Active Pharmaceutical Ingredients can be a lifesaver when it comes to drug formulation. But what happens when that API expires? Can you still use it? And if so, how long is it safe to do so?
In this article, we'll tell you everything you need to know about using expired API in drug formulation.
What is an Active Pharmaceutical Ingredient?
An active Pharmaceutical Ingredient (API) is any substance or mixture of substances intended to be used in the manufacture of a drug (medicinal) product and that, when used in the production of a drug, becomes an active ingredient of the drug product. Such substances are intended to furnish pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure and function of the body.
APIs are produced by processing chemical compounds. In a biologic drug, the active ingredient is known as a bulk process intermediate (BPI). Active Pharmaceutical Ingredient is the main component of a drug. It's the component that does all the work, and it's what's responsible for the therapeutic effects of the drug. An API can be derived from natural sources or it can be synthetic. And when it comes to drugs, synthetic APIs are the norm. That's because they're more consistent in terms of quality and they're easier to manufacture.
But what happens when an API expires? Can it still be used in a drug formulation? The answer is yes, but there are a few things you need to know first.
Why Regulate Active Ingredients?
The quality of active ingredients in a drug has a direct effect on the safety and efficacy of that drug. Poorly manufactured and contaminated active ingredients have been associated with negative health outcomes, including death, in a number of incidents over the past decades. For this reason, most countries around the world are now regulating active ingredients. Regulating active ingredients will help increase the quality and safety of drugs for consumers, and will strengthen the pharmaceutical drug supply system.
What is the Expiry Date?
This is the date after which the API should no longer be used. It's important to note that the expiry date is not a safety date, so it's still safe to use the API after this date. However, its efficacy may have decreased.
What is the Retest Date?
The retest date is the date after which the API should be retested for purity and strength. This ensures that the API is still meeting its manufacturing specifications.
This is an important date because it guarantees that the API will remain stable and effective for a certain period of time. The retest date is set based on a variety of factors, including how the API is stored and how it's transported.
What Is the Difference Between an Expired API and a Retest Date?
When it comes to expired APIs, there's a lot of confusion about what exactly that means. Let's start with the basics: an API, or active pharmaceutical ingredient, is the chemical that's used to make a drug.
An API can be used until it expires, but after that, it can't be used in drug formulation. The reason for this is that an API needs to be pure in order to be effective. And when an API has expired for a while, it can start to break down and become less effective.
That's why it's important to know the difference between an expired API and a retest date. A retest date is a date after which an API can no longer be used in drug formulation, even if it hasn't expired yet.
Can We Write the Retest Date instead of the Expiry Date?
The expiry date and the retest date are not the same things. The expired substance cannot be evaluated again for usage. Excipients can be retested, but API cannot be used after the expiration date. After one year of production, you can provide a retest date in the API, but it must be within the expiration date. The retest date is checked against the expiration date.
What does ICH Say?
Does the definition of expiry date in ICH Q7 preclude the rework or reprocessing of an expired API?
According to the definition, the material should not be used after the expiry date. The original intent of this definition in ICH Q7 was that expired API should not be used in drug product formulation.
It may be acceptable to reprocess [ICH Q7, 14.2] or rework [ICH Q7, 14.3] the expired API where the API manufacturer has all related historical GMP documentation and additional stability data on the reworked or reprocessed API. There may be registration/filing considerations that are beyond the scope of ICH Q7 in addition to the GMP considerations.
Is it possible to extend the expiry date or retest date of raw material and what is the accepted practice to determine how long it may be extended?
Manufacturing and labeling of raw materials for use by API manufacturers is outside the scope of ICH Q7. As such, retest and expiry dates, as defined in ICH Q7, do not strictly apply to raw materials and may be used in a different manner by the raw material supplier. Expiry date, as defined in the glossary of [ICH Q7, 20], applies specifically to the API.
API manufacturers may re-evaluate [ICH Q7, 7.5] and then use a raw material after the ‘expiry date’ or ‘retest date’, based on an appropriate scientific and risk-based justification (e.g., understanding of material attributes, testing, and stability). Similar justifications may be used to extend the date by which the material should be re-evaluated. It is the responsibility of the API manufacturer to ensure the raw materials are appropriate for the intended use at the time of use.
When is it acceptable for an API manufacturer to extend an API retest date?
The purpose of a retest date is to ensure that the API is still suitable for use. The API manufacturer can extend the retest date of a specific batch based on good science and long-term stability results for that API and testing of the specific batch that has been stored according to the label conditions. In some regions, regulatory authority approval of the retest date extension for the batch may be required.
If an API manufacturer wants to change (i.e., extend) the retest date for future batches of an API, then it should conduct stability testing sufficient to support the change, and include the new retest date and supporting data in a regulatory filing, as determined by regional requirements.
Can We use Expired API after Retest?
The confusion might be due to the term "expiry" being used instead of "retest" They are not the same thing. If the API COA gives a retest date, then it can be used after retesting (appropriate supporting stability data should be obtained). If the COA gives an expiry date, then it should not be used per the ICH Q7 definition of the term "expiry" as mentioned above.
The problem is that "expiry" is occasionally used incorrectly instead of "retest" on APIs. According to the ICH Q7 section, "Common practice for API is to use a retest date, not an expiration date." Expiry means that there is a known time range after which the quality of the DS or DP cannot be guaranteed. For example, stability data demonstrates degradation after a given time period. When there is no intention of extending the stability study to support a longer time point, the word expiration is utilized.
Is it Safe to use near Expired Raw Materials in Manufacturing?
It is not stated anywhere in FDA, WHO, and ICH standards, that near expiry raw ingredients can not be utilized in the formulation. Some standards recommend retesting of near expiry raw materials, but that is stated for API manufacturers.
Yes. You can use the API a few days before producing the finished dosage form as long as you ensure the stability of the finished dosage form during its shelf life. The TGA/DSC procedure can be used to determine the expiry date. Furthermore, the level of the limit of additional components indicated in the official monograph must be evaluated for safe API usage.
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Firstly, you have to ensure your Active Pharmaceutical Ingredient is still in the assay requirements range for some raw materials that passed its expired date, you have to re-test it.
If the assay is still in range (see the monograph instead the references such as USP/BP/EP) you may use that raw materials for the production/manufacturing process.
But we must use it carefully because only passing results in a retest of API is not enough to use it in the formulation. The expiry of any API is determined mainly by the assay and degradation products. If both are within the limit then you can use that API in the formulation. But if any of these results are close to the limit then it would not be good to use the same in the formulation. It is common practice for industries to use API a few days before it expires and make a product with a two or three-year expiration date.
As an example:
Assay Limit: NLT 99.5%
Degradation Limit: MNT 1.0%
If this API has a 4-year expiration date and just one month remains before it expires. If the results of the retest are Assay = 99.8% and Degradation products = 0.88%
In such cases, we cannot utilize it in the formulation of a product with a 2-year expiration date since the API will not meet the requirements for the following two years.
In the example, we will apply an excess amount of API to make its assay 100% in the end product, thus its assay will have no value in finished products. Its degradation products will be diluted in the end product, which will then be tested for a new impurity specification. As a result, it will have no value in the end product.
As a result, we do not need to be concerned with the quality of API in the end product; instead, we must ensure that the finished product meets its specifications. If you are employing raw material that is about to expire, you must have enough scientific data to ensure that it will comply for the whole shelf life of the finished product.
Can We Use an Expired API in Drug Formulation?
You might be wondering if it's safe to use an expired API in drug formulation. The answer is, it depends.
Expired APIs can lose their potency over time, which means they might not work as well in your drug product. In some cases, they might even be dangerous to use. So before you decide to go down this route, it's important to do your research and understand the risks involved.
There are a few things you can do to make sure you're using expired APIs safely. One is to test them in a lab to see how effective they are. Another is to make sure you have a good understanding of the shelf life of your product and how to extend it. With a little bit of planning and caution, using expired APIs in drug formulation can be a viable option.
Conclusion
The use of near-expired and expired raw materials in drug formulation remains a significant concern for industries lacking regulatory guidelines. Industries continue to employ near-expiry and expired raw materials based on accurate stability data and risk management data.
We can use the API having results near the limits, it is because the results of API have no value after formulation and formulated products must comply with its specification only. This is why there is no guideline for it. API must comply only at the time when it is being used in the formulation.
In addition, certain industries use the idea of 100% potency value while dispensing of API. Even after the pharmaceutical product is formulated, it is subjected to stability testing until its expiration date.
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