4 Focus Areas To Modernize Your Cleaning Validation Strategy

By Bilel Khedir, Opalia Pharma Recordati Group

Cleaning validation is one of the hottest topics in the pharmaceutical industry, and it is in continuous evolution. People in the quality unit who deal with it often consider it difficult, but it is necessary because regulatory inspections demand it. Team members from other units who are not implicated often consider it a waste of time and money.

The person in charge of cleaning validation must be able to explain it to everyone in the company and show its importance. For example, they must be able to explain that the correlation between the maximum level of residues tolerated and the toxicological studies used to determine the permitted daily exposure (PDE) that guarantees that cross-contamination won’t cause any harm to patients.

Like any other industry, two primary aims of the pharmaceutical industry are to reduce costs and gain time. Establishing a successful cleaning validation system might look expensive in terms of money and time, and your company’s decision makers might lean toward using a traditional system. To them, a traditional approach would look attractive. It might look inexpensive, safe, and relatively simple. But the traditional system can lead to serious problems in the long run. Furthermore, an immediate investment made for improvements after a warning letter or an inspection will never make the situation better.

A unique and different approach may look unrealistic, expensive, and difficult to implement. But innovation does not always mean immediate change. In fact, a gap analysis followed by continuous tiny changes and oriented huge investments at the right time and place are the keys to achieve concrete progress.

Small steps would be game-changing in a cleaning validation strategy. Specifically, the areas where you can dig a little deeper to make a significative change are:

• the detergents supply
• the worst-case approach
• the cleaning validation data management system
• the analytical tools you use.

I’ll discuss each of these areas below.

1. The Detergents Supply

Once you validate a detergent, you cannot change it unless you validate another. The validation of an alternative detergent can take time, money, and can impair production flow. Suppliers know this and can turn it into exploitation. You will need to retain the ability to negotiate price and challenge the supplier.

To avoid this exploitation, I recommend that you validate at least two detergents from two different suppliers to gain a good business position so that you can negotiate the price and deal with shortages easily. The validation of the two detergents does not need to be done simultaneously. You can validate the alternative detergent gradually.

Before buying from your supplier, establish clear agreement about:

• The supply chain. It must be continuous, and they should notify you about any shortage early enough to allow your company to take action (alternative validation or solutions).
• Formulation change. The supplier must notify your company of any formulation change because detergents often keep the same names after a change in formula.
• Residue determination. The supplier must provide a rapid and accurate analytical method to determine the residues of the detergent.
• Contact with the detergent manufacturer. A direct contact with the detergent manufacturer to get technical details would be very beneficial. If that is not possible, the supplier must be able to ensure contact.

2. The “Worst-Case” Approach

Generally, a risk analysis is conducted to choose the worst-case cleaning product. The score is often used to determine the worst case for cleanability and solubility. This approach can make the validation more difficult. Imagine calculating the score and finding that the product is manufactured once a year, and then you find out that the products ranked second, third, and fourth are not manufactured often (by « not often, » I mean once each two or three years). If you choose the first product (manufactured once a year), the validation would take at least three years!

The key concept in cleaning validation is “less is more.” One of the easiest solutions is that you keep the product ranked first based on the first scoring and validate it as a “special worst case,” but instead of calculating a traditional worst-case score based on cleanability and solubility, you generate a corrected cleanability score composed of two subscores. This type of scoring is already used in some industries.¹

The corrected cleanability score will be the product of the traditional cleanability score and the occupancy rate score derived from the number of lots manufactured each year. The justification for this scoring system would be made by a scientifically sound risk analysis explaining that the more a product is manufactured, the more it can contaminate equipment.

This new scoring system would yield — almost every time — a worst-case product that is manufactured often, and validation of three runs will take less time.

3. The Cleaning Validation Data Management System

I am not the type of person who would advocate for digitalizing a process just because of the trend of Pharma 4.0. When a process is not built properly, digitalizing it would not correct it. It can make it harder instead.

However, in my opinion, digitalizing cleaning validation data is not an option — it is an urgent necessity. The challenge with cleaning validation data is that it is very correlated, and updating your database to add new equipment or a new drug product can turn everything upside down.

When adding a new drug product, for example, you must check the worst-case score. If it is not a worst case in terms of cleanability and solubility, you must compare its PDE because if it has a lower PDE than the actual lowest PDE, you must look to the analytical method limit of quantitation and see if it can cover the new limit yielded by the new PDE.

For new equipment that you will need to add to the database, if it is a worst case, you must check the surface and how it would affect the limit of the residue tolerated and the limit of quantitation of the analytical method used.

This reminds me of a quote by the 2004 Nobel Prize in Physics laureate Frank Wilczek: “When things look complicated, that is often a sign that there is a better way to do it.”

By using software to manage this huge amount of correlated data, you can make the process both easier and faster.

There is plenty of software for cleaning validation. I do not advocate for a specific software, but the criteria that must be met in software to make it really useful are:

• It automatically checks if a product has a new worst-case score.
• It checks if the analytical method must be changed entirely, or if you need to lower the limit of quantitation.
• It calculates the residue limit automatically and compares it to the analytical method limit of quantitation.
• It schedules the validation runs and sends warnings about upcoming runs precisely.
• It maintains records of the residue results after cleaning and automatically generates cleaning method capability and trends.

The ideal software would also be easy to use and meet quality needs in terms of computerized systems validation.

4. The Analytical Tools Used

The analytical method used to detect residues plays a key role in accelerating the cleaning validation process. As a short-term solution, one can work on transferring all the methods used in cleaning validation from HPLC to UPLC. The game-changing step is developing a real-time testing method.

There are drug companies working on implementing process analytical technology in cleaning validation.² Some recommend using mid-infrared to detect residues in equipment directly, without swabbing or extraction.

The challenge is huge, but if you can develop a spectral method that detects and yields results in real time, it would make the flow of cleaning validation significantly faster.

Conclusion

You can change your cleaning validation strategy for the better. I know it may be challenging to convince the appropriate decision makers in your company of your point of view, especially if it’s unusual or different. You can still change what is under your control and do your best.

Acknowledgment

I would like to express my sincere gratitude and appreciation to Alya El Hedda, Ph.D., for providing invaluable guidance and for constantly motivating me and inspiring me to work harder. I would also like to express my gratitude and appreciation to Dalenda Bouslah for her guidance and support.

References

1. Porto, L. V. F. M., Fukumori, N. T. O., & Matsuda, M. M. N. (2016). Determination of the worst case for cleaning validation of equipment used in the radiopharmaceutical production of lyophilized reagents for 99m Tc labeling. Brazilian Journal of Pharmaceutical Sciences, 52, 105-112.
2. Sarwar, A., McSweeney, C., Smith, M., Timmermans, J., & Moore, E. (2020). Investigation of an alternative approach for real-time cleaning verification in the pharmaceutical industry. Analyst, 145(22), 7429-7436.

About The Author:

Bilel Khedir works for Opalia Pharma Recordati Group as a pharmaceutical development project manager and quality assurance specialist. He is also a pharmacist and MSc student in drug development. His expertise includes conducting preformulation studies and formulation of drug products, analytical methods validation, in vitro bioequivalence studies, and writing new drug products’ marketing authorization dossiers (CTD format). In his previous role at Opalia as quality assurance pharmacist, he oversaw cleaning validation, including routine cleaning and disinfection activities, and executed continuous improvement strategies. You can reach him at khedir.b@opaliarecordati.com.