Anthony DeStefano, PhD, is 2013 president of the American Association of Pharmaceutical Scientists (AAPS).

Anthony J. DeStefano, PhD

Partnering is a crucial component of the development and commercialization of any new drug product or medical device. Partnering takes many forms, from the formation of internal teams to the development of external relationships needed to move drug discovery, development, or commercialization forward.

Models for internal partnering have evolved and improved over time as the groups that bring a drug from discovery to market become better integrated and effective teams. Achieving this integration requires that the members of each group become effective and efficient at their job and become familiar with the needs of the groups (internal or external) with which they interact. Good intra-group execution combined with managing inter-group interactions results in effective hand-offs and efficient processes.

External partnering has evolved in scope over the past several years, expanding from targeted, tactical outsourcing or insourcing designed to provide specific missing capacity or expertise, to a model that is much more strategic. For small companies, the need for strategic partnering is clear, because resources are not available for them to execute the broad range of studies, manufacturing, testing, distribution, and marketing necessary to bring drugs to market on their own. External strategic partnering is important to large companies as well, as they focus their in-house efforts on core capabilities and work with external resources to provide much of the rest.

This increase in external focus has led to a changing dynamic and an increase in the number of consultants and contract research organizations (CROs). The roles of CROs have in many cases expanded from providing services for one part of the drug-development effort to, in the extreme, becoming full-service providers. 

Demonstration of the continuity of systems and processes and adherence to cGMPs is typically straightforward for internal efforts but can be difficult when dealing with external partners. For post-market contract manufacturing arrangements for drugs, FDA has issued a guidance outlining the reasoning for, and the components of, quality agreements for these arrangements. While this guidance applies to marketed products, the logic behind it applies to any external arrangement. Ultimately, the owner of the drug is responsible for assuring and demonstrating at any stage of development that the drug meets its quality standards and is manufactured and tested to the applicable cGMP standards. Written agreements serve to assure that responsibilities are clear, no crucial component falls through the cracks, and that procedures for dispute resolution are in place. 

Through its educational and networking opportunities, the American Association of Pharmaceutical Scientists (AAPS) plays an important role in partnering throughout the drug- development and commercialization process. Webinars, workshops, short courses, sessions at the annual meeting and exposition, discussion- and focus-group interactions provide venues for scientists to develop and hone their individual skills and to interact with individuals that are facing similar work-related challenges. Networking at the annual meeting, regional meetings, and cross-group interactions with regulatory scientists, CRO members, and members representing their individual technologies, provide venues to better understand the needs of other groups and develop a broader understanding of the context in which one works. 

AAPS is committed to furthering its educational and networking offerings and to working with its members to be a key resource in making partnering at all levels more effective. 

Articles

Through its educational and networking opportunities, the American Association of Pharmaceutical Scientists plays an important role in partnering throughout the drug- development and commercialization process.

Changing the Dynamic of CROs

The United States Pharmacopeial Convention (USPC) asked the Institute of Medicine (IOM) of the National Academy of Sciences to convene a workshop at which stakeholders, including pharmaceutical manufacturers, could discuss ways to update 

General Chapter <231> "Heavy Metals" (1). IOM responded positively and formed a planning committee composed of national and international experts in metal measurement and toxicity.  

The workshop took place at IOM Aug. 26–27, 2008. In an effort to promote harmonization and at USP's request, IOM invited compendial experts from Europe and Japan to attend. Because 

 <231> is relevant to food ingredients (standards are provided in USP's 

) and dietary supplements (standards are provided in 

's dietary supplement section), IOM also invited stakeholders from those sectors. 

 <231> relies on classical (i.e., wet) chemistry procedures that have been in the compendium for more than 90 years. The test suffers from a lack of instrumental output and is a nonspecific, subjective test based on the precipitation of metal sulfides from a solution with visual comparison to the color of a standard solution (2). Several groups have shown that the method routinely underestimates the levels of the few metals it was designed to detect (2, 3). Certain toxic metals thus may appear in drug products and their ingredients because of their use as catalysts or starting materials. Other metals such as arsenic, cadmium, lead, and mercury are highly toxic and ubiquitous in the environment. Not surprisingly, many of these metals also have been detected during market surveillance of dietary supplements and food ingredients (4). 

Workshop deliberations resulted in a consensus that the current classical chemistry procedure in 

 <231> is no longer suitable. Participants agreed that the current procedure should be replaced by specific and sensitive instrumental procedures that detect and quantify the broad range of metals and elements of interest in pharmaceuticals, dietary supplements, and food ingredients. 

Modern instrumental methods can identify and quantify at low levels many metals that currently are not detected by 

 <231>. Because many metals may not pose a public health risk when consumed for a brief time or at low levels, the challenge for participants was to identify metals of interest, and levels that should be monitored, especially considering the broad range of exposures posed by articles such as food ingredients. 

For certain metals (e.g., arsenic, cadmium, lead, and mercury) analysis was relatively straightforward. These substances have known toxic effects and are potential contaminants. Thus, analytical methods should be validated to detect arsenic, cadmium, lead, and mercury. The methods should detect the metals at toxicologically relevant concentrations; and pharmacopeial monographs for these metals should be revised. 

Workshop participants grappled with the questions of which metals should be monitored and to what level of detection. The European Medicines Agency (EMEA) has released a 

Guideline on the Specification Limits for Residues of Metal Catalysts

 (5). Because the metals specified in the guideline are sometimes used as catalysts or processing agents and can appear as contaminants in drug substances and drug products, EMEA recommends that pharmaceutical manufacturers test for them at levels commensurate with their toxicity.  

Workshop participants identified various reagents that may require monitoring and contain elements such as aluminum, beryllium, boron, chromium, cobalt, copper, gallium, germanium, gold, indium, iron, lithium, magnesium, manganese, nickel, silicon, silver, tin, thallium, titanium, and zinc. 

Speciation (i.e.,  valence state of the metal or its existence as an organic complex) can play an important role in toxicity. The cases of arsenic and mercury are instructive: Inorganic arsenic compounds are typically highly toxic. Dietary supplements that contain kelp or certain other nontoxic materials also contain high concentrations of essentially nontoxic organoarsenic compounds. Similarly, metallic mercury is relatively nontoxic, but inhaled mercury metal, methyl mercury, and similar organomercury compounds that can be concentrated in foods such as fish are highly toxic. Thus, workshop attendees concluded that tests for arsenic or mercury  by themselves may not yield suitable data on which to base specifications. Further, reports of total arsenic or total mercury content may unnecessarily confuse consumers about the safety of the products they consume, leading the public to question the efficacy of regulatory standards. 

 Participants agreed that several related factors must be considered when evaluating the acceptable rate and extent of exposure in vulnerable populations. Humans may experience degrees of environmental exposure to metals.  

Another consideration is the duration of exposure. Long-term exposure to lead is associated with decreased intelligence quotient, and long-term exposure to organic mercury causes neuropathic effects. Concurrent exposure to both metals has not been well studied, but risk-assessment models suggest incremental risk.  

 If analysts do not separate metal forms (i.e., perform speciation) before undertaking metal analysis, the results will report the total of all forms detected (e.g., the method will report both inorganic and organic arsenic). Workshop participants did not reach a consensus about the level of detection required for each metal. A reasonable approach might involve the development of pharmacopeial specifications for the total amount of an individual metal at some limit (worst case), and requiring manufacturers to use speciation to justify a higher limit. 

Workshop participants decided that the following tests are probably suitable for compendial metal analysis: electrothermal atomic absorption spectrometry, inductively coupled plasma–optical emission spectrometry, inductively coupled plasma–mass spectrometry, and any other methods with similar specificity and sensitivity. 

 <231> will rely on reference materials to demonstrate recovery (i.e., precision and accuracy) during sample preparation and analysis. Reference materials also are needed to establish systems suitability and quantitation or detection limits, particularly when several technologies may be used to produce acceptable results. 

Workshop participants advocated the revision of 

 <231>. Further consideration of limits for various metals will be required. Arsenic, cadmium, lead, and mercury were singled out by participants for particular attention. Other metals used in manufacture or present in starting materials will be considered using a risk-based approach. USP will continue to work with stakeholders to update General Chapter <231> using harmonized approaches and a public process of review and comment. 

 is executive vice-president and chief executive officer, 

 is chief science officer, all at the United States Pharmacopeial Convention, 12601 Twinbrook Parkway, Rockville, MD 20852-1790, tel. 301.816.8184, 

. *To whom all correspondence should be addressed. 

 26 General Chapter <231>, "Heavy Metals," pp. 133–134. 

 2.  T. Wang et al., "An Atomic Spectroscopic Method as an Alternative to Both 

 3.  USP Ad Hoc Advisory Panel on Inorganic Impurities and Heavy Metals, "General Chapter on Inorganic Impurities: Heavy Metals," 

 4.  D.R. Abernethy et al., "Adulteration of Drugs and Foods: Compendial Approaches to Lowering Risk," 

Guideline on the Specification Limits for Residues of Metal Catalysts 

Attendees at a recent workshop endorsed new methods to detect metals in drugs, dietary supplements, and food ingredients.