Only You Can Prevent Cross-Contamination
A guide to designing cleaning procedures for CMOs
By Gary A. Baker, Ph.D.
Cleaning validation may be less glamorous than process development or development and validation of key analytical methods, but development and execution of robust cleaning procedures are of paramount importance for pharmaceutical contract manufacturers. Failure to prevent cross-contamination causes potentially expensive materials to be scrapped as waste and invites regulatory action if contamination issues are not thoroughly investigated and addressed. Most critically, cross-contaminated products jeopardize patient safety.
Photo courtesy of Ash Stevens, Inc.
While it can be a challenge to have new clients support and fund the development of cleaning programs, it will be one of the most carefully scrutinized areas during the regulatory pre-approval inspection. Each client must have an equally robust cleaning program. Failure to ensure against cross-contamination can — and often does — have dire consequences.
As the FDA plans to issue its first general draft guidance on cross-contamination this year, it is essential to carefully evaluate current cleaning procedures. The following is advice for building cleaning programs from the ground up.
Before multi-use equipment is used for the process, it is advisable to initiate development of the cleaning process. While management will be horrified if product is cross-contaminated, they often take an equally dim view of an expensive fixed asset lying fallow while someone tries to figure out how both to clean it and to demonstrate that it is clean.
The most effective, and reproducible, cleaning technique is to dissolve the active compound. Of course, this can pose challenges for novel compounds for which little literature exists. The scientist developing the cleaning process should evaluate solubility in a variety of solvents, including water, acids, bases and alcohols. This rigorous exercise can often yield unexpected and desirable results. Compounds are sometimes significantly more soluble in a different solvent, potentially safer and less expensive, than initially believed.
Substances To Remove from Equipment
The short answer is “everything.” All active materials need to be removed from the equipment. Any catalysts must be removed and the removal must be verified. Toxic solvents must be removed. Finally, there should be no residual cleaning agents left behind. Even residual water can be harmful if the equipment will next be used for a synthesis that is poisoned by water. For certain applications, consideration needs to be given to microbiological contaminants.
Analytical Techniques for Cleaning Verification
Visual inspection — under “white” and UV light — can often be useful. Total Organic Carbon is useful for evaluation of water-soluble compounds, recognizing that this method is not specific for the compounds of interest. UV spectroscopy can be used. Most often, chromatographic methods will be employed.
The analytical methods that will be used to evaluate cleaning samples must be developed and suitably validated. Often, the same methods that are used to qualify the materials or the product can be adapted for verification of cleaning. It is important to confirm that the linear range and limit of detection / limit of quantitation are appropriate for the cleaning samples.
Swabs are often used to sample the cleaned equipment. Experiments should be performed to determine the amount of compound that can be transferred from the equipment to the swab and from the swab to the sample preparation for analysis. A known amount of sample can be placed on coupons, which simulate the surfaces to be cleaned. After swabbing the coupon, the tip of the swab is placed in the testing medium and sonicated. Finally, the ratio of compound detected by the analysis is divided by the amount placed on the coupon. This percentage, called the “swab recovery” or “swab transfer efficiency,” should be as high as possible; references recommend greater than 70%. However, some materials can be uncooperative and lower numbers might need to be accepted.
Operators who will perform sampling of cleaned equipment should be trained and “qualified.” Qualification means comparing a trial “swab recovery” experiment recovery and evaluate them against the standard. They meet the requirement if they are within a reasonable amount of the “standard” recovery.
The choice of swabs is important, too. Q-tips are great for use at home, but not so good for this application. There can be perfumes or emollients on Q-tips that can interfere with the analysis. Special swabs sold specifically for cleaning studies will provide the best results.
Designing Equipment-Specific Procedures
In designing the cleaning procedure, consideration needs to be given to the equipment to be cleaned. During initial operational qualification (“OQ”) of the equipment, “hard-to-clean” areas should be located methodically. Water-soluble UV-active placebos can be used to first “dirty” the equipment. The equipment can then be cleaned and inspected to evaluate any areas that still show evidence of the placebo. Photographs are useful to document the locations of the “hard-to-clean” areas. Overheads, vent lines, vacuum lines and valves are notoriously difficult to clean and to prove that they are clean. Special attention will have to be given to these sites when cleaning and sampling. Consider also cleaning (and cleaning verification) of the process area.
Executing Cleaning Procedures
The materials and equipment to be used in the cleaning process must be specified. CMOs must “qualify” cleaning materials. Obviously, the analysis is not as involved as qualification for manufacturing, but these materials must be suitable and of consistent quality. For example, if 1N Hydrochloric Acid is specified and you have 0.1N HCl, cleaning may not be as effective. Clean-in-place systems are preferable to manual cleaning because they take operator-to-operator variability out of play.
Tolerable Levels of Residue
Toxicity data can be useful in calculating permissible residue limits. Often, however, these data have yet to be developed for novel compounds. Very conservative approaches should be taken when determining permissible residue limits. In determining limits, references indicate that a 4-log reduction below toxic levels should be achieved.
Of course, all of this information must be documented. A “Cleaning Procedure Development Report” should include all of these data.
Maintaining a Robust Cleaning Program
Based on the cleaning development work, formal cleaning and analysis procedures are developed. Forms are prepared to document all cleaning activities: who is responsible for what, what equipment is to be cleaned, what materials are to be used, how is cleaning to be performed, how is cleaned equipment sampled, what are the analytical results, do the results conform to the permissible limits, and how is clean equipment secured, maintained and identified so it is ready for the next operation.
Useful in maintaining cleaning effectiveness are prepared cleaning “batch” records that detail all of the requirements and document who has completed them. One such “batch” record is used to document each cleaning campaign. After all of the cleaning and analysis is complete, the record is reviewed by the Lead Operator and by Quality Assurance. If all of the documentation is in order and the analytical verification conforms to the criteria, QA will sign off that the equipment is clean.
All activities discussed up to this point serve to verify that equipment has been suitably cleaned. It is expected that the cleaning process be formally validated, as well.
Just as with Process Validation, Cleaning Validation requires a pre-approved protocol, which details who will be responsible for what, procedures to be followed, the number of cleaning cycles that will be evaluated, the timeframe for validation and the acceptance criteria. Any special conditions, procedures or sampling should be discussed. The protocol should indicate that a summary report will be written after validation procedures are completed.
One thing to consider during formal Cleaning Validation is that “dirty” hold times should be evaluated. That is, “what is the acceptable duration between the completion of the process and the initiation of cleaning?” The concern is that it is often more difficult to clean something that has been dirty for a long time.
During Cleaning Validation, “baseline” rinse and swab samples of the equipment should be taken before it has been cleaned. Most often, these samples are loaded with compound. Rinses and swabs taken after cleaning show no residue. This is a very clear demonstration that the cleaning process is doing what it is supposed to be doing. Also, extra samples of the cleaned equipment may be taken, again to clearly demonstrate that the cleaning process is effective.
It is efficient to execute Cleaning Validation concurrent with Process Validation. This can have an advantage in that the prescribed number of cleaning replicates and analyses can be conducted more efficiently, particularly in the analytical laboratory.
After the prescribed number of replicates, a Cleaning Validation report is prepared. The report summarizes all of the cleaning activities. Were there deviations in the cleaning process? Were limits consistently met? If “re-cleaning” was required, the overall validity of the cleaning process should be questioned. Summarize the analytical data.
If there are procedural changes that are indicated by this controlled study, they should be discussed. Often, many samples will exhibit no detectable residue. Consideration can be given to removing these samples during future routine cleaning verification campaigns. “Baseline” samples are not required after validation. All changes to the cleaning process should be managed under change control.
The report should conclude with a statement as to the validity of the process. Key members of your organization, and often your client, must endorse the report.
Some interpret “validation” to mean that analysis is unnecessary if a “validated cleaning process” exists. The ramifications of cross-contamination are so significant that the risk exposure cannot be justified. Analytical verification of multi-use equipment is necessary before it can be used for another product.
Demonstrating that equipment is free of potential contaminants that could impact the quality of end product is an essential element of pharmaceutical operations.
There are many references available that discuss more technical aspects of cleaning validation. Cleaning Validation: A Practical Approach, by Bismuth and Neumann, is a very useful reference. There are also abstracts from several seminars and regulatory guidances available over the Internet.