Cross contamination must be avoided in the pharmaceutical industry at all costs. Successful cleaning validation ensures that patients are not put at risk due to cross contamination. The process can be divided into a number of sections each of which must be fully understood. Areas of concern must be addressed to ensure a successful outcome across the entire process. This spans both the manufacturing and subsequent analytical support. The data used to confirm a positive/successful cleaning validation is underpinned by the results of validated analytical methods. It is essential that these results are truly representative as patient safety is based upon the absence of equipment residues. So what are those areas of concern, what affects your ability to get a successful outcome and what do you need to consider when carrying out a cleaning validation exercise?
Figure 1. An overview of the areas to be considered to ensure success.
A detailed study of all the equipment to be cleaned must be carried out by a qualified team to ensure the chosen cleaning method will be successful. This is colloquially known as “walking the plant”. It is important to understand what can affect your cleaning results and to either engineer out those areas of concern or include them in your cleaning procedure.
Areas of concern
All product contact pipe work should be thoroughly evaluated. The geometry of the pipe work can play a vital role in a successful outcome. Multiple bends, flanges, angles of pipework and dead ends can all result in product retention and possible cross contamination. There are recorded cases in the industry of minor changes to pipework geometry resulting in cross contamination issues. Remember if you change the shape of a piece of pipework it may no longer clean as well. Specific areas to be mindful of are:
1. Service lines
2. Gaskets
3. Filter meshes
4. Valves
5. Pumps and samplers
6. Process investigations
7. Packaging lines
Design and control of cleaning methods
Good cleaning procedures are fundamental. A procedure that has been used for years may not necessarily be the best. A review of the methods should be carried out at validation to determine their suitability and effectiveness. Procedures should include factors such as:
1. Operation of valves during cleaning
2. Filling pipework with solvent and allowing dissolution time
3. Refluxing solvent around system and through condenser return lines
Manual cleaning is very subjective. Two different operators may not necessarily clean to the same degree. In order to achieve reproducibility it is critical that all operators carry out the procedure in the same way. Very detailed procedures and training are required to ensure the successful outcome of a manual cleaning exercise. It is sometimes easier to alter plant layout so that Clean in Place (CIP) can be performed in place of manual cleaning. For example, moving a pan filter from beside the vessel to the floor below can result in a double bonus. The pan filter can then be washed using a CIP procedure and the move also results in a loss of a pump and extra pipework. This sort of rearrangement should be considered as it reduces risks of error.
Ensure that:
- Written procedures will deal with the outcome of a process failure based on knowledge of what can go wrong in your process.
- All process operators are fully trained and their records are up to date.
Issues with sampling and testing
A considerable proportion of the testing failures experienced in the industry are not related to the ability to clean the equipment or perform the analysis. They are solely related to the skills of the person taking the swabs. It is easy to write and train a procedure on how to carry out a swab test but it is a different thing being able to perform a test correctly and reproducibly. So what can be done to reduce this risk and help secure a successful validation outcome?
- A number of issues can be identified related to the swabbing procedure and these must all be addressed if success is to be guaranteed.
- Control of swab equipment – It is essential that all the equipment used to carry out a swab test is reliably controlled. It is extremely easy to contaminate a swab and put your whole cleaning validation exercise at risk of failure. The swab material, the solvent used, any disposable gloves etc. must be very carefully controlled to reduce the risk of possible false results.
- Test the ability of the operator to perform not only the swab procedure itself but also their skill in:
a. Being able to determine the correct area to be swabbed even when they cannot visually see where the task is being performed. Failure to swab the required area will result in either a failed swab or worse still, from a cross contamination viewpoint, a passed result which should really fail.
b. Their reproducibility in being able to repeat this exercise four times in exactly the same place.
c. It has been demonstrated that a swab taken using four wipes of the same area results in maximum recovery (>90%) from a given surface. However the ability to do this requires considerable skill and training.
All of the above require considerable skill and extensive training of the operator.
Development and validation of analytical test methods
Alongside the product manufacture, the analytical method is of critical importance when assessing the cleanliness of pharmaceutical manufacturing equipment. This, in turn, is underpinned by the development of a suitable, fit-for-purpose analytical method, designed not only to be specific to the analyte, but also able to ensure its ability to quantify at the prescribed residue limits. On the subject of residue limits, this is very much a subject in its own right and should be identified early on since this will have a direct impact on the analytical test method and its ability to detect the analyte(s) at the required level.
Determining cleanliness can prove to be a very challenging task. The residue must initially be extracted from a surface, recovered from the extraction matrix and then suitably quantified.
Very often, the starting point in the development of a cleaning method would be based upon a previously developed assay method. The main aspects to be borne in mind are: (1) attainment of suitable sensitivity to quantify at the limits, (2) specificity (between the target analyte and other matrix components) and (3) a curtailed run time to allow the requisite high sample throughput that is generally needed when analysing swab samples.
In many respects, the requirements for validating cleaning methods are closely aligned with a standard assay. However, one area that does require some time is the swabbing technique itself. A large part of the development procedure itself is focused upon deriving a swabbing procedure that allows acceptable recovery of API residues from the required surface types. Furthermore, the choice of swab surface used will be dictated by conducting a plant walk-around and subsequent risk assessment of the manufacturing facility and determination of the key ‘risk’ areas where residues are most likely to remain following manufacture.
Swabbing
Often, insufficient time is invested in the actual swabbing regime, which can ultimately lead to a less than robust final method. Each of the surface types identified (discussed previously) should be spiked with the API (at the calculated residue limit) and experiments performed to demonstrate that acceptable recovery is repeatedly obtained.
This can involve the evaluation of a number of different swabbing solvents and swab types together with optimisation of the actual swab technique. This, combined with the need to be able to repeatedly detect residues at very low levels, can contribute significantly towards the time required for successful method development and validation.
If the method is shown to have sufficient accuracy, then all of these parameters can be evaluated as a single entity. If inadequate results are obtained then each of the steps would need to be investigated individually to identify which of the component steps is responsible for the poor recovery, and allow screening of other solvents or swab material that may improve recovery. It should provide assurance that an analyte can be analysed in a matrix, which, for a finished product, would include excipients, impurities or perhaps solvents used in the manufacture of the actual API. If a cleaning agent is used, its composition should also be considered. An evaluation of specificity should first be conducted to ensure the absence of any interference between matrix components and the target analyte.
Stability of the analytical samples should also be considered; that is, the ability of the active substance to degrade once in the extraction solvent. If appropriate expiry dates are not set, significant degradation could occur, potentially giving a result that “passed” which should actually fail.
There is such an array of validation parameters that could be discussed, however this article cannot possibly do each of these justice. However, all of the critical parameters to be assessed should be identified and evaluated prior to commencement of the formal validation.
Conclusion
The overarching principle when embarking on pharmaceutical cleaning validation is to ensure that the manufacturing and analytical aspects are conducted synergistically, with good communication between manufacturing and analytical teams. This will build solid foundations to ensure that the final analytical method is able to fully encompass the requirements of the cleaning process, and can reliably and consistently quantify the required residues at the calculated limits, hence ensuring the pharmaceutical product is safe for the consumer.
