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44 October 2015 Tablets & Capsules Pharmaceutical scientists invest a lot of effort designing and selecting suitable forms (salt, solvate, crystal habit, etc.) of active pharmaceutical ingredients (APIs) to maximize their chemical stability and biopharmaceuti- cal properties. But then the API is often bathed in a pool of excipients that is itself a soup of potential impuri- ties, including organo-peroxides, reac- tive aldehydes, low-molecular-weight organic acids, metals, residual solvents, as well as a series of micro-pH envi- ronments. Subsequently, this API-excipient blend is often exposed to solvents, shear, and extreme pressures (tablet compression, roller compaction, etc.), making the API in the finished dosage form more susceptible to undesirable chemistries (higher amorphous con- tent, reactive fissures in the crystal lat- tice, etc.). So how does one explore all present and future potential exposures to excipient impurities for all imagin- able process exposures? Traditionally, one has made mini- formulations of excipients in the lab and assessed their processability and stability. But that doesn't capture the full potential of the variability of the impurity levels that could occur in other batches of the "same" material. And many suppliers don't fully charac- terize the impurity profiles of their excipients or offer a comprehensive database about them. Thus, buyer beware. (Characterization of heavy metals will soon be a compendial requirement [1].) Conducting forced stress studies [2] is a more robust approach to mapping an API's susceptibilities to potential degradation pathways and should be followed by a risk-based assessment that reveals an excipient's impurity profile. Next, one should determine the ability of those impurities to initi- ate undesirable chemistries in the final dosage form. Measuring an API's susceptibility to oxidative degradation, for example, can help you determine how much exposure to potentially oxidative pro- moters, such as organo- and hydro- peroxides, is acceptable [3]. The more robust the API is against oxidation, the more freedom you have in selecting excipients. Conversely, APIs more sus- ceptible to oxidation would force you to consider more carefully the expo- sures that could occur from current and future batches of excipients. That's not to say that variable amounts of organo-peroxides in excip- ients are always at fault. In one instance, the formation of an oxidative degradant stemmed from exposure to heat and moisture during manufactur- ing. This was addressed with process controls [4]. While it's possible to measure organo-peroxides in excipi- ents [5], few excipient manufacturers do it and the potential for batch varia- tion is often not understood or con- trolled. In another example, a registration batch of a product undergoing 12- month stability testing unexpectedly degraded, which was surprising because tests had shown that the API's temperature had to exceed 200°C before a "potential" degradant appeared. Careful study revealed the culprit: Iron impurities (at the part-per- billion (ppb) level) were binding to one of the excipients and then cou- pling visible or UV light to catalyze an iron-mediated photo-oxidation [6]. Because controlling the level of iron impurity in this product's excipients wasn't practical, formulators relied on the primary packaging and process changes to mitigate the degradation risk [7]. Not all cases of excipient impurities can be resolved with tighter controls on the excipient raw materials, and some compromises are likely during late-stage development. However, understanding the API's degradation potential first and the excipient's impu- rity potential second can offer an effective control strategy. T&C References 1.General Chapter on Heavy Metals <231>, USP 38/NF 33. 2."Stress Testing: A Predictive Tool" in Pharmaceutical Stress Testing, Eds. Baertschi, Alsante, Reed (London) 2011, pp 10-48. 3.PA Harmon, K. Kosuda, E. Nelson, M. Mowery, and RA Reed. A novel peroxy radical based oxidative stressing system for ranking the oxidizability of drug sub- stances, J Pharm Sci 95(9) (2006), 2014-28. 4.PA Harmon, WP Wuelfing, AB Harman, JC Givand, SD Shelukar, and RA Reed. Role of organic hydroperoxides on process robustness and finished prod- uct quality. AAPS Annual Meeting, Baltimore, MD, November 2004. 5.WR Wasylaschuk, PA Harmon, G Wagner, AB Harman, AC Templeton, H Xu, and RA Reed. Evaluation of hydroperoxides in common pharmaceutical excipients J. Pharm. Sci. 96(1) (2007), 106-116. 6.RA Reed, PA Harmon, D Manas, W Wasylaschuk, C Galli, R Biddell, PA Bergquist, W. Hunke, AC Templeton, and D Ip. The role of excipients and package components in the photostability of liquid formulations. PDA J Pharm Sci Tech. 57(5) (2003), 351-368. 7.AC Templeton, D Manas, H Xu, and RA Reed. Implications of photochemical activity on the manufactur- ing, packaging, labeling and use of formulated products. Fourth International Meeting on the Photostability of Drugs and Drug Products, Research Triangle Park, NC, July 2001. [Editor's note: To comment on the Back Page, visit www.tabletscapsules. com.] Robert A. Reed is vice president, regulatory (CMC) and quality at Aradigm, 3929 Point Eden Way, Hayward, CA 94545. Website: www.aradigm.com. He earned a B.S. in chemistry from Eastern Nazarene College and a Ph.D. in analytical chemistry from the University of North Car- olina at Chapel Hill. He will address this topic further during a roundtable discussion October 27 at the AAPS annual meeting in Orlando, FL: "Excipient Variability: A Fuss or a Big Deal?" Details are available here: bit.ly/ExcipVar15. b a c k p a g e Excipient variability: A very big deal sometimes