What Manufacturers Need to Know About China’s Overseas Inspections

China’s National Medical Products Administration (NMPA) has stepped up overseas inspections in recent years, and manufacturers looking to market products in China must be prepared for potential visits from Chinese inspectors. Gert Bos, PhD, FRAPS, executive director and partner with Qserve Group, addressed the topic during a session at the recent RAPS Regulatory Conference Europe in Brussels. Bos and his Qserve China colleague, Michael Yan, answered some questions about China’s inspections program in the following Q&A.

What led China to increase foreign inspections over the past few years?

In the past, the limited availability of foreign inspectors forced China to focus on large companies and companies making high-risk, long-term implants. With an increased budget allowing for rapid increase of the available inspector pool, we see the scope widening, and many more companies are and will be subject to overseas inspections. As other leading agencies around the world have similar oversight systems in place, China intends to pick up this work as well in their rapid progression in the field of regulatory compliance, and to ensure the imported products are safe for the Chinese population.

NMPA has performed quality system audits and good manufacturing practice (GMP) inspections for many years within China. According to regulations, overseas manufacturers are supposed to have the same level of oversight. As China’s government is now significantly building up their professional inspection team, both domestic and overseas manufacturers are expected to receive more frequent and stricter inspections in the future. The published regulation has adjusted some details to be aligned with domestic practice , but there would continue to be some differences in practice. For example, the “double blind” arrangements of unannounced inspections performed in China will be very difficult to implement for overseas inspections due to the need for visa applications and logistic arrangements.

What significant changes did China make to its foreign inspection process with the release of its updated guidelines in December 2018?

In principle, the guidance did not add further requirements. It just regulates the procedure that gives an interpretation on the regulatory requirements.

If we analyze some details of the regulatory framework that is being followed up by the guidance, the following might be worth mentioning:               

·         The China agent’s responsibilities were added in article 10, the specific requirements of the authorization and its documentation requirements listed in Annex 2, and the adjustment to keep alignment with coming new regulation via China agent.

·         Scope extension: overseas sites or subcontractors for domestic products will now also need to follow this regulation.

·         The site-master file (SMF) is separated into a pharmaceutical version and a medical device version.

·         A new Annex (5) has been added covering the format of the “oversea inspection advanced notice.” It is to be issued after reviewing the SMF and is used to notify the manufacturer of the inspection plan, including location, timing, etc. An application for delay (with proper reason) must to be submitted by the manufacturer within 10 working days after receiving the notice.

·         Complaints, whistleblowing or similar clues that might indicate a violation might also lead to an inspection.

·         The number of inspectors per visit might be increasing.

·         Some adjustments have been made to the response timelines.

·         A result of minor non-conformities will no longer be classified as “meeting the requirement.”

·         Refused or unable to notarize documents has been added to the scenario of noncooperation, which will be classified as “not meeting the requirement” directly.

·         A traceability system requirement is now clearly required in article 32.

What criteria does China's NMPA use to select sites for foreign inspection?

Until there are sufficiently trained personnel available to inspect all companies exporting products to China, it will be a risk-based decision considering the risk factors identified from registration approval—surveillance inspection, testing, complaints and whistleblowing, vigilance, etc.

What are the possible results of an inspection?

If there’s something wrong, it could lead to “risk control measures” taken. These include interviewing the holder, ordering corrections within a specified time limit, issuing warning letters, suspending import customs clearance filing, suspending importation of the medical device, suspending sales and use, supervising product recall and even revoking the import approval. In addition, NMPA may schedule further inspections.

What information, if any, is made publicly available about inspection results?

The inspection result, of which mainly the content in Annex 6, will be shared with the public on the NMPA/CFDI website, mainly about the defects and manufacturer/agent information, but in quite a transparent manner.

What do we know about results of previous inspections and what issues have been identified as problematic?

The results of individual assessments are available in Chinese on the website of the NMPA. At this moment, it is a bit early in the process to analyze trends in the dataset.

What are the most important things companies need to know about NMPA's procedure for overseas inspections?

For overseas inspection, NMPA will notify the China legal agent in advance and give a rough timeline. As the time for the inspection approaches, final dates will be confirmed between NMPA and foreign companies through discussions. Key elements for companies to consider in preparation include:

·         Start learning China’s regulations and standards as soon as possible, and do not leave this solely in the hands of your China team or China agent!

·         Facilitate teamwork among the quality, regulatory affairs, R&D and clinical teams, as well as the China agent.

·         Staff responsible for managing the supply chain need to be involved, and they also will have to accept the inspections; this needs to be contractually agreed upon.

What are the key differences between NMPA inspections and inspections conducted by European and US authorities?

First of all, one needs to consider the different culture, regulations and different understanding of the standards. Next, the scale and focus might differ. For example:

·         Three or more inspectors, possibly with additional observers, will perform the inspection in parallel. Make sure you have enough translators and moderators onsite.

·         The inspection team is expected to have a thorough knowledge and relevant background, including tech-file reviewer, testing engineer, etc., in addition to the GMP inspector. And don’t forget the bigger team behind the audit. Inspectors may check in with the headquarters team after the day’s work if they’re not sure of some issues, so be sure to give reasonable justifications for anything that may be seen as questionable.

·         Inspectors may take pictures or videos for use as evidence.

·         Inspectors may take samples themselves or ask manufactures to ship them to NMPA for further testing.

How can device makers address language and cultural differences with Chinese inspectors?

The inspections will be performed in the Chinese language, although some inspectors may speak fluent English. It is necessary for manufacturers to be well prepared and to make sure the key resources are available, including good translators with proper QA/RA/R&D and relevant device backgrounds. Be well prepared in advance with necessary documents and logistics accounted for. Mock inspections combined with on-site training typically help a lot.

What are some key "dos and don'ts" for companies selected for inspection by NMPA?

The top eight might look as follows:

·         Don’t take the inspection personally.

·         Don’t be adversarial.

·         Don’t try to control the inspection—it is the regulators’ inspection.

·         Communicate any special circumstance or needs.

·         Ask questions if you are unsure of something.

·         Make corrections if possible. If the inspector(s) can’t find documents, try to locate and present them. If you can’t find something, say so.

·         If you can’t make corrections, let it be.

·         Be mindful that the Chinese cultural expectation is to respect the auditor.

What should companies do if they don't pass the inspection?

If non-conformities are raised:

·         Provide a statement or explanations within 10 working days after receiving the result notice from NMPA if there’s any disagreement.

·         Provide the progress of the corrective action preventive action (CAPA), or detailed CAPA plan if it is not possible to finish correction in time, within 50 working days after receiving the result notice.

·         Apply for relieving the risk control measures taken by NMPA after CAPA is performed.

·         Prepare for the additional inspection if needed.

·         Recall products where appropriate.

·         Ensure knowledgeable support to work on closure of CAPAs, and to smooth communication with the inspection team during follow up.

Gert W. Bos, PhD, Fraps
Michael Yan
Post date: June 12, 2019
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