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Long term staility studies output handling

Mohammed Zghoul

Sat, Dec 11, 2010 5:15 PM

Dear all;

the relation between assay,dissolution,Related substances and even physical test results and test

intervals e.g. 3,6,9,12,18,24,36...

are concidered as a time seriese in statistics.

there is a differance whene we compare the results of 3 Vs 6 and 24 Vs 36

while there is a 3 months to 12 months period

so we cant say the drop dow from interval to another should not exceed 5%

it maybe like this 3 to 6 +/-3% with tolerance and from 12 to 18 4% with tolerance and so on.

the question is how can i deside that a result at an interval in the study for a certain Batch/product.

should be investegated there something wrong with it inspite of being withen shelf life limits?

assay of a product:

initial 3 6 9 12 18 24 36 48 60

101.1 99.1 98.3 96.0 94.0 95.5 94.5 97.1 91.3 92.1

limit: (90-110)%

regards

Mohammed

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Marc Gordon

Sun, Dec 12, 2010 12:47 AM

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Dear Mohammed,

Regarding your question, my thought is that guidelines indicate that the key is to always compare a time

point back to the initial value. For example, the "ICH HARMONISED TRIPARTITE GUIDELINE STABILITY

TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS Q1A(R2)" states the following:

"If long-term studies are conducted at 25C 2C/60% RH 5% RH and significant

change occurs at any time during 6 months testing at the accelerated storage

condition, additional testing at the intermediate storage condition should be

conducted and evaluated against significant change criteria. The initial application

should include a minimum of 6 months data from a 12-month study at the

intermediate storage condition.

In general, significant change for a drug product is defined as:

1. A 5% change in assay from its initial value; or failure to meet the acceptance

criteria for potency when using biological or immunological procedures;

2. Any degradation products exceeding its acceptance criterion;

3. Failure to meet the acceptance criteria for appearance, physical attributes, and

functionality test (e.g., color, phase separation, resuspendibility, caking,

hardness, dose delivery per actuation); however, some changes in physical

attributes (e.g., softening of suppositories, melting of creams) may be expected

under accelerated conditions;

and, as appropriate for the dosage form:

4. Failure to meet the acceptance criterion for pH; or

5. Failure to meet the acceptance criteria for dissolution for 12 dosage units. "

Note that in item 1 it specifies from its initial value, not from an intermediate time point to a later time

point. Therefore, if the Total Content changed from T=0 being 100%, to T=3 months being 96%, and T=6

months being 92%, even though the change between time points never exceeded 5%, since the total at

6 months compared to the initial value was greater than 5%, it is a "significant change.


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Marc

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Mohammed Zghoul

Sun, Dec 12, 2010 1:31 PM

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Dear Mr. Gorden;

what about the acceptance cretiria (90-110)% in some cases and (50-120)% for presirvative in some

cases the 5% is impossible to reach, how we can conduct the acceptable drop down to the acceptance

cretiria if the product meets all acceptance cretiria concerning impurities, related

substances,assay,Dissolution and physical test?

the comparison between any test point with the initial point to not exceed 5% change from 0 to 60 then

there is an acceptable drop down from interval to the next one as below by applying liniarity:

test point 0 3 6 9 12 18 24 36 48 60

result 100.00 099.75 099.50 099.25 099.00 098.50 098.00 097.00 096.00 095.00

drop down 0 0.25 0.25 0.25 0.25 0.5 0.5 1 1 1

why do we make it (5%) while acceptance cretiria varies from product to another?

i think that the 5% is in case of (95-105)%! but in case of 90-110 or 80-120 what it should be?

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Marc Gordon

Mon, Dec 13, 2010 11:08 PM

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Dear Mohammed,

Acceptance Criteria and ICH "significant change" are two separate items. If you fail your assay

acceptance criteria, that is usually a shelf-life limiting event. However, you can have a significant change

and still continue with your stability program and have a longer shelf life, as long as you still meet your

Acceptance Criteria and can explain why the significant change should not shorten your shelf. I have

had significant changes that were within the Acceptance Criteria limits, and I justified the significant

change due to assay variability limitations, and the FDA accepted the justifications. Regarding another

aspect of your queries, if the Acceptance Criteria are tighter than the significant change criteria, then

significant change becomes irrelevant and only your Acceptance Criteria matter.

You also appear to be mixing up the criteria for different tests. The 5% significant change only applies to

assay values, while degradation limits are based on a separate ICH requirement, and dissolution is based

yet a different set of parameters. You need to be familiar with the specific sections of the guidelines

that pertain to the different tests. I recommend that you carefully read the entire set of ICH guidelines.

It will take some time, but you find it very helpful.

Marc

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Marc Gordon

Mon, Dec 13, 2010 11:16 PM

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Dear Mohammed,

As I hit the reply button, I realized that I should have specified when I wrote "If you fail your assay

acceptance criteria, that is usually a shelf-life limiting event" by adding " at that storage condition." You

can, of course, usually drop down to test results at a lower temperature/RH storage condition to justify

a longer shelf life but with limitations on the storage conditions.


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Marc

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Mohammed Zghoul

Tue, Dec 14, 2010 3:03 PM

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Dear Mr. Gorden;

thank you for your answers.

i want to ask you about the delay time allowed between the manufacturing date and incubation date

the maximum delay time and the period of time allowed for studying a sample since we withdraw it

from the climatic chamber for long term stability?

thank you

Best regards

Mohammed

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Marc Gordon

Wed, Dec 15, 2010 12:01 AM

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Dear Mohammed,

From a regulatory point of view, I don't know that there is a set maximum allowable period between the

manufacturing date and the set up date in a stability chamber. However, if this interval exceeds 30 days

(I have seen other periods used as well), it is good practice to mandate in your SOPs that the product will

be completely retested, and the new set of release tests will become the T=0 stability data. Then the

driver to get the lot's stability set up completed in a timely fashion becomes the desire to avoid the time

and expense of retesting, and the fact that you may be shortening your shelf life since the lot that is set-

up on stability has undergone some period of aging before your stability test starts, but from a shelf life

perspective the aged material is treated as if it was freshly prepared.

The companies that I am familiar with have often used a period of around 30 days as the maximum

delay time between when a sample is pulled from a stability chamber and when it must be tested by.

This interval is somewhat company dependent, and should be specified in your company's SOPs (you

should add it to your SOPs if it is not there now).

Regards,

Marc Gordon

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raymond maikokera

Wed, Dec 15, 2010 12:08 PM

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Dear Gordon

I am interested in the maximum allowable period between


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1. manufacturing date and the set up date in a stability chamber

2. maximum delay time between when a sample is pulled from stability chamber and when it must be

tested

you said the period is company dependent and some goes up to 30 days.

Does it mean that there is no set period in ICH guidelines?

we use +/- 3days for accelerated stability and +/-7 days for long term stability studies but I do not know

where these time frames come from.

On a different stability issue; after statistical analysis of stability data, I found that most of the p-values

for the quantitative parameters are below 0.25 although they all meet the acceptance criteria. How do I

discus the data in the results analysis report?

regards,

Raymond Maikokera

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PRASAD BEDKIHAL

Fri, Dec 17, 2010 7:40 PM

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Dear All,


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In this case as Raymod mentioned the maximum allowable time frame for completion of analysis, is

there any time period for withdrawal of the samples from Stability chambers? This is practical situation

where it is not always possible to pull the samples from chambers on the exact period.

Regds

Prasad

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siva prasad mylapuri

Sun, Jun 5, 2011 4:58 PM

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Dear all,

what ever Mr.Raymond Maikokera said,we are also follwing the same in my organisation.But i to dont

know which guideline it said like that.As per my knowledge it is a logical thing.For accelarated testing

there is very less due (+/- 3 days) is there because, in accelated studies we are using higher temp and

humidity condition,so if due period is more degradation will increase,in long term we are using the

actual drug storage condition,if due time more also it may not effect more,so as per logic it may be

fixed.


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Regards

Siva prasadarao mylapuri

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raymond maikokera

Fri, Sep 16, 2011 2:46 PM

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Hi all

may someone help me or refer me to an article where i can have thorough understanding of statistical

analysis of stability data, like after 6 months accelerated and at long term. how does one comment on

the p-values below 0.25 for certain parameters which still meet the acceptance criteria?

Regards

Raymond

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