Live Recap: Lifecycle Management for Cleaning Validation

As we all know, collinear production has become the most important production method in the pharmaceutical industry, which can not only effectively reduce construction and operating costs, but also improve economic benefits. And in today's common situation of contract production, its industry logic has become clearer.

However, with the co-line production of multiple products, there are also many management problems such as drug contamination and cross-contamination, whether it is from the perspective of being responsible for patients or avoiding the impact of subsequent pollution incidents on enterprises, cleaning verification has undoubtedly become a problem that pharmaceutical companies attach great importance to.

So what's the problem? As a pharmaceutical company, what does a cleaning verification entail? How is cleaning verification carried out efficiently and orderly? How to develop a clean verification strategy?

On November 24th, Zhao Chenggang, cleaning SME of Porton Longevity Factory, gave a live lecture on the theme of "Life Cycle Management of Cleaning Verification", which had a clear answer to the above questions, and conducted in-depth analysis and interpretation of the design and development of cleaning process, the selection and calculation of residue limits of cleaning targets, the implementation points of cleaning process verification, and the life cycle management of continuous cleaning process verification.

01. Policy changes in clean verification are becoming more "scientific"

Although the requirements for cleaning verification are obviously different at different stages in various countries, they are emphasizing several key elements, paperwork, research on cleaning capabilities, establishment of cleaning methods, etc., which are the key to determining effectiveness.

Through nearly 20 years of policy changes in cleaning verification, we can find that on the one hand, the government intelligence department is increasingly focused on cleaning verification. Its requirements are also becoming more and more scientific and reasonable, and according to such laws, its scientificity and rationality will continue to increase in the future.

02. The key point of design and development is to "adapt to local conditions"

The purpose of cleaning is actually through the organic and reasonable combination of the four elements of heat, mechanical force, chemical cleaning power and time, and according to the cleaning principle and the different mode of action of cleaning, the design and development of various cleaning processes are born.

Factors such as flow and impact force have different performance on the cleaning effect, and in general, there are four points that require special attention in the design and development of the cleaning process.

⭐ First, the cleaning process needs to be identified and its importance to the cleaning process assessed;

⭐ The second is to define the key parameters of cleaning and the selection of cleaning agents;

⭐ Then there is the cleaning residue in the cleaning process and the ability of the detergent to remove;

⭐ Finally, the development of sampling methods and analysis methods and the identification of equipment and tools to be cleaned.

All in all, the flexibility to change strategies according to changing circumstances is the key point in the design and development of clean processes.

03. The selection and residue of clean targets are "particularly important" for limit calculation

Cleaning targets are residues of concern in cleaning validation, and for non-sterile production processes, typically include active ingredients, microorganisms and cleaning agents; For aseptic production processes, bacterial endotoxins are also added. In the selection of cleaning targets, the biggest problem of enterprises is the lack of adequate evaluation of cleaning targets.

According to the overall process or the actual content, the logical selection of cleaning agents is one of the main points.

As for the calculation of the residue limit of the cleaning target, the first thing to emphasize is that visual inspection, as the most commonly used method in the cleaning stage of the equipment, has the advantage of direct realization and will not cause pollution to the equipment. The disadvantage is that it is strongly influenced by the subjectivity of the visual inspector, and it is difficult to ensure the consistency of the visual inspection.

Therefore, for cleaning verification, visual inspection cannot be used alone as an inspection standard, but should be used as a supplement to the wipe and reflux sampling testing standards. A visual inspection and documentation of the results must be carried out after each wash, which should be used as the first acceptance criterion for the acceptance limit of cleaning verification.

The more important active substance limits and their calculation methods are the most significant and important part of the entire cleaning verification process.

In other words, if cleaning verification is an important measure to reduce the risk of contamination and cross-contamination during pharmaceutical production, then the active substance residue limit is an important criterion in cleaning verification and a key indicator to judge the effectiveness of cleaning methods.

In the process of development of the pharmaceutical industry, a variety of different calculation methods and standards have been generated for the residue limit of active substances in cleaning verification, each with different scope of application, advantages and disadvantages.

Among them, the commonly used calculation methods of active substance residue limits mainly include PDE method, TDD method, toxicological limit method and general limit method.

Of course, the use of many methods should have their own priorities, and in general, PDE limit method should be preferred when the corresponding data is available. But in fact, no matter what kind of calculation method, what kind of calculation method, in fact, the core is the same, that is, to fully assess the impact of residues on subsequent products, whether it will have toxic side effects on patients.

04. How to implement cleaning verification correctly

First of all, once again, emphasize why cleaning verification should be done, why the official does not accept cleaning to qualify, but to emphasize a rationality for each link of cleaning verification. The official consideration is not only the final result, but also the reasonableness verification process of the entire cleaning process.

So how exactly do you verify cleaning?

In general, the implementation of the cleaning verification plan is mainly divided into four stages: development stage, preparation stage, implementation phase and monitoring stage.

Among them, the development stage emphasizes the preparation of a draft cleaning process according to the product portfolio, production mode, equipment structure and material, and preliminary testing in the laboratory; According to the data of multiple batches of laboratories, draft regulations and confirmation drafts for the cleaning process of pilot batches are prepared; According to the progress of production process development, implement cleaning confirmation in the pilot plant/GMP workshop, improve and optimize the cleaning process; Identify basic possible cleaning processes.

05. The continuous monitoring of cleaning capacity should pay more attention

What is continuous cleaning process confirmation, China's GMP appendix "Confirmation and Verification" requires the implementation documents of continuous process confirmation, mentioning: "continuous process confirmation should be carried out in accordance with the approved documents, and a corresponding report should be formed according to the results obtained".

In terms of cleaning verification verification, traditional cleaning verification focuses on proving the effectiveness of the cleaning method through the confirmation of the procedure. However, a great deal of practical experience suggests that considering cleaning validation in a life-cycle approach is a better approach. In the process of cleaning method application, it focuses more on the transformation from the confirmation of cleaning effect to the development of cleaning method and continuous confirmation.

Therefore, it requires the continuous monitoring and management of cleaning methods, which is a continuous understanding, development and control of the cleaning ability of enterprises. The focus is not only on the second stage of cleaning process validation, but also on the first stage of cleaning method development and the third stage of continuous cleaning verification and the identification of cleaning capabilities. This is what pharmaceutical colleagues should focus on.

Question: Does the cleaning solvent selection have to have good solubility?

The principle of cleaning mainly includes four elements: physical and mechanical force, chemical dissolvency force, temperature and time. When choosing a cleaning solvent, it is recommended to choose a solvent with good solubility, so that during the cleaning process, the cleaning target can be effectively dissolved in the cleaning solvent, so as to achieve the purpose of cleaning the target from the surface of the equipment and ensure the cleaning effect.

Question: Good teacher, equipment that is not used often, does it need to be limited for cleaning, and how long is the limit?

There are two very important inspection items in cleaning verification management, namely CHT (cleanholdtime) and DHT (dirtyholdtime). For equipment that is not used frequently, or equipment that has been cleaned, CHT (cleanholdtime) needs to be examined to determine the cleaning retention time of the cleaned equipment.

Q: What are the residue monitoring standards for cleaning agents?

Because its ultimate purpose is to ensure patient safety and product quality safety, the PDE method is also applicable to the residue monitoring standard of the cleaning agent, and its cleaning verification residue standard can be established according to the relevant toxicological data of the cleaning agent used.

Q: Should wiping and rinsing samples be approved before using the device for production?

Yes, the test results of the wipe and rinse samples need to be approved and meet the acceptable standards for cleaning of the next product before the equipment can be used for the next product.