Cleaning of biopharmaceutical equipment
Abstract: Biopharmaceutical equipment, due to the special characteristics of the composition of the drug itself and the production process, has the characteristic of being more likely to form residues and more difficult to clean than general pharmaceutical equipment.
The 2010 version of the Good Manufacturing Practice (GMP) clearly requires that the cleaning method should be validated to confirm the effectiveness of the cleaning to effectively prevent contamination and cross-contamination.
The purpose of this paper is to provide a systematic review of the requirements for cleaning validation in various recent regulations in force, the selection of cleaning agents and the development of cleaning methods for biopharmaceutical equipment, the determination of testing methods, the determination of cleaning cycles, and revalidation.
Keywords: cleaning validation; production equipment; biological products
Biological products have a complex composition, volatility, the use of raw materials are mostly biologically active substances, the removal of ineffective components of the process is complex, the final product is required to be aseptic, and the difficulty of cleaning equipment.
The whole production process has a high risk.
In order to ensure that the products are safe, effective and ultimately sterile, it is necessary to do a good job of cleaning verification.
Biological products production process is more complex, generally includes: cell recovery, virus culture, virus harvest, concentration, purification, (inactivation), preparation, filling, lyophilization, packaging and other steps, different process steps require the use of different production equipment.
It is generally recognized that the equipment that is in direct contact with the product (intermediate) is the key production equipment, such as fermentation tanks, preparation tanks, filling machines, etc.
In this paper, we present the key production equipment that is in direct contact with the product (intermediate).
This paper summarizes the requirements of various regulations on cleaning verification, and the process of cleaning verification of biologics production equipment to determine the cleaning method, the determination of the detection method, the determination of the cleaning cycle and re-verification to discuss.
1, all kinds of regulations on the cleaning verification requirements:
"Good Manufacturing Practice (2010 Revision)" has been implemented on March 1, 2011, requiring pharmaceutical companies to ensure that the production equipment clean.
Article 143 of GMP states: ? Cleaning methods should be validated to confirm their cleaning effect to effectively prevent contamination and cross-contamination.
Cleaning validation should take into account the use of equipment, cleaning agents and disinfectants used, sampling methods and locations and the corresponding sampling recovery rate, the nature and limits of residues, the sensitivity of residue testing methods and other factors.? [1] According to the U.S. Code of Federal Regulations CFR 211: ? Pharmaceutical companies are required to clean, maintain, and sanitize equipment and utensils at appropriate intervals and in accordance with official or other established specifications to prevent malfunctions or cross-contamination that can alter the safety, identity, concentration, quality, or purity of the drug product, thereby assuring the quality of the drug product.?
The National FDA inspection of drug manufacturing facilities will be based on GMP, requiring pharmaceutical companies to provide valid, continuous cleaning validation data and reports that demonstrate that a specific cleaning program consistently cleans the equipment within certain predetermined limits; sampling and analytical methods must be scientifically sound and provide sufficient scientific rationale to support this validation.
The principle of WHO GMP 155 for cleaning validation is that the cleaning method should be validated to demonstrate that it cleans effectively to prevent contamination and cross-contamination.
Cleaning validation should take into account the use of equipment, cleaning agents and disinfectants used, sampling method and location, and the corresponding sampling recovery rate of the nature and limits of residues, the sensitivity of the residue test method and other factors. [2]
2 , Selection of cleaning agents and development of methods for biopharmaceutical equipment
2.1 In the implementation of cleaning and cleaning validation, the selection of appropriate cleaning agents and cleaning methods is the most critical first step in cleaning validation.
The first consideration is which cleaning agent to choose.
The choice of cleaning agent should in general be based on an analysis of the most difficult substance to clean, which may be the active ingredient of the drug or an excipient of the drug.
The most difficult substances to clean are different depending on the production process and the production equipment.
The choice of cleaner should be based on the specifics of the equipment and the residue.
It is important to consider the safety of the cleaner, non-hazardous, non-corrosive to the equipment, easy to clean and have a sensitive enough method of detecting the residue of the cleaner.
In addition, should also be aware of the impact of water, the nature of the water, purity, hardness on the cleaning effect of detergents have an impact.
[3] General cleaning agents for biopharmaceutical equipment are purified water, 1% to 2% strong alkali solution (to remove protein residues), 1% to 2% sodium carbonate solution , ethanol, water for injection (the last cleaning) and so on.
2.2 Process equipment cleaning methods, usually can be divided into manual cleaning methods and automatic cleaning methods, or a combination of both.
The choice of cleaning method should take into account the material of the equipment, the structure, the use of equipment and cleaning effect and other aspects.
The main feature of manual cleaning is that people hold cleaning tools to clean the equipment, usually need to disassemble the equipment to a certain extent, and transfer to a designated area, more cumbersome, human influence factors.
But some cleaning equipment or areas can only be cleaned manually.
For example, some small-volume fermenters need to be disassembled and cleaned.
Automatic cleaning (CIP) means that the equipment is automatically cleaned according to a certain program, which is more demanding, but the reproducibility of automatic cleaning is better.
2.3 The development of cleaning methods of SOP should generally include: the scope and object of cleaning, the responsible person, sanitary ware, detergents and disinfectants, whether or not online cleaning, whether or not the equipment needs to be disassembled, the step-by-step guide to the cleaning process, the cleaning process of monitoring and record-keeping, how to check the cleaning, cleaning, cleaning of the qualification standards, cleaning after the . How to store the equipment, the expiration date of the storage.
3 detection methods after cleaning
3.1 In the selected cleaning agents and cleaning methods for cleaning, but also should be tested for cleaning effect.
Sampling of equipment after cleaning generally have the final drenching water sampling and wiping sampling of two kinds.
After the sampling is completed, it is necessary to test the sample, for non-critical equipment, especially specialized equipment, generally only requires no visible residue after cleaning.
For some simple biopharmaceutical equipment, the cleaning method for the use of a certain concentration of sodium hydroxide treatment, the corresponding detection method is through the determination of the final PH of the rinse water to determine whether it has reached the standard of cleaning.
For some critical equipment, especially online cleaning equipment, the total organic carbon (TOC) detection method, through the detection of organic carbon content in the water to speculate the content of impurities in the water, this method is widely used in the cleaning effect detection, and the TOC detection method has the advantage of time-saving, energy-saving, energy-saving and emission reduction [4].
3.2 cleaning validation of the analytical object is the residue, cleaning validation of the analytical method used in the need for methodological validation, if the use of the National Pharmacopoeia standards, the verification of the method can be omitted, but the need to test the method and the test instrumentation of the system adaptability of the validation.
The detection of residues in the cleaning validation is generally quantitative or limited detection methods, according to the pharmacopoeia standard, its analytical methodology validation should include: method specificity, accuracy, precision (reproducibility, intermediate precision) linearity and range, detection and limit of quantification and so on. [5]
4 Determination of cleaning validity and re-validation
4.1 Determination of the validity of cleaning
Validation of cleaning validity is generally carried out in accordance with the following methods: after the end of the cleaning in accordance with the cleaning procedures for drying of the equipment, storage, storage period of every period of time in the different parts of the most difficult to clean consecutive samples, to check the limits of microbial residue when the microbial measurement When the results of microbial determination close to the microbial residue standards, this time the equipment to maintain clean time that is the validity of the cleaning, after the production process after the cleaning of the equipment should not exceed the validity of this period.
4.2 Re-validation
If the concentration or variety of cleaning agent changes, or cleaning procedures have been significantly modified to increase the production of relatively more difficult to clean the product or the production of product changes, major changes in the equipment, equipment cleaning procedures have reached the re-validation cycle, etc., should be carried out in order to ensure that the cleaning is effective and the quality and safety of biological products.
References:
[1]Good Manufacturing Practice 2010[S]
[2]WHO Cleaning Validation Guideline TRS-937[S]
[3]Zhou QK. Sun Wei. Cao Fenglan. Hang TJ. Discussion on the cleaning validation of pharmaceutical GMP production equipment[J]. Straits Pharmacology, 2011, 23(12)258-259.
[4]Wang Yan. Liang Yi. Feasibility study of online total organic carbon analysis applied to clean validation[J]. Mechatronics Information, 2010, 23:24-29.
[5]Chen Wenqiu. Validation of analytical methods in cleaning validation[J]. Chinese Pharmaceutical Industry, 2005, 14(4): 17-19.