Continuous compliance inspections for pharmaceutical products are set to become the new normal. Are pharmaceutical companies ready?

Fang Jianchun, Reporter for China Pharmaceutical News

On December 29, 2016, at the Guo’erzhao Hotel in Beijing, more than 200 newly appointed *** drug inspectors—representing the 649 drug inspectors nationwide—sincerely received their bright red inspector certificates and solemnly raised their right hands to take an oath: “Ensuring the quality of pharmaceutical products is my mission and duty…” The emergence of the *** drug inspectors marks the beginning of a transition for China’s drug inspector workforce toward greater professionalism and specialization.

In recent years, as China’s drug regulatory philosophy has shifted from “emphasizing approval over supervision” to process-based regulation primarily relying on inspections, the *** flying inspections have wielded considerable authority in addressing major drug safety issues such as those involving ginkgo leaf and calf blood, as well as in verifying clinical trial data. These inspections have exposed and penalized numerous non-compliant enterprises, effectively deterring improper practices within the pharmaceutical industry.

At the oath-taking ceremony, Bi Jingquan, Director of the National Medical Products Administration, pointed out that inspectors must leave no stone unturned when it comes to any issue that could potentially affect the quality and efficacy of pharmaceutical products. During the drug registration review stage, inspectors should rigorously scrutinize the authenticity, consistency, and feasibility of market launch scale. In follow-up inspections under the Good Manufacturing Practice for Pharmaceuticals, they must ensure that the production process remains continuously compliant and that data are complete, authentic, and traceable. In targeted inspections triggered by specific concerns, inspectors should be adept at exposing “unwritten rules” and severely crack down on illegal and non-compliant activities...

All of this demonstrates the National Administration’s unwavering determination to intensify inspections across the entire pharmaceutical industry chain and build a team of drug inspectors who are highly competent, efficient, and fully committed to their duties. For pharmaceutical companies, facing ongoing compliance inspections in 2017 will become the new normal.

How many companies were flagged during last year’s inspection?

In 2016, inspections had become the dominant theme in pharmaceutical regulation.

According to statistics compiled by the National Administration’s Review and Verification Center (hereinafter referred to as the Verification Center) as of late December last year, a total of 611 enterprises/variety types were inspected throughout the year, with 515 inspection teams dispatched.

During the GMP certification inspection, 6 items failed to pass, and 3 warning letters were issued.

During GMP follow-up inspections, the inspections are primarily guided by issues and risk signals identified in enterprises and products, and are conducted based on the principle of risk-based management. The 179 enterprises/medicines subject to inspection include manufacturers with multiple batches of substandard results in quality sampling, vaccine manufacturers, blood product manufacturers, some enterprises that received warning letters in 2015, manufacturers of products identified as posing higher risks through comprehensive analysis, and sterile pharmaceutical manufacturers that were certified by the provincial bureau in the first half of 2016.

In the GMP follow-up inspection—“double random” approach—651 non-sterile pharmaceutical manufacturing enterprises that had passed provincial-level GMP certification inspections in the first half of 2016 were subject to follow-up inspections. Thirteen enterprises were randomly selected for these follow-up inspections.

During on-site inspections of drug registration and manufacturing, a total of 36 on-site inspection reports were completed, among which 6 varieties did not pass the inspection.

During the GMP spot inspections of pharmaceutical products, 35 companies were inspected throughout the year. We recommended revoking the GMP certificates of 11 companies and initiating investigations against 11 companies. Among these, 6 Chinese medicine companies had their GMP certificates recommended for revocation, with 2 being placed under investigation and 1 having its production temporarily suspended; 4 biochemical pharmaceutical companies had their certificates revoked.

Following last year’s “Shandong Vaccine Incident,” the National Administration also launched unannounced GSP inspections of pharmaceutical companies. Starting from October last year, it conducted surprise inspections at 41 enterprises across 25 provinces, revoking GSP certificates and suspending the Drug Trading Licenses of 23 enterprises.

A total of 371 institutions were inspected for clinical trial data, and 166 drug products have been fully audited.

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A relevant official from the General Administration’s Inspection Center stated that, during GMP follow-up inspections of pharmaceutical products, numerous issues were identified in biochemical drugs—particularly significant gaps in raw material management, supplier management, production systems, and quality control systems. In on-site inspections of drug registration and manufacturing, problems related to data authenticity persist, with prominent concerns about data reliability, insufficient process validation, unstable production processes, inconsistencies between actual production processes or parameters and those approved, failure to conduct thorough research and evaluation, and submission of excessively small batch sizes—issues that could pose serious quality and safety risks when scaling up production for market launch. Furthermore, during clinical trial data verification, the primary issues found were non-compliance and, in some cases, the untraceability of certain clinical trial data.

It is reported that last year, provincial drug regulatory authorities stepped up inspection efforts, particularly in the areas of traditional Chinese medicine decoction pieces and pharmaceutical distribution, revoking numerous licenses. Currently, data on these cases are being compiled. Through this series of regulatory measures, the regulatory framework of the National Administration becomes strikingly clear: by conducting continuous inspections, it aims to standardize corporate behavior, crack down on illegal and non-compliant activities, and—through rigorous and scientific supervision and inspection—manage safety risks while ensuring a fair market order, promoting optimization of industrial structure, and facilitating supply-side reform.

What kind of team is the pharmaceutical inspector?

“Today is a big day—a wonderful day—for pharmaceutical inspectors. For the first time, we have the opportunity to express our emotions. At the moment of taking the oath, a profound sense of responsibility and mission—to safeguard the quality of medicines for the people—filled my heart,” said Ding Jianhua, Director of the Pharmaceutical and Chemical Regulatory Division of the National Administration and Director of the Inspection Center, his voice tinged with excitement during the oath-taking ceremony. Behind these emotions lies the image of an invisible yet vital team—carrying a heavy burden as they strive to ensure the safety of medicines for the people.

In 1995, China’s pharmaceutical GMP certification program was just getting off the ground, and pharmaceutical certification inspectors began to take the lead in certification inspections. After more than 20 years of development, although most inspectors still work part-time, they continue to play an extremely important role.

Relevant officials from the Inspection Center introduced that China’s team of pharmaceutical inspectors has undergone more than 20 years of development, going through three distinct phases: initial exploration, team expansion, and refined enhancement. The 891 inspectors appointed between 2009 and 2011 serve as the backbone for national GMP-related inspections and on-site inspections of registered manufacturing facilities, making significant contributions to pharmaceutical regulatory efforts.

It is understood that in 2015, the certificates of national pharmaceutical GMP inspectors began to expire one after another. During routine assessment and management, the National Administration discovered that some inspectors were no longer capable of performing pharmaceutical inspection tasks. Additionally, certain inspectors were unable to continue fulfilling their inspection duties due to retirement, changes in their job roles, or personal health issues, creating an urgent need to bring in fresh talent. Starting in 2015, the Administration’s Inspection and Verification Center began initiating the recruitment and renewal of inspector certifications.

Through a rigorous selection process, the Inspection and Verification Center screened 450 inspectors from the original pool of 891 inspectors and also selected 199 core inspectors from provincial inspector teams to join the national inspector roster. The center subsequently organized four training sessions for the appointment of national GMP inspectors for pharmaceutical products and one training session for inspectors specializing in blood products. After passing on-site inspections and assessments, the Administration publicly announced the appointments in two batches last year.

The assessment for this appointment of *** inspectors was particularly rigorous and can be seen as a warm-up phase for building a dedicated team of inspectors. “The National Administration conducted a thorough evaluation of the candidates’ age, *** capabilities, work experience, and inspection history to ensure that the inspectors will be able to effectively fulfill their sacred duty of pharmaceutical inspections in the future. The elimination rate among the original inspectors was close to 50%,” said a relevant official from the Verification Center.

In the past, many enterprises at various levels and in different contexts have expressed concerns about the inadequate qualifications of drug inspectors, as well as inconsistencies in inspection impartiality and standardization. In this round of re-certification and appointment process conducted by the National Administration, special emphasis has been placed on the selection and training of inspectors with regard to their competence, impartiality, and integrity. The head of the Verification Center Office pointed out that upholding integrity and self-discipline, as well as objectivity and fairness, are fundamental requirements for inspectors.

In inspector training, the content places greater emphasis on regulatory trends and is highly targeted. For example, case-based teaching is integrated with issues identified in pharmaceutical inspections over recent years. Key areas of focus include critical elements of quality management at pharmaceutical manufacturing enterprises, data reliability, drug registration requirements, management of sterile drug production, and sharing of practical inspection cases. Particular attention is paid to practicality and relevance.

In addition, the Inspection Center has categorized newly appointed inspectors—based on their competency profiles and diverse work experiences—involving areas such as traditional Chinese medicine, biological products, chemical drugs, and radiopharmaceuticals—and has established a database of inspection team leaders and inspectors. During actual inspection assignments, inspectors corresponding to the specific type of product are assigned, thereby ensuring the scientific rigor and effectiveness of inspections. This categorization also lays the foundation for implementing the State Council’s requirement of “double random inspections with public disclosure.”

“***Drug inspectors are like sparks—may this tiny spark ignite a raging fire and ensure that drug quality and safety reach the high standards set by the state, the people, and the General Administration,” said Ding Jianhua.

Zhang Hua, deputy director of the Shanghai Drug Review and Verification Center and a China GMP inspector accredited by the World Health Organization, revealed that inspectors’ actual work is extremely demanding. “They spend over 200 days a year at inspection sites—once inspections begin, they’re on-site during the day and writing reports at night, working more than 12 hours a day. Moreover, with regulatory information being open and transparent, the responsibility is immense, placing considerable demands on inspectors’ *** capabilities, endurance, and physical stamina.”

At the oath-taking ceremony, Director Bi Jingquan sounded the war drum—“dong dong”—for drug inspectors across the country. He urged them: “Inspectors must not stay in offices; they must be on the front lines every single day!”

All the issues of concern to the industry have been clarified.

In fact, several issues within the industry have long been a thorn in the side during pharmaceutical inspections. Following this oath-taking ceremony, relevant officials from the Pharmaceutical and Chemical Regulatory Division and the Inspection Center, as well as frontline inspectors, provided special clarifications.

1. How can we avoid local protectionism during inspections?

Currently, due to limitations in staffing, China has not yet established a dedicated team of full-time drug inspectors; instead, a significant portion of inspectors are part-time. As a result, it is inevitable that inspections will encounter resistance from local protectionism. In the fiercely competitive pharmaceutical market, inconsistent inspection standards among inspectors have become one of the key concerns for enterprises.

Yang Shiyou, Deputy Director of the Anhui Provincial Bureau and an inspector with the *** agency, frankly admitted that during inspections, they often encounter resistance from local authorities—especially when it comes to “putting family aside for the greater good” in regard to pharmaceutical companies within the province. However, over the past two years, as the regulatory authorities have stepped up supervision both during and after the fact, and made inspection results fully public, pharmaceutical regulation and inspection have reached a new level. Taking Anhui Province as an example, the province is a major producer of traditional Chinese medicine and herbal slices, making regulatory oversight particularly challenging. Starting in 2014, the province began publicly disclosing all inspection results and conducting comprehensive analyses of defect reports. This not only urged companies to promptly address deficiencies but also helped the public understand these defects, thereby preventing misunderstandings and unnecessary panic. “At first, when we started publishing inspection results, there was tremendous resistance. Competitors from within the province even used our publicly available reports to woo customers and put pressure on local companies. But we stood firm under this pressure and encouraged companies to continuously improve their product quality. In less than two years, what initially seemed like a crisis turned into an opportunity: our companies gained widespread recognition from customers, and the market once again came back into our hands. In 2016 alone, Bozhou City revoked 12 pharmaceutical GMP certificates,” Yang Shiyou said. He added that today, strict regulation and the establishment of a well-ordered market are now widely recognized by both industry insiders and the general public, and Anhui Province will continue to maintain its current level of commitment and intensity in this work.

It is reported that, since October of last year, the Drug and Chemical Regulatory Division and the Inspection Center have swiftly implemented the State Council’s directives on “double-random” inspections and transparent law enforcement. On December 8, they dispatched the first batch of 13 “double-random” inspection teams to nine provinces to carry out these inspections. In the next phase, the “double-random” inspection approach will place greater emphasis on increasing the sampling rate for enterprises producing traditional Chinese medicine decoction pieces, which will greatly help address the issue of local protectionism in inspections.

II. Is there a gap between domestic enterprises and foreign-invested enterprises?

Zhang Hua, an inspector with extensive experience in both domestic and overseas inspections and previously working for both foreign and state-owned enterprises, pointed out that while foreign companies indeed excel over their domestic counterparts in R&D and drug quality, they still fall short when it comes to fully complying with China’s laws and regulations. Some foreign companies have set up factories in China but find themselves at a disadvantage in terms of communication with their headquarters—even to the point where headquarters are completely unaware of China’s pharmaceutical regulatory laws and regulations. China launched overseas inspections in 2011. To be fair, foreign-invested enterprises do indeed offer valuable lessons for domestic companies in areas such as plant equipment, staff qualifications, and effective operational practices. However, at the factory production level, foreign companies often know very little about China’s laws and regulations—and some even treat them differently. Some claim to meet China’s regulatory requirements yet fail to keep even basic training records required by China’s GMP standards. Moreover, some foreign companies fail to report significant product changes simply because they don’t attach sufficient importance to compliance, while others deliberately try to sidestep regulations through cunning maneuvers. Additionally, certain foreign companies come up with various excuses to avoid inspections, conceal the true origins of active pharmaceutical ingredients, and even obstruct or outright refuse inspections altogether. Therefore, when it comes to compliance, whether foreign or domestic enterprises, we must all apply the same standard and take the laws, regulations, and industry norms seriously.

3. What changes have been made in the working methods of the newly appointed *** inspector?

Inspector Yan Zhaoguang from the Verification Center stated that, following the National Administration’s strengthened supervision during and after the event, the entire system is now required to adhere to the “Four Essentials and Two Responsibilities.” Inspection results are now publicly disclosed and transparent, and inspectors face even higher demands in terms of professionalism and technical expertise. After the government institutional reform, provinces have implemented a “three-in-one” integration. Although the number of inspectors has seemingly increased on the surface, their effectiveness has actually weakened. Despite the National Administration’s efforts to provide extensive training, the results have not been particularly impressive—indeed, as the saying goes, “different trades are like different mountains.” In the past, inspections mainly focused on whether licenses were present or absent. Now, however, inspections must cover the entire process control, extending even to the supply chain level. This poses a significant challenge for inspectors.

It is reported that the National Administration is accelerating efforts to build a dedicated team of pharmaceutical inspectors. In the initial phase, it has adopted a strategy of hiring external experts on par with internal staff to address the shortage of personnel. Taking the U.S. FDA as a reference, its pharmaceutical inspection agency boasts a workforce of over 5,000 personnel. Judging from the size of China’s pharmaceutical market, there remains a significant gap in regulatory capacity.

At the meeting, some inspectors specializing in flying inspections also pointed out that today, there are various so-called “training courses” in society that teach companies how to evade inspections and conceal problems. In fact, the best approach to dealing with inspections is simply to be “honest and trustworthy.”

“This year, we will continue to take a problem-oriented approach, focusing our inspections on biochemical drugs and traditional Chinese medicine decoction pieces. We’ll also keep refining and issuing GMP appendices. We hope that companies will remain consistently compliant and avoid crossing the red lines,” said a relevant official from the Inspection Center.

Inspector’s Chronology

In 1995, a total of 23 training sessions were held for pharmaceutical GMP inspectors, training 2,642 inspectors. Subsequently, in four batches, “National Pharmaceutical GMP Certification Inspector Certificates” were reviewed and issued to 469 pharmaceutical GMP inspectors.

Starting in 2007, we began selecting and training 104 international inspectors. We also carried out a re-selection and re-appointment process for pharmaceutical GMP inspectors. In total, we organized 15 training sessions for the appointment of pharmaceutical inspectors and re-appointed 891 national pharmaceutical GMP inspectors.

In 2011, we jointly organized 10 vaccine training workshops with the WHO and established a team of 100 vaccine inspectors.

In 2016, the reappointment process for *** drug inspectors was launched. The first batch of 649 *** drug inspectors took the oath and began working with valid certificates. Led by the Personnel Department of the General Administration and assisted by the Verification Center, another 42 inspectors were selected as reserve candidates for international inspections. Currently, the training and assessment phase for this *** stage has been completed.