In the manufacturing industry, it is generally believed that the economy of mass production comes from "Large scale", i.e. the increase in yield, the reduction of fixed cost shared by each unit of products, thereby reducing the cost per unit of products, namely, the mass manufacturing model
As a special commodity, drug is directly related to human health and life safety. For the mass manufacturing of sterile freeze-dried injections, not only the yield and production scale of the drugs should be taken into consideration, it also needs to ensure the sterility in the drug production process and the quality of the final products. The mass manufacturing of sterile freeze-dried injections has the following characteristics:
Determination by product and market
In the massing manufacturing of freeze-dried injections, the drugs produced are generally chemical medicine or traditional Chinese medicine. The production cost of unit product is reduced through the mass manufacturing model so as to maximize the profits. CMO commissioned processing enterprises usually adopt the mass manufacturing model, while some enterprises with best-sellers, high value-added products or exclusive varieties may also adopt this production model. According to the author’s understanding, in India where the pharmaceutical industry is relatively developed, multiple 40~50㎡freeze dryers and automatic feed system are applied in the freeze-dried injection mass manufacturing workshops of some enterprises to produce high value-added anti-tumor drugs.
Modular design workshop
After years of project practice and experience accumulation, for the mass manufacturing of freeze-dried injections, modular design is generally adopted at present to achieve high yield and replication of workshop production. Such modular production workshop has at least four large freeze dryers, with the freeze drying area per freeze dryer of 40㎡. For the load of 7ml vials with 22mm diameter, each freeze dryer load can reach about 90,000 units. In the project cases that the author is involved, such production workshops can achieve at least four "Four-in and four-out" per working day, i.e. feeding of four freeze dryers, yielding of four freeze dryers, and the loading and unloading of a total of about 720,000 vials. As the daily production capacity is in 100,000 units as the measurement unit, it poses huge challenges to the raw materials, packaging materials, production management and quality assurance system.
Highly customized design
Different from the conventional freeze-drying injection workshop, mass manufacturing sterile freeze-dried injection workshop adopts highly customized design. From the workshop concept design, to the final workshop put into operation, all aspects of issues need to be taken into consideration.
Firstly, customized design of time
In mass manufacturing, time is the most important (Time is the money), including the production shift, product freeze-drying cycle, process equipment speed matching, etc. For example, prior to the conceptual design, it is advisable to optimize the freeze-drying process of the product to minimize the freeze-drying cycle so that it can be controlled within a reasonable range. Excessively long freeze-drying cycle will affect the production shift and equipment utilization; excessively short freeze-drying cycle may have the "transport" and "digestion" problem between different batches of freeze-dried products. For the supporting process equipment, it requires that the core equipment, such as the filling line, inlet and outlet system and freeze dryers, etc., can operate 24 hours/day, 250 working days without downtime, so as to achieve the set goal of "Personnel break without equipment downtime ". The speed connection should even to calculated to as precise as "seconds", taking into account different emergencies in the production process, so as to make full use of all the capacity of the equipment, without the waste of valuable time in the future production.
Secondly, customized design of building structure
Customized design is required for the building structure according to the process and equipment. If standard workshop is adopted, it will be very difficult to implement a mass manufacturing workshop. The structure and layout of equipment are particularly important for the implementation of mass manufacturing.
For example, to improve the utilization rate of the freeze dryers and the transfer speed of the vials, in the mass manufacturing mode, the standard design of the freeze dryer body is double-door opposite side layout, with the vial loading side door and vial unloading side door. The vial loading side door is generally in the form of small door, responsible for the transfer of vials to the freeze dryer after filling; the vial unloading side door is in the form of large maintenance door + small door, responsible for the transfer of vials out of the freeze-dryer after freeze drying and plugging.
As a workshop is equipped with at least four freeze dryers, to reduce the size of the clean room, the cold trap of the freeze dryer is design in the bottom of the body. And there are certain requirements for the bearing point of the body and cold trap, the hole size of the connection and the tube well position. Synchronized equipment is required for the building to accurately design the beam position, with the need to use two-story design or basement design, etc., hence the requirement for architectural design is also very high.
Thirdly, customized design of the production line equipment
For mass manufacturing sterile freeze-dried injection workshop, it is particularly important to ensure stable and efficient production, and reduce the operating costs in the later phase as much as possible.
In the aspect of stable production, the upstream and downstream equipment can be integrated through the systematic concept to reduce the risk in the operation. For example, the filling machine and automatic feeding and output system adopt the integrated design to reduce the use of conveyor belts and buffers, so as to avoid the occurrence of inversion of vials and other problems.
In the aspect of efficient production, currently the simultaneous filling of the same freeze dryer by two and more units of filling machine can be achieved in the technical level through the automatic feeding and output system, so as to shorten the loading speed of the freeze dryer and improve the production efficiency. In the aspect of operating cost reduction, smaller grade B clean area can accommodate more freeze dryers through the COMBO design of freeze dryer without sacrificing the maintenance. In the design of the production line, the grade A area used for the core area can be reduced through the systematic design. The optimization of the aforementioned design can greatly reduce the operating costs of the HVAC system in the later phase.
Application of automation and less manpower technology
Due to the large volume of production between mass manufacturing batches, the risk of drug contamination in the production process is relatively high, hence automation equipment should be used as much as possible during the production process. It can not only to avoid human cross-contamination, but also prevent the various errors incurred by human intervention. In the aspect of sterile transport, the application of automation can mainly realize the unmanned plugging, liquid drug entering into the filling machine and the vial access to the freeze dryer.
The traditional solution for the transfer of the rubber stopper on the filling machine generally adopts the means of airtight bucket or aseptic bag packaging removal. The airtight bucket or aseptic bag is opened manually in the PASSBOX with grade A environmental protection. And the rubber stopper is poured into the rubber stopper vibration bucket in the filling machine mechanically or manually. Such manual operation method not only increases the operation amount of personnel in the sterile room, but also requires the consideration of the usage cost for the airtight bucket or aseptic bag later.