Fully Automatic CIP Design Based On Quality And Risk Control System

The new version of GMP puts forward specific requirements for cleaning validation and risk control, emphasizing that all parts in contact with drugs must use “repeatable” and “recordable” cleaning methods to remove residues in the production process, aiming to reduce human errors , to reduce potential quality risks in the production process.

In recent years, there have been frequent safety accidents in my country’s pharmaceutical industry, mainly in the field of small-volume injections. Many companies do not pay attention to the cleaning verification of the product production stage, and the production process is not strictly controlled, resulting in cross-contamination and excessive microorganisms in the pharmaceutical production process. In serious cases, the test is qualified when leaving the factory, but it becomes an unqualified product in the hands of the user.

The reason is that the quality management is not strict, the quality awareness of employees is weak, and the lack of risk control-related knowledge training is only one of the reasons; in addition, the design of the cleaning system is flawed, the dependence on on-site operators is too strong, and the degree of automation is not high. All may lead to serious drug quality accidents.

Risk control exists in every link of the pharmaceutical process. We need to determine the control points with different weights through research and analysis, and take measures to control the risk within the acceptable range of regulations and process requirements, and in the long-term production control The same level has been maintained.

This requires us to understand the cleaning steps and process parameters of different equipment cleaning processes, determine reasonable operation and control methods, summarize some risk control measures and methods, use various measurement and analysis techniques, and integrate the practical experience of automation control theory. To design a fully automatic CIP system with preventive self-maintenance function.

In the working process of CIP, there are two kinds of risks: one is internal operation risk; the other is external operation risk.

Inherent operational risk refers to the risk existing in the design, mainly focusing on the design of the operating parts of various devices used in CIP, the design of its own pipeline and the design of self-cleaning ability. External risks include public system risks, interconnection risks, interactive operation risks, risks in pipeline design, and risks in its own cleaning-in-place function.

Usually a professional CIP supplier starts with external risk assessment in order to determine the specific structure of CIP. For example, we can understand from the CIP design of a batching system how risk assessment can promote the optimal design of CIP system step by step.

In terms of economic benefits, cleaning does not directly produce any benefits, but cleaning takes up a lot of production time, and at the same time consumes a lot of resources, energy, and chemical substances. For pharmaceutical production, cleaning must be taken seriously.

For the weighing and preparation of sterile preparations, the batching system is often used, especially the multi-tank system (more than 3 tanks). After each batch of liquid preparation is completed, strict cleaning work is required, and a professional CIP system is required. . The general cleaning process includes traditional processes such as flushing-alkali cleaning-rinsing-finishing-purging-sterilization. Generally, according to the traditional CIP design concept inherited from the food industry, it may be determined to use a double-tank CIP product, one for the injection water storage tank and one for the purified water/cleaning liquid storage tank, and then configure the corresponding valves, switching pipelines, Pump, cleaning liquid replenishment system, PLC control system, thus forming a complete cleaning system. However, if we look at it from the perspective of risk assessment, this is not necessarily reasonable. After cleaning verification analysis and calculation, we can indeed determine the flow rate and time required to clean the tank and pipeline, so as to determine the selection of various components, but the most important risk design principle in the CIP design principle is: the design of CIP must Consider minimizing the risk impact on the object to be cleaned.

First of all, you can compare the flow rate required for cleaning with the risk relationship between the storage tank and the public system. If the flow rate of water for injection used for cleaning is less than half of the circulation flow provided by the public system, you can consider passing it directly through the pipeline. The pressure of the system pipeline is used to complete some pipeline and tank cleaning work, which can save a water for injection storage tank and a large number of auxiliary protection distribution components, such as respirators, valves and additional pipelines. From the perspective of risk assessment, the smaller the surface area directly in contact with drugs, the fewer components, the lower the risk; at the same time, with the reduction of components, the overall operation risk, maintenance risk, and control risk are significantly reduced. If one storage tank is reduced, the daily maintenance of this storage tank can be canceled, the frequency of work can be accelerated, the production rhythm will be accelerated, and the overall production cost will be further reduced.

At present, this technology has been verified abroad for many years and has been proven to be reliable, with low energy consumption and low cost. In the past two years, foreign advanced pharmaceutical factories have generally adopted this concept of risk assessment to build or modify cleaning systems. From the above example, we can see that through risk assessment, we can optimize the structural design of a CIP, reduce some unnecessary components, and make the whole system more streamlined and run more efficiently.

Similarly, we can look at how to design a fully automatic CIP system with preventive self-maintenance function from the internal risk assessment.

In a CIP system, if it is evaluated according to the theory of risk assessment, then the highest risk is some moving parts. When the life of these moving parts is close to the design value, the entire operating state is already in an unknown area. For example, the start-up diaphragm valve that is often used on CIP, no matter what material the diaphragm is made of, has a limit on the life of the number of switches. In the range of switching times close to 90%~100% of the design life, the diaphragm due to long-term deformation Stress loss is already in an unknown state, and the user cannot judge when the diaphragm will be damaged during this period, and the leakage of the diaphragm valve will cause foreign matter to be mixed into the cleaning water, and the light one will cause abnormal cleaning results or the risk of cleaning failure , Seriously, it will cause a major safety accident of cross-contamination. In recent years, domestic news has reported similar major safety accidents, such as the recall of a certain brand of beverages containing excessive chlorine, and the recall of a certain brand of dairy products with “blue milk”. These are all caused by cross-contamination. The possibility and high harm of this risk have been exposed.

In the same way, other moving parts will have similar problems. For example, the pumps and conversion panels used in the entire CIP system may have similar problems. Therefore, we need to sum up experience and lessons, incorporate these risks into our risk assessment system, and start from design to solve or reduce the chances of these risks occurring.

Imagine if we can record the operating parameters of these moving parts in the control system, then, according to the concept of preventive self-maintenance, we can consider designing the function of parts replacement reminder, so that we can control the risk before it comes Naturally, the risk can be controlled within the expected range.

Similarly, in the entire pharmaceutical production process, the unprofessional and uncertain human operations have brought more uncertain risk factors to pharmaceutical production. The adoption of fully automated production equipment has a considerable effect on reducing the overall risk. At the same time, in the case of rising labor costs year by year, establishing an automated production process will also help companies reduce the impact of social and environmental factors in the competition.

The CIP cleaning system is not just a set of equipment, but a set of technical services of “quality and risk control system”. The added value of profit is also in the link of technical services and cleaning verification. Value is based on customer needs and risk control system control systems and cleaning validation procedures.

How to develop a product that not only conforms to GMP standards but also adapts to China’s national conditions will be a long way to go. It is certain that starting with the quality and risk control system is the embodiment of the core value.

Reliable CIP design comes from a deep understanding of production cleaning process, personnel operation, environment and control system. Risk control can be said to be everywhere. From the selection of various components used in the system to the programming of the control system, to the assembly of the final product, factory verification, transportation, installation, commissioning, and operation, all need to be carefully considered. From the design life of the components to the actual service life, from the design environment to the actual use environment, from the designed working conditions to the actual working conditions, and even the quality of the operators, we need to carefully consider. It can be said that each set The design of CIP is a practice of quality management and risk control system.