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Novel excipient regulation in China

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Cloris Tian, Senior Regulatory Manager, APAC, Shanghai, China Yuwei Heinzel, Head of Pharma Registration Germany, Merck KGaA, Darmstadt, Germany writes about the opportunities and challenges for the pharmaceutical industry in the face of new excipient regulations in China

China is currently one of the most promising pharmaceutical markets. However, the outstanding opportunities are accompanied by substantial challenges for companies who want to manufacture, import or sell drugs in China. New regulatory requirements are leading to important changes, especially regarding excipients used in drug manufacturing. In fact, Chinese excipient regulation is a globally unique situation.

With a population of 1.4 billion and an ageing society, China is a highly attractive market for pharmaceutical companies. To keep pace with the demographic developments and the ever-growing needs in the healthcare sector, the Chinese authorities have issued major reforms over the past decades. The most recent ones have already significantly increased regulatory efficiency and transparency, while to some extent also resulting in better alignment with international standards.

A globally unique situation for excipients
In August 2019, the China Drug Administration Law was revised; the changes went into effect on 1st December 2019. This law aims at enhancing drug safety and improving public health. Although it includes most of the previous reform outcomes, keeping pace with the constantly evolving regulatory requirements remains an enormous challenge, and efficiently planning and implementing all necessary steps is a major undertaking.
As far as excipients for the use in drug manufacturing are concerned, the situation in China is unique: no other country has higher regulatory requirements for excipients. Every single excipient used in drugs sold on the Chinese market, including those used in imported goods, must be registered – a huge challenge, especially for players who are not familiar with the Chinese regulatory system. Whoever wants to manufacture and market pharmaceutical products in China, needs a partner with long-standing expertise in regulatory affairs and experience with Chinese authorities and business practices. This said, it is helpful to cast a glance at the milestones of the current regulations.

The evolution of excipient regulation in China
2001 marked the starting point of the regulatory focus on excipients. Article 11 of the Pharmaceutical Administration Law stipulated that excipients used for pharmaceutical production should meet the requirements for medicinal use. This very general wording led to quite inconsistent approaches. Some Chinese provinces regulated excipients as APIs, while others did not regulate them at all. In 2005, the China Food and Drug Administration (CFDA) issued the Pharma Excipient Dossier Requirements for industry, proposing excipient registration according to the same process as APIs with 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 (ChP).

In the following years, China’s pharmaceutical industry developed rapidly, resulting in a broad range of new, improved medical products. However, the approval process could not keep pace and had to be supplemented and improved on numerous occasions. Prompted by a substantial backlog in drug review, the Chinese State Council initiated reforms to enhance transparency and efficiency of both the drug and the excipient approval process. Apart from increasing the number of reviewers from the previous 100 to approx 800, the review scheme for excipients was revised substantially, changing from the stand-alone review to a bundling review scheme first, which was followed by the current co-review process.

In addition to these developments, the Chinese regulatory authorities also engaged in an intensive exchange with the US Food and Drug Administration (FDA), the respective EU authorities and the European Directorate for the Quality of Medicines & HealthCare (EDQM). Moreover, China has been a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) since 2017. The implementation of the ICH guidelines in China is an ongoing process.

The co-review process for excipients
The co-review process went into law in December 2017. According to CFDA announcement No. 146, 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. The registrant can then 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 starts 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 finalised, the drug manufacturer receives approval. At the same time, the status of the co-reviewed excipients is changed to ‘Active’ on the CDE platform.

In the first quarter of each year, pharmaceutical excipient manufacturers must submit annual reports to the CDE in order 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 NMPA (previously 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.

Dossier requirements and pharmacopoeia compliance 
Just like the individual process steps, the content of the dossier must fulfil very specific requirements. General information on the company and the excipient itself, such as its name, structure, characteristics, approval and usage information, must be included in the registration dossier. Detailed information on the manufacturing process is also required, together with a list of equipment and process validation data. Finally, the dossier must comprise quality control specifications with descriptions of the analytical and validation methods.

The level of detail required for the registration dossier is based on the excipient classification as revised by the NMPA in July 2019. Excipients are classified into products with or without a history of use in approved drugs. The latter includes completely new molecules, as well as molecules with simple changes to their structure or a changed route of administration. Products with a history of use are in turn divided into two groups: excipients that are included or not included in the Chinese Pharmacopeia (ChP) or the pharmacopoeias of the European Union, the United States, Great Britain or Japan.

As confirmed in announcement No 56, which went into effect on 15th August 2019, the NMPA has also identified low-risk excipients that are exempted from mandatory registration. Among these exemptions are corrigents, like sweetening agents, colourants or pH adjusters. However, the final decision on whether a certain excipient needs to be registered must be confirmed by the CDE and depends on its use in a given drug formulation. In general, all excipients used in drugs for the Chinese market must be compliant with the ChP, as stipulated in the Chinese Pharmaceutical Administration Law issued in 2019. The current ChP edition includes 270 excipient monographs. The goal for the 2020 edition is to add another 100 excipient monographs and to promote the harmonisation with other national pharmacopoeias in the European Union, the United States and Japan.

Seizing the Opportunities 
The reforms made over the past years have led to a much more efficient and transparent excipient registration process. In addition, the recent regulations have started to harmonise the registration procedure with international standards. Now both domestic and foreign companies are subject to the same registration requirements. And, most importantly, all companies have an equal opportunity to tap the potential of the Chinese pharmaceutical market. However, some challenges remain: as there was no transition time, many excipient manufacturers now lack the technical dossiers they need for successful registration. As a result, many drug manufacturers cannot yet register their products in China. Finally, the ChP has not yet been fully harmonised with other international compendia, which forces global pharmaceutical companies to perform additional comparisons of methods and cross-validation checks.

The co-review process requires a firm command of the Chinese language and familiarity with Chinese business practices. It is therefore highly recommended to work with an agent in China, as the relevant dossiers and the registration platform are only available in Chinese. In addition, close cooperation and clear communication between the excipient manufacturer, the drug applicant and the CDE are essential to understand the complex requirements and foster an efficient process. Nevertheless, the fast-growing Chinese pharmaceutical market is highly attractive and holds tremendous potential. Together with an experienced partner, these challenges can be overcome. The results are both rewarding and achievable.

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