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A guide for improving the planning and preparation of future validation work.
After weeks and months of planning, protocol writing, review, and protocol approval having been gained, cleaning validation can begin. There remain several things, however, that a cleaning validation study director should have also considered, planned for, and communicated during that preparatory period, such as the fact that validation work frequently requires support from other groups within the manufacturing facility. Careful and thoughtful coordination and communication are also required to ensure seamless performance of procedures, testing, analysis, and reporting. This article presents a guide on how to continuously improve planning and preparation for future validation work.
Training is a critical aspect of a successful validation execution. Prior training, performed and documented well in advance of validation activities, can ensure successful execution. Validation personnel should be familiar with methods of gowning for the areas in which they will be performing sampling. Knowledge of operation of plant utilities can greatly streamline execution, especially if facility technicians or operators are not available. Knowledge of facility cleaning procedures and operation of facility cleaning equipment, including clean-in-place (CIP) equipment, can greatly enhance the success of the execution. Of course, personnel performing sampling, or assisting with sampling, should be trained to perform those duties. It is often advantageous to perform off-line sampling, prior to execution, as a “dress rehearsal” to ensure success on the day of execution. This rehearsal can identify any potential pitfalls, answer any questions, and evaluate the robustness of the validation protocol as well as the abilities of the validation personnel. Training should be conducted in accordance with the requirements of the local facility and should be documented in accordance with the requirements of local standard operating procedures.
Validation personnel, although familiar with manufacturing procedures and equipment, do not perform the procedures or operate the equipment on a regular basis. Manufacturing support is, therefore, frequently needed to support validation activities.
Validation work is not the primary focus of the manufacturing group, despite the benefits. Careful coordination of equipment and resources (people), and sometimes utilities, is necessary to ensure operation of washers, CIP skids, and performance of manual cleaning procedures are performed and documented in a timely and efficient manner. Manufacturing personnel are often keen on assisting, but manufacturing management must be informed and kept “in the loop” for best results.
Validation personnel should meet with the appropriate manufacturing personnel and present the cleaning validation plan, complete with timelines to include a schedule of personnel, equipment, and utilities required, and for how long these resources will be required.
Validation personnel rarely, if ever, order their own supplies and deliver their own samples to outside contract laboratories for a host of reasons.Logistics support is essential any time large amounts of validation supplies are required. Total organic carbon (TOC) test kits, extra commodities used to challenge and test washers, and CIP detergents, if utilized, all need to be ordered ahead of time. These items are stocked for manufacturing use and are ordered as needed. Most facilities do not keep an extra supply of inventory on hand because of space constraints or by procedure, so involving the logistics group up front will ensure that there are adequate validation supplies on hand when needed. If any microbiological testing will be performed, the appropriate supplies (replicate organism detection and counting [RODAC] plates, sterile container for rinse samples, endotoxin tubes, etc.) should be stocked and available in the area in which they will be utilized.
Logistics personnel should also be informed if validation test samples will be shipped to an outside contract laboratory for testing and should be made aware of the material being shipped. Special considerations may be required if the samples pose any type of hazard. Shipping conditions (fragile, refrigerated, etc.) and any time-sensitivity requirements should be communicated in advance to the logistics group as well as valid shipping addresses for outside contract laboratories.
Validation personnel should have an accurate estimate of supplies required, including a modest overage as a safety factor. They should also share the validation plan with logistics to ensure potential long-lead items are procured in a timely manner and on-site when they are needed.
It is also important to remember that there may be procedures in place for bringing materials into controlled spaces. Test kits and sample bottles may need to be decontaminated for a specific contact time before they can be used. Validation protocols may need to be printed on autoclave paper and autoclaved into the space in which the documents are needed.
Proper planning will assist protocol execution.
Communication with the quality control laboratory, whether the on-site laboratory or an off-site contract laboratory, will ensure test samples are received, analyzed, and reported in a timely manner.
Some analytical tests require prep work up front for standards and may require extra reagents and other test supplies. It would be most unfortunate, for example, to drop off rinse samples for high-performance liquid chromatography (HPLC) analysis, only to find out that halfway through the testing the lab ran out of reagent. Some tests are time-consuming and may require one or more technicians to complete the analyses. Careful scheduling of sampling may be required if there is no off-shift or weekend laboratory coverage.
Validation personnel should share the test schedule with the appropriate laboratory personnel. It would be, and is, extremely rude to suddenly submit 50 TOC samples to the lab without prior warning.
Validated test methods are also required, and laboratory personnel must be trained on these methods and demonstrate the ability to perform them. Test methods should be supplied, and training should be completed, far in advance of validation sampling.
Validation personnel should be familiar with, and if required, trained in, procedures for submitting samples to the quality control laboratory. Some chemistry samples and most microbiology samples require refrigeration while awaiting testing. If an outside contact laboratory service is used, internal logistics assistance may be required for sampling shipping. Coordination with the internal logistics group is necessary to ensure that the proper shipping forms are completed and that shipping requirements are met.
Most organizations have budgeted for validation work, and it is important to keep close track of validation costs from an hourly standpoint for validation personnel through to the cost of validation equipment and supplies as well as outside contract laboratory services. If an internal laboratory is used, it is equally important to track the cost of technicians as well as the cost of laboratory supplies and equipment.
Internal organizations supporting validation work should be provided a cost center or account charge number through which their time and resource costs can be charged to the validation account. Careful monitoring of these expenses can assist with future validation planning.
Purchase orders should be generated in advance, allowing adequate time for reviewing and processing.
Validation work is frequently performed during planned shutdowns. This can be a good idea, because validation personnel do not have to compete with manufacturing for equipment time. It can be problematic, however, if the utility you might need (water for injection, purified water, city water, steam, clean steam, or electricity) is not available during the planned downtime. Communicate validation plans early and often with facilities management to ensure uninterrupted service not only to the area in question, but also to onsite laboratories that may be performing your validation sample testing.
Sometimes in the heat of the moment of validation sampling, it is easy to remember to complete sample labels but forget to record similar data on the data collection forms attached to your approved protocol, or vice versa. Often there is a validation assistant, and sometimes it can be challenging to determine where to draw the line of who records what. The person performing the sampling should always complete the data entry on the data collection form, but the assistant may complete associated sample labeling right up to date, initials, and time. These three items should always be recorded by the person who is performing the work. Data recording, including corrections, should always be in accordance with the local current good manufacturing practices (cGMP) requirements.
Sample labels can be pre-printed with information such as protocol identification and sample identification. Sample-specific information, such as sample date, sample time, and the name or initials of the validation personnel performing the sampling should be recorded at the time the work is performed. Because cleaning validation and cleaning validation sampling can involve water or other solvents, it is best to ensure that the ink used to pre-print labels and to record sample-specific information is waterproof or resistant to solvents in use. Information required for sample labels should be in accordance with local requirements.
If the data collection form is designed in the performed by/verified by format, it is best to have an assistant present to verify that the required sampling has been performed.
The approved protocol may require documentation of equipment identification numbers and calibration data (including last calibration and next calibration). This information must be recorded in accordance with local requirements.
Date and time entries for labels and data collection should be in accordance with local requirements as well.
Often production operators, maintenance technicians, or facility engineers may be required to cycle or operate equipment used during the performance of validation work. Everyone who contributes to the performance of cleaning validation should sign a signature log attached to the protocol.
Formats for names and initials, if required, should be in accordance with local requirements. Signatures should be recorded the day the validation work is performed to avoid exception documents after the fact.
Supporting documents, such as scale printouts, pH meter printouts, water temperature reports, and parts washer cycle reports should also be documented in accordance with local requirements.
It can be helpful to have a checklist of all documents required to tick off the completion of documents, or the recording of required signatures, or the collection of reports as the events occur. Failure to obtain a signature or report may result in the added time and expense of gowning to re-enter a classified area.
If protocol requires that the parts and equipment subjected to cleaning validation be taken out of service, this should follow the appropriate local requirements to accurately identify the parts and equipment as out of service. Out-of-service tags or signs should meet local requirements for the environment in which they will be used and should be completed accurately in accordance with local requirements.
The old adage “prior planning prevents poor performance” rings very true in a cGMP environment. The recommendations herein are based on the authors’ experiences in the field, where most were positive and some not so positive. These guidelines have been compiled in an effort to assist with the logistics associated with the performance of cleaning validation activities.
Kevin M. McLaughlin*, firstname.lastname@example.org, is a Senior Consultant at Sequence QCS, 2100 Gateway Boulevard, Morrisville, NC.
*To whom correspondence should be addressed.