How often should GMP CTUs be requalified? This is not a simple question to answer. Determining the appropriate requalification interval and testing approach used on GMP Controlled Temperature Units depends on numerous factors.
The first question to address is the need: Do CTUs (Controlled Temperature Units) used to store GMP materials require more than an initial qualification and what guidance does the FDA provide on this?
The Code of Federal Regulations Title 21 §211.68(a) states that: “Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained.” The “shall be routinely…checked…to assure proper performance” part of that statement clarifies that CTUs do require more than an initial qualification and expects that a lifecycle approach is implemented to maintain compliance.
The second question to address is the interval: How often should a CTU such as a freezer or refrigerator be requalified?
The regulation cited above indicates “routinely”, which is intentionally non-specific. Given the diversity of drug manufacturing technology and products, a one-size-fits-all approach would not make sense. To establish a CTU requalification cycle that is effective, the organization must understand its process, the storage requirements of the product, the design and capability of the CTU, and potential risks to the stored product. (Note: use of the term “product” here also includes stored raw materials or other GMP impact items with storage condition requirements). Intervals for requalification are typically established in the timeframe of years, and the number of years that is defined as a suitable interval can be determined based on the factors listed below:
Know the process.
How does this CTU and the storage condition it provides fit into the GMP process for the product being stored?
Know what is or will be stored in the CTU.
What temperature range is indicated for the product? What degree of excursion conditions can be tolerated and for how long? What is the criticality or value of the stored product?
Know the equipment and supporting procedures.
How old is the CTU and what is the expected useful life? How well has it performed over time? Has there been any history or pattern of alarms? Have there been any component failures? What is the preventative maintenance (PM) history? What are the quantity and locations of monitoring sensors?
Know the risk.
All of the above items should be weighed against risk. The cost of a temperature excursion or failure on the product should be considered. Is the storage of this product spread across multiple CTUs to diversify the risk of failure in any single CTU? Assessing risk involves understanding the value of what is stored in each CTU and the potential cost of an adverse event.
Once these factors are evaluated and understood, a requalification cycle for the CTU that aligns with the product requirements and risk can be determined. Keep in mind that the type of CTU can also influence the approach. A warehouse qualification, for example, should have mapping studies performed at the seasonal extremes of summer and winter if it has walls that face the outside and is therefore potentially impacted by weather conditions.
The third question to address is the testing approach: What type of mapping study is indicated?
This should be determined by the most recent prior qualification and an evaluation of the CTU’s performance, as well as the potential risk toward the stored product. The requalification study should repeat the previous qualification mapping with respect to the sensor locations, data collection interval, and study duration to provide the best comparison against previously collected mapping data. For operational chambers, a dynamic or “as-is” mapping study, with stored product present, is typically appropriate. Care should be taken not to disturb the stored product or to cause an excursion while placing or removing mapping sensors.
Overall, consider establishing a minimum standard in your CTU requalification that is supported by good rationale and a schedule that will identify potential issues with the operational performance of your units sooner rather than later. The lifecycle approach that the FDA prescribes, when applied toward GMP CTUs, helps to assure that drug products are safe and effective while also being practical and beneficial from a business perspective.
Additional detail and guidance can be found in industry publications such as ISPE’s Good Practice Guide for Controlled Temperature Chambers.
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Alcami : Jul 25, 2018 2:00:00 PM
