Blinded by the light - are you looking after your medicines properly
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When a veterinary medicine is administered to an animal, it should be as safe and efficacious as when first manufactured, and should usually look the same. Maintaining the quality of a medicine depends in part on how it is stored in the practice. This module is designed to help practising vets understand more about the stability of medicines, the reasons for, and meaning of, storage and handling recommendations in product literature, and how to interpret these in practice.
By doing this module, you will learn about:
the legislation on expiry dates of medicines
where to find information on storage recommendations
stability including light-sensitivity
the difference between single-use and multi-use presentations in terms of stability and shelf life
how to store medicines in the veterinary practice, and when out and about
stability issues around using or storing medicines outside the terms of the licence
using fridges and proper temperature monitoring
The expiry date
All veterinary medicines are labelled with an expiry date. This is the date before which the batch of medicine is expected to remain ‘fit for purpose’ (if stored under the conditions as defined on the label). The UK Veterinary Medicines Regulations (VMRs) require that the expiry date is displayed on all packaging (immediate and outer), even on very small containers such as blister strips or ampoules. The expiry date is usually expressed as EXP month/year, which means that the product may be used up to the last day of that month. The VMRs state that: “No person may supply a veterinary medicinal product that has passed its expiry date”. (UK Government 2013) In other words, it is an offence to supply a veterinary medicine that has passed its expiry date. Checking the expiry date at the point of dispensing or administration is essential. Also there should be system in the practice for checking stock regularly to ensure that any out-of-date medicines are removed and disposed of.
Special storage requirements
Some veterinary medicines might need to be stored and used in a particular way to ensure that their quality is maintained. The VMRs require that information on special storage conditions is displayed on the packaging and in the package leaflet. However, if the immediate pack is very small, and there is not enough room on the label, the storage precautions may be displayed on the outer carton and package leaflet only. (UK Government 2013) The absence of storage conditions on a package leaflet or outer carton means that there are no special storage requirements for maintaining the quality of the medicine.
Sometimes a label on an immediate container might state “Keep the container in the outer carton”. This is usually because it has not been possible to include all the instructions for safe and effective use on the immediate label. In such cases, it is important to keep the medicine in the outer carton, with the package leaflet that provides the full information. If storage in the outer carton is required to protect the medicine from light, it will usually state this as the reason. In general, it is always good practice to store containers in outer cartons when instructed to do so.
Information on shelf life and special storage conditions are also detailed in the Summary of Product Characteristics (SPC), a copy of which is publicly available for all UK authorised products in the Veterinary Medicines Directorate’s Product Information Database. The NOAH Compendium of ‘datasheets’, contains information from the SPCs for most authorised veterinary medicines; storage information will usually be under “Pharmaceutical precautions” in the product monograph.
Medicines can degrade through chemical, physical or microbiological effects. A stable medicine is one that has minimal changes, either chemical, physical or microbiological.
Chemical instability of a medicine usually means reduced potency because of a decrease in the content of the drug substance and an increase in unwanted degradation products. The presence of degradation products is undesirable either because their safety is not known, or because they have known adverse effects.
The rate of degradation depends on the inherent stability of the drug substance. Potential degradation pathways are evaluated during the development of a medicine. The most usual causes of chemical instability are:
hydrolysis (the breaking of chemical bonds because of a reaction with water)
then oxidation (a reaction involving a loss of electrons that is promoted by the presence of oxygen), and
then photolysis (the breaking of chemical bonds by the transfer of light energy).
As a general rule, low molecular weight drugs (small molecules) tend to be more stable than large molecular weight drugs (e.g. insulin, monoclonal antibodies, some antibiotics), and solid formulations tend to be more stable than aqueous formulations. Even if a drug substance is quite unstable, it may still be possible to select a formulation type or use excipients (inactive ingredients) to enable a medicine with a suitable shelf life to be developed. For example:
drugs susceptible to hydrolysis may be formulated as non-aqueous oily suspensions or presented as powders to be reconstituted with water just before use.
drugs susceptible to oxidation may be formulated with excipients with antioxidant properties or, if the presentation is a sealed system such as an injection vial, the air headspace may be replaced with an inert gas.
The rate of degradation also depends on environmental conditions. High temperatures, humidity and light tend to speed up chemical reactions. The likelihood of expsoure of the product to high temperatures can be reduced by applying temperature storage requirements. Exposure to humidity and light can be prevented by selecting appropriate packaging materials.
The potential for the dosage form to change physically is no less important than its chemical stability. Some changes may be cosmetic, but many can affect the performance and efficacy of the medicine. Physical changes include:
changes in colour
separation of phases in a liquid system
softening of tablets, so that they can no longer be divided equally
hardening of tablets, so that the rate of release of the drug substance (which is a necessary pre-requisite to absorption) is affected.
All veterinary medicines should be of acceptable microbiological quality to ensure the safety of the treated animal and because micro-organisms may reduce the therapeutic activity of the drug substance. Even non-sterile medicines must have a low bioburden of micro-organisms and be free of certain pathogenic strains (the actual limits for each formulation type are defined in the European Pharmacopoeia). (EDQM 2019) These microbiological requirements must be maintained over the shelf life of the medicine. Because microbial spoilage may occur with time and during use, products may be formulated with antimicrobial preservatives.
Every veterinary medicine has a quality (shelf-life) specification, which is approved by the regulatory authority as part of the authorisation of that medicine (VICH 2007). The specification is a list of tests, references to analytical procedures and acceptance criteria to ensure appropriate quality. Essentially, the shelf-life specification provides confirmation that the product:
has a consistent appearance
is what it says it is
contains the right amount of drug
does not contain anything that should not be there (within specified limits)
and performs how it should, for example, includes test(s) to show that:
tablets release the drug into solution sufficiently quickly, or
tablets can be readily divisible into equal parts, or
a suspension can be readily and uniformly resuspended.
Pharmaceutical companies must carry out standardised stability studies to provide the evidence that the product will always meet the quality criteria. (VICH 2019) Stability studies are done to find out how the quality of a veterinary medicine might change with time and under different environmental conditions. Preliminary studies help companies decide on the most appropriate formulation and packaging materials. Confirmatory studies allow them to establish a shelf life for the medicine (used to calculate the expiry date), and to determine whether there are any special storage requirements. These studies are an important part of the dossier that must be submitted to the regulatory authority before a veterinary medicine can be granted a marketing authorisation. The standardisation of stability studies means that data generated on a limited number of batches can be used to predict the shelf life of any other batch manufactured and packaged in the same way. Nevertheless, companies are obliged to conduct an annual stability programme (on at least one batch per year), and report any out-of-specification results to the regulatory authority. If such a result occurs, it could lead to product recalls or a variation to reduce shelf life. However, a one-off result could be an anomaly, so the regulatory authority would wait until the next time point to see whether this was the case before making any changes.
Stability studies to determine shelf life are done under defined temperature and humidity conditions. (VICH 2007) The exact conditions depend on the region of the world in which the company wishes to market the product. In Europe, to market a product intended to be stored at room temperature, the company must carry out studies that last as long as the intended shelf life at 25°C and at a relative humidity of 60%. (VICH 2007) The temperature of 25°C has been calculated as the mean kinetic temperature for Europe, allowing for the fact that the actual climatic temperature in this region may fluctuate above and below this value. Over a period of a year or more, a stability sample stored continuously at 25°C will receive the same thermal stress as a medicine stored under normal ambient temperatures, even in Mediterranean countries of Europe. The relative humidity is based on a similar calculation.
In addition, shorter-term studies must be done under higher temperature and higher humidity conditions (typically 40°C and 75% relative humidity for 6 months, or 30°C and 65% relative humidity for 12 months). (VICH 2007) These exaggerated or ‘accelerated’ storage conditions are intended to identify whether there might be any untoward effects because of a more prolonged excursion outside normal climatic conditions, such as what might be encountered during, for example, transportation.
At regular, pre-defined intervals the veterinary medicine in its final package is sampled and tested against the shelf-life specification. The objective is to find out whether the parameters that might affect the efficacy, safety and performance of the product are compromised on storage, and whether the product complies with the specification limits. (VICH 2007)
For medicines that show little change, the conclusion is that the product in its pack is satisfactorily stable, and there will be no need to include any special temperature or moisture storage requirements on the label.
If the medicine is stable at the long-term condition, but unstable at one or more of the accelerated conditions, this indicates that a temperature storage precaution is needed. In such cases, the label on the medicine will include, either “Do not store above 25°C” or “Do not store above 30°C”, depending on the actual data.
If the data suggest that the medicine is sensitive to humidity, it may be possible to improve the stability by using a more moisture impermeable pack, for example, a glass instead of a plastic bottle. Alternatively, it may be sufficient to include a warning such as “Keep the container tightly closed”.
If the medicine is unstable under all conditions, including long-term, it may be appropriate to reduce the intended shelf life or consider storing it in a fridge. In such cases, separate studies would be conducted to confirm suitable stability under refrigerated conditions. However, it should be noted that, although low temperatures usually improve chemical stability, they can affect physical stability. Therefore, it may be necessary to conduct freeze-thaw studies (in which the product is exposed to repeated cycles of freezing and thawing). This is to identify any risk that the container might break on freezing, or that there might by precipitation or denaturation of any of the ingredients as the temperature decreases. In such cases, the label may include a statement of “Do not refrigerate” or “Do not freeze”.
Studies are conducted on the medicine in its immediate package, according to standardised test conditions. (VICH 1999) These are done to show that exposure to light (using a light source combining artificial indoor and outdoor daylight, and near UV light– 320 to 400 nm) during storage will not result in any unacceptable change. (VICH 1999) If a change does occur, it may be possible to modify the container to provide better light protection (e.g. using an amber-coloured vial) or to show that the outer carton provides appropriate protection. In such cases, an instruction to “Keep the container in the outer carton in order to protect from light” may be applied. (VICH 1999)
The statements “Protect from light” or “Protect from direct sunlight” are usually used for larger volume medicines that are likely to be stored on farms, and where the medicine (as packaged) needs to be protected from light or direct sunlight.
Examples of medicines needing to be protected from light
Metronidazole solution for infusion: There is no authorised metronidazole product for injection in animals. However, metronidazole intravenous infusion authorised for humans is sometimes used in animals under the Prescribing Cascade. Metronidazole 5 mg/mL is available as a ready-to-use solution in 100-mL (500-mg) single-dose plastic bags. Prolonged exposure to light will cause a darkening of the product. (Trissell 2018) In keeping with this, the SPC (section 6.6) states “Keep container in the outer carton in order to protect from light.” (Metronidazole 500mg/100mL infusion) Individual bags should not be delivered to the practice uncovered; they should be placed inside a dark place (e.g. a box). There is no need to cover the undiluted solution during an infusion lasting up to 60 minutes.
Metoclopramide solution for injection: Metoclopramide is available as a solution for injection (containing metoclopramide hydrochloride 5mg/mL: three brands are authorised for use in animals: Emeprid; Metomotyl; Vomend) Metoclopramide hydrochloride is photosensitive and protection from light during storage is recommended. (Trissell 2018) The SPC for Metomotyl says “Keep the vial in the outer carton in order to protect from light.” and that for Vomend states “Store in the original carton”. However the SPC for Emeprid states “does not require any special precautions”. The reason for this inconsistency is not clear. All three products are in amber vials, which helps to protect them from light. But it would seem to be reasonable to keep all three in their outer containers until use. Metoclopramide is sometimes given as an infusion over 24 hours. (Ramsay 2017) Administration by infusion is not mentioned in the SPCs and so is an unauthorised use of these products. It is interesting to note that one of the SPCs for a human brand of metoclopramide (although not authorised for use by infusion in humans or animals) includes the following information “Any dilutions of metoclopramide 5 mg/mL Injection should be protected from light during infusion. Degradation is indicated by a yellow discoloration. Such solution must not be used.” (Metoclopramide 5mg/mL Injection 2016)
Several veterinary medicines are presented as multidose products. Although such products will have an expiry date for the unopened container, the labelling may indicate that the product should not be used xx days, weeks or months after first opening or broaching. This applies to all parenteral and ophthalmic preparations, and other medicines for which there might be a risk of microbiological proliferation, or physical or chemical degradation after the container is first opened.
Studies are done to establish how long a multidose medicine may be used for, after opening, while remaining of acceptable quality. These studies are designed, as far as possible, to simulate the use of the product in practice.
Medicines for parenteral or ophthalmic administration are always manufactured to be sterile (which means the complete absence of living organisms) and must remain sterile until first use. However, sterility can no longer be guaranteed once the immediate package is broached. If the product is for multidose use, either it will contain an antimicrobial preservative or the formulation will itself be self-preserving. The in-use study will test the efficacy of the antimicrobial preservative system to bacterial and fungal challenge. This is to simulate the microbial contamination that might occur in practice.
Sterile multidose veterinary medicines usually have a 28-day in-use shelf life. This is because the EU guidelines indicate that, from a microbiological point of view, the in-use shelf life should not normally exceed 28 days for aqueous preserved sterile products and non-aqueous sterile products unless a more rigorous test for preservative efficacy (repeat microbial challenge) has been conducted and shown to be successful. (EMEA 2001; EMEA 2002) Note that different brands of the same drug might have different in-use shelf lives. See the panel below for examples of in-use shelf-lives.
Examples of in-use shelf-lives
Vetmedin (pimobendan) solution for injection: Shelf life after first opening the immediate packaging: use immediately.
Cerenia (maropitant) solution for injection: Shelf life after first opening the immediate packaging: 28 days.
Zycortal (desoxycortone pivalate) suspension for injection: Shelf life after first opening the immediate packaging: 120 days.
Medetomidine solution for injection. Different brands of this drug have different in-use shelf lives: for example 28 days for Dorbene Vet, Medetor, Sedastart and Sedator, but 3 months for Domitor.
After breaching a sterile multidose product, the use-by date must be written on the label to ensure it is not used beyond the in-use expiry date. Also, the Veterinary Medicines Regulations state that: “No person may administer a veterinary medicinal product to an animal unless…the product has a marketing authorisation authorising its administration in the United Kingdom, and the administration is in accordance with that marketing authorisation”. (VMD 2013) So, if a product’s SPC (which is part of the marketing authorisation) states: “Following withdrawal of the first dose, use the product within 28 days”, it follows that use after this date would be an offence.
Some products are more susceptible to bacterial growth, but are formulated with a sufficient level of antimicrobial preservative so that they meet the European Pharmacopoeia test for antimicrobial preservation. Some products, because of their composition, are self-preserving so do not need any added preservative, but must still pass the test for antimicrobial preservation. The studies that companies conduct must simulate the use of the product in practice, usually the worst-case scenario, so that there is confidence that a 28-day in-use shelf life is appropriate under all usage patterns.
Also, for each multi-dose container, the maximum number of likely withdrawals is identified. The marketing authorisation holder then simulates this and shows that the stopper meets the standard requirements (i.e. there is no shedding of bits and the stopper reseals to prevent ingress under applied pressure). Sometimes, there might be a warning about how often the stopper can be punctured. For example, the SPC for Metomotyl (metoclopramide) states: “ The stopper should not be punctured more than 20 times .” This is because of the risks of stopper fragmentation and lack of self-sealing.
Some medicines are ready-to-use, whereas others need some manipulation (e.g. reconstitution, dilution) before use. If the medicine is being used exactly as described on the label or package leaflet, appropriate studies will have been conducted to support administration in this way. For example, if the product is a solution for use in drinking water (or milk) to be administered over several hours, data will have been provided to show that the medicine, diluted as directed, will be sufficiently stable at normal temperature and in ambient light for this length of time. Similarly, if the label or package leaflet describes that an injectable medicine may be administered by infusion, information will be provided in the leaflet about which infusion fluids are compatible with the medicine. In all cases, a statement on the label or package leaflet will indicate the maximum shelf life for the diluted product, and whether any special precautions need to be observed during administration. In contrast, if the manipulation of the medicine is ‘off-label’ (e.g. dilution in a fluid not listed as compatible in the SPC), there will be no data to assure the stability of the product and the vet must take responsibility for its administration in this way.
Medicines need to be stored in accordance with the recommendations on the label or package leaflet. This means that a veterinary practice must have facilities to store and (if necessary) transport medicines under ambient conditions (bearing in mind that some may need to be stored at a temperature not exceeding 25°C), under refrigerated conditions and, if appropriate, in a freezer.
The temperatures of all areas where medicines are stored should be monitored and recorded. Weekly recording is normally appropriate for ambient temperature storage areas but this frequency should be reviewed as necessary, for example, during extreme weather.
Suitable fridges can be purchased in a variety of sizes. A domestic fridge may be used, as long as it is dedicated to medicine storage only and temperature records show that it is capable of maintaining the temperature consistently and reliably between 2°C and 8°C.
Digital max/min thermometers or dataloggers are recommended for fridges and freezers. These should be placed appropriately (that is, not in the door or against the back cooling plate) so that the readings show the actual temperature of the medicines.
For max/min thermometers, it is recommended that the probe is put into a buffer (or thermal brake). (Mosedale 2018) This helps to reduce the incidence of temperature spikes when the fridge door is opened. The maximum and minimum temperatures should be recorded once a day and the max/min readings re-set. This will give complete temperature coverage since the last reset. A separate max/min thermometer is needed for fridges with temperature monitoring, unless the in-built thermometer records max/min temperatures and can be reset daily (rather than just giving a readout of the current temperature). It is not sufficient just to record the temperature displayed once or twice a day.
Dataloggers are becoming more popular. They provide more readings and show the time and duration of any temperature excursions. However, they still need to be checked daily, and the readings downloaded weekly and reviewed.
In all cases, any anomalous readings should be investigated and the reasons and corrective actions should be recorded. If temperatures are going higher or lower than the acceptable range, the veterinary practice should carry out a risk assessment to be assured that the medicines affected are still safe to use. This would include considering the duration of the temperature excursion and may involve contacting the Marketing Authorisation holder(s) of the affected product(s) for advice. The actions and decisions should be documented.
If medicines are carried in a vehicle, they should be transported at the correct storage temperature. This may mean using an in-car fridge or insulated cool box. Care should also be taken when transporting ambient temperature medicines if there is a risk that the temperature range specified on the label is likely to be exceeded.
Storage of medicines and compliance with these requirements are inspected as part of the VMD’s inspections of veterinary practice premises or the Royal College of Veterinary Surgeons (RCVS) assessment of those practices registered in the RCVS Practice Standards Scheme, to ensure that all veterinary practices comply with the VMRs.
For further reading, the BSAVA guide to storage of veterinary medicines is a useful source of information. (BSAVA 2019)
Clients should be told about any special storage requirements when the medicine is supplied. This is especially important if medicines are not supplied in their original containers. A requirement of the Veterinary Medicines Regulations when supplying a veterinary medicine (other than AVM-GSL medicines) is to “advise on its safe administration and on any warnings or contraindications on the label or package leaflet”. (UK Gov 2013) For example, clients receiving fridge items should be reminded that the medicine must be placed in a fridge as soon as possible.
Information about how to store authorised medicines and any special precautions related to authorised uses is in the product’s SPC, as well as on the packaging and in the package leaflet. In specific instances when it is necessary to use a product in an unauthorised way, it is worth contacting the marketing authorisation holder’s technical information department because the company may have relevant stability data. Veterinary specials are unauthorised products and so they will not have an associated SPC. Nevertheless the specials manufacturer should provide storage information. Often such products will have a short shelf life.
Complying with expiry dates, in-use shelf lives and storage conditions is important to ensure that a medicine remains of a suitable quality over the duration of its shelf life. Moreover, complying with expiry dates is a legal obligation for veterinary professionals. Information on the appropriate storage and use of an authorised veterinary medicine can be found on the packaging, in the package leaflet, and in the Summary of Product Characteristics. Clients should also be told about any special storage requirements for a medicine when a medicine is supplied.
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How we produced this module
Our modules start with a detailed outline and electronic literature search. We commission a collaborating author, who is a specialist in the module topic, to write a draft module. The collaborating author on this module was Gill Clarke MRPharmS, Veterinary Medicines Directorate. The draft was circulated unsigned to topic specialists, practising first-opinion vets and pharmaceutical companies. There is a rigorous editing and checking process and the result is a module that is evidence-based, impartial and relevant to clinical practice. The final module is unsigned because it is the result of collaboration.
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EMEA (2001) Maximum shelf-life for sterile medicinal products after first opening or following reconstitution, EMEA/CVMP/198/99 [online]. Available: https://www.ema.europa.eu/en/maximum-shelf-life-sterile-medicinal-products-after-first-opening-following-reconstitution[Accessed: 9 June 2019]
EMEA (2002) Note for Guidance: In-use stability testing of veterinary medicinal products (EMEA/CVMP/424/01) [online]. Available: https://www.ema.europa.eu/en/use-stability-testing-veterinary-medicinal-products-excluding-immunological-veterinary-medicinal [Accessed: 9 June 2019]
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Mosedale P. (2018) Preparing for the Practice Standards Scheme medicines assessment part 1. In Practice 40: 210–3
Trissell L. (2018) Handbook on injectable drugs. 20th ed. American Society of Health-System Pharmacists.
UK Government (2013) The Veterinary Medicines Regulations 2013 (S.I. 2013/2033) [online]. Available: http://www.legislation.gov.uk/uksi/2013/2033/contents/made [Accessed 9 June 2019]
Veterinary Medicines Directorate (2013) The Veterinary Medicines Regulations [online]. Available: http://www.legislation.gov.uk/uksi/2013/2033/regulation/8/made[Accessed 15 July 2019]
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Veterinary Prescriber (2019) Good Veterinary Dispensing Practice [online]. Available: https://www.veterinaryprescriber.org/subscribers-content/good-veterinary-dispensing-practise[Accessed 15 July 2019]
VICH (2019) International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products [online]. Available: https://www.vichsec.org/ [Accessed 9 June 2019]
VICH (2007) Guideline on stability: Stability testing of new veterinary drug substances and medicinal products. VICH GL3 [online]. Available: https://www.ema.europa.eu/en/documents/scientific-guideline/vich-gl3-stability-testing-new-veterinary-drug-substances-medicinal-products-revision-step-9_en.pdf [Accessed 20 June 2019]
VICH (1999) Stability testing: Photostability testing of new veterinary drug substances and medicinal products, VICH GL5 [online]. Available: https://www.ema.europa.eu/en/vich-gl5-stability-testing-photostability-testing-new-veterinary-drug-substances-medicinal-products [Accessed 9 June 2019]