Excipient Control Strategies in China

As China emerges as a significant supplier of pharmaceutical ingredients, it must assure other countries of the safety of its excipients. China's State Food and Drug Administration (SFDA) intends to revise its excipient-control regulations to protect consumers at home and abroad. The agency has begun to meet with international trade organizations such as the International Pharmaceutical Excipients Council (IPEC) to hear industry's concerns. The author describes the contacts between SFDA, IPEC, and other international bodies. The article explains what SFDA has learned and how it may adjust its regulations for the future.

As China's role in the global pharmaceutical market increases, the Chinese State Food and Drug Adminstration (SFDA) and many China-based pharmaceutical manufacturers and excipient producers are beginning to collaborate with their international counterparts on excipient-control issues. Compliance with appropriate good manufacturing practices (GMPs) throughout the entire excipient distribution supply chain and an understanding of international regulatory and pharmacopeial excipient controls are critical components for ensuring that pharmaceutical excipients are safe and of acceptable quality. The recent tragedies related to contaminated glycerin and other products sourced from China underscore the need for safe excipients.

China's proposed new license requirements for the manufacture and use of excipients

During the last two years, several regulatory developments related to the manufacture, importation, and use of excipient ingredients in China have taken place. In the past, China has required certain types of licenses for the manufacture and use of excipients in the country. Recent proposed changes to the registration requirements, however, could significantly affect the future availability of excipients produced in China for the country's domestic market and for export.

SFDA issued new Drug Excipients Registration Application Materials requirements on June 21, 2005. The regulation covered various excipient-registration requirements, including those for imported excipients. In December 2005, SFDA revised these requirements and proposed a new set of regulations to control excipients used in products marketed in China. The regulations would establish new GMP and manufacturing rules for excipients produced in China and new requirements for obtaining an import license for pharmaceutical excipient ingredients that are produced outside of China.

To obtain an import license under these proposed regulations, excipient manufacturers would be required to provide additional detailed information concerning the manufacture of their pharmaceutical ingredients and specific additional data to substantiate the excipient's safety for its intended use. The regulations would apply to new excipients and commonly used compendial excipients that have been used for years in China. The level of data and information that the proposed regulations would require significantly exceeds what has been previously required in China. The requirements also exceed the amount of information generally required in other major market countries, especially for compendial excipients. The proposed regulation would require the pharmaceutical manufacturer to obtain a copy of the license for each excipient in its formulation from each of its excipient suppliers to support the use of these excipients in drug products made in China.

Proposed regulations for excipients that are produced domestically in China are similar to those for excipients that are imported into China from foreign manufacturers. Domestic excipient manufacturers must meet a higher quality and GMP standard than China has typically required in the past, and they must supply more information to SFDA about their products and processes. In addition to the current requirement of being registered with SFDA, excipient manufacturers would also be routinely inspected for GMP compliance. The regulations as applied to domestic Chinese excipient manufacturers will significantly affect these domestic excipients' availability and cost. Additionally, the proposed import license requirements would potentially increase costs significantly for all multinational excipient companies who intend to supply their excipients to China. The requirements could cause some companies to stop supplying the Chinese market because of cost and intellectual-property concerns.

The licensing requirements for imported excipients are somewhat different from those for domestic Chinese manufacturers and contain many criteria that are especially difficult for many excipient manufacturers to meet (see sidebar, "SFDA's proposed requirements for obtaining an import license").

SFDA proposed requirements for obtaining an import license

In the past, excipients used in China were regulated in the same manner as drugs or active pharmaceutical ingredients (APIs). The domestic implementation of licensing requirements was somewhat inconsistent for excipients, however. SFDA proposes to separate the regulation of excipients to facilitate improved control of quality for both domestic and imported excipients. The goals of their proposed excipient regulations are to improve the quality of excipients, minimize safety risks, and to align SFDA regulations with international standards. In developing the excipient regulations, SFDA has proposed to use the basic principles of its drug regulations as a foundation for excipient regulation. The proposed regulations, however, do not recognize the significant differences between excipients, APIs, and drug products in terms of typical international regulatory requirements.

The International Pharmaceutical Excipients Council of the Americas (IPEC-Americas), a trade association of manufacturers of excipients and drug products, has led an industry coalition representing excipient producers and users that works with SFDA to clarify the requirements for obtaining a Chinese import license and to assist SFDA in achieving its goal of improved excipient quality and safety. IPEC-Americas representatives have attended meetings with SFDA to discuss the differences between excipient regulations in the US, Europe, and Japan and the proposed excipient regulations in China. A coalition coordinated by the International Pharmaceutical Excipients Council (IPEC) has requested several changes to the proposed regulations to achieve better harmonization with international standards and requirements. The IPEC Coalition includes IPEC Americas, IPEC Europe, and the Japanese Pharmaceutical Excipients Council (JPEC).

Status of proposed licensing regulation

The IPEC Coalition, in collaboration with the US Department of Commerce, presented the industry's concerns to SFDA at a meeting of the Joint Commission on Commerce and Trade (JCCT) in March 2006. This discussion, along with several follow-up meetings in April 2006, resulted in a fairly favorable first step toward improved excipient regulation. The IPEC Coalition and other participants provided SFDA with information about the regulation of excipients in the US, Europe, and Japan and identified problem areas in SFDA's proposed regulations that would significantly affect both excipient manufacturers seeking import licenses and pharmaceutical companies who would use these materials in China.

SFDA informed the participants that, unlike in most developed countries where pharmaceutical manufacturers essentially regulate their use of excipients with limited regulatory agency oversight, China's government must be responsible for excipient quality. SFDA believes that many Chinese pharmaceutical manufacturers do not have good systems in place to properly qualify excipient suppliers and control excipient quality. SFDA believes that the government must step in to provide adequate protection to Chinese consumers. Accomplishing this goal may require some type of excipient licensing system, according to the agency.

On the other hand, SFDA wants to draft regulations based on appropriate international standards and does not want to impose unrealistic regulations on imported excipients. The agency expects to be able to review the same type of information used to establish excipient quality and safety that is required by international regulatory authorities during the drug-registration process. Since most regulators outside China do not require significant detailed information to be submitted for compendial excipients, SFDA may relax its proposed license requirements for these types of materials.

SFDA and the Coaltion agreed that detailed safety and manufacturing information should be required for the licensing of new excipients and that the regulations should reflect the different needs for evaluating compendial excipients versus new excipients.

SFDA stated that it will study the excipient GMPs and other guidelines provided by the IPEC Coalition to further revise its excipient regulations. SFDA expressed a desire to learn from other countries' success and to use that experience to develop excipient regulations for China. SFDA also noted that although the new excipient regulations have been proposed, no firm implementation date had been set, and that it was unlikely that they will be finalized until 2008. SFDA will use the time to carefully review and assess the documents supplied to them, as well as the various presentations made during its meetings with IPEC Coalition representatives.

One outcome of the 2006 meetings was the recognition of the need to hold an excipient conference in China to discuss how excipients are regulated globally. Such a conference would facilitate SFDA's collaboration with industry for a mutually beneficial resolution of the licensing requirements. In 2007, the IPEC Coalition has continued to help SFDA develop excipient regulations that are science-based and achievable without causing undue regulatory burden that may result in some excipient manufacturers exiting the marketplace.

IPEC–CCPIE excipient-control strategies conference

More than 150 people participated in an International Excipient Control Strategies Conference in Beijing on March 13–14, 2007. The conference was organized by the China Center for Pharmaceutical International Exchange (CCPIE), IPEC Americas, IPEC Europe, and the Japanese Pharmaceutical Excipient Council (JPEC), with help from the Research and Development-Based Pharmaceutical Association Committee (RDPAC) in China. The meeting attracted at least 30 SFDA division directors and other agency personnel, plus many Chinese and international excipient and finished-drug manufacturers.

The conference was designed to provide the pharmaceutical and excipient industry, SFDA, and several major pharmacopeias an opportunity to interact on topics related to the control of excipients used in pharmaceutical products marketed in China and the rest of the world (see sidebar, "Goals of the International Excipient Control Strategies Conference").

Goals of the International Excipient Control Strategies Conference

Speakers at the conference included Zhang Wei, director of SFDA's Department of Drug Registration; Wang Ping, deputy general secretary of the Chinese Pharmacopeia; Dr. Agnes Artiges, director of the European Pharmacopoeia; Dr. Kiyomi Ueno, director of the Japanese Pharmacopeia's standards division; Dr. Roger Williams, chief executive officer of the US Pharmacopeia (USP); and Dr. Catherine Sheehan, USP's director of excipients. Several industry speakers from IPEC member companies described how pharmaceutical excipients are evaluated for safety and controlled for quality throughout Europe, Japan, and the US. Song Ming Xian, director of the regulatory division of the Sichuan Provincial Food and Drug Division, summarized current SFDA excipient GMP regulations and described the need for a Chinese industry association dedicated to improving excipient quality.

Zhang Wei, director general of SFDA's registration department, gave the opening speech, which provided interesting information about what direction SFDA may take when it revises the draft excipient regulations. He provided his vision of how SFDA might regulate excipients in the future.

In his speech, Wei addressed many of the issues that the IPEC Coalition had raised regarding SFDA's draft regulation, and he indicated that more flexibility is warranted. Wei recommended that the licensing requirements for the most common compendial excipients could potentially be eliminated and that a DMF-type system be established for premixed and coprocessed excipients. He stressed, however, that a detailed licensing system would need to be set up to control excipients intended for injections because of the high level of risks associated with these materials.

SFDA's concepts regarding this regulation have changed significantly since the agency proposed its original draft. At that time, it appeared that the agency would publish a regulation that would create great difficulties for industry without benefiting consumers. The ongoing dialogue between the IPEC Coalition and SFDA seems to have influenced the debate over the regulations in a positive way.

All the speakers described how excipients are controlled from various perspectives in each major market region. The excipient conference provided a valuable overview of global excipient regulations.

After the conference, Wei reported that the expected redraft of SFDA's excipient regulations in China would be postponed until 2008 and that some changes might be based on comments made to the agency.

IPEC discussed the formation of an industry-based excipient working group in China, which is currently being explored. IPEC proposes to organize an excipients organization in China that would be similar to other IPEC groups. Each group originally formed after a major excipients conference at which it became obvious that such a group would benefit the industry, pharmacopeias, regulatory agencies, and consumers. IPEC hopes to form an excipients working group in China in late 2007 and has continued working with SFDA since the March 2007 conference on excipient controls.

SFDA visits US manufacturing facilities

IPEC Americas worked with the US Department of Commerce to enable SFDA to visit two excipient-manufacturing facilities and one API-manufacturing facility. SDFA representatives conducted visits during their trip to the Annual JCCT meeting in Washington, DC, on April 9–12, 2007. SFDA wanted to tour excipient and API facilities to see how US manufacturing facilities for excipients and APIs meet GMPs. The agency also wanted to understand how manufacturing processes for these materials are controlled in the US.

The seven-person SFDA delegation and its hosts from the US Department of Commerce toured three US ingredient-production facilities at the invitation of IPEC-Americas members. On April 9, the group toured Colorcon's "Opadry" manufacturing facility in West Point, Pennsylvania, and saw FMC's "Avicel" manufacturing facility in Newark, Delaware. On the next day, the group visited Johnson & Johnson's Wilmington, Delaware, plant, which produces APIs for the company's finished drugs (see sidebar, "Officials visit drug-manufacturing facilities").

Officials visit drug-manufacturing facilities

These productive visits helped establish a good working dialogue between SFDA, the Department of Commerce, and the US pharmaceutical and excipients industry. The SFDA representatives were impressed with the level of GMP controls in place at the abovementioned companies. They planned to use the information they gained to modify the excipient and API control strategies they will implement in China.

Recent events affect SFDA's improvement plans

Since the April meetings, several international events have highlighted concerns about the quality and safety of excipients and other food ingredients and products sourced from China. More than 100 people died in Panama after taking drugs that were contaminated with Chinese-produced glycerin that was adulterated with diethylene glycol, a poisonous chemical used primarily to manufacture antifreeze. Chinese-produced toothpaste that contained diethylene glycol was found in various US locations. Many pets in the US died from Chinese-sourced pet food ingredients that had been contaminated with melamine. Various other quality problems involving Chinese products have surfaced and received much media coverage. In addition, several high-profile corruption charges have been made against former SFDA officials. Some charges resulted in the imposition of the death penalty.

These events have put tremendous pressure on the Chinese government and SFDA to immediately eliminate corruption and strengthen regulatory controls of the manufacture of food and drug products, including excipients and food additives. SFDA has taken several measures to exercise oversight, but the magnitude of the problems will require much of the agency's resources in the coming months. It is uncertain how these problems will affect the timing of SFDA's planned revisions to its excipient regulations and SFDA's desire for flexibility in harmonizing regulations with international agencies.

IPEC's future

IPEC will continue to work closely with SFDA to help the agency improve its excipient-control systems and establish a sound approach to maintaining excipient safety and quality for products produced in China for the domestic and international markets.

SFDA has invited IPEC to participate in an upcoming SFDA internal training program in October 2007. IPEC will provide training to SFDA inspectors and reviewers regarding international excipient-control strategies, excipient GMPs, and DMF systems. IPEC will provide a full-day seminar for SFDA personnel on Oct. 29, 2007.

IPEC hopes to announce the formation of an IPEC Excipient Working Group in China at the SFDA training session. The working group would act as a focal point for collaboration on excipient issues between SFDA and the domestic and international excipient and pharmaceutical industries.

IPEC Americas is also helping the US Food and Drug Administration establish improved excipient-control systems for the importation of excipients from China and other countries. FDA formed a task force in response to the recent tragic events and is trying to determine the best approach to prevent these tragedies from occurring again. FDA asked IPEC Americas for assistance because IPEC has drafted many excipient-control guidelines such as the IPEC–Pharmaceutical Quality Group Excipient GMP and Auditing Guidelines, the IPEC Good Distribution Practices Guideline, the IPEC Americas Certificate of Analysis Guideline, and the IPEC Americas Significant Change Guideline for Bulk Pharmaceutical Excipients.

IPEC Americas' latest effort is the development of an Overall Excipient Qualification Guideline that outlines a process for qualifying the entire excipient supply chain from the manufacturer to the user. This guideline reflects the international concern about excipient safety. IPEC Americas plans to launch the first phase of this guideline at its Regulatory Affairs Conference on Sept. 10–11, 2007.

The ongoing collaboration of industry groups such as IPEC with SFDA and FDA will effectively provide appropriate excipient controls that benefit the consumer by improving drug safety and quality. This collaboration and dialogue will also ensure that new regulatory requirements are reasonable and do not create non-value-added costs in the system that would unnecessarily increase drug prices without providing any further improvements in safety to the consumer.

David R. Schoneker is chairman of the International Pharmaceutical Excipients Council of the Americas. He also is director of global regulatory affairs at Colorcon, 1936 West Point Pike, West Point, PA 19486, tel. 215.699.7733, dschoneker@colorcon.com.