Expiry and shelf life of drug products
Dr Ashok Omray, Advisor Pharma Operations, Ex AVP, USV and Ex-President, ICPL, comprehensively explains the relevance and significance of expiry dates and shelf life of medicines and details how these aspects are decided by pharma scientists to ensure optimal efficacy and safety of the drug formulations
Do we know whose prime concern is it to have a reasonable shelf life, moderate storage conditions and long expiration periods of the drug products? None other than the manufacturers, and in turn, the people who develop the products.
I may use the shelf life and expiration date synonymously in the later part, but conceptually for me, these two terms are slightly different. Mostly for export, a pre-shipment sample is required and a minimum of 80 per cent of shelf life is also requested by the customers. Imagine for a product with 18 months life if three months are lost before the shipment then the product will hardly have 12 months for usage. You may recall during the recent COVID 19 pandemic a series of extraordinary steps were taken by DCGI (CDSCO) to regulate the import and clearance of goods from the ports and materials with lesser available shelf life were allowed to be cleared. The availability of drugs and raw materials for manufacturing is very important. Even within the country, logistics are very difficult due to geographical and climatic problems to retain the utility of the product in good condition. Environment-controlled transportation is still a difficult proposition in India (both due to cost and availability). The consumers come in the picture much later and only when they are faced with short expiry products and when they are compelled to purchase more than required units due to the packaging or available commercial pack.
By rule of the thumb, most of my pharma marketing friends will agree, if one cannot have a product life of at least 18 to 24 months, better to not market such products. And if somebody demands 60 months expiry then also it is not worth marketing, indirectly it implies that the product is going to be on chemist shelf for such a long time. Such products are not in demand or are obsolete. It is sometimes suggested to have smaller batch sizes of slow-moving and highly specialised products. This will apply to specific or outdated molecules, drugs for some rare type of diseases in a particular place or additional strengths of the same molecule where all the strengths are not equally prescribed.
Unlike food, which is normally prepared for immediate consumption or to be used within a short duration, drugs have to be manufactured much in advance. They have to undergo critical tests and examination and they will be purchased and used only when the need arises, so equating food with drugs will not be prudent. The element of taste, appearance and smell is most important in foodstuff so its treatment in the context of shelf life and expiration has to be dealt with separately. However, its relevance with drug expiration will be at times quoted since both are meant for good health and life.
The question that needs to be answered is: What happens to near expiry or expired products which are returned by the retailers as non-saleable goods? Normally huge stocks are dumped to wholesalers and retailers towards the end of the financial year (FY) which helps to show a lot of green in the annual balance sheets. A situation like this is a common phenomenon and is not aimed to show any company or individual’s approach. It is also important to view a situation if the product could not be shipped due to a shortfall in the 80 per cent shelf life demanded by the customer. Such batches are repacked and diverted to other customers or markets. Ambitious and well-defined SOPs for the handling of returned or expired goods and raw materials (which are within the company only) are written by professionals, it is important to know and evaluate how seriously these SOPs are implemented.
It is not uncommon to find a lot of expired raw materials available in the manufacturing premises during internal audits. The companies having international business with highly regulated markets compulsorily follow their SOPs, my concern is for companies manufacturing for the domestic market only.
Few questions that must be answered by the regulators, industry and stability experts are as follows. These are not my views but possibilities that have been talked about, practised and requested to be considered by regulators:
- Is it advisable to give a new lease of life to the existing material or batch of the expired product if it is found to be compliant with the specification?
- How to evaluate that the labelled expired product is safe for use or consumption?
- Is it advisable to give extended shelf life to the materials (after test and analysis) which are procured from other vendors?
- Is it safe and legally acceptable to divert the expired but safe and compliant products with a new identity to rural supplies or third world countries or semi-regulated markets at a discounted price?
- Whether the ongoing or extended real-time stability studies and data collected from there be used to give extra life to the otherwise expired batch?
- Let us be very candid on behalf of drug companies – small or big quantities, relatively cheaper or costly products, the destruction is a direct loss to the business. Under such situations what is the stand that they think may be justified and within the regulations?
Let us be totally dispassionate and study and evaluate the situation in relation to day to day life. We may understand and appreciate the issues that keep on haunting us whenever we buy medicines. Nobody wants to use drugs but practically everybody is using them. Needless to say, drugs are needed only if there is a condition and doctors recommend the same. Drugs (the term drug is used here to represent the final form in which they are consumed – tablets, capsules, syrups etc.) are foreign substances to the human body and therefore they are likely to have some predictable and few unpredictable but possible undesired effects (normally defined as side and toxic effects). Drugs administered orally or by the parenteral route are expected to reach the bloodstream whereby they can reach to site and elicit the desired pharmacological effect.
There are many other substances that the body needs and if there is a deficiency then they are supplemented and in present-day terminology, we call them supplements or micronutrients or immunity-enhancing agents etc.
Across the globe, there are multiple systems of therapies or treatments being practised. What has come to be universally accepted are the drugs of chemical origin and popularly called ‘Allopathy’ or ‘ANGREZI DAWAYEN’ in India. Irrespective of the system followed the drugs must be taken only when required and prescribed by the experts or medical practitioners for the duration advised. Internationally the acceptance of the drug substances/Active Pharmaceutical Ingredient (API) and drug products (formulated preparations) has assumed new dimensions due to sourcing them from any part of the world. This has led to the need for globalisation and a common code of practice and uniformity of the dosage based on design and therapeutic equivalency (for efficacy purposes).
In India and even in other parts of the world, the consumers, as well as the manufacturers, demand why there must be an expiry date for the drug substances, drug product and excipients. Two things which are always on the agenda of governments and health insurance companies –
- How can we reduce the prices of drugs?
- Why the drugs have an expiry date? or How to increase shelf life?
On the first issue the discussion will be endless, the manufacturers have 1000s of reasons to justify the price but customers have 10000 reasons to demand price reduction in the marketplace for the Brand, Branded Generics and Generics there are very wide price variations. The question should be that does this have any bearing on the quality of the medication? Like any other commodity or food items, nobody is ready to accept if there can be different quality standards for the drugs and hence all the products of a particular chemical substance and the dosage forms must be identical with respect to use and efficacy.
The people, in general, may or may not be aware that near expiry goods are removed from the chemists’ shelf and returned to the manufacturers well before actual expiry dates. Mostly, the customers do not buy a near expiry drug product. The manufacturers also realise the problem with limited shelf life or expiration of the drugs. The logistics and distribution are elaborate processes and it may take about a couple of months from the date of manufacturing, for a drug product, to reach the retailer or Dispensing Pharmacy. This duration may be even longer for the remote places and more so if the climatic conditions (rains, floods, excessive summer or cold) are not favourable and the connectivity is poor. Let us have confidence that the drugs we buy are not going to expire in a month or two. Invariably most of the drugs carry an expiration period of 24 to 36 months and one may get the product at the most 6 months from the date of manufacturing so there is ample time for its usage even if there are surplus or extra units. The chemist is not going to take surplus quantity as a return from the customer but it is always possible to buy limited or required quantity at a time. One must ask for such a pack which is good for an individual for a single treatment course. I do agree that wastage of any type is not acceptable. It is criminal that when in our country people are still struggling to get their food and basic amenities, we should waste the drugs.
For me, most important is the optimal effect from any drug product and obviously, the expiry period of the drugs must not haunt buyers. The expiry dates for the drug products are determined based on a series of studies that have to be conducted before the product is licenced for manufacturing and made available for commercial purposes.
I have a few questions and if we answer these truthfully then we may resolve the problem of the expiry of drugs to a great extent. Let us attempt to candidly put our response to each of the following (that includes me as well) –
- How often we really have a look at the drug product pack and focus on the manufacturing, expiry dates and storage conditions (for the last situation, i.e. Storage, unless advised by the doctor or the chemist the drugs can be stored at a convenient place in the house, still avoiding extremes of light, heat, moisture and freezing.
- What would be the ideal shelf life or expiration period for a drug product?
- What do you understand by the term ‘expiry date’ and in your opinion should the drugs have an expiry period?
- Are you compelled to buy quantity more than required, is it because of the minimum saleable quantity or the doctor’s prescribed brand is not available in desired units?
- Do you ever ask your doctor what should you do with the excess quantity leftover?
- Has your doctor on his/her own advised you what to do with the extra quantity of the drugs?
- Do you believe your doctor and have complete faith in his approach?
- Do you follow the drug usage and regime (frequency and no. of days) recommended by the doctor or stop the medication when you feel you are alright?
- How and where you normally store/keep the drugs in the house?
- What different types are drugs are always available at home that you consume without any prescription or advice?
- Do you want to keep the surplus reserved for future use without doctors’ advice for yourself or any other member of the family showing similar symptoms?
- Do you have a well defined or have you developed a well-defined system for identification and dosage frequency of the drug from the leftover quantity?
- Are you following the storage conditions for different drugs as recommended by the manufacturer on the product label?
- At what frequency you review your personal medicine chest and what all observations you make?
- Are you a philanthropist and want to serve society by free distribution of the surplus drug that you bought but did not use?
- Do you think if you could donate the surplus medicine stocks to some NGO who in turn will distribute to those who need medicines and cannot afford them?
- How do you decide the use of the drug? Are you retaining the original packaging with all the details printed and legible?
- Do people frequently come asking for medicines from you and you want to oblige them from your inventory?
Few unrelated questions, if we have the answers that will help us to think positive –
- When do you normally retire from your office wearing clothes (No. of years)?
- How frequently do you buy the vegetables and treat them as fresh?
- Do you stock some grains and cereals at home, if yes then for how many weeks or months?
- After how many days (except deep-frozen) you normally stop using or consuming the foodstuff stored in the refrigerator (both cooked and uncooked)?
- When you buy the grains, spices, eatables do you look for the date of manufacturing and best before or use before dates?
I am sure under the best of storage conditions (hermetically sealed containers, stored in good conditions – not excessive heat or humidity) most of the lentils, groundnuts, flours, pulses, biscuits, dry fruits, wafers, snacks etc. start showing the presence of insects and sometimes develop foul smell and we normally discard them. We have all the reasons for not using them as they may affect our health and we may fall sick. The reasons for things going bad – the larvae of insects grow over a period of time and start eating grains (very common in rice and dals) and increase bioburden leading to microbial growth. The vegetable oils used for cooking/frying may start getting rancid over time due to the oxidation process of the unsaturated fatty acids in oils. Repetitive opening and closing of the containers allow outside air and humidity to ingress and accelerate hydrolytic, reductive and oxidative processes leading to degradation and eventual spoilage of the foodstuff.
Let us turn towards some common chemicals used in the kitchen – common salt (NaCl), baking soda (NaHCO3), citric acid, tartaric acid, starch, milk sugar (lactose) and even talcum powder, washing soda (Na2CO3) etc. Do you think you can keep on using these things for years together and do you buy these in bulk quantities? The answer is NO because their physical condition deteriorates with time due to exposure and atmospheric conditions though there may be no chemical changes. Similarly, starch, sugar etc. start lumping, losing their free flow characters and develop some unwanted smell (maybe due to microbial growth).
Drugs by nature are chemicals and more complex than the above listed simple chemical compounds. The materials of vegetable and herbal origin have their intrinsic problems. The drug dosage may be as low in micrograms and may go to a few grams (in divided doses). To provide the form as a suitable dosage, a number of inactive additives (called excipients) are used and these are mostly derived from natural sources. These non-drug materials are also chemical in nature and they facilitate a lot of functions to make the drug products to be administered with ease and make them release the active drug at an appropriate site. We all know gums, sugars, starch, stearates, polymers, waxes, calcium phosphates, talcum, various types of clays and earth materials, yes, these are invariably used in tablet and capsule formulations. The objective behind the use of additives is to improve the drug dispensability, stability, dissolution, absorbability, diffusion across the body membranes and eventually the efficacy. When we talk of oral liquids (syrups and suspensions), injectable formulations and even topical preparations like lotions, gels, creams etc. the non-drug or inactive chemicals (excipients) make the major part of the formulations. The most important liquid is water which is used in abundance during processing and for most of the liquid preparations – it is the biggest enemy of all the chemicals from the stability point of view.
I think most of us, rather all of us look for 100 per cent value for money. You do not accept Rs. 99 if the payment due is Rs. 100/-. While buying anything we always want to see that the weighing scale must show more than the label and must measure more than the volume asked for. Likewise, I also look for 100 per cent activity of the drug as per label till the time it is good for use. Right from our childhood and school days, we have been told to preserve the things (paper, clothes, foodstuff and vegetables) well protected from excessive heat, direct sunlight, moisture and even from freezing conditions. This only suggests that the climatic conditions (surrounding environment) are very much responsible for the condition of human health and other things equally.
You may or may not know that in the case of drug formulations and drug substances 100 per cent content or 100.00 per cent purity or content is rarely observed on analysis while manufacturing exact amounts have to be added and if necessary, the assay/potency corrections are applied to bring the active incorporation to 100 per cent as per formula. The processing, handling and purity of all other chemicals are very critical to arrive at the finished product with 100 per cent active levels. In general, a drug formulation is generally cleared as compliant if the contents are found to be in the range of 90 per cent to 110 per cent of the claim (the limits are permissible to allow for the handling and analytical variations). Wherever overages are added the lowest and highest limits are modified accordingly.
Let me come down to the very basic and rudimentary logic. If we do not eat stale or old foodstuff (including vegetables, processed foods, canned fruit juices, sweets, snacks etc.) and also do not consume the packed goods beyond their labelled date for usage, why should we compromise for drugs. If we have accepted that for any eatable there is a period during which it will taste good and also retain its nutrition value subject to packaging and storage and recommended method of handling and processing then our mindset must change for the drugs also. We happily accept the “use before of best before” for snacks and other eatables. Now you will appreciate my set of questions which I had raised in the earlier part of my writeup. The issues of expiry of the drugs and surplus or leftover medicines may get resolved broadly if the dispensing practice starts in India as it is practised in the western world. We must also note that we never complain about the dispensed medicines supplied by the doctors’ dispensary. The reason, it is exactly as per count for the number of doses and number of days and we do not pay separately for it. Instead of simple drug stores, if we have dispensing pharmacies, most of the expiry related issues may not arise. If the people buy the drugs on prescription only and from a particular pharmacy or retail shop, the following situations may also not arise :
- Excess or surplus or leftover units.
- The loss and leftover due to packaging configuration
- Storage issues
Not getting the exact number or quantity, instead, the commercial unit pack created problems are more for the tablets, capsules and syrups/suspensions (which constitutes about 70 per cent of the commercial products). For dry syrups, ampoules, vials, sachets, eye drops, lotions, gels, creams and ointments such problems are rarely encountered.
For non-prescription and OTC drugs, the above situations are normally not encountered because one has the freedom to buy as per need and these items generally do not require stringent storage conditions. I shall cover the scientific rationale of arriving at the expiration period, storage conditions and how to deal with expired drugs after a while. Let us try to study all that is written or printed on the drug product labels and what is its significance. If you have noticed with many a product pack, there is a product information leaflet (PIL) which may be at times as big as the tabloid newspaper (can be seen in the packs of imported medicines from the US) size with a very fine print. In our country, PIL is a must only for new drugs so after four years it may disappear. It is not mandatory for the consumer to read and understand but it is good for the prescriber so that they can explain to the consumer. The most significant information on the product label is the product name, quantity, contents, storage conditions, direction for use, batch no., manufacturing and expiry dates (and price).
For any drug product to be most effective and efficacious it has to compulsorily meet the quality specification set for it either in the official compendium or generally acceptable quality norms throughout its usage. Based on the geographical and prevailing climatic conditions the countries have been divided into various (I, II, III, IV A and IV B) climatic zones. The expiration periods are scientifically derived based on the behaviour of the products in multiple packs (simulated in case of very large bulk packs) at accelerated storage conditions of temperature, relative humidity, light, permeability of the packaging material and a host of several other parameters. We must understand that India is considered to have extreme environmental factors, temperatures range from sub-zero to 50 deg; C and humidity from 25 to 95 per cent (the stability studies are performed as per Zone IV B hot and higher humidity). Light barrier attributes can be provided for light-sensitive products in the form of packaging like amber coloured plastics or glass, aluminium foil etc. Our basic observations from daily life must help us to understand that the environmental factors may lead to fading of colours of fabric to cracking of skin (effect of light and dryness) hence the chemicals which have highly reactive chemical groups can undergo various types of reactions involving environmental changes and may cause hydrolysis, reduction, oxidation, photolytic degradation and auto-degradation into isomeric and polymorphic forms. High humidity in coastal regions cause corrosion of metals also and the heat during April – June during summers may touch even 50 deg. C. All these factors may have an impact on the chemical integrity and thereby reduction in the content of the active form of the drug substance leading to a chain reaction of drug inactivation and loss of therapeutic efficacy.
If we start respecting drugs like other things of everyday use, we shall be much happier. The only exception with the drugs – bulk purchase for economy reasons must not be encouraged. Immediate disposal after the course completion or recovery is necessary. The drugs purchased on retail on the doctors’ prescription must not be kept for later use by yourself or any other member of the family (except under extraordinary conditions bulk creams, gels, ointments, dusting powders etc. provided they are kept properly closed under recommended storage conditions). It is not always true that the freezing or cold conditions will keep all the drug products also in a good condition like refrigerated and frozen foods. Very lively examples are liquid and semi-solid products which may separate, solidify and lose their texture, consistency and uniformity as a result the product will not be usable. So, storage in cool conditions must not be confused with a refrigerator or freezer.
- Cool – implies temperature between 8 and 15 degree C.
- Cold – Storage not exceeding 8 degrees but between 2 and 8 degree C.
- Freezer – Storage between – 20 and – 10 degree C.
- Controlled Room Temperature – Thermostatically controlled working environment of 20 to 25degree C with brief deviations between 15 and 30 degree C
- Warm – Temperature between 30 and 40 degree C
- Excessive Heat – Any temperature above 40 degree C
We are hearing that the Pfizer COVID 19 vaccine has to be stored at a temperature – 70 deg. C. Similarly, storage of lotions, pastes, cosmetic creams, gels and medicated ointments in the refrigerator will also make them unsuitable and ineffective and they are labelled not to freeze.
Why drugs expire and have a shelf life?
This is a trillion-dollar question. I remember somebody asking me about the expiry of drugs – Does it mean the drug or active material will die? Frankly speaking, I was speechless. In the literal sense, the loss of intactness of the active substance (as a fraction of the same changes into another chemical, called degradation product) may lead to the formation of therapeutically inactive material. The per cent active content is reduced to that extent and this may have an impact on the efficacy, blood levels of the drug and ultimate recovery of the patients. The chemical changes can be confirmed or ascertained only after critical chemical or instrumental analysis but any changes in the physical characteristics is an indication of initiation of the loss of either the integrity of the chemical structure of the active drug substance or loss of performance of the dosage form. The products are considered to be expired when they fail to comply with the specification under recommended storage conditions. Besides, the physical changes are very important, in spite of no chemical degradation, they may also make the product non-suitable for use.
The product development or formulation development is therefore a very scientific exercise for any drug substance be it Acetaminophen or Aspirin (supposed to be relatively simple low molecular structures) to highly complex multiple cyclic structures having several reactive or sensitive functional groups or large protein molecules. Most people think what is big deal in making pharma dosage forms (including big businessmen in the field of pharma), mix a few substances and fill in the capsules or compress into tablets. We must know that even the capsule shells (gelatin) are themselves a very sensitive material and requires stringent storage conditions. Gelatin may pick up moisture and soften and due to permeation of moisture the contents may start degrading. In dry conditions, with relative humidity below 45 per cent, the capsule shells may become brittle because the gelatin needs a definite level of water to retain its form.
By this time, we have very well understood that to keep the drug products in good condition it is important to:
- Use the best quality materials free form impurities and microbial contamination.
- Quality specification and vendors are well defined, they are finalized after testing, validation and vendor audit.
- Use the quantities after applying purity correction and all the materials must be tested and certified before use.
- The process under clean atmospheric/climatic/environmental conditions.
- By way of converting the drug substances into formulations, the approach is to stabilize the same, make it palatable and the drug must be available to the system in a predefined pattern.
- The quality of the finished product must be maintained for a longer duration and be available at an affordable price.
Accelerated stability studies to arrive at shelf life and storage conditions
I may not like to call it expiry date because that sends the wrong signal or bad vibes. We also need to believe that the expiry periods are not arbitrarily decided on somebody’s whims. The scientists work on the product development with the basic concept that all the chemicals are highly reactive by nature and in combination with other materials or due to external environmental conditions, the degradation processes may be accelerated. This article is not about the science for dosage form development but it is about how to keep products safe, effective and intact for a longer duration of time. The quality standards are set so that there is a level of acceptable quality, it may be noted that the compositions are not altered without serious considerations. The expiration of drugs, is the time till the product retain the minimum level of pre-determined standards (physical, chemical and microbiological) and once that threshold is crossed on either side (+/-), there is a need to review its efficacy. Normally the degradation lowers the quality and acceptability. Determination of the expiry and shelf life of the drug products has been a global task and there have been consistent efforts for uniform understanding of the subject for more than the last three decades. The formation of ICH (International Council for Harmonization) has been a great effort in this direction. It started as the International Conference of Harmonization way back in April 1990 with the US, Countries from Europe and Japan as the principal participants. The need for uniformity became more relevant due to global drug supplies steered by countries in Asia (mainly India and China). The climatic conditions from Sahara-desert to most of Europe, the Americas, Asia and Antarctica are so varied that the same set of product formulation may or may not stand the test of time in the same packaging.
For the patient/customer and dispensing chemist it is important to follow the directions:
- Take the drug as directed by the physician
- To be sold on the prescription of the registered medical practitioner only
- Store under certain conditions (they vary for different products)
Other information may be more technical and regulatory compulsions so I do not want to elaborate on them.
The formulation and the packaging coupled with the recommended storage conditions make the complete package for its extended use in any part of the world. The accelerated stability studies and real-time stability studies are the integral parts of formulation research and development. Unless the products show their stability under accelerated climatic conditions for extended periods, in order to assign a tentative but reasonable shelf-life, they cannot be introduced in the market. Besides forced degradation and compatibility studies, the satisfactory products are subjected to accelerated stability studies in multiple packaging to take a decision for the product and package. The actual shelf life for the product may be extendable after the completion of the real-time stability studies.
The storage conditions for stability testing are:
- Temperatures – 25, 30 and 40 deg. C with various combinations of relative humidity ranging from 60 per cent to 80 per cent.
- Exposure to UV light and normal light for photosensitive materials.
The dry conditions (low humidity) are also important for liquid and semi-solid products in permeable plastic packages as the moisture from within may permeate to outside in extremely dry conditions (RH below 40 per cent) thus destabilising the product texture and physical form. Certain products by virtue of the knowledge of the nature of active constituents require low-temperature storage (Cold 2- 8 deg. C, to be frozen store below -20 deg. C to – 10 deg. C).
Based on the above-accelerated stability behaviour of the products, immediate or primary packaging is decided and storage conditions are recommended for keeping the products. The control on the storage becomes erratic once the goods leave the manufacturing premises due to transportation, storage at the warehouse and final storage at the retailer and consumer’s end. The accelerated stability conditions give the confidence of the stability due to transit rigours and variations called EXCURSION.
It is not so that the conditions are applicable to drugs of chemical origin only, the same applies to drugs of vegetable and herbal origin. They are more prone to microbial contamination due to moisture and other factors. How do you think if the tablets pass from the system without fragmenting (dissolution and absorption are subsequent stages) you may still have the effect and get cured? Nothing is permanent and therefore, the drugs do not die but become less effective due to changes in physical and chemical form hence the shelf life and expiry have to be assigned.
Few points to take home:
- Never try to use the drugs where the exact identity and usability cannot be determined.
- Preferably retain the primary pack (secondary pack if available) till the last unit is consumed.
- The leftover quantity (in case the units purchased were more than to be consumed) can be retained in the original packaging without exposure and can be considered for future use subject to its expiry date and the storage conditions subject to doctors’ concurrence.
- Better do not offer your leftover drugs to others.
- If it does not hurt much, destroy the leftover quantity after consulting the doctor.
- Consider drugs your friends of emergency and avoid indiscriminate use of the surplus or leftover quantities.