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Understanding European GMPs and new rules from China for excipients are crucial for formulating solid-dosage drugs.
Understanding the regulatory requirements in the countries in which a drug will be manufactured or sold is crucial. Pharmaceutical Technology interviewed Yuwei Heinzel, head of Pharma Registration with Merck KGaA in Darmstadt, Germany, and Cloris Tian, senior regulatory manager for Merck KGaA in Asia-Pacific and China, about regulations of excipients for solid-dosage drugs.
PharmTech: What do you see as the most significant regulatory changes related to excipients used in solid-dosage drugs?
Heinzel (Merck): Regulatory authorities are increasingly demanding stricter quality management in excipient production and use, which affects both excipient suppliers and pharmaceutical manufacturers. Since March 2016, excipient users in the European Union must define and implement good manufacturing practice (GMP) requirements for excipients, including comprehensive risk assessments for each excipient. The EU excipient risk assessment guidelines (1) capture both the intended use and source of the excipients. Its main topics cover the determination of appropriate GMP based on type and use of excipient, the determination of an excipient manufacturer’s risk profile, as well as confirmation of application of appropriate GMP.
However, while regulations regarding GMP for APIs clearly define what is needed for compliance, the EU excipient risk assessment guidelines are-as their name suggests-not more than guidelines that offer tools and a framework but do not prescribe how to implement them. They neither provide detailed instructions nor a clear definition of appropriate GMP for excipients. This is the responsibility of the manufacturing authorization holder.
In China, regulatory authorities have gone a decisive step further: regulatory compliance is required not only for APIs, but also for excipients used in drug manufacturing. In fact, it is mandatory to register all excipients used in drugs sold on the Chinese market, including those used in imported drugs-a globally unique situation.
PharmTech: Can you summarize China’s co-review procedure and explain how this affects excipients?
Tian (Merck): Excipients came into regulatory focus in China in 2001 when article 11 of the Pharmaceutical Administration Law (2) stipulated that excipients used for pharmaceutical production should meet the requirements for medicinal use. This very general wording led to quite inconsistent approaches. In 2005, the China FDA (CFDA) proposed that excipient registration be done according to the same process as APIs. This included a stand-alone review by the Centre of Drug Evaluation (CDE) for import and novel excipients, and by the local FDA for excipients described in the Chinese Pharmacopeia.
The reforms were triggered by a substantial backlog in drug review. China’s pharmaceutical industry had developed rapidly in the interim, resulting in a broad range of new, improved medical products. However, the approval process couldn’t keep pace with these rapid innovations. In 2015, the Chinese State Council initiated substantial reforms aiming at establishing a more transparent and more efficient process for drug approval and, as a result, also for excipient approval. The number of reviewers was increased from the previous 100 to approximately 800 and a ‘co-review’ process was established.
As of December 2017, according to CFDA announcement No. 146 (3), all pharmaceutical excipient manufacturers or owners, domestic or foreign, must submit their dossiers to the CDE. After a successful completeness check, a registration number is created on the CDE registration platform. Then the registrant can issue a Letter of Authorization (LOA) to its customers (i.e., the drug manufacturers) for their respective drug application. In fact, the drug manufacturer or owner can only submit an application if it provides valid registration numbers for all excipients used.
After successful submission by the drug manufacturer, the CDE commences the assessment process. The applicant must answer questions regarding the product and is informed if there is a deficiency letter for the API, excipient, or packaging material. If so, the CDE contacts the respective excipient registration owner. Once this assessment has been finalized, the drug approval is issued to the drug manufacturer. At the same time, the status of the co-reviewed excipients is changed to ‘A’ for ‘Active’ on the CDE platform.
In the first quarter of each year, pharmaceutical excipient manufacturers must submit annual reports to the CDE to keep their registration number active. If certain excipients have already been successfully registered in the context of previous drug reviews and have maintained their registration number, there may be no need for a new review and the National Medical Products Administration (NMPA) (formerly the CFDA) can use the excipient registration data directly. However, another technical review may be necessary if the CDE decides that the use of the excipient has changed.
PharmTech: Have there been any regulatory changes for other ingredients, such as colorants?
Tian (Merck): In China, the classification of excipients as listed in the Chinese Pharmacopeia (ChP) was proposed in 2018 (4), which has since then served as the basis for the dossier requirements for excipients. The revised dossier requirements were published in a recent announcement in July 2019 (5). The amendments also include changes to the exemption list for low-risk excipients.
Apart from corrigents, flavors, spices, pH adjusters, and inorganic salts, the exemption list for low-risk excipients also includes pigments (colorants) and inks, more precisely iron oxide, plant carbon black, and cochineal, as well as benzene-free inks for capsule inscription. Generally, the exempted excipients can be used without going through the complex review and registration process. However, the final registration exemption of an excipient needs to be confirmed by the CDE and depends on how the excipient is used in the drug formulation.
1. EC, 2015/C 95/02, Guidelines of 19 March 2015 on the Formalized Risk Assessment for Ascertaining the Appropriate Good Manufacturing Practice for Excipients of Medicinal Products for Human Use (2015).
2. Drug Administration Law of the People’s Republic of China (2001), Article 11, p. 3, unodc.org (2001).
3. CFDA, Circular of China Food and Drug Administration on Adjusting the Review and Approval Matters of the Drug Substance, Excipients and Packaging Materials (2017 No. 146) (2017).
4. Chinese Pharmacopoeia Commission, www.chp.org.cn.
5. National Law Review, “China Amends DMF System on Drug Packaging,” natlawreview.com (Sept. 19, 2019).
Supplement: Solid Dosage Drug Development and Manufacturing
When referring to this article, please cite it as J. Markarian, “Considering Excipient Regulations,” Solid Dosage Drug Development and Manufacturing Supplement (April 2020).