Name: failure of cleaning verification in pharmaceutical industry due to uncleanliness of stainless steel surface
Uploaded: 2017-08-11T15:00:00
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1. Sample Solution
<ol>
	<li>Calculate the cleaning limit (CL) for a drug based on the maximum allowable carry-over (MACO) according to the therapeutic dose criteria. 
	NOTE: Here, the cleaning limit (CL) for drug A has been calculated to be 2.4 &#181;g per 50 cm2 based on the maximum allowable carry-over (MACO) according to the therapeutic dose criteria. The cleaning verification is executed at the 50%, 100%, and 150% cleaning limit. The cleaning verification has been assessed for two formulations (2.5...

<ol>
	<li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Validation of cleaning processes (7/93). Guide to inspections validation of cleaning processes. , (2004).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Warning Letter: 320-12-08, Gulf Pharmaceuticals. , (2012).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Warning Letter: 320-12-058, Novartis Internationsl AG. , (2012).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Warning Letter: 05-10, Teva Parenterals Medicines, Inc. , (2009).</li><li>. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Warning Letter: 320-14-09, Tianjin Zhongan Pharmaceutical Co., Ltd. , (2014).</li><li>Mantel, M., Wightman, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Influence+of+the+surface+chemistry+on+the+wettability+of+stainless+steel.">Influence of the surface chemistry on the wettability of stainless steel.</a> Surf Interface Anal. 21, 595-605 (1994).</li><li>Odaka, K., Ueda, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Dependence+of+outgassing+rate+on+surface+oxide+layer+thickness+in+type+304+stainless+steel+before+and+after+surface+oxidation+in+air.">Dependence of outgassing rate on surface oxide layer thickness in type 304 stainless steel before and after surface oxidation in air.</a> Vacuum. 47, 689-692 (1996).</li><li>Kerber, S. J., Tverberg, J. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stainless+Steel+Surface+Analysis.">Stainless Steel Surface Analysis.</a> Adv. Mater. Processes. , 33-36 (2000).</li><li>Kusumaningrum, H. D., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Survival+of+foodborne+pathogens+on+stainless+steel+surfaces+and+cross-contamination+to+foods.">Survival of foodborne pathogens on stainless steel surfaces and cross-contamination to foods.</a> Int J Food Microbiol. 85, 227-236 (2003).</li><li>Liu, L., Pack, B. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cleaning+verification+assays+for+highly+potent+compounds+by+high+performance+liquid+chromatography+mass+spectrometry:+Strategy,+validation,+and+long-term+performance.">Cleaning verification assays for highly potent compounds by high performance liquid chromatography mass spectrometry: Strategy, validation, and long-term performance.</a> J Pharmaceut. Biomed. 43, 1206-1212 (2007).</li><li>Lambropoulos, J., Spanos, G. A., Lazaridis, N. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Development+and+validation+of+an+HPLC+assay+for+fentanyl,+alfentanil,+and+sufentanil+in+swab+samples.">Development and validation of an HPLC assay for fentanyl, alfentanil, and sufentanil in swab samples.</a> J Pharmaceut. Biomed. 23, 421-428 (2000).</li><li>Chisti, Y., Moo-Young, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Clean-in-place+systems+for+industrial+bioreactors:+Design,+validation+and+operation.">Clean-in-place systems for industrial bioreactors: Design, validation and operation.</a> J. Ind. Microbiol. 13, 201-207 (1994).</li><li>Haidar Ahmad, I. A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cleaning+verification:+Exploring+the+effect+of+the+cleanliness+of+stainless+steel+surface+on+sample+recovery.">Cleaning verification: Exploring the effect of the cleanliness of stainless steel surface on sample recovery.</a> J Pharmaceut. Biomed. 134, 108-115 (2017).</li></ol>

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 th...

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.S. Food and Drug Administration (FDA) requirements1. Numerous warning letters due to inadequate cleaning2,3,4, failure to validate the cleaning verification method, and failure to follow cleaning procedures5 have been issued by the FDA. 21 CFR &#167;211.67 outlines the requirements needed for successful cleaning verification.
It is the standard in industry that the validation of the analytical methods for cleaning verification is performed on stainless steel coupons with the same surface/finish as the manufacturing equipment. Stainless steel coupons (e.g., 50 cm2) are used to represent equipment surfaces for cleaning verification experiments in the laboratory. During the development and validation of these analytical methods, the sample of interest (i.e., the residues that should be recovered from the surface of the equipment) is spiked at the target residue onto the stainless coupon determined by the maximum allowable carry-over (MACO) limit. 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. The procedure should explicitly detail the swab type, number of swabs used, the diluent, the amount of solvent used, the exact sweeping pattern, the number of strokes applied to the sampling surface, the amount of time spent swabbing/extracting the samples, the method of detection (ultra-violet, fluorescence, mass spectrometry, total organic carbon, etc.), the extraction technique of the material from the swab head, etc.
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.g., Fe, Cr, and Ni)6,7,8. 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 levels9,10,11. The standard deviation in recovery of ten replicates on one coupon can be up to 14% and 26% on five coupons9. It is important to note that the relative standard deviation (Srel) values increased with increasing number of replicates or with increasing the number of coupons used (i.e., five coupons instead of spiking five times on the same coupon)11. 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.e., type and composition of base, acid, and surfactant), the cleaning time, temperature (typically 60 - 80 &#176;C), contamination type, and the presence of hard to clean parts12. Based on the type of drug product, CIP solutions 100 and 200 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 properly13.

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		<col style="width:265pt" width="353" />
		<col style="width:401pt" width="535" />
		<col style="width:250pt" width="333" />
		<col style="width:48pt" width="64" />
	</colgroup>
	<tbody>
		<tr height="21" style="height:15.75pt">
			<td height="21" style="width:265pt;height:15.75pt" width="353">stainless steel coupons</td>
			<td class="xl67" style="width:401pt" width="535">&#160;GlobePharma (New Brunswick, NJ ).&#160;</td>
			<td class="xl16" style="width:250pt" width="333">SS316-20RA-50cm2</td>
			<td style="width:48pt" width="64"></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">Clean in place solutions (CIP100 and CIP200)&#160;</td>
			<td class="xl68" style="width:401pt" width="535">were obtained from Steris Corporation (Mentor, OH)</td>
			<td>1D10BG</td>
			<td>Alkaline detergent and acid detergent, respectively</td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">Positive displacement pipettes</td>
			<td class="xl68" style="width:401pt" width="535">Gilson (Middleton, WI).&#160;</td>
			<td></td>
			<td></td>
		</tr>
		<tr height="34" style="height:25.5pt">
			<td height="34" style="height:25.5pt">HPLC grade water</td>
			<td class="xl68" style="width:401pt" width="535">Millipore Milli-Q Advantage Water Purification System (Darmstadt, Germany)&#160; or from Honeywell Burdick &#38; Jackson (Muskegon, Michigan)</td>
			<td>7732-18-5</td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">HPLC grade Methanol</td>
			<td class="xl68" style="width:401pt" width="535">EMD</td>
			<td>MX0475-1</td>
			<td></td>
		</tr>
		<tr height="17" style="height:12.75pt">
			<td height="17" style="height:12.75pt">glacial acetic acid&#160;</td>
			<td class="xl68" style="width:401pt" width="535">EMD</td>
			<td>MAX0073P5</td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">HPLC grade Acetonitrile&#160;</td>
			<td class="xl68" style="width:401pt" width="535">J.T. Baker (Avantor Performance Materials, Center Valley, PA)</td>
			<td>75-05-8</td>
			<td></td>
		</tr>
		<tr height="17" style="height:12.75pt">
			<td height="17" style="height:12.75pt">Trifluoroacetic acid</td>
			<td class="xl68" style="width:401pt" width="535">J.T. Baker (Avantor Performance Materials, Center Valley, PA)</td>
			<td>75-05-8</td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl17" height="21" style="height:15.75pt">Chromatography column Zorbax Eclipse</td>
			<td class="xl68" style="width:401pt" width="535">&#160;XDB-C18, 4.6 x 100 mm, 3.5 &#181;m HPLC column</td>
			<td>UNSPSC &#8211; 41115709</td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">Vanquish UHPLC system&#160;</td>
			<td class="xl68" style="width:401pt" width="535">Thermo Fisher Scientific, Germering, Germany</td>
			<td></td>
			<td></td>
		</tr>
		<tr height="21" style="height:15.75pt">
			<td class="xl16" height="21" style="height:15.75pt">Branson B8510 Ultrasonic cleaner&#160;</td>
			<td class="xl68" style="width:401pt" width="535">Branson Ultrasonics (Danbury, CT, USA)</td>
			<td>model (8510-D7H)</td>
			<td></td>
		</tr>
	</tbody>
</table>

failure of cleaning verification in pharmaceutical industry due to uncleanliness of stainless steel surface

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. Assessment of cleaning the surface of the coupons with clean-in-place solutions (CIP) gave high recovery (&#62;90%) and reproducible results (Srel&#8804;4%) regardless of the conditions that were assessed previously. The approach was successfully applied for cleaning verification of small molecules (MW &#60;1,000 Da) as well as large biomolecules (MW up to 50,000 Da).

Representative results from the initial attempts for cleaning verification for drug A are summarized in Table 2. Before the coupons were cleaned according to the detailed procedure in the experimental section, inconsistent results were obtained at different spike levels, for various ratios of API/excipient, different analysts, and even for the same analyst at different days. The observed variability in the recoveries needed to be addressed, as some of the results failed t...

Watch this Scientific Journal Video about Failure of Cleaning Verification in Pharmaceutical Industry Due to Uncleanliness of Stainless Steel Surface at JoVE.com

Failure of Cleaning Verification in Pharmaceutical Industry Due to Uncleanliness of Stainless Steel Surface

The lack of a well-defined procedure that consistently cleaned coupon surfaces was identified as the major contributor to low and variable recoveries in cleaning verification. This manuscript describes the correct protocol of cleaning stainless steel coupons.

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 ...

The overall goal of this work is to obtain high and reproducible recoveries of pharmaceutical residues from the surface of stainless steel coupons by applying the best practices for analytical cleaning method development for small molecules, therapeutic proteins and antibodies. This method can help answer key questions in the field of cleaning verification in the pharmaceutical industry, such as why cleaning verification of manufacturing equipment fails. The main advantage of this study is that it shows the procedure to properly clean the surface of the stainless steel coupons used for analytical method validation.To start this experiment, prepare sample solutions of the drug dissolved in the diluent of choice after calculating the cleaning limit for a drug. Clean the stainless steel coupons by rinsing with water and wiping the surface twice for 10 to 15 seconds. Then, repeat this rinsing and wiping step with methanol to eliminate any residual deposit.To perform the advanced cleaning approach using clean in place solutions, immerse the coupons in high performance liquid chromatography or HPLC grade water and sonicate for two minutes. Immerse the coupons in 0.1%alkaline detergent solution in HPLC grade water and sonicate for two minutes. Immerse the coupons in HPLC water again and repeat two minute sonication.Then, immerse them in 0.1%acid detergent solution in HPLC water and sonicate for two minutes. Finish with two minute sonication in HPLC water. Next, using a double-sided tape, mount the stainless steel coupons on the bottom of a 250 milliliter plastic beaker.Hold the beaker during the procedure to facilitate spiking and swabbing and to avoid accidents. Use a positive displacement pipette to infuse a defined drug volume, at a desired concentration and formulation, in a whirly pattern on the coupon surface. Once the coupon surface is dry, dip a dry swab in a vial with two milliliters of diluent.Press the swab against the inside of the vial to remove excess solvent. Use even, overlapping side-to-side strokes to firmly wipe the coupon surface with one side of the wet swab, until the total 50 square centimeter test area is wiped. Use the same side of the swab to repeat the wiping process.Swab each of the four edges of the coupon twice. Rotate the coupon 90 degrees and use the other side of the swab, now rotating the direction of wiping by 90 degrees. Repeat the cleaning using this side of the swab in the same fashion, making sure to wipe all the four edges of the coupon twice.After the surface wiping, use scissors to cut the swab head into the solvent vial. After that, repeat the whole swabbing procedure using a second swab, while rotating the coupon 90 degrees toward the same direction chosen before. Next, sonicate the vial containing two swab heads for five minutes.Then, vortex the vial for 10 seconds. Finally, transfer the solution into an HPLC vial and label it as the working solution. To recover the sample, prepare the control solutions by mixing 200 microliters of each coupon spiking or sample solution with 1, 800 microliters of diluent.Use these solutions to run chromatography according to the text protocol. Calculate the recovery of the swab working solution based on the relative area under peaks of the working and control solutions. Repeat this process for three coupons to calculate the average recovery and the relative standard deviation.Before the coupons have been cleaned, recovery results for different spike levels were inconsistent, regardless of active pharmaceutical ingredient or API excipient ratio, different analysts, or even different day for the same analyst. The majority of the recovery results had high relative standard deviation. The observed variability in the recovery was not eliminated when several different parameters were adjusted, including swabbing technique, the diluent, the spiking solvent, the pH of the spike and the diluent, the spiking technique and the extraction technique.The difference between the individual recovery at each coupon surface and the average recovery shows that the average recovery is different from one coupon surface to another, therefore, it is very likely that the observed variability comes from the differences between the coupon surfaces. After following the coupon cleaning described in this protocol, the recovery results were reproducible from one trial to another, with minimal difference in recovery between the coupons. The coupon cleaning performed here resulted in the recoveries being higher than 90%Furthermore, relative standard deviation values for each spiking level were acceptable and smaller than the results obtained before the cleaning.Once mastered, the cleaning of the coupons can be done in less than 30 minutes, if performed properly. While attempting this procedure, it's important to remember how to spike and recover properly without losing the analyze of interest. After watching this video, you should have a good understanding of how properly clean stainless steel surfaces to obtain high and reproducible recoveries of the residues.After its development, this technique paved the way for researchers in the pharmaceutical industry to provide reliable cleaning data for manufacturing processes.

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