Figure 1: Limit calculation example of an OSD manufacturing (all figures provided by the author).

This article originally appeared in issue 6 / 2025 of journal Pharmind.
Available here with permission of the publisher.

Résumé

An effective cleaning validation is one essential piece for a successful regulatory inspection in the pharmaceutical industry. It is an ongoing challenge to develop and maintain a cleaning validation program that meets all regulatory expectations. A robust program includes strategies for cleaning process development, product bracketing, grouping of equipment, training of operators, analytical methods and analytical sampling as well as acceptance criteria and limit setting for cleaning validation. This article will look at the preparation required to move cleaning validation activities into a digital platform. Digital data handling has several advantages and the author wants to show some of the key aspects also with a view on digital transformation in pharma manufacturing. More than that, the aim of digital transformation might be, to get a faster decision if new formulations can be implemented on site, or if they are a new worst case. Also this aspect will be discussed.

Introduction

Within the pharmaceutical industry, there has been a significant number in articles and publications related to digitalization over the last years already. This article intends to look into the ongoing discussions surrounding digitalization and focus on the single aspects related to cleaning processes, their documentation as well as optimization.

The objective is to map out the potential benefits and underline advantages that are achieved when transitioning from traditional paper-based systems to an environment where these processes are supported by validated digital solutions.

Through this article, the author wants to raise the awareness about the predominance of manual and paper-based protocols within the pharmaceutical industry. Very often, there is a lack of dialogue among relevant stakeholders and cross-functional teams regarding the digitalization of these processes. During discussions you can identify that a lot of Pharma professionally still think that paper-based processes are still efficient and effective as they stand. The author hopes that after reviewing this article the advantages of digitalization in cleaning is getting very obvious.

Notes For Paper-Based Documentation

Cleaning validation is an important aspect of quality assurance in pharmaceutical manufacturing. It plays a crucial role in ensuring that manufacturing equipment is properly cleaned to prevent cross-contamination between products, which can have possible implications for patient safety, product integrity, and its effectiveness.

To initiate a cleaning validation project in pharmaceutical manufacturing to validate a cleaning process, a set of fundamental activities must be undertaken. These tasks often involve calculations, tables, and data analysis like the project planning, calculation of total product contact surface, maximum safe carryover (MSC) limits calculations, bracketing activities and worst case product identification.

For these activities validated digital tools can be a significant improvement on data integrity. The author wants to explain this statement with an example of a table used for MSC limits calculations in an Oral Solid Dose (OSD) manufacturing (fig. 1).

Figure 1 is an example of how the MSC could be assessed using different ways of calculating acceptable carryover limits incl. health-based exposure limits mentioned in EU Annex 15¹.

Questions directly related to these types of tables might be:

1. Is the source of the data known?
2. Who entered the data?
3. Is the data approved by appropriate subject matter experts (SMEs)?
4. When and who did the last change of the data?
5. Is there a procedure to initiate workflows when the figures or calculations need to be updated in the table?
6. How is the company making sure that all relevant colleagues are working with the latest version of the table?

To address these challenges effectively, various approaches have been observed. In the context of paper-based systems, the most time-consuming task is typically the document approval workflow. This process involves printing the document and circulating it among relevant stakeholders for their signatures - often a long-winded and slow procedure.

Subsequent steps in the document management process include the storage of the physical hard copy in an archive room, as well as a scanned version in a digital location, such as a SharePoint site. These measures, however, present multiple difficulties, particularly when the content of a document needs to be updated - e.g., when introducing a new product. The employees are then required to verify that they are working with the correct version of the document by comparing the archived hard copy, the scanned copy, and the most current electronic file.

To overcome these highly inefficient and error-prone practices, companies may turn to alternatives such as password- protected files or electronic document management systems (DMS). Through such systems, the validated and approved documents are stored and made accessible in a more streamlined and secure manner.

Figure 2: Master data table in a digital validated cleaning validation tool.

Digitalization in Validation – Worst Case Identification

Implementing a validated digital tool can address several concerns associated with traditional paper-based documentation processes. Here are a few ways in which a digital system can improve efficiency and compliance:

1. Document Generation: The system enables the creation of specific user profiles with varying levels of access, such as author, reviewer, and approver. This ensures that only designated individuals identified by the organization can access documents and perform relevant tasks, thereby maintaining control and integrity throughout the document lifecycle.
2. Change History: With each user logging into the system using their unique credentials, all actions taken on a particular document can be tracked immediately. This feature captures who made changes, when they were made, and the reasons behind those changes, ensuring full traceability and improving Good Documentation Practice (GDP) compliance.

For example, when calculating the MSC, the initial step in a validated digital software solution would be to enter the socalled master data (fig. 2) into the system. This creates an accurate record right from the outset, streamlining the subsequent steps and ensuring consistency across the entire process also taking into account a change management process in case of any changes are required.

Figure 2 provides a list of master data necessary for conducting the MSC assessment. The scope and detail of the master data are key on the strategy employed for determining the safe carryover limit, which is identical to the manual tabulation method previously discussed. However, the use of master data within validated software offers clearly some advantages.

One key benefit of validated software is that users are prevented from random adding or deleting parameters simply because they seem to be relevant for a specific product. This level of control means that a minimum data set - the master data - must be input and authorized by designated individuals. This requirement ensures consistency, as the safe carryover calculation is always calculated using the same data set across all products and equipment.

In the author's interactions with quality assurance professionals, he has learned that they appreciate having definitive guidance regarding the required master data. In the current landscape, there is considerable uncertainty about what elements must be evaluated, often leading stakeholders to consider excessive and potentially irrelevant data. This additional scrutiny can result in prolonged times to complete the assessment using the traditional manual methods. Conversely, in a digital software environment, there is clear instruction on which parameters need to be assessed, which can expedite the completion of each assessment.

Utilizing the master data along with the software's built-in logic for calculating the MSC, the digital system consistently identifies the limits using exactly the same data and calculation background. Consequently, the software can pinpoint the MSC limit for each piece of equipment, and this determination can be conveniently displayed within the software interface outlining the Surface Acceptable Limit (SAL, fig. 3).

The use of digital tools for cleaning validation activities, such as maximum safe limit identification, shows the potential benefits of transitioning from a paper-based system to a digitalized approach. One of the primary advantages is increased compliance, facilitated by having a real-time history log where all actions can be easily traced. This ensures that data are always attributable, legible, contemporaneous, original, and accurate (ALCOA). By leveraging these digital advantages, organizations can achieve a higher standard of data integrity and process efficiency, ultimately enhancing the quality assurance of their cleaning validation procedures.

Figure 3: SAL identified by digital software.

On the form sheet (fig. 4), you can observe fields that operators must complete by hand. In addition to recording the temperature and humidity, the operator is also required to note down the time of inspection of the measuring device, alongside with their initials and the date. The fields for temperature and humidity are highlighted in orange because these are the critical pieces of information needed. The fields highlighted in blue, on the other hand, are there to confirm when and who performed this reporting task.

Should this process be conducted using validated digital software, the operator would first log in to the system with unique credentials. Upon accessing their daily schedule, the task for reading the humidity and temperature would be listed. The operator would read the sensor measurements and input the values directly into the system, which would automatically capture and store details about who performed the task and when.

While the paper form sheet is typically filed and archived unless out-of-specification (OOS) data are detected, digital tools offer enhanced capabilities. They provide a clear visualization of temperature trends (fig. 5), potentially across different seasons, offering insights into the consistency of these values.

Comparing the completed form sheet (fig. 4) with the graphic evaluation of the digital tool (fig. 5) it is obvious that the graphic evaluation has significant advantages. On the graphic evaluation you can identify easy:

1. What are upper and lower limits?
2. Position of data related to the limits.
3. Can a trend be observed?

The identification of the details above lead to the fact that you get a much better understanding of data.

Figure 5: Graph to monitor temperature in the storage room using a digital tool.

Ongoing Verification of Cleaning Process

Utilizing such a digital tool not only streamlines data capture but can also facilitate the statistical evaluation of the data over time. This may even allow for adjustments in the frequency of checks, potentially reducing the workload for operators.

Additionally to the improved process understanding the statistical evaluation of the process capability (Cpu, fig. 6) can be used for a risk-based cleaning validation approach to determining the level of effort, formality and documentation². Current guidance documents like the ASTM E3106-22 Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation³ are outlining that it is recommended that cleaning processes use technologies to measure, control, and record critical cleaning input/output variables to detect critical failures and ensure reliable and consistent process performance. Also it is outlined to evaluate the data from these approaches statistically. Models can be developed and subsequent runs can be compared to the model to determine whether the cleaning is equivalent to the model or used for real-time release of equipment (refer to section 9.4.5.1 and 9.4.5.2 of ASTM 3106-22).

These activities will not be possible using the traditional paper-based/logbook documentation. In this case it can only be realized by additional efforts transferring the data into a digital system manually.

Figure 6: Temperature profile of a cleaning incl. Cpu using digital software solution.

Digitalization of Forms in Manufacturing Rooms

In addition to documentation associated with cleaning product contact surfaces and cleaning validation activities, there are other hygiene-related actions within manufacturing environments that necessitate thorough documentation. One such example is the cleaning of manufacturing rooms. The current practise to document the location/room where cleaning shall be performed is to use forms/logbooks like the one shown in fig. 7.

Figure 7 illustrates how cleaning activities, which are listed on the left side of fig. 7, are recorded by the initials and signatures of the operator who carried them out. However, this approach fails to capture essential details such as the duration of the cleaning task or the exact time it was performed, as evidenced by their absence from fig. 7. Being a paper-based form, it is only accessible in the specific manufacturing room where the cleaning takes place. Consequently, reviewing this form requires physical presence in the area.

Figure 7: Documentation of cleaning of a manufacturing room (monthly activities).

The document shown in fig. 7 is reviewed monthly by the responsible person. When non-compliance is eventually detected, it triggers an investigation. However, significant delays between the occurrence of the event and its discovery can hinder the investigative process, as personnel may struggle to recall the specifics of the incident, incl. what happened, when it happened, and why.

Implementing a digital software solution for manufacturing room cleaning activities (fig. 8) can enhance the monitoring of the rooms' current status, indicating whether they are clean, dirty, or in the process of being cleaned. It also facilitates the tracking of the time required to complete a cleaning task. By utilizing a digital tool, there is immediate clarity on all executed activities, improving oversight and the timely identification of any issues.

Moving away from paper-based processes, such as cleaning validation and logbook activities the author has discussed before, into a digital software tool can significantly streamline operations.

The following time-consuming activities may be eliminated with the adoption of digital solutions:

1. Preparing the document, incl. updates to dates and other relevant details manually.
2. Printing the document; this also has a sustainability benefit, as it reduces paper use.
3. Manually amending the printed document, if necessary, which may require additional handwriting.
4. Physically distributing the printed document to the location where it is needed.
5. Manually completing the paper forms, logbooks, or instructions.
6. Collecting the completed documents for later review and archiving purposes.
7. Having the documents reviewed by the responsible person.
8. Archiving the physical document, which includes filing and managing storage space.
9. Locating the document during inspections or audits, a process that can be time-consuming and challenging if records are extensive.

Remarkably, the author has found that a pharmaceutical manufacturing site with approx. 500 employees prints over 170,000 sheets of paper every year. With all the handling steps mentioned above, this equates to roughly 3 full-time equivalents (FTE) dedicated solely to managing these printouts.

Figure 8: Overview of cleaning activities in manufacturing room using digital tool.

Digitalization Promotes Optimization

In this article the author has discussed several examples of moving form paper documentation to a digital tool. The examples have all in common that a digital tool will deliver real time data instead of reviews taking place after a certain amount of time. Also the process understanding is improving using a digital tool, because you are able to review and evaluate the data in a more proper way (even use statistical evaluation and models). Based on this improved process understanding the possibilities of optimizations can be identified and often also evaluated much easier. If you are looking ahead into the aspect of using Artificial Intelligence (AI) in pharmaceutical operations, the digitalization happening today is definitely the first step to get the data feed for this new technologies.

Conclusion

This article has explored the potential of using a validated digital software tool, to manage a wide array of activities, from cleaning validation, like maximum safe limit identification to environmental hygiene monitoring and even routine logbook tasks. The most significant advantage of utilizing a digital tool is the enhanced quality control it offers by having all data readily accessible at any time. Implementing validated digital software enables the evaluation of data through statistical tools or other methods, ensuring that all site activities are under control, thus safeguarding both patient safety and the quality of pharmaceutical products.

Références

1. EudraLex – Volume 4 – Good Manufacturing Practice (GMP) guidelines – Annex 15 Qualification and validation, Mar 2025. health.ec.europa.eu/document/download/7c6c5b3c-4902-46eab7ab- 7608682fb68d_en?filename=2015-10_annex15.pdf
2. Walsh A, et al. The Shirokizawa Matrix: Determining The Level Of Effort, Formality, ans Documentation In Cleaning Validation. Dec 11, 2019. www.pharmaceuticalonline.com/doc/the-shirokizawamatrix- determining-the-level-of-effort-formality-documentationin- cleaning-validation-0001
3. ASTM International, 2022. E3106-22 Standard Guide for Science-Based and Risk-Based Cleaning Process Development and Validation. ASTM E3106, West Conshohocken, PA (USA). store.astm.org/ e3106-22.html

The links were last accessed on 12. Mar 2025.