Identifying and Characterizing Pharmaceutical Impurities in Less Time with Greater Certainty
Industry Insight Nov 22, 2013
This week saw ACD/Labs release the white paper, "Unified Laboratory Intelligence for Impurity Resolution Management" in which they discuss the need to identify and characterize impurities in pharmaceutical drugs quickly and with confidence.
We caught up with Ryan Sasaki, director of Global Strategy at ACD/Labs, to learn more about this and to understand how ACD/Labs helps enable researchers to identify and characterize impurities.
AB: Obviously we need to consider the toxicity of any impurities that appear in pharmaceutical drugs, are there any other reasons why pharmaceutical companies would be keen to minimize impurities?
Ryan Sasaki (RS): It's not simply toxicity; there are other unwanted safety side effects that may affect the commercial viability of a drug. Furthermore, impurities can also negatively impact the bioavailability and efficacy of the active pharmaceutical ingredient (API). Negative effects will depend on the nature of the impurity e.g. efficacy or dosage form performance reduced via reactions such as hydrolysis, electrophilic reactions (by aldehyde and carboxylic acid derivatives), oxidation or degradation (by peroxides or metals).
Regulatory agencies, including the FDA and ICH, mandate dose dependent thresholds for reporting, identification and qualification of impurities. For example, in the development of a formulated drug substance the FDA requires that all impurities introduced in the proposed process above 0.1 area percent need to be isolated and structurally characterized.
In addition, process chemistry groups spend time developing the most practical manufacturing routes and maximizing production yield is a high priority for process chemists. The quantities of various impurities that are present, can diminish the overall yield. The greater the number of impurities can make the process harder to keep in control and can be more demanding on QA/QC efforts.
Finally, the separation of impurities from the drug substance can be a huge undertaking which requires sophisticated, expensive, and time-consuming separation techniques. Significant efforts are made to simplify techniques required to separate impurities as they scale up from lab scale to manufacturing scale.
AB: Your recent white paper states that Impurity Resolution Management helps increase collaboration, how does this lead to increased productivity?
RS: The story we most often hear about the identification, characterization, and elucidation of impurities is that there is a lot of useful knowledge and information about a given impurity available at the time of determination. However, access to this information is a very big challenge. For example, Cummings et. al wrote a piece for the American Pharmaceutical Review that stated the most difficult problem a spectroscopist can encounter is a request for structure elucidation of a complete unknown with no sample history. Without any knowledge of the chemistry route, starting materials and impurities in them, as well as the solvent used, a significant effort can be required to determine the structure of all but the simplest compound. Impurity Resolution Management is a strategy specifically targeted at capturing live chemical and analytical impurity information from different cross-functional groups in drug development to give them real-time access to information and sample history.
AB: What can be done by manufacturers to decrease the occurrence of impurities in their drug formulations?
RS: The incorporation of good process/synthetic chemistry practices and separation science and method development philosophies and techniques. The goal is also to improve and leverage process knowledge as more experience is gained. Data mining (query/search) can help provide insight into historical campaigns bringing compounds to market by identifying details of process steps achieving maximal elimination of certain types of impurities.
AB: What are the main techniques for removing impurities from drug substances?
RS: Removing impurities can be challenging so the key is to control the occurrence and ensure it is below the recommended and established thresholds defined by regulatory agencies. Above certain thresholds, impurities require identification and characterization. Recrystallization is often the preferred experimental approach to removing impurities but extractions, selective adsorbents and chromatography are also common. There are a variety of techniques that are employed in the pharmaceutical industry to reduce, control and characterize impurities. Some examples are GC, HPLC, Capillary Electrophoresis, Optical and NMR Spectroscopy along with a series of hyphenated techniques.
AB: How does ACD/Labs enable researchers to identify and characterize impurities?
RS: We do this in a number of ways by helping drug development organizations put their analytical data into context. By managing the life-cycle of the API and the fate of its respective impurities, cross-functional groups can not only access data generated by other groups but also understand the context of that data to help them quickly and efficiently answer new questions. For example, when a structure elucidation group receives a characterization request for a newly identified impurity, they can quickly obtain and drill down on a full sample history and access live data of related impurities for quick comparisons and faster problem-solving.
One of the data management challenges in this environment is that the data generated is acquired by many different instruments from different manufacturers, which leads to a highly diverse collection of instrument data formats. ACD/Labs has built a vendor-neutral data management platform that enables a seamless capture of these diverse sets of data in one environment. Furthermore, the ACD/Spectrus platform enables scientists to connect their data with chemical structures, reaction-schemas, etc. to tell the story of their data and decisions. Having all this information in one place greatly simplifies access to this information as well as the creation of reporting elements that may be required for regulatory submissions and responses.