Cleaning verification

A procedure whose effectiveness has been proven by a documented program providing a high degree of assurance that a specific cleaning procedure, when performed appropriately, will consistently clean a particular piece of equipment to a predetermined level of cleanliness. 

There are two types of analysis needed for cleaning verification (1) active (2) soap. Since residual amounts of active and soap are to be determined, the methods need to be very sensitive. For measuring the active, the assay or the content uniformity method can be employed (if the sensitivity of the existing method is acceptable). If the sensitivity of the current assay or content uniformity method is not acceptable, then modifications can be made to an existing method or a more sensitive test method is developed. 

Utilize micro-HPLC to obtain a sharp peak (increase S/N). 

If the sensitivity is still not sufficient, then a different detection techniques or analytical technique may need to be employed (for example, LC-MS and fluorescence detection, capillary electrophoresis, ion mobility spectrometry, etc.). These alternate methods and/or detection techniques may have higher sensitivity than HPLC with UV detection. Since the new method will be a simple method (peaks from APl(s) and/or functional excipients), development of these methods should be simple and fast. MS is generally more 

What is the difference between Extractables and Leachables The following definitions are taken directly from PQRI [43]. 

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Other recent applications of FT-IR in pharmaceutical analysis include reaction monitoring by fiberoptic FT-IR/ATR spectroscopy140 and stability studies of pharmaceutical emulsions using FT-IR microscopy.141 A novel equipment cleaning verification procedure using grazing angle fiberoptic FT-IR reflection-absorption spectroscopy was described by Perston et al.142... 

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. 

The manufacturing route, raw materials, and chemicals must be well controlled and meet strict quality requirements (e.g., purity of raw materials, chemicals and intermediates, process steering control, cleaning verification). 

Though in competition with other analytical techniques, CE has proven its potential and necessity to be used for the characterization of small-molecule pharmaceuticals. Due to the versatility of the system, CE can be applied for the determination of physicochemical properties, identification, purity and stability analysis, and cleaning verification of the drug substance, its precursors, process chemicals, the drug product, and its excipients. 

Plant operations Real-time water quality Cleaning verification Waste stream monitoring and control... 

It is important to remember that cleaning procedures should at least be in the final stages of development, as equipment and facilities in the pilot or proposed manufacturing plant are involved, and the development of the cleaning verification test methods must be complete. 

It is appropriate to discuss cleaning verification in a little more detail since the principle of cleaning verification is currently very widely used in development facilities. The main difference between verification and validation is in the number of events captured. For validation, the requirements to refer to a cleaning process as validated are that, first of all, three identical batches of a single... 

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-... 

Cleaning verification is more likely to occur, as opposed to fullblown validation. 

The manufacture of CTMs often falls within the domain of the research and development department and is often manufactured in development facilities. This is a typical example of development batches. These batches will be used in human patients, however. It is very important that the equipment be proven clean prior to the manufacture of the CTM. The previously manufactured material may have been developmental in nature, but could seriously alter the effect of the CTM if contamination were to occur, thus undermining essential pivotal studies. Likewise, cleaning after the manufacture of the CTM should be subjected to cleaning verification and thoroughly documented. 

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. 

Although swab selection is not included as a requirement in Table 15.3, it is a parameter that should be considered at some point in the development of a swab assay. From a practical view point, it could be evaluated once for a facility and then replicated on all other compounds. Cleaning verification methods for swabs... 

Although swab assays are different conceptually than both the impurity and the potency assay, the same scientific rationale governs the development of these assays. Many of the references listed in Table 15.4 outline different validation approaches. Seno outlined validation practices in the Japanese pharmaceutical industry for cleaning verification,23 and Kirsch outlined an approach for swab method validation that is consistent with ICH guidelines for method development.24 An important aspect of any cleaning-verification assay begins with swabbing the... 

TABLE 15.4 Selective Analytical Techniques for Cleaning Verification with Associated Analytes and Reported LOD, if Available... 

Robustness is the capacity to remain unaffected by small, but deliberate, variations in method parameters. In a typical HPLC validation this exercise would include minor variations in flow rate or pH of the buffer. When considering cleaning verification, this parameter may be extended to extraction time of the swabs, pH of extraction solvent, etc. However, it is fairly uncommon to evaluate such parameters due to the above-mentioned variability that may be found in swab methods. 

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