Equipment cleaning residue limits

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. 

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. 

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... 

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. 

Analytical methodology—This section should refer to the specific analytical method(s) to be used for the specific products, cleaning agents, and equipment for the protocol being evaluated. Many companies choose to have the detailed analytical methodology described in a separate report and reference only the report number in the actual protocol. There are certain parameters that should be included in the actual protocol, however. For example, the sensitivity of the analytical method, expressed either as the LOD or LOQ, should be included in the protocol since it will be necessary that the sensitivity of the analytical method be below the acceptance criteria for the residues so that a result of none detected can be interpreted, ft must be remembered that none detected does not mean that there was no residue present, but only that the level of residue was below the limit of detection of the analytical method. 

The acceptance criteria may also specify limits on microbial counts, endotoxin, particulate matter, and other parameters appropriate or significant for the particular product. The author remembers one protocol that specified the absence of a characteristic odor that was indicative of a certain residue and was a sensitive yet simple measure of whether or not the equipment was adequately cleaned. 

Determining what is an acceptable amount of residue remaining on the equipment is at the very heart of cleaning verification and validation. The determination of acceptable carryover limits for pharmaceutical equipment and facilities is actually addressing the question of What is clean To those who feel that equipment and facilities should always be cleaned to the level of analytical detectability, I will only say that approach is certainly always acceptable, and in some cases, a very reasonable approach. In most cases, however, cleaning to the lowest level of analytical detectability has a couple of major disadvantages. The first problem with this approach is that current analytical capability is so incredibly sensitive that the previously manufactured product(s) can almost al-... 

Based upon the advantages of the other techniques presented prior to LC-MS, large volume injection HPLC-UV, and HPLC-CAD, the decision to use electrochemical detection would be driven primarily by a unique analytical need, equipment availability and previous experience of the analytical chemist. A complex chemical matrix should not be of concern at most there could be some residual cleaning agent and residual excipients in addition to the active pharmaceutical ingredient. Since the matrix in cleaning verification is typically simple, electrochemical detection would not be the primary detection technique. However, the sensitivity afforded by ECD is excellent and can meet the most stringent of the acceptance limits outlined in Table 15.2. 

The objective of cleaning validation of equipment and utensils is to reduce the residues of one product below established limits so that the residue of the previous product does not affect the quality and safety of the subsequent product manufactured in the same equipment. 

The hazardous nature of azide manufacture necessitates simple facilities, which are easy to keep clean and tree from grit and residues, provide protection to the operator through the use of barriers and remote control, yield only limited-size batches, and permit unimpeded access to reaction vessels. In general, because of the similarity between the processes utilized by different manufacturers, there is little difference between the facilities and equipment used at the various locations. 

Many excipients are produced using multipurpose equipment. Fermentation tanks, reactors, dryers, grinders, centrifuges and other pieces of equipment are readily used or adapted for a variety of products. With few exceptions such multiple usage is satisfactory provided the equipment can be adequately cleaned according to written procedures. Equipment that contains tarry or gummy residues that cannot be removed easily should be dedicated for use only with limited portions of a process. 

Organic solvents Remove adhesive and solder paste residues have a wide-process window can clean at room temperature do not oxidize or corrode metals Solvents and solvent vapors may he flammable high cost may be slow drying limits on VOCs and ozone-depleting solvents (ODSs) require explosion-proof equipment... 

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