Regulatory Open Forum

We acquired an immediate release oral tablet drug from another company a few years ago. Currently in Phase 2 of development. We have adopted the placebo tablet specification that was established by the previous sponsor. The specification includes tests for Appearance, Micro and Disintegration per USP <701> with a time limit of NMT 15 min. At the 24-month test point, the Disintegration results are trending upward (range 10-13 min depending on the batch). We fear at the 36-month test point we may be OOS. We do not believe the Disintegration test is required for placebo tablets as the test has no impact on safety. The 15 min time limit is not listed in USP <701> so I believe the time limit is established based on what is appropriate for the formulation. We did tweak the formulation slightly to prevent some minor chipping of the tablets that was witnessed with earlier batches. Options include increasing the time limit (ex. to NMT 30 min) or removing the test from the specification altogether. We are leaning toward removing the test. I'm curious what others have experienced as far as inclusion of the Disintegration test for placebos? Do you typically conduct this test on placebo? Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
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This message was posted by a user wishing to remain anonymous

If the active has this test then placebo also need to have the same test, unless you plan to remove for both and go instead for a dissolution test if the time to dissolve is greater than 30 mins.
Original Message:
Sent: 18-Mar-2021 10:29
From: Tom Stothoff
Subject: USP 701 Disintegration Testing of Placebo Tablets

We acquired an immediate release oral tablet drug from another company a few years ago. Currently in Phase 2 of development. We have adopted the placebo tablet specification that was established by the previous sponsor. The specification includes tests for Appearance, Micro and Disintegration per USP <701> with a time limit of NMT 15 min. At the 24-month test point, the Disintegration results are trending upward (range 10-13 min depending on the batch). We fear at the 36-month test point we may be OOS. We do not believe the Disintegration test is required for placebo tablets as the test has no impact on safety. The 15 min time limit is not listed in USP <701> so I believe the time limit is established based on what is appropriate for the formulation. We did tweak the formulation slightly to prevent some minor chipping of the tablets that was witnessed with earlier batches. Options include increasing the time limit (ex. to NMT 30 min) or removing the test from the specification altogether. We are leaning toward removing the test. I'm curious what others have experienced as far as inclusion of the Disintegration test for placebos? Do you typically conduct this test on placebo? Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

Hi Tom,
I have a different take on this to the previous reply - no need for disintegration testing assuming the placebo is a standard IR oral dosage form.
Disintegration change won't impact blinding or patient experience.
Spec for appearance and absence of active should suffice.
Also, if standard IR tablet excipients are used I would even question need for stability at all.  Stability studies are required only in cases where there is reason to suspect that the placebo product will undergo changes in its physical characteristics or degradation eg, hardness or appearance.
Finally, note no need to declare a shelf-life in an IND therefore you can manage shelf-life internally under PQS/GMP & potentially justify any disintegration change as not critical to quality.

------------------------------
Kind regards,
Roy Jamieson (BPharm Hons, GPhC, MTOPRA, MAPS, RAPS)

Regulatory CMC Consultant
OkerPharma Consultancy AB

E: roy.jamieson@btinternet.com
T: +46 (0)708467411
www.linkedin.com/in/roy-jamieson-62019821
------------------------------

Original Message:
Sent: 18-Mar-2021 11:23
From: Anonymous Member
Subject: USP 701 Disintegration Testing of Placebo Tablets

This message was posted by a user wishing to remain anonymous

If the active has this test then placebo also need to have the same test, unless you plan to remove for both and go instead for a dissolution test if the time to dissolve is greater than 30 mins.
Original Message:
Sent: 18-Mar-2021 10:29
From: Tom Stothoff
Subject: USP 701 Disintegration Testing of Placebo Tablets

We acquired an immediate release oral tablet drug from another company a few years ago. Currently in Phase 2 of development. We have adopted the placebo tablet specification that was established by the previous sponsor. The specification includes tests for Appearance, Micro and Disintegration per USP <701> with a time limit of NMT 15 min. At the 24-month test point, the Disintegration results are trending upward (range 10-13 min depending on the batch). We fear at the 36-month test point we may be OOS. We do not believe the Disintegration test is required for placebo tablets as the test has no impact on safety. The 15 min time limit is not listed in USP <701> so I believe the time limit is established based on what is appropriate for the formulation. We did tweak the formulation slightly to prevent some minor chipping of the tablets that was witnessed with earlier batches. Options include increasing the time limit (ex. to NMT 30 min) or removing the test from the specification altogether. We are leaning toward removing the test. I'm curious what others have experienced as far as inclusion of the Disintegration test for placebos? Do you typically conduct this test on placebo? Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

This message was posted by a user wishing to remain anonymous

Isn't there a reason why its called a placebo in an active/placebo study? The EU regulatory interpretation is a bit confusing! At a phase 2 stage, if the disintegration time seems to trend upwards, I'd think that the active tabs also should be trending upwards? You did not talk about the active disintegration results. It may not be a safety issue but it could impact bioavailability/bioeq performance especially if its at phase 2 stage depending on the type of study in a particular therapeutic area..
Original Message:
Sent: 19-Mar-2021 04:05
From: Roy Jamieson
Subject: USP 701 Disintegration Testing of Placebo Tablets

Hi Tom,
I have a different take on this to the previous reply - no need for disintegration testing assuming the placebo is a standard IR oral dosage form.
Disintegration change won't impact blinding or patient experience.
Spec for appearance and absence of active should suffice.
Also, if standard IR tablet excipients are used I would even question need for stability at all.  Stability studies are required only in cases where there is reason to suspect that the placebo product will undergo changes in its physical characteristics or degradation eg, hardness or appearance.
Finally, note no need to declare a shelf-life in an IND therefore you can manage shelf-life internally under PQS/GMP & potentially justify any disintegration change as not critical to quality.

------------------------------
Kind regards,
Roy Jamieson (BPharm Hons, GPhC, MTOPRA, MAPS, RAPS)

Regulatory CMC Consultant
OkerPharma Consultancy AB

E: roy.jamieson@btinternet.com
T: +46 (0)708467411
www.linkedin.com/in/roy-jamieson-62019821

Original Message:
Sent: 18-Mar-2021 11:23
From: Anonymous Member
Subject: USP 701 Disintegration Testing of Placebo Tablets

This message was posted by a user wishing to remain anonymous

If the active has this test then placebo also need to have the same test, unless you plan to remove for both and go instead for a dissolution test if the time to dissolve is greater than 30 mins.
Original Message:
Sent: 18-Mar-2021 10:29
From: Tom Stothoff
Subject: USP 701 Disintegration Testing of Placebo Tablets

We acquired an immediate release oral tablet drug from another company a few years ago. Currently in Phase 2 of development. We have adopted the placebo tablet specification that was established by the previous sponsor. The specification includes tests for Appearance, Micro and Disintegration per USP <701> with a time limit of NMT 15 min. At the 24-month test point, the Disintegration results are trending upward (range 10-13 min depending on the batch). We fear at the 36-month test point we may be OOS. We do not believe the Disintegration test is required for placebo tablets as the test has no impact on safety. The 15 min time limit is not listed in USP <701> so I believe the time limit is established based on what is appropriate for the formulation. We did tweak the formulation slightly to prevent some minor chipping of the tablets that was witnessed with earlier batches. Options include increasing the time limit (ex. to NMT 30 min) or removing the test from the specification altogether. We are leaning toward removing the test. I'm curious what others have experienced as far as inclusion of the Disintegration test for placebos? Do you typically conduct this test on placebo? Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

Apologies for not stating in my original post. We conduct single-point dissolution at 45 min for the active tablets. This is also a global program so we have an IND as well as an IMPD for Canada/EU.

------------------------------
Tom Stothoff
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

Original Message:
Sent: 19-Mar-2021 09:39
From: Anonymous Member
Subject: USP 701 Disintegration Testing of Placebo Tablets

This message was posted by a user wishing to remain anonymous

Isn't there a reason why its called a placebo in an active/placebo study? The EU regulatory interpretation is a bit confusing! At a phase 2 stage, if the disintegration time seems to trend upwards, I'd think that the active tabs also should be trending upwards? You did not talk about the active disintegration results. It may not be a safety issue but it could impact bioavailability/bioeq performance especially if its at phase 2 stage depending on the type of study in a particular therapeutic area..
Original Message:
Sent: 19-Mar-2021 04:05
From: Roy Jamieson
Subject: USP 701 Disintegration Testing of Placebo Tablets

Hi Tom,
I have a different take on this to the previous reply - no need for disintegration testing assuming the placebo is a standard IR oral dosage form.
Disintegration change won't impact blinding or patient experience.
Spec for appearance and absence of active should suffice.
Also, if standard IR tablet excipients are used I would even question need for stability at all.  Stability studies are required only in cases where there is reason to suspect that the placebo product will undergo changes in its physical characteristics or degradation eg, hardness or appearance.
Finally, note no need to declare a shelf-life in an IND therefore you can manage shelf-life internally under PQS/GMP & potentially justify any disintegration change as not critical to quality.

------------------------------
Kind regards,
Roy Jamieson (BPharm Hons, GPhC, MTOPRA, MAPS, RAPS)

Regulatory CMC Consultant
OkerPharma Consultancy AB

E: roy.jamieson@btinternet.com
T: +46 (0)708467411
www.linkedin.com/in/roy-jamieson-62019821

Original Message:
Sent: 18-Mar-2021 11:23
From: Anonymous Member
Subject: USP 701 Disintegration Testing of Placebo Tablets

This message was posted by a user wishing to remain anonymous

If the active has this test then placebo also need to have the same test, unless you plan to remove for both and go instead for a dissolution test if the time to dissolve is greater than 30 mins.
Original Message:
Sent: 18-Mar-2021 10:29
From: Tom Stothoff
Subject: USP 701 Disintegration Testing of Placebo Tablets

We acquired an immediate release oral tablet drug from another company a few years ago. Currently in Phase 2 of development. We have adopted the placebo tablet specification that was established by the previous sponsor. The specification includes tests for Appearance, Micro and Disintegration per USP <701> with a time limit of NMT 15 min. At the 24-month test point, the Disintegration results are trending upward (range 10-13 min depending on the batch). We fear at the 36-month test point we may be OOS. We do not believe the Disintegration test is required for placebo tablets as the test has no impact on safety. The 15 min time limit is not listed in USP <701> so I believe the time limit is established based on what is appropriate for the formulation. We did tweak the formulation slightly to prevent some minor chipping of the tablets that was witnessed with earlier batches. Options include increasing the time limit (ex. to NMT 30 min) or removing the test from the specification altogether. We are leaning toward removing the test. I'm curious what others have experienced as far as inclusion of the Disintegration test for placebos? Do you typically conduct this test on placebo? Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------

I have found that placebo testing varies depending on company philosophy, all of which will work. Conservatively, disintegration may be part of placebo testing to ensure that the blind is maintained (i.e. if the tablet does not disintegrate at all, then could affect the blind). We typically also test for absence of active, which I do not see part of your testing, that can potentially avoid a lot of headaches in the future.

------------------------------
Robert Blanks RAC
VP, Regulatory Affairs and Quality Assurance
[Ardelyx]
Auburndale MA
United States
------------------------------

Original Message:
Sent: 18-Mar-2021 10:29
From: Tom Stothoff
Subject: USP 701 Disintegration Testing of Placebo Tablets

We acquired an immediate release oral tablet drug from another company a few years ago. Currently in Phase 2 of development. We have adopted the placebo tablet specification that was established by the previous sponsor. The specification includes tests for Appearance, Micro and Disintegration per USP <701> with a time limit of NMT 15 min. At the 24-month test point, the Disintegration results are trending upward (range 10-13 min depending on the batch). We fear at the 36-month test point we may be OOS. We do not believe the Disintegration test is required for placebo tablets as the test has no impact on safety. The 15 min time limit is not listed in USP <701> so I believe the time limit is established based on what is appropriate for the formulation. We did tweak the formulation slightly to prevent some minor chipping of the tablets that was witnessed with earlier batches. Options include increasing the time limit (ex. to NMT 30 min) or removing the test from the specification altogether. We are leaning toward removing the test. I'm curious what others have experienced as far as inclusion of the Disintegration test for placebos? Do you typically conduct this test on placebo? Thank you.

------------------------------
Tom
Senior Director, Regulatory Affairs CMC
Chicago
------------------------------