Regulatory Open Forum

Does anyone know the source of the requirement for annual stability batches?  In the CFR or a guidance or elsewhere?  I've looked, and I've found in the CFR where it talks about requiring stability data, but since it refers specifically to setting expiry dating, that seems to only apply to initial licensure.  I've not been able to find the specific requirement for putting one batch per year on stability.

This has come up as a general question in my company, but particularly when we are bringing an additional manufacturing facility online, and the question comes up: Do we have to put one batch from each facility on stability, or just one batch of the DS/DP (since the products from the facilities have been shown to be comparable).  I can make the argument that you need a check on both facilities to make sure nothing unexpected is happening with the product, but it would be helpful to have a regulatory reference to back it up.

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Rachel Thornton
Associate Director
UCB
Smyrna GA
United States
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Dear Rachel,

True, it doesn't written anywhere in the CFR's but if we try to understand the statutory languages it is pretty clear,
 
21CFR211.166 it states that: "There shall be a written testing program designed to assess the stability characteristics of drug products".  (pre-post both)
part 21CFR 211.170 states that: "reserve samples from representative sample lots or batches selected by acceptable statistical procedures shall be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the reserve sample....The results of the examination shall be recorded and maintained with other stability data on the drug product".

I agree there is no explicit requirement for annual lot stability studies. However, the FDA Inspection Guide on "Expiration Dating and Stability Testing for Human Drug Products" states under Stability Testing B.1: "it is imperative that stability studies are not limited only to initial production batches but a portion of annual production batches be the subject of an ongoing stability program"

Although the Inspection Guide is dated October 1985, the webpage was last updated April 2009. Outside of the US, the WHO stability guideline states:  Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability program"A similar statement is made for API. As discussed in previous sections, confirmation that batches continually conform to the stability related material attributes should be an acceptable scientific justification to negate the need to do further routine (including annual) stability studies.

Go to the page10(96) or sec 2.2 of the below WHO guidance documents

http://apps.who.int/medicinedocs/en/m/abstract/Js19133en/

Hope this will help,

Best Regards,

-------------------------------------------
Amit Jain
United States
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Original Message:
Sent: 10-01-2013 11:03
From: Rachel Thornton
Subject: FDA requirement for Annual Stability batches

Does anyone know the source of the requirement for annual stability batches?  In the CFR or a guidance or elsewhere?  I've looked, and I've found in the CFR where it talks about requiring stability data, but since it refers specifically to setting expiry dating, that seems to only apply to initial licensure.  I've not been able to find the specific requirement for putting one batch per year on stability.

This has come up as a general question in my company, but particularly when we are bringing an additional manufacturing facility online, and the question comes up: Do we have to put one batch from each facility on stability, or just one batch of the DS/DP (since the products from the facilities have been shown to be comparable).  I can make the argument that you need a check on both facilities to make sure nothing unexpected is happening with the product, but it would be helpful to have a regulatory reference to back it up.

-------------------------------------------
Rachel Thornton
Associate Director
UCB
Smyrna GA
United States
-------------------------------------------

Also, 
Bear in mind that facilities are not necessarily comparable as they have their own bioburden profile. So function of product and QC controls could be the same but your contaminants or the amount may not be. This is also considered in stability when you are running more than 1 location or a critical vendor gets their product from a new facility (actual new facility or a location that has not supplied you before) within their organization.

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Frances Akelewicz
Owner & Principal
Practical Solutions
Yardley PA
United States
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Original Message:
Sent: 10-02-2013 14:24
From: Amit Jain
Subject: FDA requirement for Annual Stability batches

Dear Rachel,

True, it doesn't written anywhere in the CFR's but if we try to understand the statutory languages it is pretty clear,
 
21CFR211.166 it states that: "There shall be a written testing program designed to assess the stability characteristics of drug products".  (pre-post both)
part 21CFR 211.170 states that: "reserve samples from representative sample lots or batches selected by acceptable statistical procedures shall be examined visually at least once a year for evidence of deterioration unless visual examination would affect the integrity of the reserve sample....The results of the examination shall be recorded and maintained with other stability data on the drug product".

I agree there is no explicit requirement for annual lot stability studies. However, the FDA Inspection Guide on "Expiration Dating and Stability Testing for Human Drug Products" states under Stability Testing B.1: "it is imperative that stability studies are not limited only to initial production batches but a portion of annual production batches be the subject of an ongoing stability program"

Although the Inspection Guide is dated October 1985, the webpage was last updated April 2009. Outside of the US, the WHO stability guideline states:  Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability program"A similar statement is made for API. As discussed in previous sections, confirmation that batches continually conform to the stability related material attributes should be an acceptable scientific justification to negate the need to do further routine (including annual) stability studies.

Go to the page10(96) or sec 2.2 of the below WHO guidance documents

http://apps.who.int/medicinedocs/en/m/abstract/Js19133en/

Hope this will help,

Best Regards,

-------------------------------------------
Amit Jain
United States
-------------------------------------------






Original Message:
Sent: 10-01-2013 11:03
From: Rachel Thornton
Subject: FDA requirement for Annual Stability batches

Does anyone know the source of the requirement for annual stability batches?  In the CFR or a guidance or elsewhere?  I've looked, and I've found in the CFR where it talks about requiring stability data, but since it refers specifically to setting expiry dating, that seems to only apply to initial licensure.  I've not been able to find the specific requirement for putting one batch per year on stability.

This has come up as a general question in my company, but particularly when we are bringing an additional manufacturing facility online, and the question comes up: Do we have to put one batch from each facility on stability, or just one batch of the DS/DP (since the products from the facilities have been shown to be comparable).  I can make the argument that you need a check on both facilities to make sure nothing unexpected is happening with the product, but it would be helpful to have a regulatory reference to back it up.

-------------------------------------------
Rachel Thornton
Associate Director
UCB
Smyrna GA
United States
-------------------------------------------

Good Morning,

The annual stability requirements come from two avenues:

1. Your post approval stability commitment that can be found in your dossier (3.2.P.8.2)
2. PIC/S (and yes, FDA is now a member of PIC/S)

I am unable attach the pdf from the PIC/S website but the document(s) you are looking for is:

PE 009-10 Part I for Drug Product
PE 009-10 Part II for Drug Substance

This will give you a clear directive for annual stability pulls as well as a narrative you can cut and paste into your dossier for 3.2.P.8.2.

I hope this helps,
RL

-------------------------------------------
RL Johnson RAC
Consultant, Regulatory Affairs
PAREXEL
Denham Springs LA
United States
-------------------------------------------






Original Message:
Sent: 10-01-2013 11:03
From: Rachel Thornton
Subject: FDA requirement for Annual Stability batches

Does anyone know the source of the requirement for annual stability batches?  In the CFR or a guidance or elsewhere?  I've looked, and I've found in the CFR where it talks about requiring stability data, but since it refers specifically to setting expiry dating, that seems to only apply to initial licensure.  I've not been able to find the specific requirement for putting one batch per year on stability.

This has come up as a general question in my company, but particularly when we are bringing an additional manufacturing facility online, and the question comes up: Do we have to put one batch from each facility on stability, or just one batch of the DS/DP (since the products from the facilities have been shown to be comparable).  I can make the argument that you need a check on both facilities to make sure nothing unexpected is happening with the product, but it would be helpful to have a regulatory reference to back it up.

-------------------------------------------
Rachel Thornton
Associate Director
UCB
Smyrna GA
United States
-------------------------------------------

For a while, I made some slides for this forum concerning 21 CFR Part 211, ICH Q10, and PIC/S.

You can watch here at http://wp.me/p2EoXX-10X

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President and Principal
http://www.regulatorydoctor.com
Riner VA
United States
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Original Message:
Sent: 10-03-2013 11:50
From: RL Johnson
Subject: FDA requirement for Annual Stability batches

Good Morning,

The annual stability requirements come from two avenues:

1. Your post approval stability commitment that can be found in your dossier (3.2.P.8.2)
2. PIC/S (and yes, FDA is now a member of PIC/S)

I am unable attach the pdf from the PIC/S website but the document(s) you are looking for is:

PE 009-10 Part I for Drug Product
PE 009-10 Part II for Drug Substance

This will give you a clear directive for annual stability pulls as well as a narrative you can cut and paste into your dossier for 3.2.P.8.2.

I hope this helps,
RL

-------------------------------------------
RL Johnson RAC
Consultant, Regulatory Affairs
PAREXEL
Denham Springs LA
United States
-------------------------------------------






Original Message:
Sent: 10-01-2013 11:03
From: Rachel Thornton
Subject: FDA requirement for Annual Stability batches

Does anyone know the source of the requirement for annual stability batches?  In the CFR or a guidance or elsewhere?  I've looked, and I've found in the CFR where it talks about requiring stability data, but since it refers specifically to setting expiry dating, that seems to only apply to initial licensure.  I've not been able to find the specific requirement for putting one batch per year on stability.

This has come up as a general question in my company, but particularly when we are bringing an additional manufacturing facility online, and the question comes up: Do we have to put one batch from each facility on stability, or just one batch of the DS/DP (since the products from the facilities have been shown to be comparable).  I can make the argument that you need a check on both facilities to make sure nothing unexpected is happening with the product, but it would be helpful to have a regulatory reference to back it up.

-------------------------------------------
Rachel Thornton
Associate Director
UCB
Smyrna GA
United States
-------------------------------------------

Rachel,

Under 21 CFR Section 211.166, a firm should have a written stability testing program.

As for test intervals, generally speaking:

every 3 months - 1st year after FDA approval.
every 6 months - 2nd year.
12 months (annually) - from 3rd year and thereafter.

To show your minimum cGMP practice, at least annual testing would be considered "compliant" or "satisfactory" although you may want to test more frequently near the end of the anticipated exp date.

Please read more at http://wp.me/P33LGu-1zw

-------------------------------------------
President and Principal
http://www.regulatorydoctor.com
Riner VA
United States
-------------------------------------------






Original Message:
Sent: 10-01-2013 11:03
From: Rachel Thornton
Subject: FDA requirement for Annual Stability batches

Does anyone know the source of the requirement for annual stability batches?  In the CFR or a guidance or elsewhere?  I've looked, and I've found in the CFR where it talks about requiring stability data, but since it refers specifically to setting expiry dating, that seems to only apply to initial licensure.  I've not been able to find the specific requirement for putting one batch per year on stability.

This has come up as a general question in my company, but particularly when we are bringing an additional manufacturing facility online, and the question comes up: Do we have to put one batch from each facility on stability, or just one batch of the DS/DP (since the products from the facilities have been shown to be comparable).  I can make the argument that you need a check on both facilities to make sure nothing unexpected is happening with the product, but it would be helpful to have a regulatory reference to back it up.

-------------------------------------------
Rachel Thornton
Associate Director
UCB
Smyrna GA
United States
-------------------------------------------