November 1, 2022 • 13 mins
Bringing a drug or device to market can be arduous. In this interview with Debra Barngrover of Biologics Consulting, we learn how a consultant can help bring your picture into focus. Guest: Debra Barngrover Host: James C. Taylor
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:01):
our company name is biologics consulting.
And the reason for that is we are consultants but what would you use a consultant for joining me is Deborah barn Grover to talk about why you would hire a consultant,
this is inside of biologics.
(00:29):
And with me now is Deborah barn Grover and Debra.
Why don't you tell them a little bit about yourself?
Okay.
Well I've been with biologics consulting for a little over 11 years now as a senior consultant in the chemistry manufacturing and controls area called CMC.
Prior to that I was in industry with both small and large companies helping develop a wide variety of products proteins,
(00:52):
gene therapy,
cell therapy,
small molecules devices,
you name it?
We we developed it.
So I have I have a lot of background in both process development and now regulations of those products and how to get them approved by the various agencies.
Okay thank you for sharing that.
And the crux of what we're going to talk about today is the various things that we can do for people as biological logic consulting.
(01:20):
What are our services that we we provide?
Just an example.
Well an example is a regulatory gap analysis which is how we often start a lot of our engagements with clients and a regulatory gap analysis is where we look at what studies that the sponsor has done today to both develop and validate the product and tests and then what needs to be done and compare that to what needs to be done for the next stage.
(01:48):
Either the initial idea.
Phase 23 I.
N.
D.
Or B.
L.
A.
And so the company this really gives them an idea of what further work they need to do,
how much more development they need to get to sort of to the finish line,
whatever that is at this point in time.
And the real goal is then to be minimizing requests from the agency is they're reviewing the I.
N.
D.
B.
L.
A.
(02:08):
For missing studies and data because those requests will always delay your review and approval of wherever you want to be.
And so the idea is that you're you're developing this regulatory strategy if you will for how you're going to get to that next stage of your development process.
Okay.
And as the gap analysis limited in terms of who can take advantage of it?
(02:37):
No,
certainly not any company large or small can take advantage of that.
And I'll give an example of where we had a specific case study where the gap analysis led to a very successful development strategy for unique situation.
You know,
each product and process is very unique.
The guidances are very general and so it's always a case of how do you apply those guidances to your specific case?
(03:02):
And that's what we do a lot of so we had a small company that came to us that it in licensed and approved drug from a much larger company.
Uh the part of why the large company was wanting to sell this product off is the CMO that had made it for 16 years was going out of business.
And so the first thing the small company had to do was find a new CMO and then transfer this process,
(03:24):
get it validated so that they could continue to make the product and sell it.
But since it was a very small market doing a full validation program of three large run,
I was just going to make so much product,
it was going to financially ruin the company.
They just couldn't afford to make that much product.
And so we developed a strategy and actually worked it with the FDA and modify this.
(03:47):
That because the,
the equipment was being transferred from the previous CMO to the new O C M.
O.
We could support the validation just by doing a lot of equipment validation and qualification,
not having to actually run the full process.
And in the end they only had to run one run split into three key steps that they could get data from three different run,
(04:09):
so to speak.
And that was sufficient to satisfy the FDA requirements for validation.
And that is an example of,
of a situation with a a smaller sized company.
But do we ever do this sort of work for larger companies?
We definitely do.
(04:30):
And that's often in conjunction with a large writing project that the company is,
is faced with,
such as a meeting package or often a B L.
A large companies don't really want to maintain a large in house regulatory team that only gets used from time to time because they're not writing blogs constantly and so what or they don't want to pull the subject matter experts from their normal day jobs to write the BLS.
(04:56):
So we will come in with a team of highly trained writers.
The first step again will be a gap analysis just against,
you know,
what are the B.
L.
A.
Requirements?
What what studies do they have,
what studies are still coming,
What studies do they probably need to think about?
And then we can turn to writing the B.
L.
A.
We're very adaptable to the working and writing styles of different companies because we've done a lot of different ones,
(05:18):
but we're knowledgeable of all the nuances that the FDA and or other agencies are looking for because again,
not everything is in guidance is a lot of times,
it's just knowledge of having written several documents like this in the,
in the past and bringing that knowledge to the writing project to make it more effective and more efficient.
(05:40):
Now,
our consultants here have extensive process development experience.
So do we ever provide process development troubleshooting for people who are in a bit of a jam?
Absolutely.
That's another key piece of what I do.
It might be very simple questions about,
(06:01):
you know,
I've got an essay that's not working,
what can we look at there or it might be a much more involved one.
And a specific case that happened not too long ago is we had a manufacturer of a product that was a mixture of peptides.
And the problem was is they made one drug product just fine looked great and they went to make their second run and suddenly the peptides were degrading very severely during the manufacture of the drug product.
(06:28):
So we performed a very complete root cause analysis investigating over 60 potential root causes and finally narrowed it down to three.
It was such a complex process that there were actually three different root causes involved.
And so the first one is,
it turned out that the synthesized peptides that they've gotten from some new lots had quite extensive heavy metal elemental impurity contamination in the peptides.
(06:52):
And we traced it back to the manufacturer who eventually confessed that a plant engineer had gone to their local hardware store and replace some of the hardware on the purification equipment with some brass pieces instead of sustain this deal that they were supposed to use.
And so this these brass pieces were leeching lots of heavy metals into the peptides.
So we had a long talk with that manufacturer about good manufacturing practices and you know,
(07:18):
making sure that you don't substitute equipment when it's not the appropriate quality.
And they also instituted a quality agreement between the drug product manufacturer and the peptide manufacturers so that the peptide manufacturer would alert the sponsor when there were changes made in their manufacturing process so that they wouldn't have this kind of surprise happening.
But that that wasn't enough.
(07:39):
Even when we got cleaner peptides,
we discovered that the formulation which had basically just been kind of pulled off the shelf was just not sufficiently robust if you will to accommodate any potential peptide impurities and manufacturing variation.
And so we instituted a crash formulation development program to help them come up with a more stable and robust formulation.
(08:03):
And lastly,
we discovered that the larger scale drug product manufacturing,
which is what they've done for their second run,
meant that they had a longer manufacturing process that higher temperatures which in and of itself accelerated this degradation that we were seeing.
So we had to rework the manufacturing process to minimize the that time frame and higher temperatures.
(08:23):
And when they instituted all these changes,
we had been successful drug product changes so we can work,
you know,
in,
as I said,
very short term quick answers or very detailed analysis as we have done in this case.
Alright,
so you can break it down like,
you know,
you were Sherlock Holmes analyzing a case in terms of this was not just a single element.
(08:47):
There were it was it was a cascade of things,
several things all contributing to the degradation and you can do that I'm assuming because of the years of expertise that you and the others in in the department have correct?
That's correct.
We've learned to look at the big picture.
You know you never want to stop at the first root cause you find because often you know that might answer part of the question but you fix that and you know something else then becomes the issue and you haven't really fixed the overall process.
(09:16):
So that's why we've learned to do what we know is very extensive root cause analysis and make sure we look at all possible factors.
Not just the first one we find it also sounds like there's a little bit of teaching involved because the fellow that decided that it really didn't matter what type of nuts and bolts he used created at least part of the problem.
(09:39):
And so not only did you have to find out that was the problem,
but you had to remind the manufacturer that you need to do.
You follow the good manufacturing practice?
When I first started in this industry,
I started in the S.
O.
P.
S.
And I wondered why we had so many instructions on how you do this and you and the way you do this.
(10:03):
And then as a story such as yours comes along,
it becomes clear why you have to follow the good clinical practice and the other parameters that are established in order to run uh development processes.
Am I correct in that very definitely,
you know a lot of people look at the good Manufacturing practice guidelines and think it is,
(10:26):
you know,
very long and detailed,
but they're all developed from experience,
you know,
the FDA and the MEA and other health authorities have done a lot of inspections of plants,
they've seen a lot of issues come across,
so they have learned,
you know,
what things can go wrong and that's why they write these good manufacturing practice guidelines to cover a whole host of different sorts of ways that you can best control your manufacturing process and,
(10:53):
you know,
make sure that you produce a quality product uh every time.
And that's the main issue thing that we always want to think about when we're in the pharmaceutical manufacturing is the patient who expects to have that quality product and expects to have it every time they take it.
And that's what we're always aiming for.
Awesome.
(11:13):
Now,
you mentioned that one of the things that using our services can do for people is that it can reduce the amount of wasted time that you company might experience if they were trying to do things that they didn't either have the staff for or the knowledge for.
And in this industry,
(11:36):
would it be fair to say that time really is money.
Oh absolutely.
The faster you can get a product on the market,
the faster you can,
you know,
start to recoup some of your investment in the very involved development and clinical development process.
So,
you know,
reducing your B.
L.
A.
Writing from two years to a year or less is you know it could be several million dollars of revenue that you now can obtain based on that.
(12:01):
It certainly outweighs the cost of the of you know we bring in terms of being able to write that the L.
A.
Much faster,
awesome.
And is there anything else about what we provide that you would want people to know?
Well you mentioned training and that is certainly something that we do sort of on a daily basis as part of providing advice and consultation to our clients.
(12:28):
We also do develop standardized training courses on demand or as part of a working with other with specific training companies.
And so there's several times that a client will come to us and they want a specific GMP type related course that cover certain topics that we can certainly develop for them based on our expertise.
(12:51):
Thank you to Deborah barn Grover for joining us if you'd like more information,
just email us at insight at biologics consulting dot com.
That's insight at biologics,
consulting all one word dot com.
The executive producer of incited biologics is chris cray Hansel.
This episode is produced and edited by James Taylor.
Technical supervisor is Jeff.
The incited biologics theme is by tom Rory Parsons.
(13:13):
I'm James Taylor thank you for joining us.
our company name is biologics consulting.
And the reason for that is we are consultants but what would you use a consultant for joining me is Deborah barn Grover to talk about why you would hire a consultant,
this is inside of biologics.
(00:29):
And with me now is Deborah barn Grover and Debra.
Why don't you tell them a little bit about yourself?
Okay.
Well I've been with biologics consulting for a little over 11 years now as a senior consultant in the chemistry manufacturing and controls area called CMC.
Prior to that I was in industry with both small and large companies helping develop a wide variety of products proteins,
(00:52):
gene therapy,
cell therapy,
small molecules devices,
you name it?
We we developed it.
So I have I have a lot of background in both process development and now regulations of those products and how to get them approved by the various agencies.
Okay thank you for sharing that.
And the crux of what we're going to talk about today is the various things that we can do for people as biological logic consulting.
(01:20):
What are our services that we we provide?
Just an example.
Well an example is a regulatory gap analysis which is how we often start a lot of our engagements with clients and a regulatory gap analysis is where we look at what studies that the sponsor has done today to both develop and validate the product and tests and then what needs to be done and compare that to what needs to be done for the next stage.
(01:48):
Either the initial idea.
Phase 23 I.
N.
D.
Or B.
L.
A.
And so the company this really gives them an idea of what further work they need to do,
how much more development they need to get to sort of to the finish line,
whatever that is at this point in time.
And the real goal is then to be minimizing requests from the agency is they're reviewing the I.
N.
D.
B.
L.
A.
(02:08):
For missing studies and data because those requests will always delay your review and approval of wherever you want to be.
And so the idea is that you're you're developing this regulatory strategy if you will for how you're going to get to that next stage of your development process.
Okay.
And as the gap analysis limited in terms of who can take advantage of it?
(02:37):
No,
certainly not any company large or small can take advantage of that.
And I'll give an example of where we had a specific case study where the gap analysis led to a very successful development strategy for unique situation.
You know,
each product and process is very unique.
The guidances are very general and so it's always a case of how do you apply those guidances to your specific case?
(03:02):
And that's what we do a lot of so we had a small company that came to us that it in licensed and approved drug from a much larger company.
Uh the part of why the large company was wanting to sell this product off is the CMO that had made it for 16 years was going out of business.
And so the first thing the small company had to do was find a new CMO and then transfer this process,
(03:24):
get it validated so that they could continue to make the product and sell it.
But since it was a very small market doing a full validation program of three large run,
I was just going to make so much product,
it was going to financially ruin the company.
They just couldn't afford to make that much product.
And so we developed a strategy and actually worked it with the FDA and modify this.
(03:47):
That because the,
the equipment was being transferred from the previous CMO to the new O C M.
O.
We could support the validation just by doing a lot of equipment validation and qualification,
not having to actually run the full process.
And in the end they only had to run one run split into three key steps that they could get data from three different run,
(04:09):
so to speak.
And that was sufficient to satisfy the FDA requirements for validation.
And that is an example of,
of a situation with a a smaller sized company.
But do we ever do this sort of work for larger companies?
We definitely do.
(04:30):
And that's often in conjunction with a large writing project that the company is,
is faced with,
such as a meeting package or often a B L.
A large companies don't really want to maintain a large in house regulatory team that only gets used from time to time because they're not writing blogs constantly and so what or they don't want to pull the subject matter experts from their normal day jobs to write the BLS.
(04:56):
So we will come in with a team of highly trained writers.
The first step again will be a gap analysis just against,
you know,
what are the B.
L.
A.
Requirements?
What what studies do they have,
what studies are still coming,
What studies do they probably need to think about?
And then we can turn to writing the B.
L.
A.
We're very adaptable to the working and writing styles of different companies because we've done a lot of different ones,
(05:18):
but we're knowledgeable of all the nuances that the FDA and or other agencies are looking for because again,
not everything is in guidance is a lot of times,
it's just knowledge of having written several documents like this in the,
in the past and bringing that knowledge to the writing project to make it more effective and more efficient.
(05:40):
Now,
our consultants here have extensive process development experience.
So do we ever provide process development troubleshooting for people who are in a bit of a jam?
Absolutely.
That's another key piece of what I do.
It might be very simple questions about,
(06:01):
you know,
I've got an essay that's not working,
what can we look at there or it might be a much more involved one.
And a specific case that happened not too long ago is we had a manufacturer of a product that was a mixture of peptides.
And the problem was is they made one drug product just fine looked great and they went to make their second run and suddenly the peptides were degrading very severely during the manufacture of the drug product.
(06:28):
So we performed a very complete root cause analysis investigating over 60 potential root causes and finally narrowed it down to three.
It was such a complex process that there were actually three different root causes involved.
And so the first one is,
it turned out that the synthesized peptides that they've gotten from some new lots had quite extensive heavy metal elemental impurity contamination in the peptides.
(06:52):
And we traced it back to the manufacturer who eventually confessed that a plant engineer had gone to their local hardware store and replace some of the hardware on the purification equipment with some brass pieces instead of sustain this deal that they were supposed to use.
And so this these brass pieces were leeching lots of heavy metals into the peptides.
So we had a long talk with that manufacturer about good manufacturing practices and you know,
(07:18):
making sure that you don't substitute equipment when it's not the appropriate quality.
And they also instituted a quality agreement between the drug product manufacturer and the peptide manufacturers so that the peptide manufacturer would alert the sponsor when there were changes made in their manufacturing process so that they wouldn't have this kind of surprise happening.
But that that wasn't enough.
(07:39):
Even when we got cleaner peptides,
we discovered that the formulation which had basically just been kind of pulled off the shelf was just not sufficiently robust if you will to accommodate any potential peptide impurities and manufacturing variation.
And so we instituted a crash formulation development program to help them come up with a more stable and robust formulation.
(08:03):
And lastly,
we discovered that the larger scale drug product manufacturing,
which is what they've done for their second run,
meant that they had a longer manufacturing process that higher temperatures which in and of itself accelerated this degradation that we were seeing.
So we had to rework the manufacturing process to minimize the that time frame and higher temperatures.
(08:23):
And when they instituted all these changes,
we had been successful drug product changes so we can work,
you know,
in,
as I said,
very short term quick answers or very detailed analysis as we have done in this case.
Alright,
so you can break it down like,
you know,
you were Sherlock Holmes analyzing a case in terms of this was not just a single element.
(08:47):
There were it was it was a cascade of things,
several things all contributing to the degradation and you can do that I'm assuming because of the years of expertise that you and the others in in the department have correct?
That's correct.
We've learned to look at the big picture.
You know you never want to stop at the first root cause you find because often you know that might answer part of the question but you fix that and you know something else then becomes the issue and you haven't really fixed the overall process.
(09:16):
So that's why we've learned to do what we know is very extensive root cause analysis and make sure we look at all possible factors.
Not just the first one we find it also sounds like there's a little bit of teaching involved because the fellow that decided that it really didn't matter what type of nuts and bolts he used created at least part of the problem.
(09:39):
And so not only did you have to find out that was the problem,
but you had to remind the manufacturer that you need to do.
You follow the good manufacturing practice?
When I first started in this industry,
I started in the S.
O.
P.
S.
And I wondered why we had so many instructions on how you do this and you and the way you do this.
(10:03):
And then as a story such as yours comes along,
it becomes clear why you have to follow the good clinical practice and the other parameters that are established in order to run uh development processes.
Am I correct in that very definitely,
you know a lot of people look at the good Manufacturing practice guidelines and think it is,
(10:26):
you know,
very long and detailed,
but they're all developed from experience,
you know,
the FDA and the MEA and other health authorities have done a lot of inspections of plants,
they've seen a lot of issues come across,
so they have learned,
you know,
what things can go wrong and that's why they write these good manufacturing practice guidelines to cover a whole host of different sorts of ways that you can best control your manufacturing process and,
(10:53):
you know,
make sure that you produce a quality product uh every time.
And that's the main issue thing that we always want to think about when we're in the pharmaceutical manufacturing is the patient who expects to have that quality product and expects to have it every time they take it.
And that's what we're always aiming for.
Awesome.
(11:13):
Now,
you mentioned that one of the things that using our services can do for people is that it can reduce the amount of wasted time that you company might experience if they were trying to do things that they didn't either have the staff for or the knowledge for.
And in this industry,
(11:36):
would it be fair to say that time really is money.
Oh absolutely.
The faster you can get a product on the market,
the faster you can,
you know,
start to recoup some of your investment in the very involved development and clinical development process.
So,
you know,
reducing your B.
L.
A.
Writing from two years to a year or less is you know it could be several million dollars of revenue that you now can obtain based on that.
(12:01):
It certainly outweighs the cost of the of you know we bring in terms of being able to write that the L.
A.
Much faster,
awesome.
And is there anything else about what we provide that you would want people to know?
Well you mentioned training and that is certainly something that we do sort of on a daily basis as part of providing advice and consultation to our clients.
(12:28):
We also do develop standardized training courses on demand or as part of a working with other with specific training companies.
And so there's several times that a client will come to us and they want a specific GMP type related course that cover certain topics that we can certainly develop for them based on our expertise.
(12:51):
Thank you to Deborah barn Grover for joining us if you'd like more information,
just email us at insight at biologics consulting dot com.
That's insight at biologics,
consulting all one word dot com.
The executive producer of incited biologics is chris cray Hansel.
This episode is produced and edited by James Taylor.
Technical supervisor is Jeff.
The incited biologics theme is by tom Rory Parsons.
(13:13):
I'm James Taylor thank you for joining us.
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