When manufacturing highly potent solid oral dosage forms, taking an effective approach to cleaning the equipment used is paramount.
Dr. Kevin Robinson (KSR) of Manufacturing Chemist recently caught up with process experts at PCI Pharma Services to learn more about cleaning validation and verification, the differences between the two … and why they’re so important.
Cleaning Validation and Verification in a High Potent Granulation Suite – November, 2022, | As seen in Manufacturing Chemist.
Cleaning Validation Specialist
Analytical Technical Lead
Ben Potter (BP), Validation Manager at PCI Tredegar, describes cleaning validation as “a documented process which proves that a cleaning procedure can effectively remove drug product, agents and microbial contamination from a speciﬁc piece of equipment to below the scientiﬁcally set maximum allowable carryover limit. Importantly, the procedure must be reproducible.”
For example, a robust cleaning validation programme will:
- Assess a new product and/or process for general cleanability in the laboratory prior to being introduced into a GMP production environment.
- Ensure that the cleaning procedures are adequate for new products, processes and/or new equipment when placed in a GMP production area.
- Ensure the safe removal of product residues,microbial contamination, and cleaning agents to acceptable levels prior to manufacturing the next product (utilizing the same or shared equipment).
- Provide ongoing assurance that the validated status of the cleaning procedures is maintained with a cleaning verification frequency.
“At PCI Tredegar,” adds Amala Alex (AA), Cleaning Validation Specialist, “cleaning validation is in place for any shared equipment that’s used to manufacture and package drug products. When cleaning validation is not set up — or prior to completion — we adopt a standard approach for all products and equipment by performing cleaning verification.” “Cleaning verification is a controlled process to determine the effectiveness of a cleaning process for a specific event and is generally applied when a cleaning validation programme has not been developed or completed. Examples might include Investigational Medicinal Products (IMPs) or commercial items that don’t have enough data points. It’s proven to be the most risk-averse approach when validation is in the planning stage.”
KSR: What challenges must be considered when developing a robust cleaning method?
AA: As much work as possible needs to be completed upfront to minimize the amount of development that’s done on the actual equipment. Critical factors include different batch sizes, campaign lengths, the potency of the drug product, market considerations, carryover limits and the next product and detergent selection for the removal of that product.
Richard Parry (RP), Analytical Technical Lead, adds: “Starting with the right equipment is key to supporting effective cleaning. The most basic consideration is that the machinery has an appropriate surface ﬁnish, lacks crevices and can be easily cleaned. However effective a cleaning system is, the most critical thing from a cleaning validation perspective is that all the parameters affecting the cleaning process are consistent. Periodic checks alone are not sufficient; as such, alarms for ﬂow rate or pump pressure and temperature are essential.”
Each time a new product is introduced into a facility, the following considerations need to be assessed:
- Can the new drug be effectively cleaned?
- Can the residue be detected at low enough levels to confirm cleaning?
- Does the mode of action present specific risks to existing drugs?
- Do existing drugs present a risk to the new one?
RP: It’s important to have a range of detergents to provide different cleaning modes of action for different types of molecule. Appropriate detergents are selected by running lab-scale cleaning trials. This is something that’s traditionally done by suppliers of cleaning additives, but, as most suppliers aren’t able to handle potent drugs, this needs to be done in-house at PCI. Suppliers of cleaning agents often recommend the degradation of molecules, but this presents its own risks. A highly potent molecule is less likely to be degraded to something more harmful — as would be the case with less potent molecules — but unless there is sufficient evidence to suggest otherwise, degradation products must be treated as a patient risk and therefore addressed accordingly.
BP: Clients often provide permitted daily exposure (PDE) values, which can be used to establish verification limits. Occasionally, however, such data isn’t known. In these instances, PCI uses an approved external contractor to calculate the value. These factors are then accounted for during the new product introduction (NPI) process by the Development and Analytical teams to assess the best validation method for the drug product. Once the product information is known, the next step to consider is the equipment to be used and whether it’s suitable for the effective cleaning process or designed method. Factors such as shared equipment surfaces, the equipment train, and individual surface areas are assessed with the Engineering team, which helps to establish the hard-to-clean areas.
The most critical thing from a cleaning validation perspective is that all parameters affecting the cleaning process are consistent.
RP: Some equipment parts represent more of a cleaning challenge than others. Hard, flat 316 L stainless-steel surfaces, for example, are easy to clean and sample reliably. Materials such as EPDM, however, present difficulties. At the low levels required to clean highly potent molecules, surface interaction becomes more relevant, as does the potential for chemicals being absorbed and leaching gradually with time. In such cases, the preference is to dedicate parts to specific projects. That said, not every part that presents a challenge can be dedicated. For example, the multilayer stainless-steel gauze filters used in our fluid bed drying technology are not easy to clean or swab; but it’s simply not practical to dedicate these because of the amount of time required to fabricate them. Our method for these parts is, following the initial wash-in-place, to apply a second cycle in the parts washer. Additionally, as swabs can’t identify what’s inside the layers of the gauze filters, PCI performs rinse sampling as a further measure.
Some materials can limit the choice of appropriate cleaning agents. For example, soft metals will be more prone to corrosion by caustic cleaning solutions and plastics may deform when washed at high temperatures. Such limitations cause restrictions on the TACT (temperature, agitation, concentration and time) cleaning model. As time is not a major requirement to achieve effective cleaning, this can be addressed during the method development stage, along with factors such as the concentration of the cleaning agent, the chemicals added using detergent pumps and/or the temperature of the cleaning medium. Attrition is more relevant, as increasing pressure or changing spray balls/jets is required to achieve more attrition on equipment. In this instance, requalification of the system is required to ensure that spray coverage and consistency are maintained.
AA: Material of construction is a key consideration when determining change parts or dedicated tooling for each product. To Richard’s point, materials such as EPDM and PTFE make for difficult sampling because of their porous nature. In these instances, the best option is to dedicate the contact part for each product and run detergent studies on them. In terms of operator safety and protecting the drug product, work instructions and forms are in place to clean individual pieces of equipment. Furthermore, gowning procedures are implemented in all PCI’s facilities to ensure operator/product safety and minimise any risk of cross-contamination. Such steps are vital when handling a range of highly potent materials in a multiproduct facility such as PCI Tredegar.
KSR: You referenced both validation and verification earlier. Could you talk a little more about the distinction between the two processes?
RP: Verification provides constant assurance that equipment is clean between product changeovers, whereas validation shows that a cleaning process is under control. In the early stages of manufacture — particularly for clinical trial products — it’s not practical to validate as there are too many potential changes to both the dosage form and the manufacturing process at that stage of the product’s lifecycle. The other constraint on validation is ensuring that the process has been sufficiently developed. Additionally, the transfer and scale-up of cleaning activities can be unpredictable; further development may be needed when equipment changes are made.
AA: For most products, cleaning validation would traditionally mean the end of routine verification, with more periodic and spot checks being done as a requalification exercise. This is not always the case for potent drugs and a risk assessment can show that continued verification is required as well as validation.
BP: No single process is more favourable than another. It’s more about when to validate and when to perform verification. Essentially, verification and validation are similar processes. The main difference is that verification is a knowledge-building exercise; it ensures that a sufficiently robust strategy has been developed that subsequently makes validation possible. Once a sufficient amount of verification has been performed, the method can then be validated via a documented study. If a cleaning process is validated before sufficient data is gathered, the risk is that revalidation would be required, which is much more labor-intensive. Verification is, therefore the most risk-averse process and should be employed until the cleaning process has been sufficiently developed. Some other points to consider include the following:
- The scale-up of a cleaning process is not always as predictable as scaling-up of a manufacturing process, so verification may be preferred until an established full-scale process is in place;
- Validation is not required for IMPs when cleaning verification is performed;
- The cleaning acceptance limit is identical for validation and verification processes, which also includes any safety margins built into the initial calculations of the PDE in the event of small excursions identified within the equipment train.
Ultimately, cleaning validation is the expected procedure for commercial products, often requiring continuous development and verification to reach an acceptable endpoint. Until then, cleaning verification is the safer route for product and patient safety as it provides 100% assurance that there is no carryover of one product to another.
KSR: Lastly, why should PCI be regarded as a trusted partner when it comes to high-potency cleaning validation and verification?
BP: PCI ensures a high-level standard approach to both processes when planning a robust cleaning programme for any substance used in our multiproduct facility. Our original Contained Manufacturing Facility (CMF) for the development and production of highly potent drug products, launched in 2013, has provided almost a decade of high-level operational knowledge in this area in terms of how product cleaning methods are developed and used, and how detergent removal works. This experience and the associated successes led to the recent construction of a second CMF and a state-of-the-art highly potent packaging facility, both of which provide significant expansions to our existing capabilities to better serve the clinical and commercial marketplace.
AA: We have also established very strong relationships with our suppliers during this time, which means we remain at the cutting-edge of highly potent processing and cleaning methodologies. Together with a robust approach to documentation and a very effective gating process for all new products introduced to the site, this ensures a proven strategy when it comes to the handling, processing and cleaning of highly potent products. The overall goal is to ensure product, patient and operator safety throughout the entire clinical-to-commercial life-cycle.