4 ms·

Is there any frontline research that addresses this you could refer me to? From my very limited knowledge, this is currently what is preventing biosimilar drugs

Is there any frontline research that addresses this you could refer me to? From my very limited knowledge, this is currently what is preventing biosimilar drugs from reducing the cost of expensive biologic drugs (e.g. Insulin and other enzyme based orphan drugs) unlike generics for regular drugs

mattkrause 4y ago
Some keywords you might want to try include: - Replication error: copying DNA, transcribing it into RNA, and translating that into proteins uses processes that make mistakes. There are all sorts of interesting mechanisms for catching these, both in vivo and during sequencing. Try here for error rates: https://pubmed.ncbi.nlm.nih.gov/1805967/ https://pubmed.ncbi.nlm.nih.gov/1805967/ - Spontaneous mutation: A consequence of replication errors is that unwanted genomic changes sometimes arise in engineered organisms: you carefully make bacteria—-or a mouse—-with one mutation, but it develops another. Say “spontaneous mutation” around a large enough group of grad students and one will cry because it can derail experiments in hard-to-control ways https://pubmed.ncbi.nlm.nih.gov/ https://pubmed.ncbi.nlm.nih.gov/ Everything in biology is full of feedback loops and compensatory mechanisms. Knocking out one gene or brain region may have a direct effect on some output, but may also affect a bunch of other genes/regions (in many ways), which in turn…
trap_goes_hot 4y ago
I am not aware of any research that is addressing heterogeneity issues in a general way. (Caveat: Not a formally trained scientist, I work in manufacturing) One of the products we manufacture is a protein that is expressed by an organism that we engineered (recombinant dna). The way we (and everyone else) achieve homogeneity is by purifying the protein. We develop this purification strategy at the research stage, after we characterize the protein (solubility, stability, size, hydrophobicity, etc). As 'research' turns into 'product', we iterate over this to improve yield, minimize processing times, lower raw material costs, etc and come up with an effective manufacturing process that we can make money on. I liked the article, but in my opinion, the 'personal biomaker' idea is something we are not close to implementing given the state of tech we currently have - at-least for proteins.
- ackbar03 4y ago
  Thanks for this, this was quite insightful to an outsider. Not sure if you will still see this follow up question but what do you feel in the production stage that is the most challenging or costly process? Effective and accurate DNA rocombination? Filtering for high yielding cells? Or the purification stage?
  - trap_goes_hot 4y ago
    By the time the process gets to our team, it is established and stable. Our team is not at liberty to tinker with the process in any way. To put it another way, if there is a high variability in the process, it won't get to the manufacturing stage. It will still be in the development stage where all those issues are ironed out. (There is also regulatory oversight on this that would have prevented us using a highly variable process) I suppose the most challenging aspect to manufacturing is the operational discipline. Getting people to give a shit about following our procedures, documenting everything accurately, and avoid taking shortcuts - all on a daily basis. This is where all the flowery HR philosophies that you read online go to die. I'll speak in general terms about cost so I don't get fired ;) To give you a sense - In terms of raw material cost and other consumables, our cost/milligram is in cents, but we sell it for about 3000 times that price. It might sound a lot, but its actually not. The reason is simple, even before we start making any money - we're already in debt - Tens of millions of dollars spent on research, product development, compliance/regulatory, buying production equipment, construction of facilities, IP, etc. Then there is the general overhead in terms of paying people's salaries, benefits, 401k, operational overhead, paying interest on business loans, misc business costs - advertising, marketing, distribution, etc etc. Some of these are fixed costs, some are not so we need to buffer for those as well.
    - ackbar03 4y ago
      > It might sound a lot, but its actually not. Yes, unfortunately I understand why the huge markup is a necessity to cover R&D costs. I am close to people who are on these prohibitively expensive orphan drugs. What surprised me however was that when the patent for it expired, I thought prices would decrease as generics came in. Unfortunately as I learned more, it seems that biologics are so hard to produce unlike regular drugs, where Indian pharmaceutical companies can immediately come in with generics. Even though detailed information on the production process is available on the patent, it seems production variability/heterogeneity is still a major obstacle, and I was just curious where in the whole development process is this the most difficult to control for. Anyways, thanks for taking the time to respond with your insight!

mattkrause 4y ago

Some keywords you might want to try include: - Replication error: copying DNA, transcribing it into RNA, and translating that into proteins uses processes that make mistakes. There are all sorts of interesting mechanisms for catching these, both in vivo and during sequencing. Try here for error rates: https://pubmed.ncbi.nlm.nih.gov/1805967/ https://pubmed.ncbi.nlm.nih.gov/1805967/ - Spontaneous mutation: A consequence of replication errors is that unwanted genomic changes sometimes arise in engineered organisms: you carefully make bacteria—-or a mouse—-with one mutation, but it develops another. Say “spontaneous mutation” around a large enough group of grad students and one will cry because it can derail experiments in hard-to-control ways https://pubmed.ncbi.nlm.nih.gov/ https://pubmed.ncbi.nlm.nih.gov/ Everything in biology is full of feedback loops and compensatory mechanisms. Knocking out one gene or brain region may have a direct effect on some output, but may also affect a bunch of other genes/regions (in many ways), which in turn…

trap_goes_hot 4y ago

I am not aware of any research that is addressing heterogeneity issues in a general way. (Caveat: Not a formally trained scientist, I work in manufacturing) One of the products we manufacture is a protein that is expressed by an organism that we engineered (recombinant dna). The way we (and everyone else) achieve homogeneity is by purifying the protein. We develop this purification strategy at the research stage, after we characterize the protein (solubility, stability, size, hydrophobicity, etc). As 'research' turns into 'product', we iterate over this to improve yield, minimize processing times, lower raw material costs, etc and come up with an effective manufacturing process that we can make money on. I liked the article, but in my opinion, the 'personal biomaker' idea is something we are not close to implementing given the state of tech we currently have - at-least for proteins.

ackbar03 4y ago
Thanks for this, this was quite insightful to an outsider. Not sure if you will still see this follow up question but what do you feel in the production stage that is the most challenging or costly process? Effective and accurate DNA rocombination? Filtering for high yielding cells? Or the purification stage?
- trap_goes_hot 4y ago
  By the time the process gets to our team, it is established and stable. Our team is not at liberty to tinker with the process in any way. To put it another way, if there is a high variability in the process, it won't get to the manufacturing stage. It will still be in the development stage where all those issues are ironed out. (There is also regulatory oversight on this that would have prevented us using a highly variable process) I suppose the most challenging aspect to manufacturing is the operational discipline. Getting people to give a shit about following our procedures, documenting everything accurately, and avoid taking shortcuts - all on a daily basis. This is where all the flowery HR philosophies that you read online go to die. I'll speak in general terms about cost so I don't get fired ;) To give you a sense - In terms of raw material cost and other consumables, our cost/milligram is in cents, but we sell it for about 3000 times that price. It might sound a lot, but its actually not. The reason is simple, even before we start making any money - we're already in debt - Tens of millions of dollars spent on research, product development, compliance/regulatory, buying production equipment, construction of facilities, IP, etc. Then there is the general overhead in terms of paying people's salaries, benefits, 401k, operational overhead, paying interest on business loans, misc business costs - advertising, marketing, distribution, etc etc. Some of these are fixed costs, some are not so we need to buffer for those as well.
  - ackbar03 4y ago
    > It might sound a lot, but its actually not. Yes, unfortunately I understand why the huge markup is a necessity to cover R&D costs. I am close to people who are on these prohibitively expensive orphan drugs. What surprised me however was that when the patent for it expired, I thought prices would decrease as generics came in. Unfortunately as I learned more, it seems that biologics are so hard to produce unlike regular drugs, where Indian pharmaceutical companies can immediately come in with generics. Even though detailed information on the production process is available on the patent, it seems production variability/heterogeneity is still a major obstacle, and I was just curious where in the whole development process is this the most difficult to control for. Anyways, thanks for taking the time to respond with your insight!