{"id":4450,"date":"2026-09-30T10:22:05","date_gmt":"2026-09-30T10:22:05","guid":{"rendered":"https:\/\/28.feihuaweiye.com\/part-1-validation-of-cleaning-processes-in-pharmaceutical\/"},"modified":"2026-11-07T06:51:33","modified_gmt":"2026-11-07T06:51:33","slug":"part-1-validation-of-cleaning-processes-in-pharmaceutical","status":"publish","type":"post","link":"https:\/\/28.feihuaweiye.com\/pt\/part-1-validation-of-cleaning-processes-in-pharmaceutical\/","title":{"rendered":"(PART 1) Validation of Cleaning Processes in Pharmaceutical"},"content":{"rendered":"\t\t<div data-elementor-type=\"wp-post\" data-elementor-id=\"4450\" class=\"elementor elementor-4450\" data-elementor-settings=\"{&quot;ha_cmc_init_switcher&quot;:&quot;no&quot;}\" data-elementor-post-type=\"post\">\n\t\t\t\t<div class=\"elementor-element elementor-element-51e7efc e-con-boxed e-flex e-con e-parent\" data-id=\"51e7efc\" data-element_type=\"container\" data-e-type=\"container\" 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200-89.5 200-200 200zm61.8-104.4l-84.9-61.7c-3.1-2.3-4.9-5.9-4.9-9.7V116c0-6.6 5.4-12 12-12h32c6.6 0 12 5.4 12 12v141.7l66.8 48.6c5.4 3.9 6.5 11.4 2.6 16.8L334.6 349c-3.9 5.3-11.4 6.5-16.8 2.6z\"><\/path><\/svg>\t\t\t\t\t\t\t<\/span>\n\t\t\t\t\t\t\t\t\t<span class=\"elementor-icon-list-text elementor-post-info__item elementor-post-info__item--type-author elementor-icon-list-text elementor-post-info__item elementor-post-info__item--type-date elementor-icon-list-text elementor-post-info__item elementor-post-info__item--type-time\">\n\t\t\t\t\t\t\t\t\t\t<time>10:22 am<\/time>\t\t\t\t\t<\/span>\n\t\t\t\t\t\t\t\t<\/li>\n\t\t\t\t<li class=\"elementor-icon-list-item elementor-repeater-item- elementor-inline-item elementor-icon-list-item elementor-repeater-item- elementor-inline-item elementor-icon-list-item elementor-repeater-item- elementor-inline-item elementor-icon-list-item elementor-repeater-item- elementor-inline-item\" itemprop=\"author datePublished commentCount\">\n\t\t\t\t\t\t<a href=\"https:\/\/28.feihuaweiye.com\/pt\/author\/admin\/ https:\/\/28.feihuaweiye.com\/pt\/2026\/09\/30\/ https:\/\/28.feihuaweiye.com\/pt\/part-1-validation-of-cleaning-processes-in-pharmaceutical\/#respond\">\n\t\t\t\t\t\t\t\t\t\t\t<span class=\"elementor-icon-list-icon\">\n\t\t\t\t\t\t\t\t<svg aria-hidden=\"true\" class=\"e-font-icon-svg e-far-comment-dots\" viewBox=\"0 0 512 512\" xmlns=\"http:\/\/www.w3.org\/2000\/svg\"><path d=\"M144 208c-17.7 0-32 14.3-32 32s14.3 32 32 32 32-14.3 32-32-14.3-32-32-32zm112 0c-17.7 0-32 14.3-32 32s14.3 32 32 32 32-14.3 32-32-14.3-32-32-32zm112 0c-17.7 0-32 14.3-32 32s14.3 32 32 32 32-14.3 32-32-14.3-32-32-32zM256 32C114.6 32 0 125.1 0 240c0 47.6 19.9 91.2 52.9 126.3C38 405.7 7 439.1 6.5 439.5c-6.6 7-8.4 17.2-4.6 26S14.4 480 24 480c61.5 0 110-25.7 139.1-46.3C192 442.8 223.2 448 256 448c141.4 0 256-93.1 256-208S397.4 32 256 32zm0 368c-26.7 0-53.1-4.1-78.4-12.1l-22.7-7.2-19.5 13.8c-14.3 10.1-33.9 21.4-57.5 29 7.3-12.1 14.4-25.7 19.9-40.2l10.6-28.1-20.6-21.8C69.7 314.1 48 282.2 48 240c0-88.2 93.3-160 208-160s208 71.8 208 160-93.3 160-208 160z\"><\/path><\/svg>\t\t\t\t\t\t\t<\/span>\n\t\t\t\t\t\t\t\t\t<span class=\"elementor-icon-list-text elementor-post-info__item elementor-post-info__item--type-author elementor-icon-list-text elementor-post-info__item elementor-post-info__item--type-date elementor-icon-list-text elementor-post-info__item elementor-post-info__item--type-time elementor-icon-list-text elementor-post-info__item elementor-post-info__item--type-comments\">\n\t\t\t\t\t\t\t\t\t\tNo Comments\t\t\t\t\t<\/span>\n\t\t\t\t\t\t\t\t\t<\/a>\n\t\t\t\t<\/li>\n\t\t\t\t<\/ul>\n\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<div class=\"elementor-element elementor-element-7ab156d elementor-widget elementor-widget-text-editor\" data-id=\"7ab156d\" data-element_type=\"widget\" data-e-type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t\t\t\t\t\t\n<h3 style=\"text-align: justify;\"><strong><span style=\"line-height: 3;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">1. INTRODUCTION:<\/span><\/span><\/span><\/strong><\/h3>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Validation of cleaning procedures has generated considerable discussion since agency documents, including the Inspection Guide for Bulk Pharmaceutical Chemicals and the Biotechnology Inspection Guide, have briefly addressed this issue. These Agency documents clearly establish the expectation that cleaning procedures (processes) be validated.\u00a0<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">This guide is designed to establish inspection consistency and uniformity by discussing practices that have been found acceptable (or unacceptable). Simultaneously, one must recognize that for cleaning validation, as with validation of other processes, there may be more than one way to validate a process. In the end, the test of any validation process is whether scientific data shows that the system consistently does as expected and produces a result that consistently meets predetermined specifications.\u00a0<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">This guide is intended to cover equipment cleaning for chemical residues only<\/span><\/span><\/span><\/p>\n<h3 style=\"text-align: justify;\"><strong><span style=\"line-height: 3;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">2. BACKGROUND:<\/span><\/span><\/span><\/strong><\/h3>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">For FDA to require that equipment be clean before use is nothing new; the 1963 GMP Regulations (Part 133.4) stated as follows: \u201cEquipment *** shall be maintained in a clean and orderly manner ***.\u201d A very similar section on equipment cleaning (211.67) was included in the 1978 CGMP regulations. Of course, the main rationale for requiring clean equipment is to prevent contamination or adulteration of drug products. Historically, FDA investigators have looked for gross insanitation due to inadequate cleaning and maintenance of equipment and\/or poor dust control systems. Also, historically speaking, FDA was more concerned about the contamination of nonpenicillin drug products with penicillins or the cross-contamination of drug products with potent steroids or hormones. A number of products have been recalled over the past decade due to actual or potential penicillincross-contamination.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">One event which increased FDA awareness of the potential for cross-contamination due to inadequate procedures was the 1988 recall of a finished drug product, Cholestyramine Resin USP. The bulk pharmaceutical chemical used to produce the product had become contaminated with low levels of intermediates and degradants from the production of agricultural pesticides. The cross-contamination in that case is believed to have been due to the reuse of recovered solvents. The recovered solvents had been contaminated because of a lack of control over the reuse of solvent drums. Drums that had been used to store recovered solvents from a pesticide production process were later used to store recovered solvents used for the resin manufacturing process. The firm did not have adequate controls over these solvent drums, did not do adequate testing of drummed solvents, and did not have validated cleaning procedures for the drums.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Some shipments of this pesticide-contaminated bulk pharmaceutical were supplied to a second facility at a different location for finishing. This resulted in the contamination of the bags used in that facility\u2019s fluid bed dryers with pesticide contamination. This in turn led to cross-contamination of lots produced at that site, a site where no pesticides were normally produced.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">FDA instituted an import alert in 1992 on a foreign bulk pharmaceutical manufacturer which manufactured potent steroid products as well as non-steroidal products using common equipment. This firm was a multi-use bulk pharmaceutical facility. FDA considered the potential for cross-contamination to be significant and to pose a serious health risk to the public. The firm had only recently started a cleaning validation program at the time of the inspection, and it was considered inadequate by FDA. One of the reasons it was considered inadequate was that the firm was only looking for evidence of the absence of the previous compound. The firm had evidence, from TLC tests on the rinse water, of the presence of residues of reaction byproducts and degradants from the previous process<\/span><\/span><\/span><\/p>\n<h3 style=\"text-align: justify;\"><span style=\"line-height: 3;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>3. GENERAL REQUIREMENTS:<\/strong><\/span><\/span><\/span><\/h3>\n<p style=\"text-indent: 0;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>a) <\/strong>FDA expects firms to have written procedures (SOP\u2019s) detailing the cleaning processes used for various pieces of equipment. If firms have one cleaning process for cleaning between different batches of the same product and use a different process for cleaning between product changes, we expect the written procedures to address thesedifferent scenario. Similarly, if firms have one process for removing water-soluble residues and another process for non-water-soluble residues, the written procedure should address both scenarios and make it clear when a given procedure is to be followed. Bulk pharmaceutical firms may decide to dedicate certain equipment for certain chemical manufacturing process steps that produce tarry or gummy residues that are difficult to remove from the equipment. Fluid bed dryer bags are another example of equipment that is difficult to clean and is often dedicated to a specific product. Any residues from the cleaning process itself (detergents, solvents, etc.) also have to be removed from the equipment.<\/span><\/span><\/span><\/p>\n<p style=\"text-indent: 0;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>b)<\/strong> FDA expects firms to have written general procedures on how cleaning processes will be validated.<\/span><\/span><\/span><\/p>\n<p style=\"text-indent: 0;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>c)<\/strong> FDA expects the general validation procedures to address who is responsible for performing and approving the validation study, the acceptance criteria, and when revalidation will be required.<\/span><\/span><\/span><\/p>\n<p style=\"text-indent: 0;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>d)<\/strong> FDA expects firms to prepare specific written validation protocols in advance for the studies to be performed on each manufacturing system or piece of equipment, which should address such issues as sampling procedures and analytical methods to be used, including the sensitivity.<\/span><\/span><\/span><\/p>\n<p style=\"text-indent: 0;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>e)<\/strong> FDA expects a final validation report which is approved by management and which states whether or not the cleaning process is valid. The data should support a conclusion that residues have been reduced to an \u201cacceptable level.\u201d<\/span><\/span><\/span><\/p>\n<h3 style=\"text-align: justify;\"><span style=\"line-height: 3;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>4.\u00a0EVALUATION OF CLEANING VALIDATION:<\/strong><\/span><\/span><\/span><\/h3>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">The first step is to focus on the objective of the validation process, and we have seen that some companies have failed to develop such objectives. It is not unusual to see manufacturers use extensive sampling and testing programs following the cleaning process without ever really evaluating the effectiveness of the steps used to clean the equipment. Several questions need to be addressed when evaluating the cleaning process. For example, at what point does a piece of equipment or system become clean? Does it have to be scrubbed by hand? What is accomplished by hand scrubbing rather than just a solvent wash? How variable are manual cleaning processes from batch to batch and product to product? The answers to these questions are obviously important to the inspection and evaluation of the cleaning process since one must determine the overall effectiveness of the process. Answers to these questions may also identify steps that can be eliminated for more effective measures and result in resource savings for the company.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Determine the number of cleaning processes for each piece of equipment. Ideally, a piece of equipment or system will have one process for cleaning; however, this will depend on the products being produced and whether the cleanup occurs between batches of the same product (as in a large campaign) or between batches of different products. When the cleaning process is used only between batches of the same product (or different lots of the same intermediate in a bulk process), the firm need only meet a criterion of \u201cvisibly clean\u201d for the equipment. Such between-batch cleaning processes do not require validation.<\/span><\/span><\/span><\/p>\n<h4 style=\"text-align: justify;\"><strong><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">4.1. Equipment Design<\/span><\/span><\/span><\/strong><\/h4>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Examine the design of equipment, particularly in those large systems that may employ semi-automatic or fully automatic clean-in-place (CIP) systems since they represent significant concern. For example, sanitary-type piping without ball valves should be used. When such nonsanitary ball valves are used, as is common in the bulk drug industry, the cleaning process is more difficult.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">When such systems are identified, it is important that operators performing cleaning operations be aware of problems and have special training in cleaning these systems and valves. Determine whether the cleaning operators have knowledge of these systems and the level of training and experience in cleaning these systems. Also check the written and validated cleaning process to determine if these systems have been properly identified and validated.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">In larger systems, such as those employing long transfer lines or piping, check the flow charts and piping diagrams for the identification of valves and written cleaning procedures. Piping and valves should be tagged and easily identifiable by the operator performing the cleaning function. Sometimes, inadequately identified valves, both on prints and physically, have led to incorrect cleaning practices.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Always check for the presence of an often critical element in the documentation of the cleaning processes: identifying and controlling the length of time between the end of processing and each cleaning step. This is especially important for topicals, suspensions, and bulk drug operations. In such operations, the drying of residues will directly affect the efficiency of a cleaning process.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Whether or not CIP systems are used for cleaning of processing equipment, microbiological aspects of equipment cleaning should be considered. This consists largely of preventive measures rather than removal of contamination once it has occurred. There should be some evidence that routine cleaning and storage of equipment does not allow microbial proliferation. For example, equipment should be dried before storage, and under no circumstances should stagnant water be allowed to remain in equipment subsequent to cleaning operations.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Subsequent to the cleaning process, equipment may be subjected to sterilization or sanitization procedures where such equipment is used for sterile processing, or for nonsterile processing where the products may support microbial growth. While such sterilization or sanitization procedures are beyond the scope of this guide, it is important to note that control of the bioburden through adequate cleaning and storage of equipment is important to ensure that subsequent sterilization or sanitization procedures achieve the necessary assurance of sterility. This is also particularly important from the standpoint of the control of pyrogens in sterile processing since equipment sterilization processes may not be adequate to achieve significant inactivation or removal of pyrogens.<\/span><\/span><\/span><\/p>\n<h4 style=\"text-align: justify;\"><strong><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">4. 2. Cleaning Process Written<\/span><\/span><\/span><\/strong><\/h4>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Procedure and Documentation<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Examine the detail and specificity of the procedure for the (cleaning) process being validated, and the amount of documentation required. We have seen general SOPs, while others use a batch record or log sheet system that requires some type of specific documentation for performing each step. Depending upon the complexity of the system and cleaning process and the ability and training of operators, the amount of documentation necessary for executing various cleaning steps or procedures will vary.<\/span><\/span><\/span><\/p>\n<h4 style=\"text-align: justify;\"><strong><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">4.3 Analytical Methods<\/span><\/span><\/span><\/strong><\/h4>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Determine the specificity and sensitivity of the analytical method used to detect residuals or contaminants. With advances in analytical technology, residues from the manufacturing and cleaning processes can be detected at very low levels. If levels of contamination or residual are not detected, it does not mean that there is no residual contaminant present after cleaning. It only means that levels of contaminant greater than the sensitivity or detection limit of the analytical method are not present in the sample. The firm should challenge the analytical method in combination with the sampling method(s) used to show that contaminants can be recovered from the equipment surface and at what level, i.e. 50% recovery, 90%, etc. This is necessary before any conclusions can be made based on the sample results. A negative test may also be the result of poor sampling technique (see below).<\/span><\/span><\/span><\/p>\n<h4 style=\"text-align: justify;\"><strong><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">4.4. Sampling<\/span><\/span><\/span><\/strong><\/h4>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface of the equipment. Another method is the use of rinse solutions.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>a. Direct Surface Sampling<\/strong> \u2013 Determine the type of sampling material used and its impact on the test data since the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Therefore, early in the validation program, it is important to ensure that the sampling medium and solvent (used for extraction from the medium) are satisfactory and can be readily used.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>b. Rinse Samples \u2013 <\/strong>Two advantages of using rinse samples are that a larger surface area may be sampled, and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment. An analogy that can be used is the \u201cdirty pot.\u201d In the evaluation of cleaning of a dirtypot, particularly with dried out residue, one does not look at the rinse water to see that it is clean; one looks at the pot.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Check to see that a direct measurement of the residue or contaminant has been made for the rinse water whenit is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminants.<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\"><strong>c. Routine Production In-Process Control<\/strong><\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">FDA does not intend to set acceptance specifications or methods for determining whether a cleaning process is validated. It is impractical for FDA to do so due to the wide variation in equipment and products used throughout the bulk and finished dosage form industries. The firm\u2019s rationale for the residue limits established should be logical based on the manufacturer\u2019s knowledge of the materials involved and be practical, achievable, and verifiable. It is important to define the sensitivity of the analytical methods in order to set reasonable limits. Some limits that have been mentioned by industry representatives in the literature or in presentations include analytical detection levels such as 10 PPM, biological activity levels such as 1\/1000 of the normal therapeutic dose, and organoleptic levels such as no visible residue<\/span><\/span><\/span><\/p>\n<p style=\"text-align: justify;\"><span style=\"line-height: 1.5;\"><span style=\"font-size: 12px;\"><span style=\"font-family: Arial,Helvetica,sans-serif;\">Check the manner in which limits are established. Unlike finished pharmaceuticals where the chemical identity of residuals are known (i.e., from actives, inactives, detergents), bulk processes may have partial reactants and unwanted by-products which may never have been chemically identified. In establishing residual limits, it may not be adequate to focus only on the principal reactant since other chemical variations may be more difficult to remove. There are circumstances where TLC screening, in addition to chemical analyses, may be needed. In a bulk process, particularly for very potent chemicals such as some steroids, the issue of by-products needs to be considered if equipment is not dedicated. 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