Validated cleaning processes

Common reasons for GMP warning letters and deficiencies observed during pre-approval inspections include laboratory controls, production and process controls, records and reports, and validation (cleaning, process, assay, and computer)J ... 

FDA Guideline to Inspection of Validation of Cleaning Processes, Office of Regulatory Affairs, July 1993... 

Three different batch sizes were used, namely =400, =800, respectively =1200 kg in the chemical industry it is standard practice to validate a process for the available kettles and then adjust the particular batch size (minimum filling so the stirrer bar remains covered, maximum filling so no overpressure occurs and vents stay free) to achieve the requested tonnage often, campaigns of batches are run before the equipment is cleaned and refitted for the next product, see batch numbers 19. .. 23, followed by 1,. ... ... 

Berg, T., Humphreys, P., Phillips, B. and Scherz, B., Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation , PIC Publication PH 1/96. 

Several key issues have to be addressed in the downstream processing of biopharmaceuticals regardless of the expression system. The removal of host cell proteins and nucleic acids, as well as other product- or process-related or adventitious contaminants, is laid down in the regulations and will not differ between the individual expression hosts. The identity, activity and stability of the end product has to be demonstrated regardless of the production system. The need for pharmaceutical quality assurance, validation of processes, analytical methods and cleaning procedures are essentially the same. 

Summing up, a robust and easy to handle SMB-design uses 4 zones, a recycling pump fixed in respect to the columns and two pumps for the control of the outlet flow rates. Extremely high precision of all technical components of the SMB is needed. All pumps and valves have to be exactly synchronized. The flow rates should not vary by more thanl % from the preset value. All connections between the different parts of the system must be carefully optimized in order to minimize the dead volume. All columns should be stable and nearly identical in performance. If the SMB-technology is to be used in Biotechnology, GMP issues (cleaning, process and software validation) also have to be considered. In addition and as with any continuous process in that particular area, the definition of a batch could be a problem. 

Food and Drug Administration. Guide to Inspections Validation of Cleaning Processes, FDA, Rockville, MD, 2006. 

Facilities and Equipment System This includes (1) buildings and facilities along with maintenance (2) equipment IQ, QQ, calibration, maintenance, cleaning, and validation of cleaning processes and (3) utilities such as HVAC, compressed gases, steam, and water systems. 

M.L. Hamilton, B.B. Perston, PW. Harland, B.E. Williamson, M.A. Thomson and P.J. Melling, Grazing-angle fiber-optic IRRAS for in situ cleaning validation, Org. Process Res. Dev., 9, 337-343 (2005). 

The lyophilizers are cleaned using a validated clean-in-place (CIP) cycle using hot WFI. After the cleaning process, a validated sterilization cycle is mn. The qualification of the steam sterilization cycle was performed during the operation qualification (OQ) of the lyophilizer. 

In order to avoid cross-contamination, another concern with respect to equipment is the cleaning process, which must comprise cleaning SOPs to ensure adequate cleanliness. Cleaning validation must be performed based on risk assessment and worst-case scenarios. 

New products, particularly potent drug products, can present cleaning problems in existing equipment. Manufacturers must validate their cleaning processes for the new drug/dosage form. 

From the point in the process where full GMP compliance begins, the excipient should be produced in qualified equipment using a validated manufacturing process and testing should be done using validated methods. Where production equipment is not dedicated, validated cleaning methods are also needed. Full GMP compliance is required no later than the final excipient purification step or the manufacturing step where the excipient molecule has been synthesized, whichever occurs later in the process. 

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

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. 

Based upon ICH guidelines, cleaning procedures should be validated. Cleaning validation should be directed toward processing steps in which possible contamination or material carryover poses a risk to API quality. If residues are removed by subsequent purification steps in the process, cleaning procedures can be less rigorous. 

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... 

Eventually the point will be reached at which the development of a product is complete the formulation is finalized, the equipment has been selected, the analytical methods are validated, the development transfer report has been issued, and the Preapproval Inspection (PAI) is anticipated. Now is the time to consider validation of both the manufacturing and cleaning processes. Although some process validation may have also been completed or a process validation protocol may have been prepared and approved, it is likely that very little has been finished that would enable us to state that the cleaning process is fully validated. 

Documentation requirements—Several activities associated with validation of the cleaning processes may generate documentation, which may be addressed in the CVMP. They are... 

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