China has implemented a new version of its Good Manufacturing Practice (GMP) standard, and has completely adopted EU GMP cleanliness standards and introduced the “in operation” classification. Annex 1, on the manufacture of sterile medicinal products, led to a new challenge, addressed by students in a project to design a hypothetical facility for the aseptic product of an antibiotic.
The People’s Republic of China recently switched from US to EU GMP guidelines. A hypothetical facility was designed in an academic exercise by students* that provides an example of how the Chinese are looking to implement the guidelines.
Following the updated GMP guidance implemented by the Chinese State Food and Drug Administration (SFDA) in March 2011, the People’s Republic of China implemented a new version of its Good Manufacturing Practice (GMP) standard, now called China GMP 2010. The previous version, China GMP 1998, applied cleanliness grades set out by the US FDA. However, China GMP 2010 completely adopts the EU GMP cleanliness standards and the “in operation” classification was introduced.1 Therefore annex 1, on the manufacture of sterile medicinal products, led to a new challenge.
The aim of this project was to design a facility for the aseptic production of the powdered beta-lactam broad-spectrum antibiotic cefuroxime sodium that would:
Each vial of aseptic powder for injection would contain 0.75g of cefuroxime sodium (without excipients/additives) and would be packaged in the following manner: 7ml per vial, 10 vials per small box, 10 small boxes per large box and 10 large boxes per bin.
The facility was designed as a “new build” extension producing 50,000,000 vials of injectable aseptic powder of cefuroxime sodium per annum.
The flow of materials was designed to be as efficient and logical as possible. The active ingredient of cefuroxime sodium is first sent to the API temporary storeroom through a room for outer package removal, a room for decontamination and an airlock. After being sterilised, it is then weighed and moved into the filling room. Rubber stoppers and aluminium caps are transferred to a corresponding temporary storeroom through an outer package removal room, decontamination room and airlock. They would then respectively be carried into the filling and capping room after washing and sterilisation.
Meanwhile, vials would go through the washing machine, sterilisation tunnel and filling line and the sterile API would be filled into vials and the vials would then be stoppered and capped. Finally, the aseptic injectable powder would be inspected (using light), labelled and packaged. This process flow is shown in Figure 1.
Figure 1: A process flow diagram for the facility
The number one contamination risk is the filling station, thus care should be taken in the design of the piping and instrumentation, with the following design considerations.2
1. The level of automation and integration of equipment was very important for ensuring a sterile environment. This project used a filling line that covered aseptic core operations, including sterilising, filling, stoppering and capping, which is entirely fit for the “in operation” cleanliness grades given in the China GMP 2010.
2. The filling part of the screw filling machine was washed with water for injection and then sterilised, dried and re-assembled in a grade A environment. Sterilising and drying validation should be carried out after reassembly has been completed.
3. A high purity nitrogen protection technology, which can be decontaminated using a sterilised, micro-organism-retaining filter, is transferred to the filling room via a stainless steel pipe, and applied to protect the products being filled.
4. After sterilisation, rubber stoppers would be readily transferred to the stopper oscillator of the screw filling machine.
5. Using special storage tanks with sterile connection valves, the aseptic API would be poured into the powder hopper of the screw filling machine, so that the frequency, and therefore the risks to the aseptic operation, would be reduced. Sterile equipment should be connected in the grade A/B area.
6. In cases where allergenic dust of cefuroxime sodium could be generated, specific precaution would be taken to prevent cross-contamination, the generation and (dissemination) spreading of dust and to facilitate cleaning.
As shown in Figure 2, the facility comprised a total area of 2248m2 and the building dimensions were: 51m (length), 48m (width) and 6m (height).
The following building features were designed and selected to achieve the required cleanroom environment and to keep construction cost to a minimum:
Figure 2: Overview of facility layout
In conclusion, the biggest difference between China GMP 2010 and the previous 1998 GMP was that the previous version only emphasised the “at rest” classification, and the China GMP 2010 has also strengthened the quality management.
An experienced cleanroom designer should oversee every stage to ensure the successful construction of a cleanroom to the user’s satisfaction.3 It should result in a robust, ergonomic facility design, taking into account cleaning regimes, URS, production technology, the need to modify process equipment, API features and exposure risks.4 Only in this way can we really implement the core idea of China GMP 2010.
Reliance should not be placed on any one terminal process or finished product test for sterility, or other quality aspects, but rather on precise control of the entire manufacturing process and quality management.5
1. Yu Y., Lu C.Y. A Discussion on China GMP 2010 and Equipments of Injectable Aseptic Powder. Mechanical and Electrical Information of China. 2011, 29(5):20–24.
2. An B.Z., Ming Y.J., Liu Y.B., et al. The Requirement of Facility Design and Equipment for Injectable Aseptic Powder. Qilu Pharmaceutical Affairs of China. 2009, 28(6):375–377.
3. Liu M., Liu Z.C. Understanding of GMP Used in Process Design of Sterile Separation Packed Powder Injection Workshop. Pharmaceutical & Engineering Design of China. 2006, 27(3):33–36.
4. Pitcher M. Designing Isolators with Reliability. Cleanroom Technol. 2012, 20(3):19–22.
5. Zheng J.W. Automatic Infeed/Outfeed System Used in the Production of Freeze-dried Powder for Injection. Mechanical and Electrical Information of China. 2011, 29(35):30–34.
Zhang Xiulan, Zhang Heng, Yang Yihong and Wang Kai, Key Laboratory for Green Chemical Process of Ministry of Education, Wuhan Institute of Technology, Wuhan P.R. China, 430073
Wang Jia, Wuhan Pharmaceutical Industry Design Institute, SINOPHARM, Wuhan P. R. China, 430077