Ten Points to be Watched in the New Edition of GMP for Veterinary Drugs

The Veterinary Bureau of the Ministry of Agriculture and Rural Affairs of the People’s Republic of China issued the Soliciting Public Opinions on the Good Manufacturing Practice for Veterinary Drugs (Revised Draft for Comment) on June 14, 2019, which is something big to the veterinary drug industry of China because it will significantly affect thousands of veterinary drug manufacturers. And this new edition of GMP for Veterinary Drugs will continue to produce influence in terms of management philosophies, technical requirements and standards, and regulatory pressure on the industry, which sufficient attention shall be given to.

It has been 17 years since the 2002 edition of GMP for Veterinary Drugs was issued, which clearly cannot adapt to the industry development needs, with the big development of the veterinary drug industry all those years. The issuing of a new GMP for Veterinary Drugs is an irresistible trend as seen from the latest situations of veterinary drug enterprises.

I’d like to analyze for the veterinary drug industry the new characteristics and new requirements of this new edition of GMP for Veterinary Drugs according to my rich experience in the industry and in conjunction with the European and U.S. GMP implementation experience as well as the development practice of the veterinary drug industry all those years.

Firstly, quality risk management (QRM) is introduced to the new edition of GMP for Veterinary Drugs to promote the rational development of the industry. Quality risk quantization management has been a common and effective management method in Chinese and overseas pharmaceutical product management systems, which emphasizes control beforehand and prevention, manages and controls possible risks in each link of pharmaceutical production and controls critical-to-qualities with high risks in a targeted manner to stabilize product quality. There is no such requirement in the existing GMP, and the management is carried out mostly depending on experience, which is not good for controlling the quality risks. The National Medical Products Administration of China (NMPA) has joined the ICH on June 19, 2017 to become a member of its Management Committee. Predictably, China’s relevant regulation system will gradually draw on relevant guidelines of ICH in the future. The new edition of GMP for Veterinary Drugs stipulates in Articles 12-14 that veterinary drug enterprises shall adopt QRM. This new change will provide new requirements and tools for the management and practice of veterinary drug enterprises; Chinese veterinary drug enterprises shall implement the QRM work of veterinary drug management by actively adopting methods in ICH Q9.

Secondly, clean area standards have significant changes. The current 2002 edition of GMP for Veterinary Drugs adopts the British standards, i.e., clean area standards are separately class 100, class 10,000, class 100,000, and class 300,000, which are outdated and contain only static requirements but no dynamic requirements. The new edition of GMP for Veterinary Drugs adopts the EU standards to divide clean area standards into class A/B/C/D and add static and dynamic standards of suspended particle item. Those new changes will produce significant effects on aseptic veterinary drug enterprises, vaccine enterprises, and biological product enterprises. Many enterprises may need to transform their plant buildings to adapt to new requirements. Furthermore, pharmaceutical industry design entities will be busy with their business in the next two years.

Thirdly, regulated management of data is a focus. Article 3 of the draft of the new edition of GMP for Veterinary Drugs stipulates: enterprises shall implement this GMP strictly and adhere to honesty and trustworthiness and are prohibited from any falsification and fraudulence, which are issues veterinary drug enterprises must pay sufficient attention to and the foundation for the implementation of the GMP for Veterinary Drugs. Chinese veterinary drug enterprises have long been "small, scattered and disordered", however, the relevant veterinary drug industry must treat the issues with caution as China’s regulations continue to become regulated and the government continues to strengthen the management of people’s food safety and food supply chain. Regulations are no joke, violations of which will be strictly handled. Veterinary drug enterprises need to comprehensively sort out and regulate their enterprise document systems and quality cultures, to avoid serious violations.

Fourthly, software and hardware are attached equal importance to and personnel quality is required to be strengthened. The new edition requires constructing a comprehensive quality assurance system and quality risk management system according to the principle of "attaching equal importance to software and hardware" and increasing contents such as quality risk management, product quality retrospective analysis, and on-going stability program, etc. It requires strengthening the quality of practitioners, especially key personnel engaging in veterinary drug production quality management and giving full play to the role of people—the most active productivity factor in veterinary drug production. The new edition of GMP for Veterinary Drugs has clear requirements for personnel physical examination and training and pays special attention to the training effect assessment.

Fifthly, cross contamination control measures are emphasized. The new edition of GMP for Veterinary Drugs has new requirements in terms of plant building design, plant building layout, equipment selection and installation, process layout, and clean area pressure difference, etc., to strengthen prevention and control of cross contamination.

For example, Article 45 of the new edition of GMP for Veterinary Drugs stipulates: Equip the air conditioning and purification systems according to the veterinary drug varieties, production and operation requirements, and external environment condition, etc. to effectively ventilate the production area and provide temperature and humidity control and air purification and filtration to guarantee the veterinary drug production environment to meet requirements. The pressure difference between a clean area and an unclean area and between clean areas of different classes shall not be lower than 10Pa. When necessary, keep an appropriate pressure gradient between different functional areas (operation rooms) of the same cleanliness class, which shall be set with devices indicating the pressure difference and/or monitoring systems. This pressure difference requirement is clearly different from that in the 2002 edition of GMP for Veterinary Drugs and is a new requirement for the existing HVAC systems of veterinary drug enterprises, which will affect the plant building rectification of some enterprises.

Sixthly, the Quality by Design (QbD) philosophy is required to be applied in plant building design and equipment selection, and preventive maintenance is emphasized. For example, Article 35 stipulates: The location, design, layout, construction, transformation, and maintenance of plant buildings must meet veterinary drug production requirements and shall maximize the avoidance of contamination, cross contamination, confusion, and mistake and facilitate cleaning, operation, and maintenance. The QbD philosophy is also emphasized for equipment management. For example, Article 70 in the equipment part stipulates: Design, selection, installation, transformation, and maintenance of equipment must meet intended uses and shall minimize risks of contamination, cross contamination, confusion, and mistake and facilitate operation, cleaning, maintenance, and when necessary, sterilization or disinfection.

Moreover, continuous attention also needs to be paid to maintenance and preventive maintenance in equipment lifecycle management. For example, Article 82 stipulates: A preventive maintenance plan shall be made for the equipment, and there shall be corresponding records of equipment maintenance and repair. Article 83 stipulates: Equipment maintenance and repair shall keep the equipment performance, without affecting product quality.

Seventhly, cleaning validation is emphasized, and constant attention is required to be paid attention to cleaning process development. Veterinary drug enterprises shall implement the GMP in a regulated manner and prevent and try to avoid cross contamination. For workshops where multiple products are produced on the same production lines, cleaning process development and strict cleaning validation are the core tasks. For example, Article 137 stipulates: (8) Cleaning methods shall be validated to prove their cleaning effects, to effectively prevent contamination and cross contamination. Cleaning validation shall overall consider the equipment usage, the used detergent and disinfectant, sampling method and location, and the corresponding sampling recovery, residue nature and limit and sensitivity of residue inspection method, etc.

Eighthly, detailed provisions and guidance are given to the document systems of veterinary drug enterprises. Chapter VIII in this new edition of GMP for Veterinary Drugs contains provisions on document systems of veterinary drug enterprises, involving contents of 33 articles from Article 142 to Article 174. This is markedly different from the 2002 edition of GMP for Veterinary Drugs. Provisions on key documents relating to the quality system operation of a veterinary drug enterprise can all be found in the new edition of GMP for Veterinary Drugs, such as process procedure, batch record, quality standard, validation document, and standard operation procedure.

Ninthly, key elements of the quality system are stipulated more clearly. Provisions of this new edition of GMP for Veterinary Drugs on change management, deviation management, OSS management, and corrective and preventive measures are more specific and comprehensive and introduced in a special chapter. Those specific provisions can provide strong guidance and help for the regulated operations of veterinary drug enterprises.

Tenthly, the document architecture of the new edition of GMP for Veterinary Drugs adopts the international practice and the system is more perfect. The current draft of the GMP for Veterinary Drugs includes the General Principles and five annexes, separately: Annex 1 Sterile Drugs, Annex 2 Non-Sterile Veterinary Drugs, Annex 3 Veterinary Biological Products, Annex 4 Active Pharmaceutical Ingredients, and Annex 5 Traditional Chinese Medicine Preparations. Predictably, those annexes will continue to be supplemented and perfected with the implementation of the new edition of GMP for Veterinary Drugs to eventually constitute a GMP system for veterinary drugs, which is dynamically updated and covered as a whole.

To sum up, this edition of GMP for Veterinary Drugs is significantly different from the 2002 edition and will produce lasting effects on veterinary drug enterprises and relevant regulators. Practitioners need to start to study, research and pay attention to it from now on.

About the Author:

zhulikou431

Zhulikou431, as a senior engineer, PDA member, ISPE member, ECA member, PQRI member, senior aseptic GMP expert, has deep knowledge in aseptic process development and verification, drug development and registration, CTD document writing and review, regulatory audit, international certification, international registration , quality system construction and maintenance, as well as sterile inspection, environmental monitoring and other fields. In recent years, he has focused on the analysis of trends in the macro pharmaceutical field and the risk management of pharmaceutical enterprise mergers and acquisitions projects.

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