Designing facilities for aseptic filling

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Designing facilities for aseptic filling
27-Feb-2013
Design and Build | Regulatory
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 betalactam broad-spectrum antibiotic cefuroxime sodium that would:
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Mitigate any contamination risk
Offer the most simple and effective workflow for material and staff
Meet specific cleanroom classification standards
Project outline
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.
Process flow design
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.
Facility layout
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:
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The Grade B area and Grade A/B area were located in the core zone in the inner circle and the
grade D area was in located in the medium circle. Meanwhile, the general production area lay
in the outer circle. The layout met the requirement for a “homocentric circle” design, which
made monitoring and inspections more expedient and reduced the HVAC load because of the
convergence in the layout of rooms of the same grade.
Washing machine, sterilisation tunnel filling line and capping machine were installed in a line
from south to north, which was beneficial to equipment maintenance and core zone
environment control. Visual inspection using light and secondary packaging were also in a line
from east to west. The packaging area was located opposite the receiving and dispatch bays of
the warehouse.
The core zone should be kept small and compact, thus the Grade B area only included filling,
stoppering, capping and their auxiliary room. Double-ended sterilisers sealed into the walls
between the grade D and B areas allow the components from the grade B area (rubber
stoppers and aluminium caps) to be washed in the grade D area and then be deposited in the
grade B storeroom after sterilisation, meeting the requirements of China GMP 2010 – namely
that after sterilisation, the transfer and deposit of sealed containers, such as those used for
packaging materials and components coming into direct contact with the aseptically prepared
drugs should be carried out in a grade B environment and terminally washed, reassembled,
packaged and sterilised in a grade D environment.
Grade A vertical laminar flow hoods incorporate speed control fan filter units located within the
modular ceiling grid system. In addition, filling and stoppering is carried out under nitrogen
laminar flow.
Four transfer windows were provided. Discarded waste should be transferred to separate
discard storeroom via transfer window number 1. Components to be washed in the grade B
area were sent to the grade D area by transfer window 2. Grade B area clothing could easily be
put in the grade B area clothing laundry through transfer windows 3 and 4.
Clean areas for personnel, equipment or for materials were provided with airlocks through
which they could enter into production clean areas.
To avoid contamination of clean area clothing or carry-through of contaminants into the core
zone, the facility has a triple clothing changing system. Separate laundry facilities for clean
area clothing are available.
Provision of adequate working and in-process storage space permitted the orderly and logical
positioning of equipment and materials so as to avoid cross-contamination and to minimise the
risk of omission or the wrong application of any of the manufacturing or control steps.
l In the grade B corridor, grade D corridor, filling and stoppering room, capping room, light
inspection room etc, emergency doors were provided to ensure rapid personnel evacuation in
the event of unexpected incidents.
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
References
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.
*Authors
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
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