Equipment residue limits

Because of improved technology, analytical methods are becoming much more sensitive and capable of determining very low levels of residues. Thus, it is important to establish appropriate limits on levels of post-equipmentcleaning residues. Such limits must be safe, practical, achievable, and verifiable and must ensure that residues remaining in the equipment will not cause the quality of subsequent batches to be altered beyond established product specifications. The rationale for residue limits should be established. Because surface residues will not be uniform, it should be recognized that a detected residue level may not represent the maximum amount that may be present. This is particularly true when surface sampling by swabs is performed on equipment. 

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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. 

Table 6 Dividing a Total Residue Limit Among Various Pieces of Equipment...

It is important in any discussion of residue limits to understand that limits for a cleaning process may be expressed in different ways. This includes the limit of the residue in the subsequently manufactured product, the limit of the residue on the cleaned equipment surfaces, and the limit of the residue in the analyzed sample. These are all related, but they are usually different numbers. For an active ingredient in the cleaning of a finished drug product, the limit in the next product is usually calculated based on application of a safety factor (usually 0.001 or lower) to the minimum daily dose of that active in the maximum daily dose of the subsequently manufactured product. The active or level of active in the subsequently manufactured product is irrelevant unless there is information about unusual deleterious interactions. This calculation is also independent of manufacturing issues such as batch size and equipment surfaces areas, and can be calculated solely on information about the dosing of the two products as follows ... 

The following residue limits have been suggested not more than (NMT) 10 ppm or NMT 0.001% of the dose of any product appears in the maximum daily dose of another product and no residue visible on the equipment after cleaning procedures have been performed. 

The toxicity of the residual materials should be considered when determining the appropriate analytical method and the residual cleaning limits. The residue limits established for each piece of apparatus should be practical, achievable and verifiable. The manufacturer should be able to document with supporting data, that the residual level permitted is scientifically based. Another factor to consider is the possible nonuniformity of the residue. If residue is found, it may not be at the maximum detectable level due to the random sampling, such as taking a swab from a limited area on that piece of equipment... 

The guidelines above set out to help ensure the reliability of analytical results reported when compliance with maximum residue limits was monitored in international trade. These guidelines were essentially split into three parts and dealt with the analyst, basic resources required in the laboratory (including equipment and supplies), and the analysis. Chapter 8 of this volume discusses the validation requirements for analytical methods in detail, so this will not be covered in this chapter. However, it is worth discussing the importance of the analyst and the basic resources in more detail here. 

The visbreaking process thermally cracks atmospheric or vacuum residues. Conversion is limited by specifications for marine or Industrial fuel-oil stability and by the formation of coke deposits in equipment such as heaters and exchangers. 

Polymers. Studies to determine possible exposure of workers to residual epichl orohydrin and ethylene oxide monomers in the polymers have been done. Tests of warehouse air where Hydrin H and Hydrin C are stored showed epichl orohydrin levels below 0.5 ppm. Air samples taken above laboratory mixing equipment (Banbury mixer and 6" x 12" mill) when compounds of Hydrin H or C were mixed gave epichl orohydrin levels below detectable limits, and ethylene oxide levels less than 0.2 ppm, well below permissible exposure limits (46). A subacute vapor inhalation toxicity study in which animals were exposed to emission products from compounded Parel 58 suggests that no significant health effects would be expected in workers periodically exposed to these vapors (47). 

Most defects can be detected using one or more appropriate nondestructive testing techniques. However, in the absence of routine nondestructive testing inspections, identification of defects in installed equipment is generally limited to those that can be observed visually. Defects such as high residual stresses, microstructural defects such as sensitized welds in stainless steel, and laminations will normally remain undetected. Defects that can be detected visually have the following features ... 

Other considerations could include availability of reagent(s) or equipment, method for routine analyses vs limited samples, and confirmatory method vs multi-residues. Plan for method validation and/or analytical quality control. 

Although Colorado relies on standard contamination laws, the city and county of Denver specifically limit the use of residual sprays to those conditions in which foodstuffs, utensils, and equipment are covered and protected. Misting sprays may not be used in food preparation areas but are permitted in dining rooms of eating establishments. 

Metal cleaning wastes result from cleaning compounds, rinse waters, or any other waterborne residues derived from cleaning any metal process equipment, including, but not limited to, boiler tube cleaning, boiler fireside cleaning, and air preheater cleaning. 

An alternative to determining the quantity of residue left in the equipment is to monitor the effluent of cleaning solution for the presence of residue. If it can be shown that the residue is readily soluble in the cleaning solution and the test method is sufficiently sensitive, the acceptance criteria for cleanliness might involve washing until the residue drops below the quantifiable limit of the test method or reaches an acceptably low steady state in the effluent. 

The preparation and execution should follow a validation protocol, in which the scope of the method and its validation criteria should first be defined (46). The scope of the analytical method should be clearly understood since this will govern the validation characteristics that need to be evaluated. For example, if the method is to be used for qualitative trace residue analysis, there is no need to examine and validate its linearity over the full dynamic range of the equipment. The scope of the method should also include the different types of equipment and the locations where the method will be run. In this way, experiments can be limited to what is really necessary. For example, if the method is intended for use in one specific laboratory, there is no need to include other laboratories and different equipment in the validation experiments. 

Methods intended for regulatory residue condol should be designed with as much simplicity as possible to limit the variety, size, and type of glassware and equipment needed to minimize the potential for analytical error and to reduce costs. Reagents and standards must be readily available while specific instrumentation should be based on performance characteristics rather than a particular manufacturer. 

Common immunochemical assay formats to select from include the 96-well microtiter plates, dipsticks, coated test tubes, and membrane-based flow through devices. If the end-user is a trained technician working in a well-equipped laboratory and needs to detect and tentatively identify, for example, antimicrobial residues in hundreds of meat samples per day, a multiwell or other high-through-put format should be chosen. If, on the other hand, the end user is a quality control inspector at a milk factory who has limited time to find out whether the penicillin residues in the milk waiting to be unloaded exceed a certain level, the same reagents used in the first instance may require a more user-friendly format such as dipstick or membrane-based flow through device. 

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