The lyophilized drugs in the pharmaceutical industry cannot afford to compromise on cleanliness. Lyophilizer contamination results in wasted effort and resources, or worse, creates health and safety issues that can compromise a company’s reputation and customer confidence.
Detecting and quantifying trace residue concentrations of active pharmaceutical ingredients (API), excipients, and washes during lyophilizer cleaning validation procedures is one of the single largest costs associated with the manufacture of pharmaceutical freeze dried drugs.
The lyophilizer cleaning validation is a very laborious process and combined with the idle time of the manufacturing equipment is a very expensive part of pharmaceutical manufacturing cost.
The FDA clearly outlines its expectations within the lyophilizer cleaning validation under Inspections Guides. To satisfy the enumerated expectations, there can be many different approaches to cleaning verification and/or validation, based on the most efficient, cost-effective and practical approach.
There are 3 kinds of surfaces in the Pharmaceutical Industry:
Direct Product Contact: Directly contact manufactured product (or sub products that then are part of the final product) and for which there is a very high likelihood of transfer of residues and contaminants.
Indirect Product Contact: It is in close proximity to open product and where there is a remote or moderate likelihood of transfer of residues and contaminants to product, usually by a vector (Operator or Airflow)
Non Product Contact: Does not directly contact manufactured product and is not in close proximity to open product. Is unfeasible the transfer of residues and contaminants
1. Lyophilizer Cleaning validation: Risk Analysis (FMECA)
The lyophilizer has indirect product contact surfaces (see figure 1): Trays, where the vials are deposited for lyophilized (which allow their transfer and loading) and Shelves (internal part of the equipment), which supports the trays:
2. Lyophilizer Cleaning validation: Some definitions
Failure mode: the ways, or modes, in which something might fail. Failures are any errors or defects, especially ones that affect the customer, and can be potential or actual.
Potential failure mode: It is each possible failure mode without being necessary for the fault to actually occur. It usually answers questions such as: - In what way is it conceived, that the product or process could fail? - How could the component fail to meet specifications?
Potential failure causes: All causes that are assignable to each failure mode.
3. Lyophilizer Cleaning validation: Potential Failure Modes Analysis
Potential Failure Mode (N°1) = API residues from a previously manufactured product (A), spilled on the trays and without effective cleaning, can be transferred indirectly to the next product vials to be lyophilized (B).
Potential Failure Mode (Nº2) = Microorganisms, endotoxins or detergent, residual products of a previous cleaning, can be indirectly transferred to the vials of the next product to be lyophilized (B).
By evaluating the Potential Failure Modes, we can find the following potential contaminants on the manufactured products and their origin:
Potential Fault Cause (N°1) = Airborne residues transfer from the previous product, due to vacuum pulled in the lyophilizer, air currents may dislodge residues on surfaces, those residues may become airborne and those airborne residues may deposit into the vials.
Potential Fault Cause (N°2) = Airborne residues transfer due to repressurization of the lyophilizer chamber, air currents may dislodge residues on surfaces, those residues may become airborne and those airborne residues may deposit into the vials.
Potential Fault Cause (N°3) = Transfer due to lyophilizer shelves movement (vial sealing stage), residues on the bottom of the surfaces may dislodge, drop and fall into the vials.
NOTE 1: We can establish here that, the relevance of the Failure Modes is not given as a product (B) that can pick up residues of a product (A) from the shelves, but as a residue that can be transferred indirectly to the following vial product (B)
NOTE 2: As assumed for cleanrooms, it is understood that microorganisms are not "free floating", they require a means of transport to reach the product, this transport is the residues airborne particles.
4. Lyophilizer Cleaning validation: Potential Failure Modes Likelihood Assessment - Engineering perspective
From the lyophilization process, operation and engineering of the equipment we could ponder as very low or almost nonexistent the likelihood of these failure modes, due to:
4.1). The partial stoppering of the vials does not create an easy and / or direct pathway for residues streams and / or contaminants to enter the vials. See figure 2:
4.2). During the high vacuum phase (figure 3), in the lyophilization process, any residues and contaminants that become airborne are likely to be pulled in the direction of the evacuation port (butterfly valve - connection between camera and condenser). At the same time the air in the vials is being pulled upward and out in the same direction as the air in the chamber, reducing the likelihood of contaminated airborne entering the vials.
4.3). During chamber repressurization, any loose residues on the chamber surfaces, would have already become airborne and expelled through the vacuum port, furthermore, as the vials become stoppered the likelihood of transfer into vials becomes close to zero.
4.4). During vial sealing phase (figure 3), the shelves are moving and any loose residue and / or contaminant that may be dislodged in this process is likely to only fall straight down, which is not a direct pathway into the partial stoppered vials.
4.5). Physical glass particle contamination, due to broken or cracked vials also has a very low likelihood of becoming airborne. Those particles and broken vials are eliminated by hand during chamber unload and with water during washing cycles. We can additionally determine that the "visually clean" criterion will be sufficient.
5. Lyophilizer Cleaning validation: Potential Failure Modes Likelihood Assessment - Galenic Process Perspective
5.1). In contrast to direct product contact surfaces equipments, for which "adherent or tenacious" residues are more difficult to clean, for lyophilizers "loosely adherent" residues represent the worst case, and ironically it is those molecules which can readily be removed by flowing water. Therefore, the likelihood of having residues of a previous product is almost zero.
5.2). The lyophilized products are generally designed to be reconstituted by water alone for patients use. Therefore, from the QbD, it is known that these product residues can be removed with water alone during the cleaning process. Moreover, most modern lyophilizers with automatic CIP (Clean in Place) cycles operate with WFI water alone, without adding any type of detergent or cleaning solution.
6. Lyophilizer Cleaning validation: GMP Criticality Assessment
For this assessment we will establish:
Severity of Damage (S) = 1 to 5 (No patient damage - Serious / Catastrophic patient damage)
Occurrence Likelihood (P) = 1 to 5 (Unlikely to occur - Frequently occurs)
Criticality Level (CR) = S x P
CR1 = High Criticality - It is necessary and vital to establish risk mitigation actions and critical control points.
CR2 = Medium Criticality - Evaluate according to the RPN (risk priority number) obtained, actions and critical control points needs.
CR3 = Low Criticality - It is not necessary to establish actions, the risk is acceptable and controlled.
7. Lyophilizer Cleaning validation: Risk Priority Number (RPN) Calculation
For this assessment we will establish:
Detection (D) = 1 a 5 (100% detectable - Non detectable)
Risk Priority Number (RPN) = S x P x D
8. Lyophilizer Cleaning validation: Assessment Conclusion
The GMP criticality for each Failure Mode is low (CR3), therefore the risks are controlled and would not require major mitigation and control efforts. Although the severity (for the patient) is very high, the likelihood that they actually occur is insignificant (we have already justified it in above pages from the engineering and pharmaceutical point of view).
Then, why perform cleaning validation in these type of equipment?
In addition to the usual justification that ... "it is a regulatory requirement" (since cGMP standards and related guidelines deepen about the importance of cleaning and sterilizing freeze dryers before each load to ensure an aseptic process, free from microbiological and particle contamination), and given the above analysis we can provide that:
A). According to PRN calculation and "detection" systems assessment, we have obtained different priorities values for which we must (according to our particular risk analysis SOP) plan preventive actions and / or process improvements to ensure that these potential failure modes will be detected and / or minimized.
B). Cleaning Validation is one of those "preventive" actions since we have scored the "current control" actions as insufficient due to non-representative finished product sampling and quality controls that do not "look for" chemical contamination trace levels of other products with validated techniques.
C). Cleaning validation is relevant from the microbiological point of view, due to the lyophilizer design (considered an extension of aseptic processing) since operators must intervene by hand in the loading, unloading and collection of broken vials (increasing the probability of microbiological contamination).
D). We must give importance, not only to the lyophilizer shelves sterilization, but also to the vial loading trays sterilization (usually this process is carried out in an autoclave).
E). We have assumed that there is a likelihood of lyophilizer microbiological contamination, and therefore we must sterilize it; We also have established that microorganisms are not free floating and require a means of transport (any kind of particles) to effectively contaminate a product through an airborne; Then cleaning equipment to eliminate these particles and "Validate Cleaning" seems like reasonable logic.
F). We must perform an FMECA assessment in particular, for our lyophilizers technology, knowing how they operate and its own engineering, in order to adequately score the risks.
LyophilizationWorld wants to express sincerely and strong appreciation to Sergio Eduardo Reyna for this perfect and illuminating article.