The patient and monetary impacts of temperature excursions are very real. Temperature excursions outside labeled conditions may put patients at risk from a drug efficacy standpoint, and cost pharmaceutical companies and their supply chains billions. As soon as an excursion occurs, this triggers a waterfall of processes to evaluate the impact and determine whether or not the product has degraded beyond safety and efficacy. Just for vaccine shipment and storage, the World Health Organization (WHO), estimates that vaccines worth $34 Billion are wasted every year due to temperature control issues during transport and storage. As data collection becomes more sophisticated, can companies use Mean Kinetic Temperature (MKT) to save products and potentially billions in waste? ELPRO's Micalyn Harris sat down with pharma expert Patrick Girten of consulting group GDP101 to get his take on this question. In short, the answer is “rarely and only as a last resort.”
What is Mean Kinetic Temperature?
In the US, we look at the guideline USP 1079.2: Mean Kinetic Temperature in the Evaluation of Temperature Excursions during Storage and Transportation of Drug Products. We have to remember, it is just that – a guideline and not a regulation. There have not been new or updated regulations to give manufacturers and logistics companies a strict set of instructions to follow. The important part here is to realize that MKT should not be confused with a strict average, it is instead a weighted average.
According to 1079.2, “MKT integrates the time–temperature history by making assumptions about the kinetics of a product’s chemical degradation. Therefore, MKT takes into account the fact that long temperature excursions at slightly elevated temperatures can be just as, or more, impactful than short temperature excursions at elevated temperatures.” What does this actually mean? MKT is a weighted average, where more emphasis is placed on the temperature and how long the product was at a certain temperature. In the end, MKT calculation results in one temperature based on overall time and temperature data.
Is Mean Kinetic Temperature globally accepted?
Companies have to be careful supplying product to different regions because MKT is not globally accepted. Depending on the region, country, and manufacturer, MKT interpretations vary. Shipping and reliance on MKT can vary from origin to destination. For example,
Health Canada’s position (GUI-0069) says the use of MKT may not be appropriate in cases where:
liquids or suspensions are subject to phase change
products require refrigeration or freezing
products are biologics
data may indicate that temperature excursions have an impact on product quality
Anvisa guidance from 2017 says:
The MKT should be applied only in the cases where the scientific data related to thermal stability of the related product, used to establish the storage cares, allows temperature excursions between 2 5°C and 30 °C.
It is applicable only for products stored at room temperature, with approved storage care from 15 °C to 30 °C.
It is not proper for products requiring storage at low temperatures, such as from 2 °C to 8 °C, for example.
The US’s guidance comes from USP 1079.2 has the most detailed explanation yet allows for the most liberal use.
Who what when why and how?
Why calculate MKT if every excursion has to be evaluated by the manufacturer? In evaluating temperature excursions, MKT does have its place. With that in mind, here are some intra-US best practice recommendations based on United States Pharmacopeia (USP):
CRT (Controlled Room Temperature) and CCT (Controlled Cold Temperature) applications
For CRT, calculate going back 30 days from the high excursion and for the entire period of the excursion.
For CCT, calculate 24 hours from and including the high excursion.
USP points out that a common mistake is using 52 weeks of data in a storage environment. Why? Products don’t spend 52 weeks in the same place, so that is why 30 days is recommended. Additionally, any system (storage or in-transit) that experiences repeated temperature excursions is considered out of control. In this case, MKT cannot be used to justify any excursion because there needs to be a system-wide CAPA in place.
Ultimately, the entire drug supply chain is working towards the same goal – to provide safe, effective medications for the patient. The patient is always number one, and if at any point there is a question of an adulterated product, strict temperature guidelines must be used. For example, saying the space did not maintain X temperature, but MKT did, is unacceptable. Additionally, creative use of MKT in a warehouse application where the temperature of the warehouse is lowered to decrease the average temperature for MKT calculation is quite frankly appalling.
On the horizon is a pre-published note from USP with intent to revise 1079.2. These revisions will include the temperature excursion limits for climatic zone IVb countries (storage conditions between 15°C and 30°C). One important point made in the Stimuli Article, published in advance to give stakeholders time to react and digest, is that “every party involved in the storage and transport of finished product should have an in-depth understanding of the storage and transportation risks and have appropriate mitigation strategies in place to control these risks.” Risk assessments, including shipping lane analysis, should be performed and communicated downstream to supply chain partners.
The Stimuli Article acknowledges that these risk assessments are not always feasible or possible depending on resources, which poses a significant challenge. In reading through the fine print, there is one impactful statement that points out when MKT is appropriate. Consulting with the manufacturer is always the preferred approach, but “this can be challenging depending on data availability and the responsiveness of the drug product manufacturer.” When stability data is not known, or the manufacturer is not responsive, MKT can be a useful tool for the supply chain partner to evaluate the temperature excursion.
MKT or Manufacturer Specifications
Patrick Girten points out that one universal concept in the MKT discussion is that MKT is a special use case and the manufacturer has to specify whether or not MKT can be considered. In other words, manufacturer specifications always prevail, and here is why: it is possible for MKT to deem a product acceptable even though it has experienced a temperature excursion which would result in a degraded/ineffective product. USP goes on to say that every temperature excursion must be evaluated and is up to the manufacturer whether or not MKT is acceptable.
The Bottom Line
When we think about the fallout of temperature excursions and patient impact, drug efficacy is an obvious first. The overall cost of wasted drugs is a huge impact – who pays for it? You and I do. Someone absorbs the shockwave of investigational costs and wasted medication. This falls on the patient as drug costs are driven higher. Back to the original question…can Mean Kinetic Temperature (MKT) be used to save products and potentially billions in waste? To Patrick Girten it depends on your regional guidance and manufacturer responsiveness. Patrick always provides good food for thought. In using MKT, ask yourself if you would be willing to give a drug assessed as acceptable, using a theoretical equation based on some assumptions, to your loved ones.
Author: Micalyn Harris, President & CEO, North America at ELPRO Services, Inc.
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