PART III PROCESS SAFETY
3. Cleaning Validation
The efficiency of cleaning procedures depends highly on the design and integra- tion of equipment. Insufficient cleaning will compromise Food Safety and on the other hand over-cleaning is wasted money and pollutes the environment.
Cleaning procedures must always be developed under consideration of the prod- uct requirements.
The validation of cleaning procedures is a well known strategy (FDA, 1993) in the pharmaceutical industry to proof the sufficient removal of residues of previ- ous products, intermediates and cleaning agents as well as to control potential contaminants.
To achieve an effective and efficient cleaning validation it is often found help- ful to structure the tasks into steps, beginning from a status evaluation up to the
hygiene risk
dead space
flow direcrtion against sensor sensor not cleanable
measures not relevant
correct
FIGURE10. Examples for sensor installation.
approval procedure and to develop and follow a specified validation program to avoid insufficient and overlapping work. In many cases a structure similar to that shown in Figure 11 has been adopted.
3.1. Status evaluation
To select the equipment and corresponding cleaning procedures which have to be validated and to establish acceptance criteria and analytical methods, products (composition), processes (potential risks), equipment (construction) and cleaning procedures (cleaning agents) should be first evaluated.
Equipment may be grouped into equipment families to take into consideration the product, process, cleaning procedure and construction.. So, if several pieces of equipment are of similar construction and used for products with similar com- position and comparable concentration and cleaned by the same procedure, they are treated as belonging to the same equipment family.
To determine acceptance criteria for residual products, residual cleaning agents, for process hygiene and for routine monitoring the cleaning procedures are analysed with special emphasis on composition of product and cleaning agents. Due to the fact that a validation process cannot achieve 100% safety, rou- tine monitoring criteria and methods should be designed.. A first choice of parameters could be pH and conductivity for NaOH, Total Organic Carbon (TOC) for organic contaminants and endotoxin in the final rinse.
The analytical methods used to detect residues should be specific for the sub- stance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable (PICS, 1999). Cleanability can be assessed by test methods described in EHEDG Document No. 2 (2004) and in VDMA (1999).
STEPS RESULTS DOCUMENTATION
Selected equipment and cleaning procedures
Status Evaluation
Acceptance criteria and analytical methods
Risk Analysis Representative equipment, product and sampling locations
Cleaning Validation Master Plan
Validated analytical and sampling methods
Cleaning Process Studies
Acceptance limits
Cleaning Validation Protocol for selected representative Logbook, reports, SOPs Assessment and
Implementation
Corrective actions Assessment report
Validation of Representative Approved representative Cleaning Validation Report, Approval Transfer to other equipment Approved equipment Cleaning Validation Protocols, Reports
and Approvals
FIGURE11. Structure of a cleaning validation program.
3.2. Risk analysis
Risk analysis may be used to select representative equipment to establish and validate appropriate analytical and sampling methods and to develop and carry out a cleaning validation protocol. The representative equipment must cover all products, processes and equipment of the corresponding equipment family. Worst case conditions, encompassing processing limits and circumstances, within stan- dard operating procedures, which pose the greatest chance of failure (PIC/S, 1999), are analysed for the selection of equipment, product and sampling loca- tions as well as for the determination of acceptance limits. The processed prod- ucts, potential risks of the process step, the applied cleaning methods (CIP/manual) and the composition of the cleaning agents as well as the function- ality, the frequency of usage and the construction of the representative will be carefully examined. Equipment suitable for cleaning and removal of the most stubborn residues should be selected. Sampling locations termed critical areas which are hardest to clean or areas with conditions favourable to reproduction of micro-organisms (e.g. moisture, temperature, crevices and rough surfaces) would be identified. The range of concentration of the critical product component, cleaning procedures with the highest concentration of cleaning agents and clean- ing methods with uncertain reproducibility (manual cleaning) will be identified for the determination of acceptance limits during cleaning process studies.
3.3. Cleaning process studies
Cleaning Process Studies are carried out to validate analytical and sampling meth- ods under consideration of worst case by determination of residual products, resid- ual cleaning agents and microbial contaminants before and after cleaning. Special emphasis should be taken on the composition of the product and cleaning agents.
To predefine acceptance limits for all acceptance criteria including routine monitoring criteria, the cleaning procedures are analysed on the basis of histori- cal data and/or Cleaning Process Studies. The acceptance limits should be prac- tical, achievable, verifiable and consistent. The limit of quantitation of the corresponding analytical method must be lower than the acceptance limit. The amount of accepted product residue from one batch to the next, based on the amount of the following batch, and the amount of accepted residual cleaning agents depend very much on the kind and the sequence of products. For this rea- son, a safety factor should be considered and incorporated into the procedure.
Acceptance limits for micro-organisms on product contact surfaces depend on the surroundings, where the equipment is located and may not be higher than the acceptance limits of the respective room class.
The sampling procedure is most important for the representative validity of the results. When establishing a sampling plan it has to be considered that the contaminants will not be uniformly distributed throughout the system and that a residual contaminant will not be worn off the equipment surface uniformly. The design of the equipment should be carefully examined. Critical areas and differ-
ent materials of construction should be identified. The sampling locations must be clearly defined in the validation protocol by photographs or drawings and by detailed written descriptions for each location, including a rationale for why cer- tain sampling points will be tested. The act of sampling itself is a cleaning step.
Therefore a particular location has only to be sampled once after a particular cleaning run to reflect the true results of the investigated routine cleaning process.
After the sampling process the sampling locations have to be cleaned by appro- priate methods to remove any contamination introduced during sampling. In addi- tion the equipment has to be cleaned again according the respective SOP (Standard Operation Procedure).
For direct surface sampling swabs are used to test flat surface areas. Special focus should be drawn on hard to reach areas such as cracks, crevices, gaskets, seals. Different sampling solvents should be examined; therefore one sampling taking process would have to be designed to cater for different methods. To eval- uate the recovery effectiveness and reproducibility of the swab method, which depends on the swabbed material, the sampling solvent, the concentration range of residues and the swab pattern and sequence, recovery tests should be per- formed on all relevant material types for the relevant concentration range of residues within the validation of the detection method. A known amount of a spe- cific residue should be applied onto the surface and allowed to dry. Then the area will be sampled and the swab is analysed to determine the percentage of recov- ery. The sufficient number of swabs is estimated with different concentrations of the residues. The predetermined recovery coefficients will be used in the calcula- tion of the residues.
Indirect rinse samples only indicate when sufficient rinsing has been achieved and do not necessarily correlate with residues on the equipment surface.
Therefore, wherever possible, both methods should be used, otherwise direct sur- face sampling should be used as the preferred method. Final rinse samples are be used to test large surface areas, especially inaccessible areas of equipment that cannot be routinely disassembled. The equipment is flushed with a known amount of water and a rinse sample is collected and tested for the required parameters.
3.4. Assessment and implementation
At least before a Cleaning Validation Protocol is approved and executed, it is strongly recommended that assessment of all documents and results should be carried out. Any unacceptable results should be handled as a deviation. In the event that criteria and/or limits are unattainable under practical conditions modi- fications may be considered. Somebody must be responsible to decide if investi- gations or corrective actions are necessary under consideration of product risks and/or process capability or if the “Cleaning Validation Master Plan” including SOPs and protocols can be approved and implemented.
The personnel performing cleaning and validation must be qualified accord- ing to This means that persons who perform sampling should be trained in the application of validated sampling procedures and a training plan containing a
time schedule for persons who have to be trained and in which procedures should be issued. Furthermore, a check list for supervisions containing this information should be produced..
A time table for routine monitoring must be established. An SOP for Change Control must be available, to log any changes of product, process, equipment, cleaning and validation procedures. Validation runs should be per- formed with a minimum of 3 successful consecutive applications of the cleaning procedure.
Revalidation should be performed a) periodically and b) in the case of any change of product, equipment, cleaning procedure, etc., it has to be decided if the change will affect the cleaning procedure and if therefore the cleaning procedure has to be revalidated: The intervals of periodical revalidations have to be defined before approval. Manual cleaning methods should be reassessed more frequently than CIP.