China’s New Pharmaceutical Excipient Regulation Stresses Responsibility for Quality Assurance, Supply Chain Management (Part One)

This is the first of a two-part analysis on China’s new Pharmaceutical Excipient Measures. Part Two is available here.

On February 1, 2013, China’s “Measures to Strengthen the Supervision of Pharmaceutical Excipients” (Notice No. 212, 2012) (“Pharmaceutical Excipient Measures” or the “Measure”) came into force.  This Measure was issued by the State Food and Drug Administration (SFDA) in the wake of a recent drug contamination incident that began with the March 2012 discovery of 77 million medicinal gel capsules made from industrial gel containing chromium, a carcinogenic heavy metal.  The ensuing investigations led to the official announcement in May that 254 pharmaceutical suppliers, constituting 12.7% of capsule makers, were producing tainted products.  Ultimately, the authorities ordered 42 capsule makers to stop production, closed 84 production lines, revoked the licenses of seven companies, and referred 13 company officials for criminal prosecution..

The SFDA issued the Pharmaceutical Excipient Measures in August 2012, imposing new obligations on both pharmaceutical preparation producers (i.e., finished drug makers [“drug makers”] as distinguished from producers of active pharmaceutical ingredients) and excipient manufacturers.  The Measures place the responsibility for the quality of excipients directly on drug makers by requiring that they:  (1) audit suppliers both at the start of the business relationship and periodically throughout its duration, in accordance with the 2011 revision of pharmaceutical good manufacturing practice (GMP); (2) test batches of excipients according to relevant quality specifications; and (3) check the control records of each supplier.  Central to the drug maker/excipient producer relationship is the use of quality agreements: legally binding agreements negotiated by the parties to define mutual responsibilities for quality activities and how quality issues will be resolved, so as to ensure that the excipients produced under the agreement will be safe and are suitable for the drug maker’s intended use.

Likewise, excipient producers are responsible for taking measures to ensure the quality of their products, including:  implementing and adhering to excipient good manufacturing practices (e-GMP), as issued by the SFDA in 2006; auditing their own raw material suppliers; conducting testing on each batch of excipient produced; and notifying their customers of changes that may affect product quality.

In addition, the Pharmaceutical Excipient Measures set out an enhanced regulatory regime; namely, for drug makers, registration of their products will now include information identifying the types of pharmaceutical excipients used, suppliers, quality standards, and results of supplier audit.  Further, a supplemental application must be filed in connection with changes in excipient use and must include analytical data on the excipient as well as an audit of its supplier.

For excipients that are new to the (Chinese) market or considered high risk, prior registration and approval are required and their manufacturers must obtain a Drug Production License.  Excipient registration requirements include submission of certain requested documents and on-site inspection, in accordance with e-GMP, by provincial-level FDA (PFDA).  As for all other excipients, records of the product and its manufacturer must be established and maintained with the PFDA.  Again, appropriate documents must be provided, although on-site inspections and random testing will be conducted only as necessary.  Imported excipients will be regulated under this bifurcated scheme as well.  In addition, the SFDA will set up a national database to monitor the production and application of all pharmaceutical excipients, plus a credit reporting system for excipient producers.

For more on the Pharmaceutical Excipient Measures, read Part Two of our analysis.