The protein used to sustain life produced by a certain biopharmaceutical manufacturer can greatly reduce the side effects of chemotherapy. The manufacturer is in a leading position in the industry, but faces challenges in clean validation. The company's production facilities have stable performance, reliable operation, and advanced technology, ensuring that the production process is smooth, safe, and cost-effective. For example, the company did not use HPLC methods with very limited applicability to analyze routine wiping samples used for cleaning validation and product conversion, but instead employed non exclusive methodsTotal Organic Carbon (TOC) Analysis MethodIt saved a lot of expenses.

They are still challenging the harsh conditions of the four regions on the protein purification column in their process flow with challenging compoundsTOC verificationThe four week pilot validation study shows that the company's clean validation (routine validation and product conversion) program conducted in the laboratory is expected to increase its clean validation costs by $54000. If the company continues to operate in its current state, its cleaning validation costs will exceed $500000.

Analyzing water-based cleaning samples in the laboratory is not tedious, but it requires a lot of manpower and time, and cannot produce the expected results. However, clean validation is not just about laboratory technicians going to the production workshop to extract samples and then bringing them back to the laboratory. Assuming the testing equipment is ready, the staff still need to load the samples and wait for the processing to end. After obtaining the results, the staff even need to spend more time recording the results in the experimental notes and equipment notes, and filling out the report. The current flowchart is shown in Figure 1.

Figure 1. Sampling process diagram (click to view larger image)

According to the company's calculations, it takes a total of 895 hours to test 371 samples generated from four areas on the purification column, necessary for cleaning confirmation and product conversion, over a typical four week period. The estimated cost of these samples is 53700 US dollars. In addition, staff may need to spend 48 hours obtaining test results from the laboratory and then resume production - this is a major part of the production schedule. Therefore, the company has decided to abandon laboratory analysis methods and instead seek lower cost methods.

After evaluating multiple alternative options, the company ultimately decided to adoptSide line at line TOC analysis methodThat is, on-site analysis. Similar to online samplingThe personnel collect samples near the process flow (rather than in the process flow) and use portable analyzers for on-site analysis. On the right side of Figure 1, it is shown thatThe method fundamentally eliminates the expensive non value added steps in the previous TOC sampling process. The test results areCan be generated in just 30 minutesThe staff only need to enter the results into the production records.

The company has chosenSievers^®M9 portable TOC analyzerThe reason is that the analyzer helped it solve three major problems. Firstly, the company has validated the TOC analysis methods (Sievers UV persulfate oxidation method and thin film conductivity detection method) in its laboratory and is very satisfied with this technology. Due to the FDA's support for sideline methods, using this analyzer can greatly reduce the manpower required for recording and reporting.¹The production team can directly extract samples, analyze them using an analyzer, and quickly record the analysis results. They will not need to wait for the Quality Control (QC) department to release results and audit equipment. With the help of the side line TOC method, the sampling procedure can be carried out directly in the production workshop, away from the laboratory.

The second challenge is to demonstrate that the analysis results of the M9 portable analyzer are equivalent to or superior to the laboratory analysis results of the company. In the laboratory, staff analyze and clean validation samplesConduct standardized testing or system suitability testing before the product to verify the results. Fortunately, the program is the same as the one used for sideline analysis with the M9 portable analyzer, and the test results are "comparable" to those of the TOC method.

The third challenge is how to pass on the relevant knowledge of the instrument and method to the employees in the production department. However, it has been proven that this is not a problem at all, as the employees in the production workshop were able to proficiently use the instrument after attending a 60 minute training/skills course.

After completing the necessary change control assessment and documentation, the company realized that,Using M9 portable analyzer can immediately save a lot of costsDue to its lightweight design, the manufacturing team is able to conduct sample analysis in multiple production workshops. Including the supply costs of containers, cotton swabs, and standard samples, as well as equipment validation costs, the annual cost of using this analyzer is only $40000, far lower than the estimated $500000 required for laboratory testing.

The company compared the cost data of the laboratory TOC method with the cost data of the sideline TOC analysis method collected so far. They expect that if they leave the laboratory and directly implement the TOC method in the production workshop, it will be used annually for cleaning validation and product conversionSampling costs will be significantly reduced by 92%(Figure 2). In addition, the QC department and production team can also utilize their time more effectively. There will be no endless procrastination during the analysis process; On the contrary, the staff can record the analysis results in real time and quickly sign off on the validation plan and product conversion records (Figure 3) with certainty.

Figure 2. Side line TOC reduces costs by 92%

Figure 3. Shortening cycle time of side line TOC

Aligning production processes with FDA's Process Analysis Technology (PAT) program is part of the company's strategic plan.¹PAT is a framework aimed at improving the quality of the final product. Although changes in processes are difficult to control and record in the pharmaceutical industry, the company realizes that these changes are keeping up with the times, innovative, and can be considered a good practice. The FDA agrees and its PAT program also encourages the pharmaceutical industry to develop and implement new technologies, and the sideline TOC is a good example.

The company did not spend a lot of time and money during the transition to the sideline method, but easily and smoothly confirmed the changes in its cleaning validation method, effectively proving that the sideline TOC method is a low-cost method for implementing the PAT framework.

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