What’s the “Cleaning Meaning”? The “5 Ws” of Cleaning Validation

The Role of Cleaning Validation in the Pharmaceutical Industry

In the Pharmaceutical Industry there is some possibility of contamination and cross-contamination of products due to inadequate washing of shared facilities. This can lead to severe hazards for the patient, therefore any contamination as well as cross-contamination cannot be afforded in (imagine, for instance, what would happen if a drug for a trivial headache contained a narcotic drug instead...!).

Pharmaceutical products can be contaminated by various materials such as residues of previously used active pharmaceutical ingredient (API), raw materials, detergents, dust particles as well as microorganisms, pyrogens and endotoxins. This is the reason why an efficient cleaning of surfaces is a relevant and fundamentally important aspect. But…what’s the “Cleaning” meaning? “Cleaning” means making any article, piece of equipment and area free from product residue, dirt, marks, any unwanted matter and microorganisms.

The risk of contamination and cross-contamination can be minimized by applying suitable cleaning procedures to equipment, apparatus and processing areas. The Pharmaceutical Industry wants to achieve these main goals with the help of current Good Manufacturing Practices (cGMP). In fact, the main goal of cGMP is the prevention of products contamination and cross contamination through the implementation of an appropriate and validated cleaning program. This “program” is known as “Cleaning Validation” and can be defined in a few words as the documented evidence that cleaning procedures applied to equipment, piece of equipment or systems will obtain pre-established acceptable limits.

Nowadays, the main regulations and guidelines governing Cleaning Validation comes from Authorities like EMA, FDA, APIC, PIC / S and WHO. An important turning point came in 2012 with the introduction of the EMA/CHMP/CVMP/SWP/169430/2012 (operative since 2014, after a couple of years of adjustment), which first introduced the concept of “chronic toxicity” (PDE) in the risk assessment of the chemical cross-contamination. In the wake of the EMA, the FDA (Validation of Cleaning Processes (7/93), 2014) and WHO (Working document QAS/20.849, 2020) also aligned themselves in the following years with harmonized regulations on Cleaning Validation based on substances’ toxicity.

At this point the role of Cleaning Validation in the Pharmaceutical Industry should be a little bit clearer than before and we could try to explain the Cleaning meaning through “5 Ws”…

What Cleaning Validation will demonstrate?

Cleaning Validation will demonstrate that the cleaning procedure applied after batch manufacturing is adequate to remove possible residues of product, detergent (if any), dust, microorganisms and endotoxins and pyrogens in case of sterile products, from equipment product contact surfaces up to below pre-established acceptance limits.

The product to be investigated for potential contamination of shared equipment contact surfaces, must be selected in order to be the most critical to clean (“worst-case”), and will be representative of all the other products possibly manufactured with the same equipment. According to the current guidelines, the worst case should be selected on the basis of its solubility (in water or specific solvent), toxicity (long term) and cleanability (i.e. attitude to be washed out); but further aspects may be considered adopting a suitable scientific rationale.

If there are any products that share the same or similar formulation but different dose strength, it is possible to group up them together and select the most representative of the group, extending the validation to all the others (this approach is named “bracketing”).

In addition to residual of products, if a cleaning agent is used as adjuvant of the cleaning procedure (it may be a combination of detergent and water or other agents like chelating agents), it is necessary to demonstrate that it is properly rinsed out at the end of the cleaning.

Finally, another important aspect to consider is the microbiological contamination. At the end of cleaning, bioburden, endotoxins and pyrogens need to be within the limits established by the Pharmacopoeia, depending on the type of product (non-sterile or sterile).

Why Cleaning Validation is Important?

The main purpose of Cleaning Validation is to prove the effectiveness and consistency of cleaning in a given pharmaceutical production and packaging equipment, to prevent cross-contamination and adulteration of drug products with other active ingredients (APIs) or microbiological contamination. The goal is not only to comply with regulations, but it is also necessary to ensure patient’s safety and fulfill customers' requirements.

Overall, Cleaning Validation ensures the safety, identity, strength, and purity of the product which are the basic requirements of cGMP.

When Cleaning Validation is needed to be performed?

Efficacy of cleaning procedures is typically evaluated:

• At the end of the manufacturing or product changeover (cleaning after batch)
• At the end of a manufacturing campaign (production of subsequent batches)
• After a period of dirty state (Dirty Holding Time, DHT)
• After a period of storage in clean state (Clean Holding Time, CHT)
• After maintenance
• Periodically, after a pre-established period, on the basis of a proper risk-assessment aimed to keep the risk of cleaning failure under control

There are also some cases in which cleaning procedures require a re-validation:

• When one is establishing initial qualification of cleaning method and equipment.
• If there are some major changes in a cleaning procedure are being adopted.
• If there is a major change in the master formula.

• If the cleaning agent is changed.

How Cleaning Validation is performed?

Cleaning Validation is typically performed according to a master validation plan (Cleaning Validation Plan) that will guide the cleaning validation approach and dedicated Cleaning Validation Protocols in which all the relevant cleaning procedures, equipment, areas, analytical methods, sampling plan and acceptance limits will be reported.

Cleaning Validations are conducted by sampling the product contact surfaces with several techniques that can be contact plates, swabs and rinsing. The suitability of the sampling methods must be properly verified before their application, in order to demonstrate their capability to recover residues from product contact surfaces and for all the type of materials of which they are made of. The validation of sampling technique is usually included in the analytical method validation.

Analytical methods for Cleaning Validation can be specific or aspecific, depending on their capability to specifically detect the residue (i.e. HPLC, UV/VIS, etc.) or not (i.e. TOC, conductivity, etc.). As for sampling technique, analytical methods must be verified or validated for their intended use, depending on their complexity and according to the current ICH requests. Minimum requirement for analytical methods’ verification are selectivity, sensitivity and repeatability; further parameters may be necessary depending on the type of technique and intended use (i.e. qualitative or quantitative)

The acceptance limits can be calculated by applying different approaches (i.e. maximum dose and maximum ppm), but starting from the EMA turning point in 2014, the toxicity of the active substances (PQE, ADI or HBEL) must also always be considered and the calculated limit must be compared with that obtained by applying traditional approaches. From a worst-case perspective, the most restrictive limit obtained must be applied. How selecting the worst case product.

Where Cleaning Validation is Performed?

Cleaning Validations are performed by sampling the so called “critical points” of equipment, which are actually the “most difficult to clean” areas of the product contact surfaces. The critical points choice for Cleaning Validation purposes should result from an appropriate risk-assessment, conducted by a team made up of all the parties involved in Cleaning Validation, from the engineering responsible for installation and qualifications to the production staff that is in charge of the cleaning of the equipment. Typical aspects to consider for the selection of critical points are disassembly, dimensions, accessibility, shape and contact material surface.

Similarly to products, equipments can also share characteristics such as shape, size and cleaning procedure and therefore can be grouped using the bracketing approach. The execution of Cleaning Validation on a representative equipment of the group can be extended to all members of the group itself, leading to resources and time saving.

Future Challenges: Quality by Design and Biotech Industry

Quality by Design (QbD) principles such as design space can also be applied to cleaning validation. Well-designed laboratory-scale studies can be performed using design of experiments (DoE), and the data analyzed to understand the cleaning process. With the knowledge of large-scale equipment, one can create an approach that results in a successful cleaning validation. Given the trend to apply DoE more and more frequently to Pharmaceutical processes, one of the future challenges will certainly be to perform cleaning validations using the QbD approach.

In the last decade, especially due to the COVID-19 pandemic, the Biotech sector has experienced a strong boost. This has contributed to increase regulatory needs with regards to Cleaning Validation, until now segregated in a sort of limbo, in which biotech products were considered a middle ground between traditional ones and biological substances from a cleaning point of view. Contrary to what was thought, Cleaning Validation plays an important role in reducing the risk of product contamination and cross-contamination, also from biopharmaceutical manufacturing equipment. The increased relevance, and hence the increased need for regulation, is demonstrated by the publication of the PDA technical report TR-49 (PDA Technical Report No. 49, Points to Consider for Biotechnology Cleaning Validation, which updates the previous PDA documents on cleaning validation, including the 1998 PDA Technical Report No. 29, Points to Consider for Cleaning Validation and the 1996 monograph Cleaning and Cleaning Validation: A Biotechnology Perspective provide valuable insights for biotechnology manufacturers), issued by a task force of European and American experts in biotechnology, cleaning and regulatory field. The TR-49 has filled the gap between "traditional" cleaning of Pharma and that of “innovative” Biotech products, which share many aspects, but differ in some others. In fact, while cleaning validation for biotechnology manufacturing has many of the same elements as for other pharmaceutical manufacturing, there are enough differences that separate Technical Report, making the focus on biotechnology cleaning validation necessary for a safe production. The TR-49 it is also innovative and in line with recent regulatory trends, aligning cleaning validation practices with the life cycle approaches to validation, as enabled by the ICH Q8 (pharmaceutical development) and Q9 (quality risk management). The challenge of the very near future will be to implement the principles of cleaning validation in a widespread and effective way even in a sector as driving and dynamic as that of biotech.