Validation cleaning

Cleaning validation tests are performed to ascertain the effectiveness of the procedure used to clean pharmaceutical processing equipment (e.g., blender, 

Q is a value specified in USP 711 in USP28-NF23. NMT = Not more than. 

Method Isocratic (or gradient) HPLC with UV detection 

Typical specification limits 0.1% of maximum daily dosage for product residues Method validation Accuracy three levels in triplicate at LOQ to 20X 

Precision six replicates at LOQ NMT 20% RSD Specificity API resolved from other components in a procedural blank sample 

Before execution of the cleaning validation, the cleaning procedures should be in the form of approved standard operating procedures (SOPs). These procedures should be detailed enough to be reproducible. Parameters such as detergent type, detergent concentration, exposure time, rinse temperature/rinse time, and water pressure/flow rate should be included in the procedure. The final rinse is usually performed with water for injection (WFI). The production operators should be trained in these procedures and their training should be documented. 

Problems such as swab recoverability or interference with adhesive materials are commonly encountered during the swab selection process. It is imperative that the swab selected be compatible with the diluent, the detergents, and the chemical (active/degradant) and it cannot cause interference with the method used for residue analysis, typically FIPLC and/or TOC. A swab recovery study is required for determining the acceptability of a swab. This is performed by spiking the swab with known quantities of the various chemicals under evaluation for potential carryover. The swabs need to be analyzed by the validated method to be used in the cleaning validation studies. An acceptable level of recovery should be no less than 70% and a correction factor needs to be included in final residue calculations. 

For microbial monitoring, sterile swabs also need to be selected. Similar swab recovery studies are performed this time with microorganisms instead of chemical agents. 

In the pharmacy industry, pharmaceuticals are produced in batches, and one type of pharmaceutical may be produced after a different type with the same equipment. Thus, it is imperative that the equipment be cleaned between batches. Cleaning validation is the formal process by which a company ensures that there is no contamination from one batch to the next. Specifically, it is defined as 

The process of providing documented evidence that the cleaning methods employed within a facility consistently controls potential carryover of product (including intermediates and impurities), cleaning agents and extraneous material into subsequent product to a level which is below predetermined levels.  

FIGURE 15.1 (a) Schematic diagram of the SPME-IMS interface showing the location 

FIGURE 15.2 (a) Ion mobility spectrum of a standard solution of methylparaben, ethyl-paraben, propelparaben, butylparaben, and benzylparaben. (b) IMS spectrum of a sample blank. (C) IMS spectrum of a topical cream showing the presences of parabens at the level of approximately 1 mg/g. (From Lokhnauth and Snow, Determination of parabens in pharmaceutical formulations by solid-phase microextraction-ion mobility spectrometry. Anal. Chem. 2005,77, 5938-5946. With permission.) 

FIGURE 15.3 Ion mobility spectrum of a mixture of 25 pg of duloxetine and 100 pg of proprietary surfactant. The ion peaks labeled with R are the reactant ions, D is the duloxetine, and those labeled S are from the surfactant. (From Strege et al., At-line quantitative ion mobility spectrometry for direct analysis of swabs for pharmaceutical manufacturing equipment cleaning verification, Anal. Chem. 2008, 80,3040-3044. With permission.) 

Specificity is the ability to assess unequivocally the analyte in the presence of components, which may be expected to be present. Typically these might include impurities, degradants, matrix, etc. 

The accuracy of an analytical procedure expresses the closeness of agreement between the value, which is accepted either as a conventional true value or an accepted reference value and the value found. This Is sometimes termed trueness . 

The precision of an analytical procedure expresses the closeness of agreement (degree of scatter) between a series of measurements obtained from multiple sampling of the same homogeneous sample under the prescribed conditions. Precision may be considered at three levels repeatability (within run) intermediate precision (over time) and reproducibility (inter-laboratory). 

The detection limit of an individual analytical procedure is the lowest amount of analyte in a sample, which can be detected but not necessarily quantitated as an exact value. 

us Food and Drug Administration, Pharmaceutical cGMPS for the 21stCentury-A Risk-Based Approach Second Progress Report and Implementation Plan, 2003, available http //www.fda.gov/cder/gmp/2ndProgressRept Plan. htm accessed 27 November 2009. 

Eustace, Process analytical-chemistry - an industrial perspective, Anal. Chem., 62 (2), A65-A71 (1990). 

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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. 

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... 

Source Parenteral Drug Association. Technical report No. 29, Points to consider for cleaning validation, PDA Journal of Pharmaceutical Science and Technology 52 Nov-Dec Supplement (1998). 

Brunkow R, DeLucia D, Green G, et al. Cleaning and Cleaning Validation A Biotechnology Perspective, PDA, Bethesda, MD, 1996. 

Disadvantages Cells only grow when attached to solid substrates cells require additional attachment factor not easy to scale up more cleaning validation issues and high disposal cost more difficult to operate than suspension process... 

Finally, we will discuss the determination of the limit of quantitation or LOQ. Establishing an LOQ is required for many pharmaceutical applications such as impurity testing and cleaning validation. Limit of quantitation is the lowest concentration (%, ppm) that can be determined with acceptable precision (RSD of —5%). It is generally accepted that a signal/noise ratio at the LOQ should be at least There are... 

Cleaning validation 6 replicates at 10 x LOQ Relative standard deviation NMT 20%... 

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. 

Analytical Methodology The Heart of Cleaning Validation, Presented at the 42nd Annual Conference on Pharmaceutical Analysis, July 30, 2002, Merrimac, Wisconsin and 26th Puerto Rico Pharmaceutical Quality Association, January 28,2003, San Juan, Puerto Rico. 

HPLC applications assays, impurity evaluation, dissolution testing, cleaning validation, high-throughput screening, and chiral separations (Chapters 13-18). 

N.K. Mehta, J. Goenaga-Polo, S.P Hemandez-Rivera, D. Hernandez, M.A. Thomson and P.J. MeUing, Development of an in situ spectroscopic method for cleaning validation using mid-IR fiber optics. Spectroscopy, 18(4), 14 (2003). 

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). 

Potentially useful in cleaning validation, which is part of the manufacture of pharmaceuticals. 

The cleaning validation is required to demonstrate that, after cleaning, the equipment and surfaces are essentially free from product residues and traces of cleaning agents to prevent cross-contamination. 

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