EU GMP Annex-1

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Introduction

Annex 1 of the EU GMP is a guideline and set of specific rules describing the European Union’s requirements for the manufacture of sterile medicinal products, including what we refer in the USA as “compounding pharmacies.” EU MP Annex 1 guidelines are applicable to all EU nation states in regards to pharmaceuticals bought, sold and manufactured –  including those imported from non-member nations. The latest revision will be released in 2019, and is expected to have a greater reaching impact on QA/QC and all laboratory activities in the EU and abroad.

So, what exactly is Annex 1 of the EU GMP, and what does it mean for pharmaceutical companies operating in the USA? For the most part, USP regulations in conjunction with 21 CFR 11 dependencies satisfy EU GMP, especially Annex 1, however, it is important to ensure manufacturing processes are not simply performed within standards and regulations, but monitored thoroughly throughout the process as well.

Overview

On 20 December 2017, the European Commission published the long-awaited draft of Annex 1 “Manufacture of Sterile Medicinal Products.” In fact, it was published nearly three years after it was first announced. Many see the change over the previous (technologically outdated) versions as having a focus on Quality Risk Management (QRM)

A key driver for the change, the concept of risk management is hard to miss in the new document:

  • 92 instances of the word “risk” (only mentioned 20 times in previous version) total times mentioned is 600, so “risk” is huge.
  • 15 references to QRM specifically

The 2018 (and presumably 2019) update contains substantial additional detail on virtually every topic in the 2007 version. In addition to those noted above as potential game-changers, compliance personnel can look forward to new levels of detail on such subjects as: Trending of environmental monitoring results (meaning the existence of a dependable chart recorder/data logger of pressure differential, temperature, and relative humidity)

Two key areas of focus should be viable and non-viable environmental and process monitoring and environmental control of pharmaceutical clean rooms as the essential part of the manufacture of a quality product. Simply adhering to standards without documented, digital storage of ongoing process controls is an exercise in futility.

We are somewhat partial since we engineer and develop instruments to monitor environmental conditions in cleanrooms, and for monitoring and logging data of control processes during pharmaceutical manufacturing. However, this partiality comes form countless instances of customers, and manufacturers reporting occasions where they assumed a process control was operating within optimal standards, only to find out later in log reports there was an anomaly which compromised the process. If end-use retail products are being manufactured – there is an acceptable risk for these incursions, and worst case scenario is a product mail fail or operate undesirably. In the case of a pharmaceutical product, it may be a person’s health and wellness which is ultimately compromised.

While there is no specific language to dictate specifics on “annex compliant” negative and positive pressure monitoring, as there is for acceptable micron size in particulate monitoring, it is important to note that the language does reference the requirement to maintain environmental control process monitoring, logging data throughout the manufacturing process.

Compliance

There are many instruments on the market; some specialize in monitoring temperature. others focus on humidity. Some are standalone room air differential pressure monitors. The TV2 Cleanroom Monitor is the only instrument to perform all three actions with specifications which exceed EU GMP requirements, USP 787 requirements and provides data storage for one full year.

We are happy to consult with you regarding your temperature, relative humidity and room pressure monitoring needs – whether you re in the USA or adhering to new EU GMP Annex 1 compliance guidelines. We are here to help.

Here is a PDF of the EU GMP Annex 1

ec_annex1_20dec2017

 

 

 

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JCAHO Standards

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JCAHO temperature standards, JCAHO tissue standards, tissue storage temperatures

JCAHO Standards

The Joint Commission of Accreditation of Healthcare Organizations, issued a new standardized procedures on storing tissue samples. This new standard, PC.17.10 applies to organizations that store or issue tissue, which may include areas outside of the clinical laboratory, for example, surgery and outpatient centers and tissue banks.

Examples of tissue specimens that might be found in an organization include bone, cornea, skin, heart valves/conduits, tendons, fascia, dura, bone marrow, veins, arteries, cartilage, sperm, embryos, eggs, stem cells, cord blood, synthetic tissue (artificially prepared, human and nonhuman based), and other cellular- and tissue-based transplant or implant products.

It says in part that the organization must:
B 6. Maintain continuous temperature monitoring for storage refrigerators and freezers.
C 7. Maintain daily records to show that tissues were stored at the required temperatures.

Note: Main types of tissue storage used are: “ambient” room temperature (for example, freeze-dried bone), refrigerated, frozen (for example, deep freezing colder than –40°C), and liquid nitrogen.
B 8. Storage equipment has functional alarms and emergency back-up.

How to comply?

The easiest way to comply with this standard, without purchasing a commercial laboratory freezer with a built-in monitoring system, is by adding on a standalone temperature system that is capable of monitoring, documenting and alarming.

One such system is the Master Thermometer, manufactured by 2di. It uses a probe to sample temperature every few minutes and draws an electronic chart on its display which complies with provision B6 and C6 of the standard. It also has a built-in relay that triggers an auto dialer or strobe/siren alarm, which complies with B8 of the JCAHO standard. It stores over 1.5 years of temperature history and can be downloaded into a computer to generate a paper copy of the graph or an archived copy. An added benefit of this device is that its chart is constantly being updated and always displayed so that each person in the vicinity of the freezer is always
aware of the temperature.

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Logging temperature

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Data loggers: One way to monitor a freezer or cooler’s temperature

Data loggers are devices that can be used to sample and store temperature and/or humidity at regular intervals. Before data loggers, chart recorders used paper charts to record the information. This was useful but the amount of data they could display was limited and if the user forgot to change the chart mostly useless. The modern data logger stores the temperature history in its computer memory until it can be downloaded to a computer.

Data loggers were originally designed as weather forecasting tools, but were quickly adopted as a much better way to monitor freezers and refrigerators. Keeping stable temperature in a freezer is much more important than most people think. It is especially true when deep frozen food is stored where ten degrees can make the difference between safely stored food and food which can promote bacteria growth. The 10-degree difference in temperature might seem small, but it is crucial for deep frozen products.

Data loggers are absolutely necessary in professional freezers. The standard thermometer inside the freezer shows only the present temperature. Data loggers records temperature fluctuations all the time even when no one is looking.

There is at least one problem with data loggers that limits their usefulness. Although they record temperature history they do not display the temperature history. They must be downloaded to a computer before the history can be viewed.

Fortunately there has been an improvement to the data logger that overcomes this problem:  The TV2,
The Master Thermometer

Unlike other data loggers, The Master Thermometer works all by itself. It has a processor, its own memory and a big LCD screen, it doesn’t need a computer or any other device to display all the data it has stored in memory. Its sensors can be placed up to 300 feet from the display unit, which allows it to monitor and document temperature even in large freezers. As everything is stored in the Master Thermometer’s non volatile internal memory and is displayed on the LCD screen. A temperature chart is drawn on the LCD display so that anyone can immediately tell what has occurred within the last day, week or even month.

For more information please visit Two Dimensional Instruments: http://www.e2di.com/

Information About The Author

Rick Kaestner is the President and CEO of Two Dimensional Instruments; the worldwide leader
in providing technology to monitor, chart, alarm and record temperature and humidity. For
more information please visit their website at www.e2di.com

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How a Refrigerator Maintains its Temperature

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Recently we received a call from a panicked TV2 user. He sent a copy of his temperature history showing a number of alarms. He was convinced that the TV2 was giving false alarms. He also sent, at my request, a copy of his alarm settings. The alarm setting were set so that any time the temperature fell below 2.5° for more than two minutes an alarm was triggered. However he was logging temperature once every 10 minutes. Therefore, the alarms were not always in concert with the logged temperatures.

Although these alarm setting seem reasonable as he wanted to provide the maximum protection for vaccines stored in his refrigerator, it demonstrates a lack of understanding in how a refrigerator actually works.

Most people assume that a refrigerator quickly cools down to its set temperature stays there, steady and constant.  That is not the way a refrigerator works.  It is always warming up and cooling down. It never just sits there at the correct temperature.

When the refrigerator cools down to its set temperature the compressor turns off and waits to come on again until the temperature warms up to some set point. This is exactly like your air condition at home or in the office. The temperature is never just stable. It is always moving up and down.

How quickly a refrigerator, or you home for that matter, it warms up is due to several factors.

  1. How much insulation there is in the walls, roof, floor and door.
  2. How often the door is opened.
  3. Type of door:
    1. Glass
    2. Metal
    3. Wood 
  4. If something warmer than the refrigerator temperature is placed inside.  (This can have a major effect if the object has a large mass).
  5. Where the refrigerator is located:
    1. An office environment
    2. An un-air-conditioned warehouse
    3. Outside
  6. An in-efficient or failing compressor.
  7. Compressor settings.
  8. A poor, bad or failing thermostat.
  9. Poor contacts on a switch.
  10. Poor gaskets allowing air leakage around the door.
  11. Steady power supply.

Once a refrigerator warms up it must cool down again to the thermostat setting. How quickly it cools down is determined by several factors:

  1. The type, size and age of the compressor.
  2. The amount of insulation in the walls, roof, floor and door.
  3. The type of refrigerator door:
    1. Glass
    2. Metal
    3. Wood
  4. How well the refrigerator has been maintained
    1. How clean the refrigerator coils are.
    2. Proper air flow around the compressor and the coils.
  5. How full the refrigerator is.
  6. Where product is located inside the refrigerator.
  7. Whether the fan outlet inside the refrigerator is restricted or not.
  8. The temperature difference between the setting and the outside air temperature.
  9. Where the thermostat sensor is located inside the refrigerator.

In this case the TV2 user was confused because the temperature was moving up and down and a lot of alarms were occurring. In this particular case there was no correspondence between the alarms and the logged data points. This was because he was logging an average of all temperatures over a ten-minute period, but the alarms were set for a two-minute delay. So it was possible for the temperature to drop down below his alarm point for two minutes and then quickly warm up again within the ten-minutes period. However, he would never see the dip in temperature since all temperatures within that ten-minute period were averaged together.

We suggested that he set his log rate for once a minute. That way any momentary dips in temperature will be very visible on his temperature history chart. We also suggested that he put his temperature sensor in a vial of liquid to buffer the temperature swings. This dampens the response time of the TV2 sensor, but it probably gives a more accurate picture of the temperature of the liquids he is storing in his refrigerator.

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Using Dormitory type refrigerators to store vaccines

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An NIST study in 2009 determined that dormitory type refrigerators are completely inadequate for vaccine storage. The study which used 19 data loggers to record temperature in these small refrigerators concluded that: “ From these results, it is clear that the dormitory-style refrigerator can not be relied on to maintain vaccine storage temperatures, regardless of the packing density or storage containers used. The dormitory-style refrigerator’s performance was consistently unacceptable, regardless of vaccine storage location within the refrigerator”.

The study which can be seen in its entirety here proved conclusively that although there were some conditions where they might maintain the proper storage temperature for brief periods of time they were not adequate to store vaccines. Any changes made by clinic personal affecting the vaccine locations inside the refrigerator, placement of temperature recording devices, or the use of water bottles were not effective in protecting vaccines that had to be maintained at between 2°C and 8°C.

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A high temperature data logger

Many industries need to monitor heaters’ or ovens’ temperature over time. Most companies employ high temperature data loggers and/or temperature chart recorders since even small temperature changes, if unnoticed, can cause serious problems. Installing and operating a high temperature data logger (tips) Installation and set-up may require no more than an hour from the moment you take a high temperature data logger out of its box to the
moment it becomes operational. This largely depends on make and model being used. Some data loggers require programming which can require a
great deal of effort especially if you must learn how the software works.

Here are a few things you should keep in mind during the purchase and the installation:

(1) A high temperature data logger will not display the collected information at the site but will need a PC to view the data;
(2) If you chose a temperature chart recorder, you will be able to view the collected information at the site but will have to spend some time changing the chart and pen periodically;
(3) Make sure that you’ve chosen the right kind of sensors. There are different types of sensors for different temperature levels. For high temperature applications a thermocouple is most often used;
(4) Have the sensors calibrated by a calibration;
(5) Remember to set the proper logging rate, which can vary depending on what process you are monitoring. It will make a large difference if you are logging temperature once every 15 seconds as opposed to once an hour;
(6) Most all data loggers store information digitally where as chart recorders record information in an analog format. Temperature chart recorders – use “paper-and-pencil” to record the temperature and their mechanical mechanisms are subject to wear and tear and will eventually fail and require repair or
replacement.

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TV2 Products Warranty

Warranty

The TV2 line of Instruments is warranted by the manufacturer to be free from defects in material and workmanship for a period of twelve months after delivery. In the event of a claim under this warranty, the product or part must be returned to the factory for repair or replacement (shipping prepaid) with a Return Authorization Number. It will be repaired or replaced at the factory’s option without charge to the user. Any freight charges incurred may, at the factory’s option, be passed on to the user.

This warranty does not cover routine calibration or battery replacement. The forgoing warranty and remedy are exclusive and in lieu of all other warranties either expressed or implied.

The manufacturer shall under no circumstances, be liable for consequential or incidental damages resulting from failure or malfunction of its products. The manufacturer makes no warranty for products not manufactured by itself or for any products modified by the buyer or subjected to misuse or neglect.

Rick Kaestner

CEO

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Hygrometers

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Hygrometers are single purpose instruments that measure the amount of water in the air.  They actually measure the relative humidity, which is expressed as a percent of comparing the actual water in the air and the amount of water the air could contain if it was completely saturated. While we can at least try to guess what’s air temperature at the moment even without looking at a thermometer, it is much harder if not impossible to measure humidity without a hygrometer. Keeping a stable humidity level can be just as important as keeping the right temperature. High humidity can damage stored food, medicine, etc… just like high temperature can. The only difference is that without a hygrometer you really have no way of knowing that something’s wrong!

Older mechanical hygrometers show only the present relative humidity.  Some more expensive mechanical hygrometers record the humidity on a piece of paper so that you get an actual printed chart, increasing the hygrometers’ usefulness – chart recorders. But hygrometers alone generally only show the present RH level and, unless we spend all of our time watching the readout, they tell nothing about possible humidity fluctuations. So how do you determine that?  Analog chart recorders or digital data loggers record the RH level over time. They are great improvements over the older mechanical hygrometers.

Newer recording hygrometers can be chart recorders or data loggers. Using chart recorders or data loggers that record humidity you can determine if your stored inventory (i.e. food, medicines, electronic materials) are being stored in the proper environment. And If they have an alarm with them they will alert you if something goes wrong so you can take action.

Example: Consider this situation – your computer room is a subject to frequent humidity changes (due to improper air conditioning, for example). Everything’s all right most of the time but occasionally the humidity sharply rises and falls. If no one is present during these times you will never realize that the environment is changing. This can be a real problem for computers.  Too low humidity can lead to static discharges, and a static discharge can completely destroy a hard drive or microprocessor.

A recording hygrometer such as a chart recorder or data logger will keep a record of what happened but are not able to trigger alarms when a dangerous trend occurs.  For that you need a data viewer such as the TV2, so a text, Email or phone call can alert you if the humidity begins to drop.

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