Validated analytical cleaning method

Approaches to Process Validation Process Validation Program Periodic Review of Validated Systems Cleaning Validation Validation of Analytical methods Change Control, Rejection, and Reuse of Materials Rejection Reprocessing Reworking... 

Kirsch, R. B., Validation of Analytical Methods Used In Pharmaceutical Cleaning Assessment and Validation Analytical Validation in the Pharmaceutical Industry, Supplement to Pharmaceutical Technology pp. 40 6, 1998. 

Analytical testing (preformulation, stability, product release) is a core component of pharmaceutical operations from early R D through manufacturing of the commercial product. The original analytical methods are usually developed by the pioneer pharmaceutical firm and transferred to the provider. In some cases, the early methods are only preliminary methods and are not sufficiently robust to test the quality of downstream (clinical, commercial, and line extension) products and facility quality practices (cleaning validation). In those situations, the supplier is often asked to develop new methods, and in some cases those methods are transferred back to the client. In either scenario, the transfer of validated analytical methodology consists of the following four main tasks [52] ... 

Validation (policy, documentation, qualifications, approaches to process validation, periodic review of validated systems, cleaning validation, and analytical methods validation)... 

Cleaning validation protocols should describe the equipment to be cleaned, procedures, materials, acceptance criteria, parameters to be monitored and controlled, and the analytical methods to be employed for testing. Validation of cleaning procedures should reflect equipment to be used for key and final intermediates and APIs. The selection of cleaning procedures to be employed should be based on material solubility and cleaning difficulty. The calculation of residue limits should consider the potency, toxicity, and stability of critical materials. 

Validated analytical methods should have sufficient sensitivity to detect residues or contaminants. Residue limits should be practical, achievable, verifiable, and based upon the most deleterious residue. All cleaning procedures should be monitored at appropriate intervals to ensure that these procedures are effective during routine production. 

Analytical methods validation—As mentioned earlier, a good CVMP should allow the analytical method to develop concurrently with the product formulation, thus in the early stages of development, an analytical method may not be fully validated but may still be used for cleaning tests as the best available method. At the time of the PAI, however, and definitely by the time the formal cleaning validation occurs, a fully validated analytical method should be developed. This methods validation package should include all the standard parameters, with special attention to the sensitivity of the analytical method as expressed by the limit of detection (LOD) and... 

The FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. The user s rationale for the residue limits established should be logical, based on the manufacturer s knowledge of the materials and the practical, achievable and verifiable data. The objective of the inspection is to ensure that the basis for any limits is scientifically justifiable. However, unlike product residues, it is expected that no (or for ultra-sensitive analytical test methods, very low) detergent levels remain after cleaning ... 

The objective of improvement schemes is to study and validate each step of different analytical procedures applied by different laboratories in a collaborative manner. Such programmes usually involve groups of 20-50 laboratories. In the best case, each critical step of the procedure should be evaluated in an adapted exercise. The individual steps may be studied with a series of different materials in a stepwise manner. In principle the strategy consists of starting from the simplest matrix, e.g. pure solutions and/or mixtures of compounds in solution, for testing the performance of the detector. The analysis of more complex matrices (e.g. raw extract, purified extract) enables the separation and/or clean-up steps to be tested, whereas solid samples are used to test the entire procedure. Spiked samples can be analysed to evaluate the extraction procedure, within the limits of this evaluation (as commented in Section 2.3.1). Such an approach is actually similar to the steps that should be followed when developing and validating a new method in a laboratory. 

The efficiency of cleaning procedures should be verified through validated analytical testing with enough sensitivity for residues or detection of contaminants at acceptable levels. It is important that all surfaces potentially in contact with the product be cleaned by previously validated methods. The FDA proposes that manufacturers set limits for active principle residues after cleaning and in the product to be obtained at a subsequent production run (FDA, 1993b). A multipurpose plant should be specially monitored to avoid cross-contamination (Doblhoff-Dier and Bliem, 1999). 

Kirsch, R.B. Validation of analytical methods used in pharmaceutical cleaning assessment and validation. Analytical Validation in the Pharmaceutical Industry (Suppl. to Pharm. Technol.) 1998, 22 (10), 40-46. 

Various types of validation generally required in biopharmaceutical manufacturing include process validation, facility and equipment validation, analytical method validation, software validation, cleaning validation and expression system characterization. Combined with other elements of cGMP, including lot release testing, raw material testing, vendor quality certifications, and vendor audits, the quality of product can be consistently assured. 

Validation concepts, first noted in the worldwide industry as a quality related essential in the late 1970s, are now included and referenced as the norm for all GMP codes applicable in all countries. Validation, not even defined in the original 1976 US GMPs, has grown to cover analytical methods, computer systems and controls, cleaning methods, utilities, and processes a detailed definition appeared in the May 1996 appendix to the US GMPs. 

The cleaning validation protocol should describe the equipment to be cleaned, methods, materials, and extent of deaning, parameters to be monitored and controlled, and analytical methods. The protocol should also indicate the type of samples (rinse, swabs) to be obtained, and how they are collected, labeled, and transported to the analyzing laboratory. 

Cleaning procedures should be checked by appropriate methods after validation to ensure these procedures remain effective when used during routine production. Where feasible, equipment should be examined visually lor cleanliness. This may allow detection of gross contamination concentrated in small areas that could go undetected by analytical verification methods. 

Automated systems Process validation of unit-operations Cleaning methods Analytical methods Furthermore it must be assured that relevant documentation is up to date and available. If data from Product Quality Review (PQR, see Sect. 35.6.11) and stability testing are available they should be evaluated in order to identify any critical aspect of the processes. If not available related quality indicators, such as test results, deviations and complaints should be evaluated. 

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. 

The most common (off-line) sample preparation procedures after protein precipitation are solid phase extraction and liquid-liquid extraction. Multiple vendors and available chemistries utilize 96-well plates for solid phase extraction systems and liquid-liquid extraction procedures. Both extraction process can prepare samples for HPLC/MS/MS assay. Jemal et al.110 compared liquid-liquid extraction in a 96-well plate to semi-automated solid phase extraction in a 96-well plate for a carboxylic acid containing analyte in a human plasma matrix and reported that both clean-up procedures worked well. Yang et al.111 112 described two validated methods for compounds in plasma using semi-automated 96-well plate solid phase extraction procedures. Zimmer et al.113 compared solid phase extraction and liquid-liquid extraction to a turbulent flow chromatography clean-up for two test compounds in plasma all three clean-up approaches led to HPLC/MS/MS assays that met GLP requirements. 

DQ is performed by the supplier of the equipment or system at the supplier s factory as part of the factory acceptance test (FAT). IQ (based on site acceptance test—SAT), OQ, and PQ are performed on-site at the GMP facility. For a GMP manufacturing facility, the validation activities include the facility design, FTVAC system, environment control, laboratory and production equipment, water system, gases and utilities, cleaning, and analytical methods. Validation protocols (IQ, QQ, and PQ) are prepared for each item, listing all critical steps and acceptance criteria. Deviations are reviewed and resolved before the validation activity proceeds to the next phase. 

HPLC is the leading Analytical procedure used for the verification of pharmaceutical cleaning validation programs. HPLC provides a linear, sensitive method for quantitating low levels of residues making the chromatographic finish the most reliable part of the cleaning verification. 

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