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Clarifying GMPs for excipients used as actives.
Excipients used as active ingredients in pharmaceutical products, otherwise known as atypical actives, have received much attention during the past several months. Industry is questioning whether—and why—these unique ingredients need to comply with the International Conference on Harmonization's Q7 guideline on GMPS for active pharmaceutical ingredients (1). Pharmaceutical Technology spoke to David R. Schoneker, past chair of the International Pharmaceutical Excipients Council, to gain some insight into the ongoing debate.
A typical actives, defined as excipients that are used as active ingredients in pharmaceutical products, have been around for decades and presumably represent little or no risk to patients. They can be found in many common over-the-counter items such as rubbing alcohol (the atypical active is isopropyl alcohol) and antacids (the atypical active is calcium carbonate). So why all the recent attention over their use?
Since the International Conference on Harmonization (ICH) finalized its Q7 guideline on GMPs for active pharmaceutical ingredients (APIs) in 2000, actives have received greater scrutiny. Quality-by-design approaches and recent supply-chain security problems have encouraged this in-depth review. Industry thinking is that, even though ICH Q7 is not a legal requirement, excipients used as APIs should adhere to the guideline (1). However, most excipients are not designed to be used as an active and are produced using GMPs aligned with the 2006 International Pharmaceutical Excipients Council–Pharmaceutical Quality Group (IPEC–PQG) Excipient GMP guide (2). Requirements between the two guidelines differ, and there is controversy regarding what should be expected in terms of compliance for atypical actives.
To understand why this difference exists, it is important to step back and look at the excipient industry in general. The chemicals used as excipients are used in many industries, including chemicals and petrochemicals, food, and plastics. Only a small percentage of all these chemicals used as excipients are found in pharmaceuticals. Excipients that are supplied to the pharmaceutical industry are largely produced and intended for use as inactive ingredients in drug formulations, not as active ingredients.
There are processing differences, too, explains David R. Schoneker, past chair of IPEC and director of global regulatory affairs at Colorcon. "In general, full GMPs for APIs begin to be applied early in their manufacturing process, whereas GMPs for excipients are applied later in the process, such as during final finishing steps," he says. API makers know from the start that their material is going to be used in a pharmaceutical product. Excipient makers may not have this same knowledge. The degree of documentation and oversight of the manufacturing process also varies between APIs and excipients. "Although the principles and areas of concern are the same, there are additional second checks and oversight (e.g., additional validation) with APIs, and there is a significant cost associated with this," adds Schoneker.
At present, there are no official FDA GMP regulations that exist specifically for excipients. "They are considered drugs according to the federal Food, Drug, and Cosmetic Act, but that document only says that 'appropriate GMPs must be used,'" explains Schoneker. For this reason, the IPEC–PQG Excipient GMP guide is helpful to excipient makers looking to apply best practices. In fact, IPEC and PQG, with FDA collaboration, are working to get their excipient GMP guide approved as an official ANSI standard by the end of 2011. If this occurs, the document will become the national standard for Excipient GMP in the US, and FDA will be able to use it and reference it officially as the acceptable GMP practice for excipient manufacture during inspections.
The IPEC–PQG guide and the pending ANSI standard would apply to general pharmaceutical excipients, however, and not to excipients used as actives. And this is where a resolution is needed, says Schoneker.
Many FDA investigators expect ICH Q7 to be adhered to when excipients are manufactured for use as actives in a drug product, he says. ICH Q7 has been used by FDA as the GMP standard in a number of inspections of excipient manufacturers that were not aware that a pharmaceutical company was using its excipient as an active. In these cases, the excipients manufacturer is often caught off guard. When FDA shows up to do a routine preapproval inspection, it can result in a Warning Letter for noncompliance to ICH Q7 even though the excipient manufacturer may inform FDA that it had no intent for is material to be used as an active by its customers.
Part of this problem is due to a lack of communication between final dosage-form drug manufacturers and excipient manufacturers—it is often the case that the excipient manufacturer and/or supplier do not know the use of a particular excipient. Industry and regulators are trying to improve this dialogue through various transparency and information-sharing initiatives.
But the bottom line is that excipient manufacturers and suppliers do not want to have to upgrade their facilities or processes to adhere to ICH Q7 for excipients used as atypical actives, especially when they have little business interest in selling their excipient products for these purposes. The additional controls, documentation, and cost, in most cases, would not be worth their return on investment. As a result, they may turn away from the pharmaceutical industry and this action could lead to a shortage of supply of the atypical actives. This would be a huge problem, says Schoneker, because it could force many drug manufacturers to have to reformulate their products or it could lead to the removal from the marketplace of many commonly used products.
To address these growing concerns, IPEC has been working with PDA and other industry stakeholders to develop a guideline specifically for atypical actives that would ultimately have FDA buy-in. Some potential solutions, says Schoneker, would involve having regulatory flexibility related to GMP expectations for existing atypical actives that have been used for years without safety problems. For atypical actives used in drug products, use of the IPEC–PQG excipient GMP guide, would be an appropriate GMP to use. There may be situations where additional technical considerations or specifications are required depending on the specific aspects of a particular material and its use. These details would need to be negotiated between the excipient manufacturer and the final drug-product manufacturer based on the material's intended use, he explains. Additional technical considerations and specifications, however, are not a higher level of GMP. The separation of the two definitions needs to be discussed among industry and regulatory authorities.
"We need to have a resolution that is acceptable to excipient makers, users, and regulators that makes them feel comfortable that appropriate controls are in place and that provides security to makers and users that they are not in a position of liability," says Schoneker.
IPEC's working group on atypical actives is in the process of working through this subject and will be presenting ideas and discussions at various upcoming industry meetings. For more information, please contact IPEC–Americas at IPECAMER@aol.com.
1. ICH, Q7 Good Manufacturing Practice for Active Pharmaceutical Ingredients (2000).
2. IPEC–PQG, GMP Guide for Pharmaceutical Excipients (2006).