Cleaning processes, verification

Category II methods are intended to determine impurities in bulk drug substance, degradation products in finished drug product, or for verification of cleaning processes. These methods are further subdivided into quantitative tests and limit tests. 

Validation and Verification of Cleaning Processes William E. Hall... 

The reader will note that the title of this chapter includes a second term in addition to the more familiar term validation. True classic validation of the cleaning process is not always possible in certain pharmaceutical operations, and verification is a more appropriate description of the approach to cleaning. The application of this concept to research and development (R D) areas will be developed and discussed in this chapter. 

It is appropriate to discuss cleaning verification in a little more detail since the principle of cleaning verification is currently very widely used in development facilities. The main difference between verification and validation is in the number of events captured. For validation, the requirements to refer to a cleaning process as validated are that, first of all, three identical batches of a single... 

Product information. Name, dosage form (tablet or liquid, vial, etc.), process, active ingredients, material safety data sheets (MSDS), analytical methods, cleaning validation/verification methods, special handling requirements, etc. 

Cleaning validation is required only for surfaces of multipurpose equipment that come in direct contact with the product. When using dedicated equipment only verification of the cleaning process is necessary. Attention should be paid to so-called hot spots difficult-to-clean locations, which if improperly cleaned would lead to contamination. 

The manufacturing route, raw materials, and chemicals must be well controlled and meet strict quality requirements (e.g., purity of raw materials, chemicals and intermediates, process steering control, cleaning verification). 

Though in competition with other analytical techniques, CE has proven its potential and necessity to be used for the characterization of small-molecule pharmaceuticals. Due to the versatility of the system, CE can be applied for the determination of physicochemical properties, identification, purity and stability analysis, and cleaning verification of the drug substance, its precursors, process chemicals, the drug product, and its excipients. 

The establishment stage includes verification, qualification, and individual validation, including process validation, computer validation, method validation, and cleaning validation. These establishment stage steps shall satisfy the principal requirements in Table 6. 

In practical terms, the verification, qualification, analytical validation, cleaning validation, and process validation need to satisfy certain requirements. 

Outside of the occasional system calibration and model verification tests, the routine maintenance burden of a Raman system is quite low. Optical windows may need to be cleaned, though automatic window cleaning systems can be implemented if it is a known issue. The most likely maintenance activity is laser replacement. Some systems have a backup laser that turns on automatically if the primary laser fails. This lessens the impact of a failure if the unit is being used for closed-loop process control. With a quality instrument and well-developed models, process Raman installations need less maintenance than many competing techniques. 

Summary of the process, cleaning, and sanitization validation or verification studies performed. 

After the limits are calculated for all products that are to be processed and all equipment used, the limits are compared. The smallest limit calculated for a product using all of the calculations becomes the acceptance limit for the cleaning verification for that product. If product B, the lot to be manufactured next, is unknown at the time of manufacture of Product A, the worse case should be assumed in the calculation. For example, if the smallest lot that has ever been manufactured in the facility is 5000 dosage units, or alternatively 1 kg, those values should be used in the equation to generate a maximum allowable carryover of product A. To reiterate some of the initial points, the rationale for which equation is utilized should be documented, and the limits that are established should be practical, achievable, and verifiable based on the most deleterious residue. 

Verification of spread of materials and products during maintenance and cleaning of environmental and process air handling plant and equipment. 

Tanks used in processing liquids and ointments are equipped with fittings that can be dismantled and cleaned. Validated Clean-In-Place (CIP) equipment can be dismantled for periodic verification. 

For all major premises or equipment instruments and devices which may have critical influence on the preparation or analytical processes, a logbook should be kept. The logbook is the history of a piece of equipment or a facility and it aims at traceability and verification. The investigation of any deviation may use the logbook as a vital source of information to enable the root cause to be traced. In addition, the logbook will include records as to whether equipment is maintained on time, if rooms are cleaned on time etcetera. 

Any one or combination of the following tests can be used to assess the cleanliness of a piece of equipment. The cleanliness assessment is limited to the precision and bias of the verification technique. Failure to pass any of the specified tests requires recleaning and reinspection, and may require reevaluation of the cleaning procedures. In-process inspections to ensure the adequacy of cleaning procedures may be desirable. 

Breathing air containers must be processed by a method that encompasses inspection evacuation and purging. The cleaning procedures ensure that the container and component parts are not reactive, additive, or absorptive to an extent that significantly affects the identity, quality, and purity of the specified quality verification level of air being supplied. 

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