Regulatory Open Forum

Hi everyone,
In the CMC portions of drug and biologic applications, calculation of safety margins for exposure to various impurities are often made using average body weight assumptions. Over the years I've seen various values for this factor: 60 kg, 70 kg, 80 kg, etc. These assumptions often don't take into account the global range of body weights; an American male weighs a lot more than a Japanese female. What strategies are people using in their own companies? What single/range of body weights do you use for your calculations? What is this value based on? Are there guidances or authoritative references of value on this point?
Thanks in advance for your insights!
Bem

------------------------------
Bem Atsma MS RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------

Bem - ICH M7 uses 50 kg as the standard weight with the justification that this relatively low weight provides an additional safety factor against the standard weights of 60
kg or 70 kg that are often used in this type of calculation.

------------------------------
Glen Park PharmD
Executive Director, Regulatory Affairs and Quality Assurance
Jersey City NJ
United States
------------------------------

Original Message:
Sent: 21-Feb-2019 10:24
From: Bem Atsma
Subject: Average Body Weight for toxicology considerations?

Hi everyone,
In the CMC portions of drug and biologic applications, calculation of safety margins for exposure to various impurities are often made using average body weight assumptions. Over the years I've seen various values for this factor: 60 kg, 70 kg, 80 kg, etc. These assumptions often don't take into account the global range of body weights; an American male weighs a lot more than a Japanese female. What strategies are people using in their own companies? What single/range of body weights do you use for your calculations? What is this value based on? Are there guidances or authoritative references of value on this point?
Thanks in advance for your insights!
Bem

------------------------------
Bem Atsma MS RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------

Are you looking for an authoritative source for "average" body weight(s), or a source that might tell you whether an assumption about the relationship between body weight and safety margin is likely to hold equally true for body weights at the farther ends of the bell curve?

------------------------------
Julie Omohundro, ex-RAC (US, GS), still an MBA
Principal Consultant
Class Three, LLC
Mebane, North Carolina, USA
919-544-3366 (T)
434-964-1614 (C)
julie@class3devices.com
------------------------------

Original Message:
Sent: 21-Feb-2019 10:24
From: Bem Atsma
Subject: Average Body Weight for toxicology considerations?

Hi everyone,
In the CMC portions of drug and biologic applications, calculation of safety margins for exposure to various impurities are often made using average body weight assumptions. Over the years I've seen various values for this factor: 60 kg, 70 kg, 80 kg, etc. These assumptions often don't take into account the global range of body weights; an American male weighs a lot more than a Japanese female. What strategies are people using in their own companies? What single/range of body weights do you use for your calculations? What is this value based on? Are there guidances or authoritative references of value on this point?
Thanks in advance for your insights!
Bem

------------------------------
Bem Atsma MS RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------

Hi Bem,

When it comes to tox. assessments you could check out one of the appendices of ISO 10993-17 (that's the standard used for medical devices for tolearble intake/MOS caculations). There is a reference list of body weights you can use for MOS calculations, e.g. 70kg for an adult male and 3.5kg for a neonate. Those weights are well established for device tox. assessments and are also used by all biocomp. labs I have been working with so far.

Kind regards,
Michael

------------------------------
Michael Hottner
Köln
Germany
------------------------------

Original Message:
Sent: 21-Feb-2019 10:24
From: Bem Atsma
Subject: Average Body Weight for toxicology considerations?

Hi everyone,
In the CMC portions of drug and biologic applications, calculation of safety margins for exposure to various impurities are often made using average body weight assumptions. Over the years I've seen various values for this factor: 60 kg, 70 kg, 80 kg, etc. These assumptions often don't take into account the global range of body weights; an American male weighs a lot more than a Japanese female. What strategies are people using in their own companies? What single/range of body weights do you use for your calculations? What is this value based on? Are there guidances or authoritative references of value on this point?
Thanks in advance for your insights!
Bem

------------------------------
Bem Atsma MS RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------

Hi Bern.
Let me contribute my 2 cents. As a Toxicologist who has prepared >100 safety assessments for the FDA, I have used only the 60 kg factor. Although I agree with the proposal that 50 kg affords an additional safety margin, I would go with 60 kg. The important  aspect of the SM value, regardless of the weight uses, is its magnitude. If with 60 kg you are >10 it will be acceptable for the qualification. If <5,  you will need a WoE approach, and as I have done in the past, to use other considerations and data to provide more than one SM based on different assumptions.

Good Luck

Ron Filler
Toxicologist 
Drug Development Consultants, LLC
Bedminster, NJ
​

------------------------------
Ron Filler PhD
Pres & CEO
Bedminster NJ
United States
------------------------------

Original Message:
Sent: 21-Feb-2019 10:24
From: Bem Atsma
Subject: Average Body Weight for toxicology considerations?

Hi everyone,
In the CMC portions of drug and biologic applications, calculation of safety margins for exposure to various impurities are often made using average body weight assumptions. Over the years I've seen various values for this factor: 60 kg, 70 kg, 80 kg, etc. These assumptions often don't take into account the global range of body weights; an American male weighs a lot more than a Japanese female. What strategies are people using in their own companies? What single/range of body weights do you use for your calculations? What is this value based on? Are there guidances or authoritative references of value on this point?
Thanks in advance for your insights!
Bem

------------------------------
Bem Atsma MS RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------

Thanks for the input, everyone!
What about if a drug isn't a fixed dose drug but rather administered per body weight? In this case, someone weighing 80kg would be dosed with more drug than someone weighing 50kg. So then would it be advisable to use a higher body weight when considering worse case scenarios for impurity exposures and safety margins?

------------------------------
Bem Atsma RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------

Original Message:
Sent: 23-Feb-2019 11:25
From: Ron Filler
Subject: Average Body Weight for toxicology considerations?

Hi Bern.
Let me contribute my 2 cents. As a Toxicologist who has prepared >100 safety assessments for the FDA, I have used only the 60 kg factor. Although I agree with the proposal that 50 kg affords an additional safety margin, I would go with 60 kg. The important  aspect of the SM value, regardless of the weight uses, is its magnitude. If with 60 kg you are >10 it will be acceptable for the qualification. If <5,  you will need a WoE approach, and as I have done in the past, to use other considerations and data to provide more than one SM based on different assumptions.

Good Luck

Ron Filler
Toxicologist
Drug Development Consultants, LLC
Bedminster, NJ
​

------------------------------
Ron Filler PhD
Pres & CEO
Bedminster NJ
United States

Original Message:
Sent: 21-Feb-2019 10:24
From: Bem Atsma
Subject: Average Body Weight for toxicology considerations?

Hi everyone,
In the CMC portions of drug and biologic applications, calculation of safety margins for exposure to various impurities are often made using average body weight assumptions. Over the years I've seen various values for this factor: 60 kg, 70 kg, 80 kg, etc. These assumptions often don't take into account the global range of body weights; an American male weighs a lot more than a Japanese female. What strategies are people using in their own companies? What single/range of body weights do you use for your calculations? What is this value based on? Are there guidances or authoritative references of value on this point?
Thanks in advance for your insights!
Bem

------------------------------
Bem Atsma MS RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------

We use 70 mg/kg when making assumptions on doses per bodyweight. It is on the more conservative side but works well for a global assumption. We use this value for anything that requires a bodyweight assumption, including but not limited to safety margins, endotoxin limits and drug supply.

------------------------------
Erica Reeves
Regulatory Affairs Manager
Seattle WA
United States
------------------------------

Original Message:
Sent: 06-Mar-2019 16:14
From: Bem Atsma
Subject: Average Body Weight for toxicology considerations?

Thanks for the input, everyone!
What about if a drug isn't a fixed dose drug but rather administered per body weight? In this case, someone weighing 80kg would be dosed with more drug than someone weighing 50kg. So then would it be advisable to use a higher body weight when considering worse case scenarios for impurity exposures and safety margins?

------------------------------
Bem Atsma RAC
Associate Director, Regulatory CMC
Cambridge MA
United States

Original Message:
Sent: 23-Feb-2019 11:25
From: Ron Filler
Subject: Average Body Weight for toxicology considerations?

Hi Bern.
Let me contribute my 2 cents. As a Toxicologist who has prepared >100 safety assessments for the FDA, I have used only the 60 kg factor. Although I agree with the proposal that 50 kg affords an additional safety margin, I would go with 60 kg. The important  aspect of the SM value, regardless of the weight uses, is its magnitude. If with 60 kg you are >10 it will be acceptable for the qualification. If <5,  you will need a WoE approach, and as I have done in the past, to use other considerations and data to provide more than one SM based on different assumptions.

Good Luck

Ron Filler
Toxicologist
Drug Development Consultants, LLC
Bedminster, NJ
​

------------------------------
Ron Filler PhD
Pres & CEO
Bedminster NJ
United States

Original Message:
Sent: 21-Feb-2019 10:24
From: Bem Atsma
Subject: Average Body Weight for toxicology considerations?

Hi everyone,
In the CMC portions of drug and biologic applications, calculation of safety margins for exposure to various impurities are often made using average body weight assumptions. Over the years I've seen various values for this factor: 60 kg, 70 kg, 80 kg, etc. These assumptions often don't take into account the global range of body weights; an American male weighs a lot more than a Japanese female. What strategies are people using in their own companies? What single/range of body weights do you use for your calculations? What is this value based on? Are there guidances or authoritative references of value on this point?
Thanks in advance for your insights!
Bem

------------------------------
Bem Atsma MS RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------

Thanks, Erica. What if you routine dose is 70mg/kg or even higher? I expect you are thinking 70mg/kg is some factor higher than your routine dose? 

Your response though makes me think maybe you can look at worse case conditions in two ways:
1) Do some calculations with a high body mass (maybe 80kg) to look at how much might be dosed in that situation.
2) Do some calculations with a high per-weight dosage (maybe 10 fold higher than expected) to look at that (overdosage) situation.

------------------------------
Bem Atsma RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------

Original Message:
Sent: 07-Mar-2019 11:11
From: Erica Reeves
Subject: Average Body Weight for toxicology considerations?

We use 70 mg/kg when making assumptions on doses per bodyweight. It is on the more conservative side but works well for a global assumption. We use this value for anything that requires a bodyweight assumption, including but not limited to safety margins, endotoxin limits and drug supply.

------------------------------
Erica Reeves
Regulatory Affairs Manager
Seattle WA
United States

Original Message:
Sent: 06-Mar-2019 16:14
From: Bem Atsma
Subject: Average Body Weight for toxicology considerations?

Thanks for the input, everyone!
What about if a drug isn't a fixed dose drug but rather administered per body weight? In this case, someone weighing 80kg would be dosed with more drug than someone weighing 50kg. So then would it be advisable to use a higher body weight when considering worse case scenarios for impurity exposures and safety margins?

------------------------------
Bem Atsma RAC
Associate Director, Regulatory CMC
Cambridge MA
United States

Original Message:
Sent: 23-Feb-2019 11:25
From: Ron Filler
Subject: Average Body Weight for toxicology considerations?

Hi Bern.
Let me contribute my 2 cents. As a Toxicologist who has prepared >100 safety assessments for the FDA, I have used only the 60 kg factor. Although I agree with the proposal that 50 kg affords an additional safety margin, I would go with 60 kg. The important  aspect of the SM value, regardless of the weight uses, is its magnitude. If with 60 kg you are >10 it will be acceptable for the qualification. If <5,  you will need a WoE approach, and as I have done in the past, to use other considerations and data to provide more than one SM based on different assumptions.

Good Luck

Ron Filler
Toxicologist
Drug Development Consultants, LLC
Bedminster, NJ
​

------------------------------
Ron Filler PhD
Pres & CEO
Bedminster NJ
United States

Original Message:
Sent: 21-Feb-2019 10:24
From: Bem Atsma
Subject: Average Body Weight for toxicology considerations?

Hi everyone,
In the CMC portions of drug and biologic applications, calculation of safety margins for exposure to various impurities are often made using average body weight assumptions. Over the years I've seen various values for this factor: 60 kg, 70 kg, 80 kg, etc. These assumptions often don't take into account the global range of body weights; an American male weighs a lot more than a Japanese female. What strategies are people using in their own companies? What single/range of body weights do you use for your calculations? What is this value based on? Are there guidances or authoritative references of value on this point?
Thanks in advance for your insights!
Bem

------------------------------
Bem Atsma MS RAC
Associate Director, Regulatory CMC
Cambridge MA
United States
------------------------------