The History and Prospects of Overseas GMP Inspection in China

Carrying out the overseas GMP (Good Manufacturing Practices) inspection is a key responsibility of the National Regulatory Agency to supervise the imported pharmaceutical products. And it’s also an important measure to maintain the safety of the pharmaceutical products used by the public. In April 2011, China began to implement the pilot work of overseas GMP inspection. Through exploration and summary, a complete set of inspection procedures and systems have been formed. In this paper, the development history of China's overseas GMP inspection is reviewed, the inspection process and the treatment of inspection results are compared with the US FDA, the EU, WHO and so on. This paper analyzes the numbers, countries and types of products in the overseas GMP inspections, which carried out by China in the past decade, makes a statistical analysis of the observations found in the inspections, discusses the areas where the observations are concentrated, and focuses on the areas where the critical observations are concentrated. Finally, the trend of overseas GMP inspection in the future is prospected.


Introduction
In 1962, the US promulgated the world's first drug Good Manufacturing Practices (GMP), and subsequently established inspection procedures to comprehensively supervise the implementation of GMP by drug manufacturers.
In 1967, according to the resolution 20.34 of WHO at the 20th World Health Assembly (WHA), the expert group drafted WHO's first draft of GMP for pharmaceutical products. And then in 1968, the draft titled "Draft requirements for good manufacturing practice in the manufacture and quality control of drugs and pharmaceutical specialities" was submitted to the 21st WHA for consideration and was discussed for adoption. In 1969, Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce was proposed for inclusion in the resolution WHA 22.50, and GMP for pharmaceutical products was recommended to be implemented by the member states at the 22nd WHA. WHO published Good Practices in the Manufacture and Quality Control of Drugs in Annex 2 of the 22nd Edition of technical Report, which is the WHO's first edition of official GMP.
Since then, various national drug regulatory agencies have begun to implement drug GMP and then carry out GMP inspection.
producing enterprises, trading enterprises and medical treatment units.
On March 17, 1988, the first Good Manufacturing Practices for drugs was promulgated and implemented, requiring drug manufacturers to implement drug GMP and accept supervision and inspection. In February 1993, comprehensive revised drug GMP (revised in 1992) was released to implementation.

GMP Certification Inspection of Drugs
In March 1994, China Drug Certification Committee was established, and in November 1994, the Center for Certification of Drugs was established to undertake the drug GMP certification work. Since October 1, 1995, the application for GMP certification of drug manufacturing enterprises (workshops) and products varieties has been accepted. Since then, the system of GMP certification for drug manufacturers has been established.
In 1998, the State Drug Administration of China was established and subsequently promulgated and implemented drug GMP (revised in 1998). At the same time, the GMP certification management measures have been promulgated to implement step by step according to the type of drug dosage form. The GMP certification inspection system has also completed the transition from voluntary certification to mandatory certification.

New Stage of GMP Inspection
In 2004, the drug GMP (revised in 1998) was systematically compared with EU drug GMP and WHO drug GMP, and the comprehensive revision of drug GMP began. On January 17, 2011, drug GMP (2010 revision) was formally promulgated and implemented on March 1. The revised drug GMP content includes basic requirements and five annexes of Sterile Products, Active Pharmaceutical Substances, Biological Products, Blood Products and Traditional Chinese Medicine Preparations. Subsequently, seven annexes including Radiopharmaceuticals, Prepared Slices for Traditional Chinese Medicine, Medical Oxygen, Sampling, Computerized System Validation, Qualification and Validation, and Biochemical Products were successively issued. The basic requirements and annexes of drug GMP constitute a complete set of technical specifications, which have been widely recognized by drug regulatory agencies and international organizations such as the US FDA, the EU and WHO, and have reached the international level in terms of technical standards.

Overseas GMP Inspection
On the basis of the comprehensive integration of drug GMP (revised in 2010) with international drug GMP, the pilot work of GMP inspection for overseas pharmaceuticals was launched in April 2011, and detailed regulations on the scope of inspection, organization and implementation of inspection, and disposal of inspection results were drafted for overseas pharmaceutical manufacturers. At the same time, the inspected enterprises were required to provide site master files, basic information about their imports to China in the last three years, and basic information about their production and sales in other countries in the last three years. After a period of exploration and summary, in December 2018, National Medical Products Administration of China officially issued the regulations on the management of overseas drug and medical device inspection, and since then, the China's overseas GMP inspection has achieved phased progress.

Organization and Implementation of China's Overseas GMP Inspection
The organization and on-site inspection procedures of China's overseas GMP inspection are basically consistent with those of the US FDA, the EU and WHO (see Table 1 for comparison of inspection procedures). Note: * In principle, daily wrap-up is required, but some inspection team does not provide wrap-up on a daily basis.
There are some differences between China, the US FDA, the EU and WHO in terms of defect assessment, inspection report writing, feedback of inspection results and disposal of inspection results in overseas GMP inspection. Because WHO is not a law enforcement agency authorized by law, it can only take measures such as issuing warnings and removing from the pre certification list, other drug regulators will take appropriate regulatory action according to their respective legal mandate, combined with the impact of quality risk caused by defects on patients' health (see table 2 for detailed comparison).

Implementation of Overseas GMP Inspection
From 2011 to 2020, a total of 236 overseas drug inspection tasks were organized and completed (see Figure 1. Distribution of overseas drug inspection tasks). Due to the impact of the global COVID-19 pandemic, two inspections were completed in 2020, both of which were off-site remote inspections.

Distribution of Countries and Type of Products for Overseas GMP Inspection
In the past 10 years, overseas drug inspection has been carried out in 27 countries on five continents (see Table 3 for details). A total of 248 products involved in overseas drug inspection were distributed in five types: API, chemical drug preparation (non-sterile), chemical drug preparation (sterile), biological products and botanical drugs (see Figure  2. Distribution of overseas drug inspection by type of products).

Statistical Analysis of Observations Found in Overseas GMP Inspection
During the past 10 years, a total of 1,680 observations were found in on-site inspections, including 56 critical observations, 304 major observations and 1,320 minor observations. Figure 3. Distribution of observations found in China's overseas GMP inspection can be obtained by classifying statistics according to the chapters and annexes of drug GMP China.  Research Vol. 11, No. 1;2022 It can be seen that the observations found in inspection mainly focused on quality assurance and quality control (402 observations found, accounting for 23.9%), document management (176 observations found, accounting for 10.5%), premises and facilities (155 observations found, accounting for 9.2%), equipment (150 observations found, accounting for 8.9%), qualification and validation (126 observations found, accounting for 7.5%), sterile products management (125 observations found, accounting for 7.4%).
The critical observations mainly occurred in the following aspects. In terms of production management, 10 critical observations were found, accounting for 17.9%, for example, the risk of product contamination or mix-ups could not be effectively reduced, and the production process was not properly controlled. In terms of quality management, 8 critical observations were found, accounting for 14.3%, such as lack of risk management and unqualified personnel. In terms of quality assurance and quality control, 7 critical observations were found, accounting for 12.5%, including data integrity, inadequate OOS investigation and inadequate deviation investigation. In terms of sterile products management, 7 critical observations were found, accounting for 12.5%, including lack of Sterility Assurance Level (SAL), insufficient design of Media Fill Simulation Test, and sterilization management fail. In terms of API management, CPP/CQA and other process parameters could not be properly controlled, impurities management did not meet the requirements, intermediates were out of specification, and 6 critical observations were found, accounting for 10.7%. In terms of regulation of drug registration, 5 critical observations were found, accounting for 8.9%, such as production processes are inconsistent with the registration dossier, failure to report critical and major variations to regulatory authorities for supplementary application, and data integrity in registration materials.

Trends and Prospects of China's Overseas GMP Inspection
International and internal experiences indicate that drug inspection is the most direct, effective and systematic means of drug supervision, which can realize both source control and process supervision, so as to be "problem-oriented", comprehensively identify risks and nip it in the bud. After 30 years of unremitting efforts, drug GMP has taken root in China. China has established relatively complete drug inspection procedures, and the team of drug inspectors has begun to take shape. Overseas drug inspection can not only discover the risks of imported drugs in time, ensure drug safety of patients, but also strengthen the cooperation among national drug regulatory agencies.
On September 24, 2021, National Medical Products Administration of China officially sent a letter to PIC/S to apply for the pre-accession procedure, which also sets higher requirements for overseas drug inspection. Next, National Medical Products Administration of China should carry out in-depth work, and continue to promote the internationalization of drug inspection work process from the aspects of drug inspection regulations and technical standards, drug inspection IT system, drug inspection quality management system construction, inspector training program, etc., to let the drug inspection takes more important role in the supervision of the whole product life cycle, and make China's contribution to ensuring the safety, effectiveness and the quality of global patient medication.