Code No: TMS011 Price:450 Category: Health
Summary : Technical specifications are drawn for irreversible temperature indicator for evaluation of the loss of potency of drugs due to exposure to higher temperatures than allowable.
Possible types of indicators with required temperature and time characteristics are matched with end user’s requirements of either as a decision making tool or a monitoring tool.
Technologies & materials available in India for temperature sensitive paints and labels for pharmaceutical applications and published options are surveyed.
Taking into account the technology status in the country promising options are presented. The present status for their production is reviewed.
For those options which have yet to reach the production stage, investigations that need to be carried out are pointed out, as well as actions required for detailed evolution of parameters which are identified and suitability of the promising actions and improving the availability of temperature sensitive devices at reasonable costs.
Table Of Contents :
- Technology economy and the other aspects desired by the end users
- Requirements of ideal indicators and types possible
- published options
- Promising options their status assessment of suitability of use in Drug industry
- likely impact on use of promising option and further investigations required
- Action considered necessary for introduction of promising options.
- Need of Temperature Sensitive Indicators
- Recommended Storage Temperature
- Users Specifications
- Ideal Indicators
- Promising Options
- Further Investigations Required
- Actions Necessary for Induction of Promising Options
Primary objective of this report has been to present following aspects of irreversible temperature sensitive paints and labels suitable for pharmaceutical industry:
Techno-economic and other aspects desired by the end-users.
Requirements on an ideal indicator and possible types;
Promising option, their status and suitability of use;
Likely impact on use of promising options;
Further investigations required; and
Actions considered necessary for induction of promising options.
The report is based on published information in leading journals, papers and patent application filed on the subject. The draft was discussed with leading experts and drugs manufacturers in the country. The present (final) report incorporate their suggestions.
Need of Temperature Sensitive Indicators
In India, considerable quantity of life saving drugs, vaccines and vitamins are produced. The potency of some of these drugs are adversely affected, when exposed to temperature higher than those specified. At present, no simple means are available either to the manufacturer or the customer to check, if the phile containing the drug, vaccine or vitamins has been exposed to higher temperatures, than those recommended, during its passage from manufacturer to customer. The problem is acute in India, where storage of drugs at required temperature at retail outlets, especially, in remote areas, is either not available or effective, for most of the time, due to frequent power cuts and / or failure, more so during summers, when the ambient temperature, in most parts of the country, during major part of the day is more than 300C.
Recommended Storage Temperature
Detailed study of Indian, British and United States Pharmacopoeias showed that they all indicate only the safe recommended storage temperature of drugs, and do not specify the maximum temperature to which a drug can be exposed without significant loss of potency, nor the allowable duration of exposure to higher temperature. Recommended storage temperature as per Indian Pharmacopoeias (JP), are:
- Temperature less than 80C, for vaccines, injectables and other life saving drugs.
- Temperature less than 250C, for formulations, vitamins and other drugs.
- Temperature above 300C, for capsules, tablets and other types of non-temperature sensitive drugs.
Discussions held with the office of Drug Controller of India, New Delhi, indicated that, to the best of their knowledge, none of the pharmacopoeias published by any country, gives any guidelines, on either maximum allowable duration of exposure to higher temperature or modalities of transportation that should be adopted to minimise exposure to higher temperature.
Discussions held with the major manufacturers of drugs, vaccines and vitamins, on the need for temperature sensitive indicators on each phile for their temperature sensitive medicines revealed, that most of them are in favour of a statutory incorporation of such an indicator on each phile containing the temperature sensitive drugs. Statutory incorporation of such an indicator, they feel, will benefit both the customers and drug manufacturers immensely. The specifications of temperature sensitive indicator required by manufacturers can be summarized as under:
- Temperature of operation – 100C and 300C
- Time delays required for operation:
- For antiseras and Allied items - 30 minutes
- Other injectables - 2 hours
- Vitamins and formulation - 3 hours
- Colour change should be markedly visible by naked eye and should be irreversible.
- Should not get affected and/or poisoned by any solvent, aerosol, disinfectant or any other commonly available items.
- Size should be small enough to be fixed on drug philes an ampules.
- Reliability should be 100% (notional).
- Should be available in batch sizes, atleast to operate the automatic labeling machine uninterruptdly atleast for four hours.
- Should be non-toxic and should not pose any pollution problems.
- Cost should be low enough, not to materiality affect the delivered price of drugs.
- Should be freely available indigenously.
Ideal indicator is one which would permit the following statement to be printed on the phial. "If this spot has turned red (or any other colour) DO NOT USE THIS".
Broadly, indicators can be of the following types:
- GO-NO-GO without delay
- GO-NO-GO with required delay
- Time/Temperature indicator
- Real-Time recorder
- Multi-Temperature GO/NO GO
- Multi-Temperature with time element
End-use requirement of indicator also affects the choice of performance characteristics required. For example, if an indicator to be fixed on the phile, is being used as a decision making tool.
In this case the indicator change, must correspond very closely to the temperature and time at which product change is anticipated.
Closeness of product and indicator change leads to the problems of false positive and false negative indication. If the indicator were to change, but the anticipated change in product has not taken place, it would have given a false positive and good product would be discarded. Conversely, if the indicator did not change but the product did change, it would be a false negative and bad product would be retained.
In order to use an indicator as a decision making tool, it is important to identify the parameters of product which the indicator should measure and then carefully consider the false positive and negative indications that are likely to occur. An indicator may also be used a as monitoring tool only. For example, the retail outlets could be instructed to look inside all especially marked cases of drugs being received from manufacturers / stockiest to find "Proper shipment Indicators" where indication are to be recorded to initiate necessary action for improvement of shipment condition.
Detailed scrutiny of characteristics of different probable options revealed, that the option of dye encapsulated in a temperature sensitive membrane with precursor coated on the outer surface of the membrane, holds maximum promise and is likely to meet the requirements of drug industry. Promising options found suitable are:
For injectables and life saving drugs – Japanese Patent Nos.63, 112, 684; 63, 165, 479 and 63, 165, 480.
For vitamins and formulation – Japanese Patent No.62, 263, 176.
All the above promising options have not yet reached production stage.
The patentees of the above promising options, have claimed, that their patents are suitable for application on items of mass consumption. However, none of them, have provided application related parameters, as such detailed technical analysis on suitability of promising options taking all aspects into consideration is not feasible.
Further Investigations Required
A detailed evaluation is considered necessary to assess the suitability of each of the promising options indicated above. It will be preferable, to carry out the evaluation, firstly, at a control laboratory and subsequently on a pilot plant scale, under actual packaging conditions of a drug factory. Parameters which require further evaluation are:
Reliability of operation in controlled environment at normal packaging speeds.
Life cycle tests under different environments prevalent in Indian sub-continent.
Fixing methods of sensitive levels at normal operating speeds of labelling machines.
Immunity of labels against commonly available solvents and other items.
Acceptability of these labels by drug manufacturers, retailers and customers.
Actions Necessary for Induction of Promising Options
For induction of temperature sensitive labels on drug phile, the following actions are considered necessary:
Statutory Incorporation of Labels on Drug Philes: For statutory incorporation, Drug Controller relies on recommendations outlined in the Indian Pharmacopoeia. No pharmacopoeia in the world has till date given any guidelines on the subject. Nor statutory induction of temperature sensitive labels on drug philes, recommendations / guidelines has to be incorporated in the Indian Pharmacopoeia.
Indigenous Availability of Temperature Sensitive Labels at Reasonable Cost: Towards this indigenous production of temperature sensitive labels is essential.