tangent
05-01-03, 05:11
early version of a paper I wrote - have to find the finished version.
antibio's last much longer than labled.
-t
--
Pharmaceutical Considerations in the Pre-Hospital Care Environment
------------------------------------------------------------------------------------
Abstract: the efficacy of emergency drugs can be significantly effected by storage
Conditions, specifically, temperature, relative humidity and packaging. The situations
In which the medications are to be transported and used can also be an issue. The normal pre-hospital environment can introduce stresses that are detrimental to pharmaceutical viability.
Environmental Considerations and their effect on pharmaceutical stability.
Medications are negatively effected by temperature fluctuations and humidity. There are 3 major temperature categories that pharmaceuticals are supposed to be stored under. These are:
cold = 2-8C (35.6-46.4F)
cool = 8-15C (46.4-59.0F)
room temperature = 15-30C (59.0-86.0F)
warm = 30-40C (86.0-104.0F)
excessive heat = >40C (>104.0F)
In practice, drugs are never labeled for storage above room temperature and most have warnings about exposure to temperatures above 40C. The pre-hospital environment is often not within these boundries. A number of studies have found temperatures of drugs in storage (Dr. bags and ambulance drug boxes) as well as during shipping in Australia, Arizona and Florida to massively exceed the recommended storage temperatures. Temperatures as high as 60 - 82C (140- 180F) were reported. This is significant for several reasons:
a) Some drugs can loose up to 20% potency after exposure to such temperatures for as little as 24 hours, with potential theraputic failure as a result.
b) Expiration dates and a pharmaceutical companies legal liability end as soon as a drug is taken outside it’s recommended storage conditions.
c) The expiration date stops being a meaningful indicator of if the drug should be restocked.
d) In general, the rate of degradation doubles for every 10C raise in temperature.
The following describes, briefly, the effects of temperature and humidity as well as simple visual tests to determine if pharmaceuticals have degraded. By dosage form:
Capsules are sensitive to temperature and humidity. If it is too dry or hot, they will crack, become discolored, dark or loose their “sheen”. If it is too moist, they can become soft, swollen and stick to each other. Both extremes can lead to microbial growth and alter dissoltion and bioavailability characteristics.
Tablets should be inspected for swelling, discoloration, fusion of tablets and the appearance of crystals on the tablets or the inside of the container. If the tablets are mottled (have spots), this indicates bacterial growth. Cracks in the coating of tablets should also be a reason to discard them. If a tablet is simply discolored (generally faded), this may simply be esthetic and a detailed reference should be consulted to determine if the drug is viable.
Parental Solutions are primarily vulnerable to bacterial growth. To test, hold the bag or bottle up at eye level and swirl, take a flashlight and shine it through at a right angle. This is best done against a dark, solid background. If there is any visible particulate matter, the solution should not be used.
Solutions and suspensions in ampules and vials are vulnerable through multiple pathways. Ampules, being thinner glass, are more likely to break due to freezing and rough handling. Multi-dose vials are vulnerable to thermal expansion and contraction along their seals allowing microbial comperamise The rubber membrane is also vulnerable to heat and in time will break down. Some drugs are exceptionally vulnerable to oxygen, epinephrine is a prime example. Each use from a multi-dose vial of epinephrine will introduce oxygen and speed degradation. Drugs in dark glass are light sensitive, and generally also very temperature sensitive. Solutions with a solute dissolved in them can precipitate out, generally if exposed to cold. Most can still be used, but there are exceptions. Gradual re-warming and agitation can often bring the solute back into solution but rapid heating can harm many solutions and should be avoided.
Solutions and suspensions for oral administration
Bottled powders for reconstitution are generally very stable in their pure form, but very unstable and short lived once reconstituted.
Transdermal patches do not work well when exposed to high temperatures.
Suppositories melt at high temperatures.
Creams and ointments can break down in multiple ways. Phase separations are a separation of the components into layers. They can become dry and cake like as well as become quite liquid. This most commonly happens with either repeated freeze thaw cycles or exposure to high temperatures.
1) On shelf life and expiration dating.
Set by legal, marketing, economic and regulatory considerations. Expiration dates are cloaked in an aura of scientific authority, being based on stability testing. There are two problems with this. First, the ability to accurately predict or test the shelf lives of different dosage forms varies by dosage form. Parental solutions are fairly accurate. Testing of tablets, emulsions and related material produce results that are rarely accurate. Second, Regulatory mandates force companies to take raw test data, combine it with theoretical predictions and pass this data through some statistical equasions. The result, void of scientific reality, is used to justify the shelf life. It does not determine the shelf life, but rather gives an upper limit to the self life they can request. Shelf lives are never given for over 5 years, despite that many drugs are viable for 7, 10, 15 or even 20 years. That is within Pharmacopedia limits. In the US this is >90% (or >95% in the UK) of the labeled content. Yet drugs tend to be effective over a wide theraputic range. They are usually given in overage as the needed amount is rounded up to the most convienient dosage size. An exception to this is those drugs with a narrow theraputic index.
Legal considerations are another issue. Pharmaceutical companies do not like to see their names mentioned negativly in the news, nor do they like lawsuits. As a result, the expiration date will always be at least a year or two less than the actual shelf life (if stored correctly). As mentioned, many drugs last much longer, but the 5 year cap on dates prevents identification of the really stable ones by expiration date. At least based on US data.
Specific Drugs:
Albuterol and albuterol sulfate inhalers should be stored at 15-30C and 15-25C, respectively. Use of the inhalers at temperatures below 15C results in droplet sizes too large to be therapeutically effective and in delivered dosages that are substandard due to propellant pressure. At 0C albuterol inhalers deliver a pressure that is on average 28% below normal. (AHFS) The reverse is presumably true for use above 30C. Inhalers can burst at temperatures exceeding 49C (120F).
Aspirin is one of the only drugs that gives a distinct odor when it’s degraded. If it smells like acetic acid (vinegar) than it should not be used. It is generally very stable and will remain viable for years after expiration.
Diazepam –
Epinephrine -
Nitroglycerine once opened, will evaporate fairly quickly, leaving a tablet that looks the same but that contains no medicine. In storage, it has a tendency to migrate from tablet to tablet, resulting in uneven doses being delivered. Nitroglycerine inhalers have become popular in the pre-hospital environment as they do not have the same stability problems as the tablets. As with albuterol inhalers, temperature induced variance of delivered dose should be taken into consideration.
Oxytocin is highly vulnerable to temperature and light. If there is any discoloration of the solution, it has undergone degradation and will be sub-potent. Theraputic failure of this drug to control post-partum bleeding is frequently cited as a cause of maternal death in hot climates.
Syrup of Ipecac used post expiration is still viable, however onset of emesis will likely be delayed between 15 and 45 minutes beyond normal.
Tetracycline while not generally a pre-hospital emergency drug, is the one that everyone has been taught, and are still taught, that it becomes dangerous after expiration. This is no longer the case. To quote the AHFS Drug Information 2001 handbook, p 441: “Administration of outdated or deteriorated tetracyclines has caused a reversible Fanconi-like syndrome […] In most cases the outdated tetracycline preparation administered contained citric acid (an excipient no longer used in tetracycline preparations) which accelerated deterioration of the antibiotic during storage. Therefore, this reaction is unlikely with currently available tetracycline preparations. “ (AHFS)
Alldredge, BK, Stability of Diazepam Rectal Gel in Ambulance-Like environments, Am J Emerg Med 2002;20:88-91
Church, WH, HU, SS, Henry, AJ, Thermal Degradation of Injectable Epinephrine, Am J Emerg Med 1994;12:306-309
Gottwald, MD, Akers, LC, et al, Prehospital Stability of Diazepam and Lorazepam, Am J Emerg Med. 17(4):333-7, 1999 Jul.
Newton DW., Overheating of drugs during shipping and storage, South Med J 1995 Jun;88(6):694-5
Rudland SV, Jacobs AG, Visiting Bags: a Labile Thermal Environment, BMJ, 308(6934):954-956, Apr 9, 1994
Rudland SV, Annus T, Dickinson J, Langdon S., Adrenaline degradation in general practice, Br J Gen Pract 1997 Dec;47(425):827-8
Strauss, A., Altered Responses to Medications Exposed to Excessive Temperatures During Shipping, Southern Medical Journal, vol 88, No. 6, p696-7
Treloar A., Are the drugs in your bag effective?, Practitioner 1989 Nov 8;233(1478):1435-6
unknown, Stability of Drugs in Solution, Med Lett Drug Ther, 1996 Sep 27, 38(984):90
unknown, Particulate matter in parental solutions, Med Lett Drugs Ther 1968 May 31;10(11):42-4
Valenzuela, TD, Chriss, EA, Hammargren, WM, et al., Thermal Stability of Prehospital Medications, Ann Emerg Med. 18(2):173-6, 1989 Feb.
antibio's last much longer than labled.
-t
--
Pharmaceutical Considerations in the Pre-Hospital Care Environment
------------------------------------------------------------------------------------
Abstract: the efficacy of emergency drugs can be significantly effected by storage
Conditions, specifically, temperature, relative humidity and packaging. The situations
In which the medications are to be transported and used can also be an issue. The normal pre-hospital environment can introduce stresses that are detrimental to pharmaceutical viability.
Environmental Considerations and their effect on pharmaceutical stability.
Medications are negatively effected by temperature fluctuations and humidity. There are 3 major temperature categories that pharmaceuticals are supposed to be stored under. These are:
cold = 2-8C (35.6-46.4F)
cool = 8-15C (46.4-59.0F)
room temperature = 15-30C (59.0-86.0F)
warm = 30-40C (86.0-104.0F)
excessive heat = >40C (>104.0F)
In practice, drugs are never labeled for storage above room temperature and most have warnings about exposure to temperatures above 40C. The pre-hospital environment is often not within these boundries. A number of studies have found temperatures of drugs in storage (Dr. bags and ambulance drug boxes) as well as during shipping in Australia, Arizona and Florida to massively exceed the recommended storage temperatures. Temperatures as high as 60 - 82C (140- 180F) were reported. This is significant for several reasons:
a) Some drugs can loose up to 20% potency after exposure to such temperatures for as little as 24 hours, with potential theraputic failure as a result.
b) Expiration dates and a pharmaceutical companies legal liability end as soon as a drug is taken outside it’s recommended storage conditions.
c) The expiration date stops being a meaningful indicator of if the drug should be restocked.
d) In general, the rate of degradation doubles for every 10C raise in temperature.
The following describes, briefly, the effects of temperature and humidity as well as simple visual tests to determine if pharmaceuticals have degraded. By dosage form:
Capsules are sensitive to temperature and humidity. If it is too dry or hot, they will crack, become discolored, dark or loose their “sheen”. If it is too moist, they can become soft, swollen and stick to each other. Both extremes can lead to microbial growth and alter dissoltion and bioavailability characteristics.
Tablets should be inspected for swelling, discoloration, fusion of tablets and the appearance of crystals on the tablets or the inside of the container. If the tablets are mottled (have spots), this indicates bacterial growth. Cracks in the coating of tablets should also be a reason to discard them. If a tablet is simply discolored (generally faded), this may simply be esthetic and a detailed reference should be consulted to determine if the drug is viable.
Parental Solutions are primarily vulnerable to bacterial growth. To test, hold the bag or bottle up at eye level and swirl, take a flashlight and shine it through at a right angle. This is best done against a dark, solid background. If there is any visible particulate matter, the solution should not be used.
Solutions and suspensions in ampules and vials are vulnerable through multiple pathways. Ampules, being thinner glass, are more likely to break due to freezing and rough handling. Multi-dose vials are vulnerable to thermal expansion and contraction along their seals allowing microbial comperamise The rubber membrane is also vulnerable to heat and in time will break down. Some drugs are exceptionally vulnerable to oxygen, epinephrine is a prime example. Each use from a multi-dose vial of epinephrine will introduce oxygen and speed degradation. Drugs in dark glass are light sensitive, and generally also very temperature sensitive. Solutions with a solute dissolved in them can precipitate out, generally if exposed to cold. Most can still be used, but there are exceptions. Gradual re-warming and agitation can often bring the solute back into solution but rapid heating can harm many solutions and should be avoided.
Solutions and suspensions for oral administration
Bottled powders for reconstitution are generally very stable in their pure form, but very unstable and short lived once reconstituted.
Transdermal patches do not work well when exposed to high temperatures.
Suppositories melt at high temperatures.
Creams and ointments can break down in multiple ways. Phase separations are a separation of the components into layers. They can become dry and cake like as well as become quite liquid. This most commonly happens with either repeated freeze thaw cycles or exposure to high temperatures.
1) On shelf life and expiration dating.
Set by legal, marketing, economic and regulatory considerations. Expiration dates are cloaked in an aura of scientific authority, being based on stability testing. There are two problems with this. First, the ability to accurately predict or test the shelf lives of different dosage forms varies by dosage form. Parental solutions are fairly accurate. Testing of tablets, emulsions and related material produce results that are rarely accurate. Second, Regulatory mandates force companies to take raw test data, combine it with theoretical predictions and pass this data through some statistical equasions. The result, void of scientific reality, is used to justify the shelf life. It does not determine the shelf life, but rather gives an upper limit to the self life they can request. Shelf lives are never given for over 5 years, despite that many drugs are viable for 7, 10, 15 or even 20 years. That is within Pharmacopedia limits. In the US this is >90% (or >95% in the UK) of the labeled content. Yet drugs tend to be effective over a wide theraputic range. They are usually given in overage as the needed amount is rounded up to the most convienient dosage size. An exception to this is those drugs with a narrow theraputic index.
Legal considerations are another issue. Pharmaceutical companies do not like to see their names mentioned negativly in the news, nor do they like lawsuits. As a result, the expiration date will always be at least a year or two less than the actual shelf life (if stored correctly). As mentioned, many drugs last much longer, but the 5 year cap on dates prevents identification of the really stable ones by expiration date. At least based on US data.
Specific Drugs:
Albuterol and albuterol sulfate inhalers should be stored at 15-30C and 15-25C, respectively. Use of the inhalers at temperatures below 15C results in droplet sizes too large to be therapeutically effective and in delivered dosages that are substandard due to propellant pressure. At 0C albuterol inhalers deliver a pressure that is on average 28% below normal. (AHFS) The reverse is presumably true for use above 30C. Inhalers can burst at temperatures exceeding 49C (120F).
Aspirin is one of the only drugs that gives a distinct odor when it’s degraded. If it smells like acetic acid (vinegar) than it should not be used. It is generally very stable and will remain viable for years after expiration.
Diazepam –
Epinephrine -
Nitroglycerine once opened, will evaporate fairly quickly, leaving a tablet that looks the same but that contains no medicine. In storage, it has a tendency to migrate from tablet to tablet, resulting in uneven doses being delivered. Nitroglycerine inhalers have become popular in the pre-hospital environment as they do not have the same stability problems as the tablets. As with albuterol inhalers, temperature induced variance of delivered dose should be taken into consideration.
Oxytocin is highly vulnerable to temperature and light. If there is any discoloration of the solution, it has undergone degradation and will be sub-potent. Theraputic failure of this drug to control post-partum bleeding is frequently cited as a cause of maternal death in hot climates.
Syrup of Ipecac used post expiration is still viable, however onset of emesis will likely be delayed between 15 and 45 minutes beyond normal.
Tetracycline while not generally a pre-hospital emergency drug, is the one that everyone has been taught, and are still taught, that it becomes dangerous after expiration. This is no longer the case. To quote the AHFS Drug Information 2001 handbook, p 441: “Administration of outdated or deteriorated tetracyclines has caused a reversible Fanconi-like syndrome […] In most cases the outdated tetracycline preparation administered contained citric acid (an excipient no longer used in tetracycline preparations) which accelerated deterioration of the antibiotic during storage. Therefore, this reaction is unlikely with currently available tetracycline preparations. “ (AHFS)
Alldredge, BK, Stability of Diazepam Rectal Gel in Ambulance-Like environments, Am J Emerg Med 2002;20:88-91
Church, WH, HU, SS, Henry, AJ, Thermal Degradation of Injectable Epinephrine, Am J Emerg Med 1994;12:306-309
Gottwald, MD, Akers, LC, et al, Prehospital Stability of Diazepam and Lorazepam, Am J Emerg Med. 17(4):333-7, 1999 Jul.
Newton DW., Overheating of drugs during shipping and storage, South Med J 1995 Jun;88(6):694-5
Rudland SV, Jacobs AG, Visiting Bags: a Labile Thermal Environment, BMJ, 308(6934):954-956, Apr 9, 1994
Rudland SV, Annus T, Dickinson J, Langdon S., Adrenaline degradation in general practice, Br J Gen Pract 1997 Dec;47(425):827-8
Strauss, A., Altered Responses to Medications Exposed to Excessive Temperatures During Shipping, Southern Medical Journal, vol 88, No. 6, p696-7
Treloar A., Are the drugs in your bag effective?, Practitioner 1989 Nov 8;233(1478):1435-6
unknown, Stability of Drugs in Solution, Med Lett Drug Ther, 1996 Sep 27, 38(984):90
unknown, Particulate matter in parental solutions, Med Lett Drugs Ther 1968 May 31;10(11):42-4
Valenzuela, TD, Chriss, EA, Hammargren, WM, et al., Thermal Stability of Prehospital Medications, Ann Emerg Med. 18(2):173-6, 1989 Feb.