The Secret Life of Stability Samples

From conception to destruction, there are numerous CGMPs governing the life cycle of a sample, with multiple professionals, departments and organizations having a hand in the process. By comparison, manufacturing is a relatively closed, buttoned-down process in contrast to the stages encountered by a typical stability sample. Before individually considering the 4 major aspects of Stability Sample Control: Planning, Storage, Shipping and Tracking, walk through this bizarre real life sample odyssey:

A shipment of clinical trial supplies shipped from East-Coast US to a site in France was placed in a large condition-regulated and tamper-evident sealed container and entrusted to the most reputable company for rapid transit to its destination. The procedures of the company served as the means of tracking; just ask them where it was and when delivery was expected and they would tell you. The expected delivery date was a little late. The company hadn’t explained that the route from New York to Paris ran through Indianapolis. When the shipment arrived and the seal was broken, the container was empty. A surprised home team had to check each other that they hadn’t just dreamed that they boxed up the supplies and sealed them in. The rest of the story: In Paris customs, an inspector needed to check the contents before authorizing the delivery to its final destination. The supplies were removed and inspected and somehow set aside and not returned to the shipping container. A government employee came upon the container and knowing that it could not be shipped without being sealed, dutifully re-sealed it and sent it on its way without noticing that the container was empty. Days later as part of the Shipper’s investigation, the missing cargo was traced to the Customs facility and found on a pallet in a corner, unprotected in any way. If the originating organization had used its own container-specific refrigeration and tracking devices, the mishap could have been pinpointed within hours and corrected. The lesson is that sample control is a complex process best managed with good technology and best practices.

Stability sample planning is born with a proposed study. There is a package and a fill volume or quantity that will travel from the manufacturing process through transportation and storage for eventual testing or destruction.

Active ingredients are generally held in bulk and can be stored in warehouse size bulk containers and sampled over time into smaller protective containers on their way to testing or even pre-packaged more conveniently in smaller containers made of the same packaging material.

Packaged product will likely be in the most convenient quantities for marketing purposes which may be more or less than the number of units planned per test or test series per scheduled test interval. Ultimately, this ratio will figure in to the sample quantities necessary for the entire study. Units needed per test, pre-determined back-up units (testing/investigation) number of test stations, number of test intervals, number of required FDA Retains all contribute to the entire number of samples required.

Stability samples must be representative of the batch they were drawn from. The classic Beginning, Middle and End sampling plan is in compliance with CGMPs, but statistically sound alternatives covering situations like continuous manufacturing can work with the approval of your quality and regulatory authorities.

Labelling of samples can also take various forms. A physical label is convenient for hands-on Stabilitarians, but a bar-code, affixed or etched, or even an RFID chip can be an acceptable label.

The information covered should uniquely identify the product, batch, fill and package employed and condition the sample will be stationed at as part of the study. Some include the anticipated interval for which it will be stored, while others add that after the pull in order to prevent potential errors.

Depending on the protective degree that secondary packaging brings to a product, there should be justification for including or excluding it from the study. The WHO Stability Guidance comes closest to spelling out the criteria for including or excluding a secondary package in a study.

Bulk storage containers used within controlled Stability Chambers or Rooms should be environmentally inert (no porous/absorptive cardboard, it holds water and can even foster paper lice) and have sufficient holes or spaces to allow the free flow of air (Temp & RH). Some miss this principle by putting tight plastic lids on their storage containers. Check with your local fire marshal to confirm that plastic meets requirements in your State, County and municipality. There was a company that needed to replace a large supply of newly purchased plastic bins with wire mesh containers due to an overlooked ordinance. (Find out about these valuable insights by attending an upcoming PSDG Meeting.)

While it’s efficient to have a method of storing specific samples in locations that can be readily located, the natural progression of samples in and out, starting and finishing, keeps the open and available segments on the shelves moving around like a game of “whack a mole”. Some remedy this by “sliding everything down” as spaces open, while others have electronic mapping to pinpoint their targets.

Failing to get or return samples to the assigned environment for their storage period can potentially destroy a stability study, delay an entire project and most likely cost the organization significant resources. Employment has sometimes been terminated as a result of this type of error.

While the latest in electronics make it possible for an alarm to sound if a sample is being placed in the wrong location/environment, many have used color coded labels that match or very obviously contrast with those around them on a shelf to indicate whether a sample is in the right environment.

Undesired changes to the sample environment during storage are a challenge to be documented through a monitoring system, addressed through pre-established procedures and mitigated with validated back-up equipment and / or timely repairs.

Monitoring Systems are a key component of sample storage. Some are part of a building or campus wide system (BAS) that includes the Stability area while others are specific to the Stability area. If not precluded by the pre-existence of a wider system, the local versions can offer a little more autonomy to Stabilitarians and potentially greater flexibility in reports and trending analysis. In any case, a system should be fully validated and have an adequate back-up system/procedure in place should the primary system go off-line for any reason.

A real life example of a highly avoidable monitoring mishap was an occasion when a validation team doing as much Christmas Shutdown work as they could, legitimately and temporarily turned off a Stability Chamber monitoring system to perform their duties and then forgot to turn it back on, which went unnoticed for multiple weeks; weeks for which there was no proof that conditions were in specification. A number of best practices could have prevented this.

It’s a given that no matter how good the equipment and practices are, eventually there will be a deviation in conditions or practices and those deviations can have as many solutions as there are causes. Stabilitarians and their stakeholders should envision as many possibilities as they can imagine and outline what steps can be taken to prevent as well as recover from such eventualities. This exercise becomes the basis for documented procedures to be followed in response to disasters and deviations with an end goal of preserving samples through rapid equipment remediation or relocation to other pre-planned validated controlled environment locations. Start now to create, validate and test the places and practices that will kick in when the (previously) unthinkable happens. The biggest enemy of Stability Disaster Plans are high priced solutions that are under-utilized. Make sure your plans are practical and practice them often. Make sure management knows that these plans are protecting the very future of your organization through the preservation of your samples. News articles on the devastation and losses experienced by other companies who weren’t prepared can be an effective tool in getting management support for your Disaster/Deviation Planning proposals.

Note: This includes any sample transfer, whether in-house or internationally.

The movement of samples from one location to another has the potential to impact the characteristics or shelf life of that sample. Depending on the characteristics of the product, changes in temperature, humidity and light, as well as mechanical actions such as vibrations can be agents that will bring unwelcomed changes to a sample. A snowy ride across a frozen parking lot, especially if multiple stops are made as transportation takes samples around campus to end at a distant laboratory can cause precipitation of liquids; a similar route on a hot-humid day could cause condensation in a cool package of tablets. Turn that distance into globe-crossing endeavors and the types, numbers and degree of challenges increase by the dozens. The goal is to minimize and thoroughly document any challenges to the intended environment of the sample.

Any sample transit activity should be tightly controlled, keeping distance, time and number of handoffs as minimal as possible. Each aspect should be documented with who had custody, where did the sample go throughout the transition, how long it was out of storage, and what conditions did it experience?

Here are some historical examples of Sample transfers that belong in the Stability Believe it or Not archives.

A shipment of samples from Ireland to California was subcontracted to an unauthorized secondary shipper who decided against the scheduled non-stop flight and transferred the product to an 18 wheeled trailer in Las Vegas for a desert crossing. Product samples reached 80 C.

In a facility move in Europe, samples were moved on carts from chambers to waiting trucks, but during a work break, some carts were temporarily placed in a side hallway. These carts never completed the transit and were found weeks later in an investigation for the missing samples. Sad end to many studies.

During the routine transfer of stability samples from chambers to the testing lab across campus, the truck crew decided to zip downhill into town to pick up the company mail. Since they did not secure the rolling carts containing samples and the back doors of the truck were pinned open, guess what happened when the truck returned uphill.

The critical ingredients for successful shipping are physical protection, preservation of temperature (RH & Light limitations if necessary) and documentation, preferably in real time so location and exposure can be trended and evaluated. A number of devices of varying sophistication and expense are available to place in sample shipments. For regulatory purposes, all such devices should be validated and/or NIST traceable. Being able to see these devices prior to purchase and hearing from industry peers about their experience with them is invaluable in making a selection. PSDG Meetings are the perfect platform for gleaning such information.

An overarching element of sample control is tracking; knowing what, when, where, why, who, and how, apply to every sample in every phase throughout its existence. Therefore, tracking devices and procedures are a must in our operations. Tracking devices are more appropriate for longer transits apart from in-house hands-on transfers, but awareness of exposure to temperature dips and blasts is still important regardless of length of trip and should be noted in transfer records along with where a sample was moved from, where it went to, reason for transfer and who handed it to who (or where it was left for pick-up). For accountability purposes, so important to the demonstration of control to regulatory authorities, an accurate inventory of a sample group must be maintained from creation of the first sample to the consumption or destruction of the last, and real-time tracking methods are a superior means of accomplishing this.

Bar code readers/RFID technology can automate much of the sample transfer process in conjunction with a digitalized tracking system. Likewise, a variety of equipment and technology can record or broadcast live the location and environment of samples in shipping lanes and sound the alarm if specifications are exceeded. Depending on our level of resources and potential risk, we can match efforts to the need at hand.

To use a recently popular term; Stability Samples are existential elements of our organization, right up there with the proverbial analogy- “For want of a nail, a shoe was lost…” These small packets of proof that our products are stable for specific amounts of time when stored under specific conditions are the means of not only saving lives but keeping our companies successful and we Stabilitarians employed. We must do everything possible to ensure their integrity.