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Old 03-19-2020, 04:38 PM
KidCharlemagne is offline
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National scale pharmaceutical manufacturing of chloroquine/hydroxychloroquine - possible? How long?


Letís assume for a second that chloroquine phosphate or hydroxychloroquine is the treatment of choice until a vaccine. Does anyone have a sense of how long (or if itís even feasible in time) to ramp up manufacturing to treat, say, 200mn people? Pure speculation is perfectly acceptable.
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Old 03-19-2020, 08:27 PM
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The Made-In-China site lists the chloroquine diphosphate price as $1/kg with capacity of 1,000,000 kg so that's a start. I don't see their lead time. Expect to see scam offers of homebrew kits. Bathub COVID cure FTW!
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Old 03-20-2020, 09:11 AM
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Originally Posted by RioRico View Post
The Made-In-China site lists the chloroquine diphosphate price as $1/kg with capacity of 1,000,000 kg so that's a start. I don't see their lead time. Expect to see scam offers of homebrew kits. Bathub COVID cure FTW!
I bought some non-USP grade 99% pure CP about a 3 weeks ago when the reports about its efficacy were coming out of Wuhan. Iíve been researching the dangers of using something like this and getting mixed feedback. Obviously, any doctor or chemist is gonna have to officially say itís dangerous, but one pharmaceutical chemist said heíd probably trust the reagent grade over USP. Itís probably purer but the important question is the human toxicity of those impurities. The three potential impurities of CP synthesis all appear less dangerous than CP itself. Just have to hope they didnít use the same tub to make arsenic an hour before. I donít know if youíre a chemist, but Iíd be curious to hear your or othersí takes. Iíd probably only use it if a legit source wasnít available and pneumonia appeared to be going critical. I have an elderly mother who gets pneumonia yearly who had a bilateral lung lobectomy. Covid 19 would essentially be a death sentence so, in some cases, Iíd be willing to take a risk. Iíll await the replies of my utter insanity.
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Old 03-20-2020, 09:30 AM
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Originally Posted by KidCharlemagne View Post
I bought some non-USP grade 99% pure CP about a 3 weeks ago when the reports about its efficacy were coming out of Wuhan. Iíve been researching the dangers of using something like this and getting mixed feedback. Obviously, any doctor or chemist is gonna have to officially say itís dangerous, but one pharmaceutical chemist said heíd probably trust the reagent grade over USP. Itís probably purer but the important question is the human toxicity of those impurities. The three potential impurities of CP synthesis all appear less dangerous than CP itself. Just have to hope they didnít use the same tub to make arsenic an hour before. I donít know if youíre a chemist, but Iíd be curious to hear your or othersí takes. Iíd probably only use it if a legit source wasnít available and pneumonia appeared to be going critical. I have an elderly mother who gets pneumonia yearly who had a bilateral lung lobectomy. Covid 19 would essentially be a death sentence so, in some cases, Iíd be willing to take a risk. Iíll await the replies of my utter insanity.
How did you get a prescription for that?

And I would assume our military has some chemical engineering units who can start cranking it out... No?
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Old 03-20-2020, 09:57 AM
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I'm not in tablets, I'm in injectables (parenterals, in industry jargon)

The good news is that tablet manufacturing is much simpler, with far fewer controls needed. I don't know where CP tablets are made. If there's an FDA-approved facility making them now, that could be ramped up quickly. You'd be amazed at how fast tablet facilities can crank out pills.

In normal times, I'd assume about 12-18 months to convert an existing line to a new product and complete all the validations and inspections. A solid 6+ months of that is the FDA, which could presumably park a team at the plant and cut that Waaaay down in an emergency. With all hands, maybe the changeover could be cut in half. Perhaps some time could be saved by skipping things like stability testing (the calendar is the calendar, so a six month stability takes six months; but for a well established medicine we might decide that isn't needed in an emergency).

So my back of the envelope would be 4-6 months with a Manhattan Project effort.

That assumes the CP itself (known as the Active Pharmaceutical Ingredient, API) is readily available. APIs are typically made at a very different facility than the tablets. If API production needs to be ramped up that could be the real bottleneck. Since I don't know how CP is synthesized I can't say what's involved there. But proper production and safety of the API will be the most critical element of a tablet (I mean, something wrong with the binders isn't likely to kill anyone), so any shortcuts there would have to be taken very carefully.

As for grades and whether (say) using a reference grade, or an industrial grade is safe, well... I wouldn't take my chances. Things produced for human use are done under a very strict set of rules and oversight. Just because someone gives you a CoA for something made under "industrial" rules wouldn't be enough for me. And tiny changes or impurities can be devastating.
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Old 03-20-2020, 10:03 AM
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Originally Posted by OldOlds View Post
I'm not in tablets, I'm in injectables (parenterals, in industry jargon)

The good news is that tablet manufacturing is much simpler, with far fewer controls needed. I don't know where CP tablets are made. If there's an FDA-approved facility making them now, that could be ramped up quickly. You'd be amazed at how fast tablet facilities can crank out pills.

In normal times, I'd assume about 12-18 months to convert an existing line to a new product and complete all the validations and inspections. A solid 6+ months of that is the FDA, which could presumably park a team at the plant and cut that Waaaay down in an emergency. With all hands, maybe the changeover could be cut in half. Perhaps some time could be saved by skipping things like stability testing (the calendar is the calendar, so a six month stability takes six months; but for a well established medicine we might decide that isn't needed in an emergency).

So my back of the envelope would be 4-6 months with a Manhattan Project effort.

That assumes the CP itself (known as the Active Pharmaceutical Ingredient, API) is readily available. APIs are typically made at a very different facility than the tablets. If API production needs to be ramped up that could be the real bottleneck. Since I don't know how CP is synthesized I can't say what's involved there. But proper production and safety of the API will be the most critical element of a tablet (I mean, something wrong with the binders isn't likely to kill anyone), so any shortcuts there would have to be taken very carefully.

As for grades and whether (say) using a reference grade, or an industrial grade is safe, well... I wouldn't take my chances. Things produced for human use are done under a very strict set of rules and oversight. Just because someone gives you a CoA for something made under "industrial" rules wouldn't be enough for me. And tiny changes or impurities can be devastating.
4 to 6 months with a Manhattan Project level effort, for a drug used by humans for malaria since the 40's, when the entire country is facing financial calamity (at least)? RIDICULOUS.
  #7  
Old 03-21-2020, 03:56 PM
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Quote:
Originally Posted by OldOlds View Post
I'm not in tablets, I'm in injectables (parenterals, in industry jargon)

The good news is that tablet manufacturing is much simpler, with far fewer controls needed. I don't know where CP tablets are made. If there's an FDA-approved facility making them now, that could be ramped up quickly. You'd be amazed at how fast tablet facilities can crank out pills.

In normal times, I'd assume about 12-18 months to convert an existing line to a new product and complete all the validations and inspections. A solid 6+ months of that is the FDA, which could presumably park a team at the plant and cut that Waaaay down in an emergency. With all hands, maybe the changeover could be cut in half. Perhaps some time could be saved by skipping things like stability testing (the calendar is the calendar, so a six month stability takes six months; but for a well established medicine we might decide that isn't needed in an emergency).

So my back of the envelope would be 4-6 months with a Manhattan Project effort.

That assumes the CP itself (known as the Active Pharmaceutical Ingredient, API) is readily available. APIs are typically made at a very different facility than the tablets. If API production needs to be ramped up that could be the real bottleneck. Since I don't know how CP is synthesized I can't say what's involved there. But proper production and safety of the API will be the most critical element of a tablet (I mean, something wrong with the binders isn't likely to kill anyone), so any shortcuts there would have to be taken very carefully.

As for grades and whether (say) using a reference grade, or an industrial grade is safe, well... I wouldn't take my chances. Things produced for human use are done under a very strict set of rules and oversight. Just because someone gives you a CoA for something made under "industrial" rules wouldn't be enough for me. And tiny changes or impurities can be devastating.
My bolding.

This point was rather thrown away by OldOlds - it really deserves to be emphasised.

Here's a tablet machine with a maximum capacity of just over one million tablets per hour. Yes, that's one tablet machine's output. Now, maybe you have to get an order onto a waiting list for this model, but my first hit on google was this little number which you can pick up second hand and which runs at up to three quarters of a million per hour - yours for 120 000 Euro; you'll have to buy the punches and dies separately. The things that slow you down are cleandown between batches and the logistics of feeding the damn machines. And then there's the issue of packaging those millions of tablets and getting them to warehousing.

I'm not an expert in setting up tablet production lines either (retired from the licensing side) but OldOlds' analysis doesn't sound a million miles away to me - if you need to set up a new line rather than take over and repurpose an old one. These tablets are already being produced, right? And are on the market internationally? If that's the case then it becomes, as the OP put it, a ramping up of existing production, so far as that is possible. I would hope that could be done in less than 4 months, but that leads to the question of where manufacturing is currently taking place. For an old drug like this which is primarily used for a tropical disease, who knows where the manufacturing sites are. Depending on location, upgrading an existing line may not be that simple.

The in-between solution would be to use existing contract manufacturing lines, essentially transferring an existing manufacturing process in (including the analytical procedures etc). You may be able to shorten the start-up in that way, so this approach is a hybrid of upgrading existing lines and the process OldOlds described.

There's a knock-on issue of needing to produce medicines for many, many millions of patients worldwide - is there enough spare capacity in the system for that to be handled without causing shortages elsewhere? It'll be a challenge.

So: I'm addressing the OP; but hey, how about we find out if this stuff even works first?

j

Last edited by Treppenwitz; 03-21-2020 at 03:58 PM.
  #8  
Old 03-20-2020, 01:18 PM
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They were in vitro evidence that chloroquine was effective against the SARS Coronavirus. So it does have some positive history. As you would call that was a 2002 Coronavirus.
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Old 03-20-2020, 01:48 PM
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They were in vitro evidence that chloroquine was effective against the SARS Coronavirus. So it does have some positive history. As you would call that was a 2002 Coronavirus.
There is way more evidence than that:
https://www.thegatewaypundit.com/202...-6-days-video/
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Old 03-20-2020, 02:16 PM
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I think the following should be noted. I'm seeing a lot of stuff which would seem to imply the FDA needs to approve this. Or that the government needs to do something to "make it happen"

Doctors may prescribe any drug for any reason. If a doc believes, in his medical opinion, that Viagra will cure the common cold, he can prescribe it. He will be accountable for the outcome, of course, but nothing stops him from doing it.

A producer of a drug must show efficacy to advertise/promote a drug for a purpose.

So, if it really is that impressive (color me skeptical), then nothing stops the medical community from using it. And if CP has a really good safety profile, you can bet they are doing so. And thus, we will know in short order if this is real or not. And if it is, it will just become the de facto treatment. To the extent it's available in quantity.

I am very frustrated by the bad information that's coming from everywhere regarding how drugs are used, approved, etc.

Last edited by OldOlds; 03-20-2020 at 02:17 PM.
  #11  
Old 03-20-2020, 10:44 PM
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And if CP has a really good safety profile, you can bet they are doing so.
It doesn't. It has a long list of rather nasty side effects.
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Old 03-21-2020, 10:21 AM
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There is way more evidence than that:
https://www.thegatewaypundit.com/202...-6-days-video/
New York Governor Cuomo just announced that New York will be conducting trials using hydroxychloroquine with z-pack. He said that after Consulting with medical experts he feels it may show promise.
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Old 03-21-2020, 11:54 PM
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There is way more evidence than that:
https://www.thegatewaypundit.com/202...-6-days-video/
Haven't been able to find the studies from China and Italy, but the French study is crap.
Quote:
Six hydroxychloroquine-treated patients were lost in follow-up during the survey because of early cessation of treatment. Reasons are as follows: three patients were transferred to intensive care unit, including one transferred on day2 post-inclusion who was PCR-positive on day1, one transferred on day3 post-inclusion who was PCR-positive on days1-2 and one transferred on day4 post-inclusion who was PCR positive on day1 and day3; one patient died on day3 post inclusion and was PCR-negative on day2; one patient decided to leave the hospital on day3 post-inclusion and was PCR-negative on days1-2; finally, one patient stopped the treatment on day3 post-inclusion because of nausea and was PCR-positive on days1-2-3. The results presented here are therefore those of 36
patients (20 hydroxychloroquine-treated patients and 16 control patients). None of the control patients was lost in follow-up.
In other words, out of 26 people treated with hydroxychloroquine, ~4% died and ~12% were admitted to the ICU.
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Old 03-22-2020, 08:24 AM
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YouTube link below. How chloroquine hydroxychloroquine may help slow down covid-19. Also safety and iuse with SARS.


https://youtu.be/A1XNHNUlapk
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Old 03-22-2020, 08:41 AM
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https://www.nature.com/articles/s41421-020-0156-0

Open Access study linked above. Hydroxychloroquine effective against covid-19 in vitro.
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Old 03-20-2020, 10:39 PM
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When I was a backpacking traveller in China back in the 80's, IIRC chloroquine was no longer used to treat malaria. In fact, travelling buddies were told by doctors in HK and Singapore to flush their "if I get sick in the middle of India emergency supply" and replace it with something that had far fewer side effects.

OldOlds, you sound like an industry pro that has done this for living. Can you share your background (understand if you don't want to out yourself on these boards).
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Old 03-20-2020, 10:45 PM
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Nowadays, hydroxychloroquine (Plaquenil) is most commonly used for rheumatoid arthritis, and occasionally other autoimmune disorders.

A pharmacy board I sometimes post on has a thread about how pharmacists are handling it when doctors write Rxs for this for themselves, or a family member, and they are 99.99% the person does not have RA. I also anticipate a surge in the cost, if it hasn't happened already.
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Old 03-21-2020, 06:21 AM
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When I was a backpacking traveller in China back in the 80's, IIRC chloroquine was no longer used to treat malaria. In fact, travelling buddies were told by doctors in HK and Singapore to flush their "if I get sick in the middle of India emergency supply" and replace it with something that had far fewer side effects.

OldOlds, you sound like an industry pro that has done this for living. Can you share your background (understand if you don't want to out yourself on these boards).
I am in pharmaceutical development and manufacturing, over 25 years now. I am currently at the mid-to-senior management level (I am not an executive, but just below that). I started right out of college in actual hands-on manufacturing, and I have managed a manufacturing facility, worked as a program manager for various drug development programs and worked on a number of clinical trials.

I have a degree in a scientific discipline, but I am NOT a scientist- IMO one must do that job to claim that title, and I have worked with many "real" scientists and wouldn't put myself in that category.

Like anything, pharmaceuticals is a broad field with specializations. Mine is injectable radiopharmaceuticals, which is an odd & esoteric corner of the business. But worth noting, because I haven't had anything to do with tablets in quite a long time.
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Old 03-21-2020, 11:18 AM
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Any FDA approved drug can be prescribed for anything the Dr wants not just diseases the drug is approved for. That's called off label use . Of course the Dr has to consider if he thinks it will work and side effects or problems.
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