Cleaning Validation And Its Importance In Pharmaceutical Industry Pdf
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Cleaning Validation and Its Importance in Pharmaceutical Industry
The aim of this work is to identify the parameters that affect the recovery of pharmaceutical residues from the surface of stainless steel coupons. A series of factors were assessed, including drug product spike levels, spiking procedure, drug-excipient ratios, analyst-to-analyst variability, intraday variability, and cleaning procedure of the coupons.
The lack of a well-defined procedure that consistently cleaned the coupon surface was identified as the major contributor to low and variable recoveries. The cleanliness of non-dedicated equipment should be verified before its subsequent release for use in the manufacture of intermediates and active pharmaceutical ingredient APIs , at product change over to prevent cross-contamination. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner, and these procedures should be validated according to the U.
Numerous warning letters due to inadequate cleaning 2 , 3 , 4 , failure to validate the cleaning verification method, and failure to follow cleaning procedures 5 have been issued by the FDA. Stainless steel coupons e. During the development and validation of these analytical methods, the sample of interest i. This level is determined based on acceptable exposure limit which is defined as the limit at which a patient can get exposed with no adverse health effects no-observed-adverse-effect-level, NOAEL.
The analyst or manufacturing operator conducting the swabbing must follow a structured procedure to ensure that recoveries are reproducible regardless of who performs the swabbing. Besides all the above-mentioned factors that affect sample recovery, the surface of the coupon, and thus, the surface of the equipment also play a role. The surface of the coupon may be modified due to the deposition of a thin film of material on the surface or due to change in the oxidation state of one or more of the elements in stainless steel e.
The regeneration of the surface of the stainless steel coupons back to its original state is vital for the success of the quantitative swapping process. Studies, in which the stainless steel coupons were not properly cleaned, showed variability in recovery including analyst to another, different drugs, or various spike levels 9 , 10 , It is important to note that the relative standard deviation S rel values increased with increasing number of replicates or with increasing the number of coupons used i.
In such cases, the variability cannot be interpreted as random fluctuation. Nonetheless, their results can be explained by our finding that the cleanliness of the surface of the coupon will affect the recovery. The results described in this paper illustrate a significant increase in recovery results and decrease in variability after properly cleaning the surface of the stainless steel coupons.
Clean-in-place CIP is an automated way of cleaning the surface of equipment that involves a minimal or no disassembling of the equipment. During the CIP cleaning process, a defined procedure of consecutive wash with a base followed by an acid is executed to remove organic and inorganic residues. Surfactants, chelating compounds, or complexing agents are usually added to the CIP solutions to enhance the efficiency of cleaning any product from the surface of the equipment.
The efficiency of cleaning depends on several parameters including the choice and concentration of the CIP solutions i. Based on the type of drug product, CIP solutions and have been chosen to use for cleaning the stainless steel coupons used for cleaning verification, since it simulates the CIP process used for cleaning the manufacturing equipment.
This study reports the influence of different factors affecting the recovery of pharmaceutical residues from the surface of stainless steel coupons and recommends the best practices for analytical cleaning method development for small molecules, therapeutic proteins, and antibodies.
The lack of a well-defined procedure that consistently cleaned coupon surface was identified as the major contributor to low and variable recoveries.
High and reproducible recovery was obtained when the surface of the coupon was cleaned properly Calculate the cleaning limit CL for a drug based on the maximum allowable carry-over MACO according to the therapeutic dose criteria. The cleaning verification has been assessed for two formulations 2. Clean the coupons by rinsing and wiping the surface for 10 - 15 s twice with water and twice with methanol to eliminate any residual deposit. Perform this process in the hood as methanol is toxic and highly volatile.
Set the sonicator at room temperature. The sonicator has no power setting adjustment, therefore the time is set to give adequate cleaning results. Immerse the coupons in high performance liquid chromatography HPLC grade water and sonicate for 2 min. Immerse the coupons in 0. Mount the stainless steel coupons on the bottom of a mL or mL plastic beaker using a double sided tape. Hold onto the beaker to make spiking and swabbing processes easy.
This also minimizes some undesirable accidents such as overshooting the corner when swabbing. Infuse a defined volume at a specific concentration and formulation e. Dip a dry swab in a vial with 2 mL of diluent methanol:formic acid Firmly wipe the surface of the coupon with even, overlapping side-to-side strokes until the total 50 cm 2 test area is wiped with one side of a wet swab.
Repeat the swabbing motion as detailed in steps 3. After the sampling of the surface, cut the swab head using scissors into the solvent vial. Run the chromatography system according to the conditions listed in Table 1.
Calculate the recovery of the swab working solution based on the relative area under peak of the working solutions A W and the control solution A C. Repeat the process on three coupons and calculate the average recovery along with relative standard deviation S rel.
The chromatography conditions are listed in the material section. Representative results from the initial attempts for cleaning verification for drug A are summarized in Table 2. The first type of variability observed in Table 2 is the variability in precision as can be seen from the high S rel associated with the majority of the recovery results numbers listed in parentheses. Besides to the expected analyst-to-analyst variability data shown in reference 13 , day-to-day variability is also observed for one analyst with all other conditions not changed, as seen in the first two experiments in Table 2 at 2.
The low formulation gave the highest recovery on average, suggesting that the excipient was enhancing the recovery of the drug from the coupon. Based on the types of variability discussed above, the initial approach to improve recovery was to redevelop the extraction method and the experimental conditions to obtain consistent and high recoveries. The average recoveries on four different coupons along with relative standard deviation are shown in Figure 1 for some experiments.
The main conclusion was that none of the aforementioned changes eliminated the previously observed variability in Table 2. Within experimental error, almost all of these experiments were not considered statistically different.
It is clear that the average recovery is different from one coupon surface to another. Therefore, the coupon surface is expected to be a major contributor to the observed variability. There was a high probability that the previously observed variability in recovery was due to coupon-to-coupon variability. Moreover, some differences were observed between coupons at this formulation Figure 2. The observed variability suggested that the surface of the various coupons was not identical and interacted differently with the matrix.
The first approach to minimize the difference among the coupons was to thoroughly clean the surfaces of the coupons. Coupons used for obtaining recovery in Figure 3 were cleaned according to the procedure presented in the experimental section.
The recovery results after cleaning the coupons are presented in Figure 3. It is clear that the recovery is virtually reproducible from one trial to another and that the difference in recovery between coupons is minimized. Table 2 shows a comparison of the recovery results before and after cleaning the coupons under the same experimental conditions. Coupons cleaned with CIP solutions were then used for cleaning verification of compounds B another small molecule C and D large molecules, i.
The same conclusions drawn from experiments for drug A were applicable for drug B, C, and D detailed results shown in reference High recoveries were obtained across molecular size and physicochemical properties by applying a systematic cleaning approach for the coupons. Figure 1. Average Recovery Obtained from Four Coupons. Error bars represent relative standard deviation from four trials on four coupons.
Please click here to view a larger version of this figure. Figure 2. Figure 3. Variability in Recovery of Drug A at 2.
Solid triangles correspond to recovery values before cleaning the coupons, while open symbols correspond to the recovery values after cleaning the coupons. Table 2. The major contributor to low and variable recoveries of API residues from stainless steel coupons was traced to the lack of a well-defined procedure for cleaning of the coupon surfaces. Cleaning the surface of the coupons resulted in consistent, accurate spiked recovery and reproducible results.
With the demonstration of high recoveries from stainless steel coupons, the actual cleaning verification results obtained from the manufacturing equipment using validated method s should be accurate and precise, reflective of the residue level on the equipment with minimum risk of false negatives for product to product carryover that could jeopardize patient safety.
The initial approach followed by the analyst to troubleshoot the low and inconsistent recovery was by modifying the experimental conditions such as: percent of organic in the diluent, the spiking process, the type and strength of acid used in the spiking solution, etc.
This approach did not solve the low and inconsistent recovery issue. Nonetheless, this aforementioned problem was completely solved when the stainless steel was adequately cleaned using clean-in-place solution.
This achievement results in vastly increasing the chances of the successful pass of cleaning verification of the manufacturing equipment. It is important to note that the CIP solutions used here are limited to the pharmaceutical industry and thus suitable CIP solutions should be selected for other types of industries processed food, dairy, cosmetics, etc.
The choice of CIP solutions and the cleaning process are critical steps for the success of this process. The protocol presented here will help analysts in the pharmaceutical industry as well as other industries to better design and execute successful cleaning verification.
National Center for Biotechnology Information , U. J Vis Exp. Published online Aug Author information Copyright and License information Disclaimer. Correspondence to: Andrei Blasko at moc. Abstract The aim of this work is to identify the parameters that affect the recovery of pharmaceutical residues from the surface of stainless steel coupons.
Keywords: Chemistry, Issue , Cleaning verification, stainless steel cleaning, cleaning validation, trace analysis recovery, clean-in-place solutions, cleaning recovery.
Download video file. Introduction The cleanliness of non-dedicated equipment should be verified before its subsequent release for use in the manufacture of intermediates and active pharmaceutical ingredient APIs , at product change over to prevent cross-contamination.
Protocol 1. Cleaning Procedure for Coupons Initial approach Clean the coupons by rinsing and wiping the surface for 10 - 15 s twice with water and twice with methanol to eliminate any residual deposit. Advanced approach Using clean-in-place solutions Set the sonicator at room temperature.
Immerse the coupons in HPLC water and sonicate for 2 min.
Mainly cleaning is performed to remove product and non-product contaminating material. Ineffective cleaning can lead to adulterated product, which may be from previous product batches, cleaning agent or other extraneous material introduced into generated by the process. In many cases, the same equipment may be used for processing different products. To avoid contamination source or facility configuration there is a need to ensure that cleaning procedure must strictly follow carefully established and validated method of execution. Cleaning validation is documented evidence with high degree of assurance that one can consistently clean a system or piece of equipment to predetermined and acceptable limits. Cleaning validation is primarily applicable to the cleaning of process manufacturing equipment in pharmaceutical industry. It is necessary to have effective cleaning programs in place because of regulatory requirements.
The aim of this work is to identify the parameters that affect the recovery of pharmaceutical residues from the surface of stainless steel coupons. A series of factors were assessed, including drug product spike levels, spiking procedure, drug-excipient ratios, analyst-to-analyst variability, intraday variability, and cleaning procedure of the coupons. The lack of a well-defined procedure that consistently cleaned the coupon surface was identified as the major contributor to low and variable recoveries. The cleanliness of non-dedicated equipment should be verified before its subsequent release for use in the manufacture of intermediates and active pharmaceutical ingredient APIs , at product change over to prevent cross-contamination. Cleaning procedures should contain sufficient details to enable operators to clean each type of equipment in a reproducible and effective manner, and these procedures should be validated according to the U. Numerous warning letters due to inadequate cleaning 2 , 3 , 4 , failure to validate the cleaning verification method, and failure to follow cleaning procedures 5 have been issued by the FDA.
Pharmaceutical Manufacturers must validate their cleaning process to ensure complies with cGMP regulations. Minimizing equipment downtime has the potential to impact the efficiency and economics of pharmaceutical production. The main purpose of cleaning validation is to prove the effectiveness and consistency of cleaning in a given pharmaceutical production equipment to prevent cross contamination and adulteration of drug products with other active ingredients like unintended compounds or microbiological contamination leads to prevent several serious problems and also useful in related studies like packaging component cleaning validation. So it is necessary to validate the cleaning procedures to ensure safety, efficacy, quality of the subsequent batches of drug product and regulatory requirements in Active Pharmaceutical Ingredients API product manufacture. The benefits due to cleaning validation are compliance with federal regulations, identification and correction of potential problems, previously unsuspected which could compromise the safety and efficacy of drug products. In this article cleaning validation and importance are discussed in briefly. Download PDF here.
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Cleaning Validation Considerations for Automated Washing Systems
Part of the Cleaning Validation for the 21st Century series. Cleaning processes should not be adopted randomly or chosen simply based on what has been used in the past. They should be developed systematically with the intent of reducing the risk of cross-contamination and identifying optimal cleaning parameters for both the products and equipment to be cleaned. In the early days of cleaning validation, development of cleaning processes was rarely part of the validation process. Legacy cleaning procedures were typically validated as they already existed: acceptance limits were calculated, protocols were written, samples were taken, and a report was written.
What is cleaning validation and where does it fall in the life cycle validation scheme? How can an automated washing system be validated? This article provides insights that may help answer these questions.
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