.32 state, “For incoming production materials, identity tests and related methods should be used as described in the relevant sections of a pharmacopoeia monograph…The visual examination of a label or the material is not considered sufficient except where justified for processing aids, hazardous or highly toxic materials, other special materials...” 

Potency, Sterility, and Endotoxin testing performed on the finished product are not enough to detect changes that would indicate suitability of the API for use in compounding.  However, a test for identity only, may not provide enough information to ensure the API is fit for use in a finished product. 

Additional compendial test methods that should be evaluated include organic and inorganic impurities, enantiomeric purity, residual solvents, volatile matter, assay, and microbial enumeration.  Organic Impurities, both known and unknown can affect the quality, safety, and efficacy of drugs and should be controlled to avoid adverse effects in the finished product.  Elemental or inorganic impurities have very low permissible exposure limits in a finished product.  Verifying these impurities have been controlled is critical in ensuring that a product is suitable.   Control of enantiomers and/or isomers is also critical; as changes to their form may result in no physical change in appearance or the compounding process, but could result in a marked difference in pharmacology, toxicology, pharmacokinetics, metabolism, etc. of the finished product. 

With varying exposure limits depending on the route of administration and no therapeutic benefit to the finished product, the manufacturer’s results for residual solvents should be tested to ensure the material confirms to safety-based limits, ingredient and product specifications, and good manufacturing practices.  Volatile matter and assay value of the API to be weighed and used in compounding must be known.  Many of the USP monographs provide specifications for calculating the assay value that should be used when compounding a finished preparation.  If the substance is a hydrate, its anhydrous equivalent weight may need to be calculated.  On the other hand, if there is adsorbed moisture present, the weight of anhydrous drug substance may need to be calculated.  In addition to testing when the material is sourced, if there have been multiple entries into the container over the life of the material, it is also recommended to test the moisture content again; as additional moisture can affect potency of the finished product.  Testing of bioburden can confirm a controlled manufacturing process for API to be used in non-sterile preparations as well as verify the sterility assurance process for use of the API in a sterile finished product. 

Identifying the correct material has been sourced, verifying that the specifications are met, and the material is safe for use in finished preparations ensures the quality of a product that is used in compounding the finished preparation. 

For more information, contact ARL at 800-393-1595 or