Handling external Personnel in the GMP Environment

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18/19 February 2025
Vienna, Austria

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This article is intended to consider cleaning processes in pharmaceutical production, i.e. GMP-regulated areas. With the release of the Annex 1 to the EU GMP Guideline in August 2022, the almost all-encompassing topic of "contamination control" has come to play an important role in the context of the manufacturing of sterile products. It explicitly addresses and recommends the transfer of aseptic manufacturing strategies, including the contamination control strategy, to the manufacture of non-sterile pharmaceutical dosage forms. Cleaning processes in general are of significance there for a variety of measures. Particularly in the context of a contamination control strategy, the cleaning of surfaces that come into contact with the product, especially the control of so-called cross-contamination, should be considered. This is described in regulatory terms with regard to its validation in Annex 15 to the EU GMP Guideline in the valid version of 2015. However, within the scope of this article, only the cleaning of surfaces that do not come into contact with the product, such as surfaces of the cleanrooms themselves, will be discussed. Thus, all surfaces "subject to cleaning validation" are not part of the following observations and considerations.

Definitions/terminology

The term "contamination" is often used without considering its clear distinction from "impurity" by definition. Accordingly, contamination is merely the presence or introduction of a hazard (definition from the Austrian Food Safety and Consumer Protection Act). Thus, in contrast to an impurity, a contamination is always of exogenous origin, whereas an impurity arises during the production process and must be actively removed. As an example, an endotoxin build-up in biotechnological processes with certain production organisms (e.g.: E. coli) can be mentioned here. Exactly the same substance can occur as a contaminant in the case of microbiological contamination, for which no specific depletion or removal procedures are provided in the routine process.

Furthermore, contamination is always a question of quantity and depending on context. A distinction is made here between:

• Non-critical contamination: The concentration is below a threshold value (acceptance limit).
• Critical contamination: Quantity of contamination exceeds a risk-based threshold (acceptance limit);

We typically mean critical contamination when we refer to "contamination."

To avoid or adequately remove this contamination, cleaning processes, and other measures, are essential.

Regulatory requirements and guidelines

In order to fully understand the requirements associated with outsourcing cleaning processes to external service providers, two categories of requirements need to be identified:
1. Identifying the general requirements imposed on pharmaceutical manufacturing companies that outsource activities.
2. Then, specific requirements for personnel in the cleanroom and the cleaning process must be determined.

Basic requirements for outsourcing activities

It should be emphasized that the ultimate responsibility lies with the "marketing authorization holder", i.e. the pharmaceutical manufacturer. All parties involved, both the contract giver and the contract acceptor, must be aware of this.

This is the aim of the EU GMP Guideline in Chapter 7 ("Outsourced Activities") under point 7.7:

"The Contract Giver should monitor and review the performance of the Contract Acceptor and the identification and implementation of any needed improvement."

This is usually specified as part of a quality contract. One aspect of this requirement is the communication structure, which is an essential part of the collaboration. This defines who holds the communication roles at the client and contractor, and thus which employee is authorized to give instructions to whom. It makes sense to define a "pair" of persons with the corresponding functions for each shift. This guarantees that an employee of the contractor does not take instructions from an "unauthorized" employee of the client and, in the worst case, activities are carried out incorrectly, late or not at all.

In addition, the client must ensure that an adequate change control system is established at the contractor as service provider. This is described in Chapter 7 under item 7.12:

"The Contract Acceptor should not make unauthorized changes, outside the terms of the Contract, which may adversely affect the quality of the outsourced activities for the Contract Giver."

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These points should be clarified in advance and also recorded in writing in documents such as quality agreements.

Guidelines on personnel and cleaning (according to Annex 1)

The specifications on these topics apply equally to internal and external personnel. In addition, the requirements of the new Annex 1 can also be applied to the manufacture of non-sterile medicinal products. This is explicitly mentioned in chapter 1 ("Scope"):

“The intent of the Annex is to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, validation, monitoring and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as certain liquids, creams, ointments and low bioburden biological intermediates but where the control and reduction of microbial, particulate and endotoxin/4.2 pyrogen contamination is considered important. Where a manufacturer elects to apply guidance herein to non-sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated.“

Regarding the result of cleaning, there are the following specifications in Annex 1 under point 3:

"[...] Appropriate cleanliness levels in the “at rest” and “operational” states should be maintained."

In connection with outsourced activities in the cleanroom in general, but specifically for cleaning processes, it is crucial that all employees involved are aware of what "appropriate" means in this context and in which prerequisites, measures and processes and reflected in this degree of cleanliness.

In this context, it is also pointed out that cleaning itself involves contamination risks. This can be caused by inadequate dressing procedures of the external personnel, cleanroom behavior, cleaning techniques and the like. In particular, microbiological contamination of the cleanroom can pose a risk to the product due to the proliferation of microorganisms or the formation of (endo)toxins. This issue is addressed in point 9,23 of Annex 1:

"[...] Viable particle monitoring should also be performed within the cleanrooms when normal manufacturing operations are not occurring (e.g. post disinfection, prior to start of manufacturing, on completion of the batch and after a shutdown period), and in associated rooms that have not been used, in order to detect potential incidents of contamination which may affect the controls within the cleanrooms. In case of an incident, additional sample locations may be used as a verification of the effectiveness of a corrective action (e.g. cleaning and disinfection)."

Last but not least, the topic of training is addressed, which is extremely relevant in all aspects of outsourcing cleaning activities, as the activity is performed in the manufacturing area of medicinal products. The working environment in cleanrooms, by its nature, demands a specific behaviour and procedures, and the robustness & reproducibility of manual cleaning processes are to be considered critical. This is described in point 7.3 of Annex 1:

"All personnel including those performing cleaning, maintenance, monitoring and those that access cleanrooms should receive regular training, gowning qualification and assessment in disciplines relevant to the correct manufacture of sterile products. This training should include the basic elements of microbiology and hygiene, with a specific focus on cleanroom practices, contamination control, aseptic techniques and the protection of sterile products (for those operators entering the grade B cleanrooms and/or intervening into grade A) and the potential safety implications to the patient if the product is not sterile. The level of training should be based on the criticality of the function and area in which the personnel are working."

It is also pointed out in Annex 1 Section 2.0 relevant for the Contamination Control Strategy that Cleaning as well as Disinfection is amongst the important elements. This reflects Cleaning’s listing under point XIII.

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Importance of (cleanroom) cleaning

Macroscopically and subjectively from the point of view of the cleaning personnel, pharmaceutical production areas, in particular cleanrooms of cleanroom class A and B, are (almost) always clean or sterile anyway. Why, then, is a cleaning process, which is usually very time-consuming, necessary? The answer can be found in the sub-visual area. Among the various physical, chemical or particulate types of contamination, microbial contamination is of particular importance, in addition to cross-contamination (product or active ingredient carryover). Firstly, this has a time-dependent component due to the proliferative capacity of microorganisms; secondly, possible toxin production by microorganisms can pose an additional risk to product quality and consequently to patient safety.

This issue must be addressed again and again during the training of employees who are entrusted with the cleaning of cleanrooms. This is especially the case in class A/D cleanrooms, where sterile drugs are produced aseptically and the hazard is, so to speak, an invisible one. This eliminates the thought process "But everything is clean here! Why should I clean there?" and an awareness of the immense importance of room cleaning activities within the overall contamination control strategy is achieved and consolidated. This ensures that the non-product-contacting surfaces in these process- and product-critical areas are not only clean (free of visible impurities), but also free of visible and subvisible, microbial and particulate, impurities.

These cleaning processes of the surfaces in the production rooms of pharmaceuticals can only be subjected to a random process check as a success control. On the one hand, the environmental monitoring serves for the control, which represents a random, local microbial control of the surfaces, on the other hand, a visual inspection of the processes within the scope of the "Quality Assurance Oversight", which then represents a random sample.

Here, as well as in general, the following parameters are to be considered in the context of the evaluation of these cleaning processes:

• Experience of the persons carrying out the process
• Training of the persons carrying out the process

And thereby

• Qualification of the persons carrying out the process
• Behaviour of the persons carrying out the process

But in principle, apart from the random checks, the above points must be fulfilled, because it is not the control, but the system that is the guarantee of a robust cleaning with consistent results, and the basis for this is the correct application of the trained techniques.

The cleaning is done:

• "from top to bottom"
• "from the inside to the outside"
• "in airlocks according to the specifications (clothing, technique, products) of the subsequent higher RRK"
• "covering the whole area by correct technique (overlapping)".

Part of the training in the correct application of these cleaning techniques can be, in addition to video-supported training, a video recording of the trainee himself to enable optimization of his own procedure. Particularly in the case of higher cleanroom classes, a look beyond the end of one's nose should also be offered as part of the theoretical training and, in addition to "What is to be done?", also "Why is it done in this way?

Furthermore, especially due to the criticality in high cleanroom classes (keyword: "I am cleaning an optically clean surface"), a visualization of the cleaning success by applying fluorescent substances to test surfaces within the scope of the practical parts of a training course has proven successful. Here, a more in-depth understanding is achieved through the "learning by doing" effect. Cleaning in test rooms outside the cleanrooms in production-specific clothing with the cleaning utensils to be used can also be part of the practical training in order to highlight potential weak points, e.g. in cleaning techniques.

Due to the criticality of microorganisms in the production environment, cleaning and disinfection processes in production areas must be developed and implemented with the following considerations in mind:

• Cleaning removes contaminants, product residues and, where applicable, microorganisms from surfaces
• Cleaning and disinfection interrupt the contamination chain of microorganisms
• Cleaning removes the nutrient substrate required by the microorganisms for reproduction
• Disinfection inactivates or reduces the microorganisms
• Both serve to prevent the transfer of dirt, product residues and microorganisms into the products

A point that is discussed again and again, mainly from an economic point of view, is whether the ever-increasing regulatory pressure and workload in surface cleaning is still in proportion to the benefit. At this point, one should ask how many resources are invested in the processes of maintaining the degree of cleanliness in pharmaceutical production areas: on the one hand, in maintaining the cleanliness of the air by HVAC systems and, on the other hand, in maintaining the cleanliness of the surfaces by qualified cleaning personnel and equipment.

In general, it should be said that even when outsourcing the cleaning processes, they must be carried out by qualified personnel. One should sensitize oneself and possibly also the purchasing department and ask the following questions:

• Are you having your cleanroom ventilation system built by someone who specializes in air conditioning for offices?
• Are you having your cleanroom cleaned by someone who specializes in general building maintenance?

Improving the quality and efficiency of cleanroom cleaning can often be achieved by simple measures or changes in perspective. The measures here are to create cleaning SOPs, with illustrated instructions as far as possible, and to establish general basic cleaning techniques that are independent of the room or zone.

It is almost more important to establish an understanding that cleaning processes are an integral part of the production process and not low-priority and detached "support processes".

Outsourcing using the example of cleaning

Comparison of third-party cleaning – internal cleaning
The following comparison regarding cleanroom cleaning can be seen as an example for other fields of activity (e.g..: Maintenance and repair technicians for production equipment, ventilation systems or media systems, IT services for GMP-relevant computerized systems, ...).

Before outsourcing cleaning activities, the advantages and disadvantages of using external or in-house personnel should be recorded and weighed up in detail, especially in relation to the processes concerned. The outsourcing itself, but also the weighing up of pros and cons, should be seen as part of the contamination control strategy, particularly with regard to the new version of Annex 1. This should be carried out and documented as part of a risk assessment. Even now, in order to meet the requirements of a QRM, it is necessary to perform and document a decision based on a risk assessment. Ultimately, the impact on product quality and patient safety must always be evaluated.

The author has chosen the following seven topics and tries to compare the advantages and disadvantages of in-house cleaning and third-party cleaning:

• Process understanding
• Time resources
• Motivation
• Staff turnover
• Cleaning systems
• Suggestions for improvement
• Economic aspects

This is not a complete list, but it can serve as a starting point for an assessment, as the topics mentioned are generally relevant in all pharmaceutical manufacturing companies. This list of topics can be expanded as desired to include c ompany-specific topics if process es or products require it, such as containment requirements or radiopharmaceuticals.

Table 1: Challenge process understanding

Table 2: Challenge of time resources

Table 3: Motivation

 Table 4: Staff turnover

Table 5: Cleaning systems

Table 6: Suggestions for improvement

Table 7: Economic aspects

Based on these comparisons and a weighting of the parameters, a decision can be made below as to where third-party cleaning should be used and implemented.

Where does third-party cleaning make sense?

The following considerations are merely recommendations by the author and do not represent binding or official requirements. Consideration should be given to outsourcing the cleaning of large areas, such as "low" cleanroom classes (RRKc or D) or so-called CNC areas (CNC, "controlled not classified"), which are monitored in one or more microbiological and/or physical environmental parameters.

The outsourcing of regularly recurring cleaning activities with consistent requirements, but which do not fall under "routine activities" is also worth considering.

In such cases, "peaks" in the cleaning effort, e.g. basic cleaning during shutdown (production downtime, e.g. for maintenance purposes) or during changeover (product change during campaign production) are absorbed by increasing capacity with external personnel. This procedure generally reflects the usual use of external personnel during "peaks" in the workload. Routine operations are usually carried out by the company's own staff, who are then supported by external staff when the workload increases.

During production shutdowns, cleaning activities are often carried out "hand in hand" with preventive maintenance activities, including the cleaning of ventilation systems during the maintenance shutdown. The final preliminary cleaning before the cleanrooms are put back into operation is also a process that involves a lot of extra work for routine personnel and for which external cleaning personnel are often called in.

On the other hand, there are also areas where the use of third-party cleaning personnel is not recommended. In the aseptic production of sterile pharmaceuticals, these include the cleanroom areas of classes A and B, in particular the equipment surfaces in these areas. Depending on the production process, certain equipment surfaces should also be cleaned by in-house personnel, irrespective of the cleanroom classification. In addition to areas with sensitive process steps, this particularly applies to systems with a large number of sensitive measuring sensors or to work surfaces with critical instruments, such as scales. Lifting the scales for the purpose of cleaning the work surface underneath can have a massive impact on the subsequent weighing accuracy and result in a re-adjustment or even re-calibration. If this goes undetected, there can be a negative impact on product quality and patient safety. In addition, containment requirements may also contribute to the decision not to outsource certain cleaning processes.

What should be considered when outsourcing (clean)room cleaning?

In general, it is always a good practice to request references from potential suppliers and service providers in order to assess whether prior knowledge and expertise in the pharmaceutical environment in general and possibly for areas with specific requirements (aseptic production, multi-product plants, shift production or possibly up to continuous production) is already existing.

A standardized questionnaire (at least for the basic requirements) can be a great help, especially if outsourcing is to take place for several buildings or even subsidiaries. This facilitates a harmonized approach and also dealing with inspectors from authorities and external auditors. The following questions are examples to be expanded according to specific requirements:

• "How do you proceed with cleaning?"
• "What cleaning and disinfecting agents do you use and why?" (possibly you specify them, or even provide them)
• "Are your cleaning and disinfecting agents "ready-to-use" or individually self-mixed or diluted?"
• "What are the qualifications of your staff?"
• "How do you determine cleaning intervals for non-cleanroom areas?"
• "How do you guarantee employee training status?"

It makes sense to define and document exactly what is expected from the external cleaning company. In addition, define non-goals of the cooperation in addition to the goals, similar to a project management matrix. The non-goals here relate in particular to activities that are not to be carried out by the external company employees under any circumstances. Unfortunately, experience has shown that "well meant is not well done". Points that should in any case be part of the quality agreement include:

• Who bears the costs for the qualification? (e.g., approval for cleanroom classes)
• When is cleaning to take place?
• Who assumes responsibility for which areas?

As already mentioned, the topic of communication interfaces or contact persons plays a central role. It is essential to define where the cleaning of the company's internal personnel ends and where the cleaning of third-party cleaning personnel begins and, even more importantly, who may or should give instructions to whom. This must also be known to employees of the client in order to be able to guarantee the smooth running of the service – in this case cleanroom cleaning.

The aim of this outsourcing is a longer-lasting cooperation with the possibility of sensibly extending areas of responsibility. This can mean that, for example, certain control tasks can also be carried out, such as changing the entry lists to cleanroom areas on each working day or, for example, the administration of cleanroom clothing, since the storage areas for this are cleaned by third-party personnel anyway. Furthermore, it can make also sense to transfer the administration of the documents, such as cleaning logs for cleanrooms and equipment, which are to be filled out, to the external personnel.

What remains...

The execution of cleanroom cleaning in pharmaceutical manufacturing areas is a matter of trust when outsourcing this process. This critical and integral process step in the production flow can rarely be fully controlled in its execution. In addition, people from outside the company gain deep insights into the company's own production processes, which is naturally an important factor in the careful selection of a cooperation partner. Thus, in this area of tension in a GMP-regulated environment, it is necessary to find the balance between trust and "documented evidence", whereby a risk evaluation in accordance with quality risk management and, in the future, contamination control strategy should also be applied here in any case.

About the Author
Robert G. Schwarz is lecturer at the FH Camus in Vienna, Austria. He has 20 years of experience in aseptic processing, contamination control and clean room technology.