Analysis On Cleaning Validation Problems In Inspection Of Pharmaceutical Enterprises

Part 1 worst Condition

Theoretically, the different equipment involved in each variety should have its own cleaning operation procedures confirmed. However, in the practice of drug production, it is impossible and unnecessary for enterprises to spend manpower, material resources, and financial resources to confirm all the equipment involved one by one. This requires enterprises to select and determine the worst condition for cleaning verification through risk assessment among many conditions according to their own actual conditions. There are many factors to be considered in the worst condition, including: toxicity, solubility, color and odor of the product or material, batch and batch production, volume size and geometry of the equipment, surface roughness, and whether the material is easy to clean , Whether there are pipe diameters and dead angle parts that are not easy to clean, whether there are multiple varieties collinear, etc. The selection of the worst condition for cleaning validation requires a risk assessment to determine the worst condition.

During the inspection of pharmaceutical manufacturing enterprises, it was found that the establishment of cleaning procedures for related equipment in some production control areas by individual enterprises was far from the worst conditions in the relevant cleaning verification. For example, under item 4.5 of a company’s D-level clean area cleaning regulations (document number: *), it is stipulated that the equipment is not clean when the same type of equipment is changed, and under item 4.13.2, it is stipulated that the continuous production of the same type of equipment exceeds 2 weeks or the interval between batches of the same type When the time exceeds 3 days, clean it by changing the variety; the regulations in the above documents lack the support and basis of relevant verification data. Another example is that a company’s chemical medicine tablets and traditional Chinese medicine granules are on the same line. In the cleaning verification plan (document number omitted), Azithromycin, Banxia and Wei Granules were initially selected as the cleaning verification reference materials for the granule production line, and Analgin was selected as the tablet. For the cleaning verification reference of the production line, microbial residues were selected as one of the inspection indicators, and azithromycin was finally selected as the cleaning verification reference, which could not reflect the cleaning risk of the co-production of chemical drugs and Chinese patent medicines, and the cleaning verification report (document number omitted) The concentration of azithromycin recovery test is 100 times higher than the highest linear concentration. The cleaning verification report of the ointment vacuum emulsification mixer of a pharmaceutical manufacturer is incomplete: the equipment is used for the preparation of 4 marketed varieties and 2 research varieties, and the risk assessment for all varieties using this equipment is not carried out in the cleaning verification plan. Difficult-to-clean varieties, only use 100% ointment as the object of cleaning verification, and the cleaning of the pretreatment pot integrated with the equipment (the matrix used to prepare this variety: white vaseline and other varieties of water phase) is not included in the verification Reporting.

Part 2 Cleaning Method

Cleaning methods include cleaning methods for changing different products on the same line and different batches of the same product, cleaning methods for different production equipment, whether the cleaning method is online cleaning or offline cleaning, the choice and type of cleaning agent, cleaning time, and cleaning procedures , Cleaning operation action, concentration of cleaning agent, time interval for changing the type of cleaning agent, whether pre-washing and inspection are required, whether drying is required after cleaning, storage methods and conditions of cleaned equipment or utensils, whether the cleaning agent belongs to I, II Solvents and their impact on the environment.

During the inspection, it was found that a certain company’s cleaning operation regulations stipulated that clean clothes in different workshops should be cleaned separately, but there were no relevant regulations on special requirements for washing machines, and the clean clothes after washing shared the whole clothes room of the same workshop. Risk assessment of possible cross-contamination caused by clean environment and storage methods. Another example is an enterprise’s “Standard Operating Procedures for Cleaning and Drying Containers in General Production Areas” (document number omitted) that stipulates that the production equipment should be soaked in ethanol after production and then washed with water. However, the operator in step 1 did not operate according to the regulations during the on-site dynamic inspection. , blending with water arbitrarily with ethanol for soaking. A certain company’s “Filling and stoppering machine (filling parts) in the freeze-dried powder injection workshop, re-validation plan for the cleaning effect of the sterilization and filtration system”, “Cleaning, disinfection and disinfection of the KGS10-X2 type antibiotic bottle filling and stoppering machine in the freeze-dried powder injection workshop There are two cleaning methods (conventional cleaning method and 2% sodium hydroxide solution cleaning method) in the detachable parts cleaning procedure in the “Standard Operating Procedures for Cleaning and Sterilizing the Liquid Filtration System of the Freeze-dried Powder Injection Workshop”. The verification report shows that only one of them has been verified; the cleaning method of 2% sodium hydroxide solution requires “soaking in 2% sodium hydroxide solution for 15-30 minutes”, and the actual verification selects the soaking time as 30 minutes.

Part 3 Sampling Method And Sampling Point

Sampling methods related to cleaning validation include rinse sampling method, swab sampling method, visual inspection method, etc.

Rinse sampling is used in areas where swab sampling cannot be used, and the sample analysis results represent the sum of all removed residues in the rinse solution. The sampling process will not pollute the equipment, and there is no need to re-clean after sampling. This method is suitable for online analysis of active ingredients, cleaning agents, and bioburden of traditional Chinese medicine preparations. Since this method can only detect residues that are dissolved in the rinse solvent, it is important to ensure that the rinse solution contacts all surfaces to adequately detect residues. The key point of this method is that the sample is diluted due to washing, and the residual distribution position information is limited, which makes it impossible to detect. This method is usually limited to flushing the entire device. For older equipment, the availability or accessibility of a sampling port is a consideration.

The wiping sampling method often uses fibrous materials to wipe the surface, puts the fibrous materials with residues in the solvent, and analyzes the residues in the solvent with proven and feasible methods. Before choosing a wiping swab, you need to evaluate the properties of the swab, such as leachables and shedding. The recovery of surface residues also depends on the size and shape of the swab head or wipe and the flexibility and length of the handle. The recovery rate test of different materials must be completed before the implementation of this plan, and the same person should conduct at least three operations, which should be greater than or equal to 50%, and the RSD of the three results should be less than or equal to 20%. In order to ensure the safety of the product, the material with the lowest recovery rate should be taken as the final recovery rate with the lowest risk of pollution when calculating the residual amount.

Although the visual inspection method is intuitive and quick, it can detect small-area pollutants that are difficult to detect when sampling, and can be concentrated and accumulated. It can be used in cleaning validation and daily cleaning operations to evaluate and prove the effect, and to evaluate the relationship between the visual inspection limit and the allowable residue limit , which is suitable for judging general cleaning results; but because it cannot be quantified, it is highly subjective. For some equipment, pipelines and other surfaces that cannot be directly observed, optical equipment (such as fiberscope, etc.) or auxiliary lighting equipment should be used for inspection, so there is no single acceptance standard.

There are many kinds of pharmaceutical production equipment, and the construction and shape of each equipment are not the same. The selection of sampling points must be highly representative, and the selection of sampling points is very important. Risk factors that should be considered in the selection of sampling points include but are not limited to: equipment areas with large amounts of drugs in contact, rough and non-smooth surfaces, dead corners where cleaning agents are not easily accessible, areas where pipe diameters change from small to large, areas with low equipment pressure and low flow rates , easy to adsorb the main drug or detergent area, etc. Risk factors for microbial residues in equipment also include drains and areas prone to water accumulation. The selection of sampling points should be specified and explained in detail in the cleaning validation plan, and the actual location of the sampling points should be clearly marked with pictures, charts and symbols. Sampling points should pay attention to the special position structure of the equipment, such as slope, smoothness, polishing degree, arc angle, junction, blind pipe, weld or sealing seam, as well as feeding port, punch, filling head, pipeline, etc. place. The cleaning agent in the above-mentioned parts has a low flow rate or is difficult to reach, and it is easy to absorb residues. Generally, wipe samples are selected.

During the inspection, it was found that some manufacturers chose unreasonable cleaning methods, and the sampling plan in the cleaning verification plan did not describe the sampling location, sampling volume and sampling quantity in detail, which was not conducive to actual operation, and the rationality of the sampling points was insufficiently analyzed. For example, in the cleaning procedures of fixed hopper mixers, powder sieving machines, and vibrating screens of a Chinese medicine formula granule manufacturer, the cleaning agents are all drinking water and no purified water is used for cleaning, and the cleaning effect evaluation is only visual inspection; The wipe sampling and sample preparation records are incomplete, and there are problems such as the lack of sampling corresponding to the production batch and sampling time information; a certain company did not inspect the pre-cleaning sampling of the liquid mixing tank; The report (document number: *) is not detailed, and the type of hopper used and the sampling point for cleaning verification are not specified; a floor drain in a certain sieving room is partly located under the arc corner of the ground, which is inconvenient for cleaning and sampling; a certain In the enterprise cleaning verification report (No. YZ07-013b-2), the selected concentration of azithromycin recovery rate test is 100 times higher than the linear maximum concentration; the design of cleaning verification plan for individual equipment of a certain enterprise is unreasonable, such as: for heparin benzethonium chloride salt vacuum The cleaning validation protocol for the drying trays specified that only visual inspections were used, and no samples were taken for active residue testing.

Part 4 Residues And Analysis Methods

In the actual production process of pharmaceuticals, there may be various residues in the cleaned site and equipment, such as active ingredients (main ingredients of raw materials), excipients, solvents, degradation products, detergents, solvents, disinfectants, microorganisms, bacterial endotoxins , physical particles, etc. In the actual cleaning validation process, classification is often based on products using similar equipment combinations. Select the most toxic or most difficult to clean residues in the equipment combination of the same category as the reference substance, and use it as the target to be cleaned in the cleaning validation, and its limit is an important indicator of the cleaning validation degree.

Pharmaceutical manufacturers should choose appropriate detection methods according to the characteristics of the product to truly reflect the cleaning effect. The method validation of cleaning validation should be validated in accordance with the provisions of Appendix 9101 of the Chinese Pharmacopoeia with reference to the quantification or limit method of “determination of impurities”, covering accuracy, precision, specificity, linearity and range, as well as limits of quantification and detection limits, etc. . When pharmacopoeia methods are involved, such as bacterial endotoxin and microbial limit test methods, the applicability of the methods needs to be confirmed, and method validation is not required.

The instrumentation of all equipment involved in the cleaning validation process must be calibrated to ensure the accuracy of the data parameters obtained. The selection of relevant analytical methods should consider the nature of the substance to be detected and whether the sensitivity of the method itself can meet the detection limit of residues or pollutants. Common cleaning validation analysis methods include high performance liquid chromatography (HPLC), thin layer chromatography (TLC), spectrophotometry (UV), total organic carbon (TOC) detection method, electrophoresis analysis method, pH value and conductivity detection method Wait. High performance liquid chromatography (HPLC) has the characteristics of high specificity, high sensitivity and low detection limit. For varieties with clear components and high purity, they can basically reflect the cleaning effect. However, the cost of equipment and reference substances used in the detection is relatively expensive, and the analysis time may be relatively long. Thin layer chromatography (TLC) has the advantages of high specificity, high sensitivity and quantification. However, the end point cannot be quantified visually, and the sample preparation time is relatively long. Spectrophotometry (UV) has high specificity and high sensitivity; however, it cannot be detected quantitatively. The total organic carbon (TOC) detection method can monitor and determine organic residues including water-soluble substances online, and the samples can be quickly turned over. It is more commonly used in the cleaning verification of traditional Chinese medicine preparations; but it is only suitable for water-soluble samples and has poor specificity. Electrophoretic analysis is specific to biopharmaceuticals and has high detection sensitivity; however, it has the disadvantages of high detection cost, inability to handle denatured proteins, and long sample turnaround time. pH and conductivity detection methods are often used to judge the cleaning end point of online cleaning systems. The advantages are rapid measurement and online monitoring, economical and convenient, and wide application; however, they are only suitable for water-soluble samples and have poor specificity.

There are certain problems in the sample processing method and analysis method selection for residue detection in the cleaning verification work of some production enterprises. For example, the “F-line online cleaning and sterilization effect re-validation plan” of a certain enterprise did not confirm the analysis method of residue; The cleaning residue limit detection method of an enterprise adopts the sample processing method in “Validation Report of *** Residue Analysis Method in Cleaning Validation and Research on Recovery Rate on Different Materials” (document number: *) as “adding cotton swabs to 10 mL of water, ultrasonic treatment for 10 min”, which is inconsistent with the sample treatment method in the original record of swabbing sample inspection; the residue inspection items of a certain enterprise are unreasonable (such as only detecting detergent residue, only visual residue detection, not testing pH value after equipment lye soaking and cleaning, etc. ), the specific limit value (such as the UV absorbance is less than a specific value, etc.) is not based on sufficient basis, and all items have not been tested according to the items specified in the verification plan.

Part 5 Personnel Training

The composition and organization of personnel engaged in relevant cleaning validation is the primary condition to ensure the effective implementation of cleaning validation. For the relevant personnel involved in the cleaning validation, especially the operators who clean the equipment related to the cleaning validation, they must be strictly trained on the relevant cleaning operation procedures. Sampling operators should be the QA or QC personnel of the enterprise. They are required to have received training in the cleaning validation program, be familiar with the sampling location and sampling method, and be able to explain the requirements in the sampling process and the basic principles of the procedure. They should be regularly retrained and passed the assessment. The vast majority of enterprises pay more attention to the establishment and training of cleaning validation staff, but some companies are not comprehensive and detailed in the training content of personnel engaged in related cleaning validation. The use of ethanol disinfection gloves should be avoided before sampling to avoid contamination of the samples; the training content of a company’s personnel who performed the cotton swab wiping operation in the verification of the sampling method did not see the recovery test assessment.

Part 6 Conclusion

Carrying out effective cleaning validation work is an important measure to reduce the risks of contamination, cross-contamination, confusion, and errors in the pharmaceutical production process. Determining the cleaning validation method based on the risk assessment results can further guarantee the quality of drug production, and on this basis, improve the efficiency of cleaning validation, reduce the workload of cleaning validation, further reduce costs, and improve enterprise production efficiency. At the same time, drug inspectors should also carry out targeted inspections on the relevant content of cleaning verification based on risks during the inspection process of various drug production enterprises, so as to further improve the quality of on-site inspection work.