« Manufacturing

The International Conference on Harmonization (ICH) has finalized its guidance on stability testing for new drug substances and products, which suggests the storage conditions for the tests, among other things. The guidance, "Q1A Stability Testing of New Drug Substances and Products," published November 7, 2001, took effect on that date in the United States, Europe, and Japan. The final version of a draft guidance published April 21, 2000 (see the "Regulatory Focus" column in the July 2000 issue of PMP News), can be viewed at http://www.fda.gov/cder/guidance/4282fnl.htm. (FDA plans to publish its own stability guidance covering issues not addressed in the ICH document.)

Significant changes include a more detailed description of postapproval commitments, revisions to the text on test procedures to make them consistent with the ICH guidance "Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances," and more-detailed descriptions of storage conditions.

However, the guidance does not cover specific details of the sampling and testing procedures for particular dosage forms in their proposed container-closure systems.

Nonetheless, the guidance states stability studies on a drug substance should be conducted while it is packaged in a container-closure system that is the same as or simulates the packaging proposed for storage and distribution. Stability studies on a drug product should be conducted on the dosage form packaged in the container-closure system proposed for marketing, including secondary packaging and labeling as appropriate. Studies done on the drug product outside its immediate container can be conducted as part of the stress-testing process, and studies of the drug product in other packaging materials can be submitted as supporting information.

Storage statements for labeling should be established in accordance with the relevant national or regional requirements. The statement needs to be based on the stability evaluation, and specific instructions should be provided, especially for drug substances and products that cannot tolerate freezing. The label should avoid using vague terms such as ambient conditions or room temperature. An expiration date must be listed on the container label.

For drug products, data from stability studies should be provided on at least three primary batches, and the studies should be performed on each individual strength and container size of the drug product, unless bracketing or matrixing (techniques in which the testing frequency is reduced or certain factor combinations are not tested) is being employed.

For most long-term studies, the frequency of testing should be every three months over the first year, every six months over the second year, and annually thereafter for as long as the proposed shelf life. For accelerated studies, three time points over six months should be used. If there is significant change at the accelerated storage condition and testing at an intermediate storage condition is needed, a minimum of four time points over 12 months should be used. If bracketing or matrixing is used, it needs to be justified.

Storage conditions should test the product's thermal stability and, if applicable, sensitivity to moisture or potential for solvent loss.

For most drug substances and products, long-term samples being studied should be stored at 25° ±2°C and 60% relative humidity (RH) ±5% for 12 months, intermediate samples should be stored at 30° ±2°C and 60% RH ±5% for six months, and accelerated samples should be stored at 40° ±2°C and 75% ±5% RH for six months.

Aqueous-based products packaged in semipermeable containers should be evaluated for potential water loss in addition to other stability concerns. Intermediate samples should be treated the same way that those for regular drug products are treated. The only difference for long-term studies is to conduct them at 40% RH ±5%, and the only difference for accelerated studies is to conduct them at not more than 25% RH. It is acceptable to perform the stability studies on these products at a higher RH and derive the water loss at the reference RH through calculation. The guidance explains how to do those calculations.

Long-term stability tests on drug substances and products intended for storage in a refrigerator should be performed at 5° ±3°C over 12 months and accelerated studies should be done at 25° ±2°C and 60% RH ±5% over six months.

Long-term stability tests on drug substances and products intended for storage in a freezer should be done at -20° ±5°C over 12 months. Testing on a single batch at an elevated temperature for an appropriate time period should be conducted to address the effect of short-term excursions outside the proposed storage condition listed on the label. Drug substances and products intended for storage below -20°C should be treated on a case-by-case basis.

During the stability study if sample fails at long term condition and also at the intermediate condition what action should be taken?

Is the OOS procedure applicable for stability studies?

Based on Long Term and Accelerated stability study data how do we assign the expiration or retest date to the API?

Out-of-specification (OOS) regulatory issues have been well documented in the literature (1). Out-of-trend (OOT) stability data identification and investigation is rapidly gaining regulatory interest. An OOT result is a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study. The result is not necessarily OOS but does not look like a typical data point. This article discusses the regulatory and business basis, possible statistical approaches, and implementation challenges to the identification of OOT stability data. Representatives from PhRMA member companies met to consider these topics, review current practices, and summarize various approaches to potentially address this issue. It is noted that the identification of OOT results is a complicated issue and that further research and discussion is needed.

Dear Raghava,

The forumula to assign re-test or expiry based on long term data is "Y= up to 2X, but not exceeding X + 12 months"  where Y = Proposed retest period or shelf life, and  X = Period covered by long-term data. (Reference: ICH guideline  "EVALUATION FOR STABILITY DATA  Q1E ")

Example-1: Product:ABC,  available stability data 12 months long term, then the re-test or expiry will be 24 months

 Example-2: Product: XYZ, available stability data 18 months long term then the re-test or expiry will be 30 months.

Dear Raghava,

The forumula to assign re-test or expiry based on long term data is "Y= up to 2X, but not exceeding X + 12 months"  where Y = Proposed retest period or shelf life, and  X = Period covered by long-term data. (Reference: ICH guideline  "EVALUATION FOR STABILITY DATA  Q1E ")

Example-1: Product:ABC,  available stability data 12 months long term, then the re-test or expiry will be 24 months

 Example-2: Product: XYZ, available stability data 18 months long term then the re-test or expiry will be 30 months.

 

Dear Raghava

 1. Yes OOS procedure applies to stability studies. (Both finished pharmaceuticals and active pharmaceutical ingredients (APIs) are to be manufactured in accordance with current good manufacturing practice under section 501(a)(2)(B) of the Act. Current good manufacturing practice for APIs includes the performance of scientifically sound raw material testing, in-process monitoring, release and stability testing, process validation, and adequate investigations of any OOS result obtained from such testing). Further you may refer the guidelines for complete info.  

 2. ICH Q1E celarly outlines the procedure as how to assign shellife/retest period based on long term and accelerated stability data. The guidelines is uploaded here with for your convenince.

 T.R.Narayanappa

Dear All,

Can anybody help me out in designing a stability protocol to synchronise the effects on the product during transportation. Specifically to Europian countries.  If anybody have done such studies could reply on this.

T.R.Narayanappa

Are you refering to cold chain stability for temperature-sensitive drugs such as vaccines?  If so, I have done cold chain studies both domestically and internationally.

Best regards

Jim Darnell

President, CompliaPharm, LLC

Thank you Jim for your reply,

Yes  I am looking for both temperature sensitive products as well as the products stored at RT.  The purpose is to understand the effect of temperature/humidity variations on the products shipped from India to other countries. As the shipment would take about 2-3 months i am planning to initiate a stability study on such products.  Hope inputs from you will help me in this task.

T.R.Narayanappa

T.R.,

I would be happy to provide input.  Have you already determined the temperature monitoring type and data capture frequency?

Regards

Jim

Is the long term data + 12 months also true for prolonging the shelf life of an already marketed product?

Dear Mr.Bernard,

Long term data +12 is applicable for already marketed product.  But we should not add +12 for maximum stability tenure.   Please see the below table.

S.No.	Available stability	Shelf life
1	6 months	12 months
2	12 months	24 months
3	48 months	60 months
4	60 months	60 months

If we see the S.No 4, "+12 is not added to the 60 months.  So in the above examle the maximum shelf life is 60 months for both S.No 3 and 4. 

 Dear Bernard

Where the long-term data and accelerated data for an attribute show little or no change over time and little or no variability, it might be apparent that the drug substance or product will remain well within the acceptance criteria for that attribute during the proposed retest period or shelf life.   As per ICH guidelines the proposed retest period or shelf life can be up to twice, but should not be more than 12 months beyond, the period covered by long-term data. However the study should be continued on at least three primary batches for a period of time sufficient to cover the proposed shelf life. Based on the data so collected you can decide either to enhance or reduce the shelf life. Normal industrial practice to enhance the shelf life of a marketed product is done by collecting the stability data up to the period required to be enhanced i.e by demonstrating that the product is stable beyond the proposed shelf life.

After 60 months of shelf life can we continue the same? If yes till how long can we continue. My earlier experience we have continued upto 7 years and changed the shelf life to 7 years. Is that right or wrong. Please suggest.

In Europe at least the longest shelf life is 60 months or 5 years, after which finished products are to be destructed. For API and other materials, a retest date can be defined if described in a detailed SOP.

Dear friends,

I have gone through the discussion and sharing of information on the basis of guideline Q1e,its decision tree and purpose of stability to assign shelflife of drug substance and drug product.I was trying to understand the scientific logic for shelf life extention,role of accelerated condition stability supporting data for proposal of justifiable retest period till one is concluding with the support of long term stability data support.

The crux of the matter is why +12 months ! what is the basis of that.This is just to have better understanding of the stability management with little conceptual clarity for its intended objective.Would appreciate if some of our friend can help that way.

Thanks

Paresh Raval

Hi Paresh,

As outlined in the guideline, extrapolation of the shelf-life or retest period beyond the time covered by real-time stability data is based on a number of assumptions, namely that the pattern of change will stay the same. Given the fact that extrapolation of a shelf-life/retest period at the time of approval will be based on a rather limited number of batches and that there is no way to confirm that the underlying assumptions are indeed correct other than by generating the respective real-time data. Hence with a view to limit the maximum period of extrapolation,  the 12month as defined in the guidelines clearly constitute a convention, accepted by the three regions.

Hi

Any body in your companies adopted Bracketing and matrixing approach when there are multiple strengths and multiple packs for a product and supported regulatory filing(ANDA).  If so please share.

Hi,

I have heard from many people with similar situations on Bracketing and matixing, management of OOS results, long term stability and transportation.  It seems that everyone is asking the same questions.  Especially with regard to bracketing and matrixing, people have been a hard time understanding when and how you can implement the ICH Q1D guideline as many of the regulatory agencies will assess this differently.  In November (2008) there is a conference addressing all these issues and more.  There will be a large presence from pharma companies as well as a few regulators so it would be a fantastic opportunity to get a discussion going on these topics and find out how a wider audience are dealing with these problems.  Go to www.informa-ls.com/stability for more details.