I am a retired MD, an internist who focused on diabetes management. I made good use of exenatide and liraglutide but retired before the longer acting forms were available. I prescribe semaglutide to my wife in very low dose. She has hypertension, and a very strong FH of HTN, with both parents dying of hypertensive strokes, which was difficult to control with multiple meds that resulted in excessive fluctuation, with episodes of both moderate hyper and mild hypotension. She was mildly overweight with too much visceral fat and mild CKD with eGFR in the 45-55 range. She, like the great majority, was able to achieve but not sustain weight loss more than a few months and thus the semaglutide. This has resulted in a sustained approximate 6 lb weight loss with marked improvement in BP control on 50mg losartan and HCTZ 12.5mg with much less fluctuation and no hypotension and stable renal function, actually slightly better.
I get the med from a compounding pharmacy which I think is good quality. It's combined with Vit B6 which I think is innocuous. Drug companies object that delivery of the GLP-1's with vial and syringe leave patients subject to dosage error. However, we have been treating diabetes with insulin by vial and syringe for 100 years or so and have accommodated to that more hazardous agent. Vial and syringe delivery has multiple advantages including lower cost than auto injection devices and more importantly the ability to manage dosage, both amount and timing in a much more individualized manner depending on clinical response. This is especially important for an agent with extremely common and significant non-fatal adverse effects that are very dosage and timing dependent. It's my opinion that cheaper and more flexible GLP-1 RA availability, such as from good quality compounding pharmacies, would allow thoughtful doctors and their patients to make much more widespread use of these dramatically effective agents. However, this would demand more rather than less doctor-patient interaction which is what I fear might be happening with the TV advertised online entities.
Excuse my ignorance, but do compounders work to CGMP? Only you comment "I get the med from a compounding pharmacy which I think is good quality" How sure are you on the quality? Has FDA reviewed the CMC details of a compounded drug, as is that case with a licensed drug?
Actually, I started getting the semaglutide there during the shortage a couple of years back. At that time there were no additives and there were no FDA restrictions that I was aware of. The pharmacy I use has been in business for a number of years in the Naples FL area, part of a consortium. The pharmacists are qualified and I discussed the agent with one of the main ones. Thus far the med has been effective and side effects only minor as far as I can see so I have no reason to believe that it's not legitimate. And then what's the alternative? The use I'm making of it is not a standard indication although I have considerable expertise in this area and am very comfortable with the process. I could prescribe the med off label and pay out of pocket but the cost is prohibitive. Furthermore, the injector device is limiting as to dose unless you do the click counting technique but then you wind up using the drug past its expiration date. One last point, and perhaps you can help me on this if you have pharmaceutical knowledge. The question I have is the source of the agent for the compounding pharmacy. Do they access it somehow from the same source as the pharmaceutical company? I'd be interested to know.
Thank you so much for such a considered reply. If I can begin with the description of a 'branded drug.' As well as being a brand, the companies selling them are Product License Holders (PLHs). That means they would have to have submitted an NDA to the FDA to get their drug approved for sale (BLA if it were a biologic). There is a globally harmonized template for submitting the data relating to the entire drug development program, known as the electronic Common Technical Document, devised by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). https://www.ich.org/
The eCTD comprises three modules:
Module 3: Chemistry, Manufacturing & Controls (the entire supply chain from beginning to end).
This document is confidential between the FDA and the NDA/BLA applicant.
So, in answer to your question "Do they access it somehow from the same source as the pharmaceutical company? I'd be interested to know."
Ergo, a compounder will not know the source of any active agent, nor the excipients (non-active ingredients) used to formulate the product into a final dosage form.
As far as I know, and you will be far more familiar with compounders in the U.S. than I am, these safeguards to not apply to compounders, but I am very happy to be corrected.
Actually, forget about the previous question unless you're inclined to comment. I had a long discussion with GEMINI about the matter and think I'm pretty well informed. Mr. GEMINI is pretty much on the side of the pharmaceutical companies but I think I gave him something to think about. :)
Thanks for all that. Hate to be a bother but do you know? - Is the actual semaglutide molecule or solution manufactured in-house somewhere in a NovoNordisc factory or does some third party make it so that it might be available to others to distribute and sell than the actual developer company. I.e. where do the compounders get the agent from? Do they make it themselves? Where did they get it when it was in short supply from Novo?
No bother at all. So, Novo holdings (part of Novo Nordisk) acquired Catalent Pharma Solutions (world's 2nd biggest CDMO), in December 2024. The rationale is that Novo would have control of the supply chain, and capacity, for its GLP-1 products. Prior to that Novo Nordisk had no in-house manufacturing capability. Lilly still has no in-house manufacturing capability, which is interesting.
This is the score on compounding:
How compounders source the “agent”
Under U.S. federal compounding law, outsourcers and 503A/503B pharmacies are expected to source active pharmaceutical ingredients from FDA‑registered facilities, i.e. conventional API manufacturers rather than making the molecule in‑house. Industry commentary from the Alliance for Pharmacy Compounding and NPR notes that semaglutide API, for example, is produced in factories around the world and that compounders “use some of the same FDA‑registered facilities that the drug manufacturers use.”
In practice that means compounders buy API (often peptide powder) from registered suppliers, then do only the downstream compounding step (dissolving, formulation, filling) under their own license. They are not running full GMP peptide synthesis plants; they sit at the tail end of the value chain, more like a small‑scale secondary manufacturer than a primary producer.
Last question I promise. Is it possible for good legitimate compounders to do due diligence to make sure that the API they're using is good quality, unadulterated, and effective, essentially the same as what the pharmaceutical companies are providing.
One final comment, as a 40+ year veteran of the pharmaceutical industry and author of 2 supply chain books for Hoboken-based academic published Wiley - if a drug is not FDA approved via the NDA/BLA route, safety of the supply chain (based upon submitted Chemistry, Manufacturing & Controls data) has not been assessed a competent authority. Neither is there a pharmacovigilance process in place to collect data on adverse events. Hope that is helpful also.
I just want to say thank you both for this back and forth questioning and answering. I have had the same questions as Dr. Perry. Mr. Rees, I want to make sure I understand what you are saying. Are you saying that as long as the compounding pharmacy has the designation as a 503A/503B pharmacy, they SHOULD be using the same molecule as the brand name?
Whenever someone -- usually an elite Wellness Wonder bitch starts to sigh and say, " Do we know about the long term effects of Ozempic, etc."
I stop them and say: 70% of the population won't have a long term. Anyone who is trying to stop the use from the branded version or the compounded one is worried the public will walk form their diets and dopey exercise and endless life style hacks like Get up at 5;00AM!!
Compounding has an important but should also have a limited role in healthcare. It can help when a patient needs a medicine that is not available in the needed strength, formulation, or dosage form.
Approved medicines are developed with heavy research costs, are subject to extensive requirements for clinical evidence, manufacturing cmc, regulatory review, and ongoing safety monitoring.
This usual procedure help ensure that patients receive medicines that are safe, effective, and consistently produced. Furthermore hopefully innovative.
When affordability becomes a concern, the focus should be on working with pharmaceutical companies, regulators, and healthcare systems to make approved medicines more accessible and affordable, rather than lowering quality requirements and using compounded alternatives as a substitute.
In my view this can weaken incentives for innovation and investing and bypasses established quality requirements.
Furthermore No one will ever know if the compounded products have more or less adverse advents since compounders are not controlled by the same rules for safety monitoring.
Lastly the future innovative drugs will not be done by compounders ..
I write a fair amount of Zepbound through Lilly Direct. I always write for the 15 mg/0.5 ml bottles. As long as the patient orders the 4 vials every 6 weeks, they pay $450 for them (they have to remember to click that they don't want the supplies Lilly ships with the vials, because they charge for that and they ship the 1 ml syringes and this makes it hard to use lower doses). I instruct my patients to purchase 0.5 ml syringes at a pharmacy (or through Amazon). I start them at 0.1 ml weekly for however long they feel works for them. They can titrate up or down by 0.1 ml increments weekly depending on their results and potential side effects. Obviously, if they eventually end up on the 15 mg weekly, the out-of-pocket costs get to that $450 monthly. But I have found that the vast majority of my patients don't need the 15 mg dose. I instruct my patients to call me with any questions (I do concierge - I don't charge as much as some of the other local concierge practices - so they all have my cell phone. I understand it would be much harder to do this if a provider has 100's of patients on it). I am not concerned about them puncturing the same vial multiple times. As Dr. Perry pointed out, we have been doing this with insulin for decades.
Once a patient reaches their goal weight, we start tapering down not only the dose, but also the dosing interval.
I tell them that they will accumulate extra boxes of 4 vials since they are making the vials last longer. They need to watch the expiration dates and do "first in first out". They will eventually accumulate more vials than they are going through so they will not need to order at 6 weeks. If that happens, their next order does go to $600. But it drops back to the $450 once they get back on the 6-week schedule (I hope that makes sense).
I do not like my patients using the compounded products. A lot of the time they are paying the provider (usually an online company) not only for the medication, but for the membership. They get very little counseling. And since it is compounded, a lot of the pharmacies do not show how many mg of semaglutide or tirzepatide is actually in the syringe that has been drawn up for them.
I am a retired MD, an internist who focused on diabetes management. I made good use of exenatide and liraglutide but retired before the longer acting forms were available. I prescribe semaglutide to my wife in very low dose. She has hypertension, and a very strong FH of HTN, with both parents dying of hypertensive strokes, which was difficult to control with multiple meds that resulted in excessive fluctuation, with episodes of both moderate hyper and mild hypotension. She was mildly overweight with too much visceral fat and mild CKD with eGFR in the 45-55 range. She, like the great majority, was able to achieve but not sustain weight loss more than a few months and thus the semaglutide. This has resulted in a sustained approximate 6 lb weight loss with marked improvement in BP control on 50mg losartan and HCTZ 12.5mg with much less fluctuation and no hypotension and stable renal function, actually slightly better.
I get the med from a compounding pharmacy which I think is good quality. It's combined with Vit B6 which I think is innocuous. Drug companies object that delivery of the GLP-1's with vial and syringe leave patients subject to dosage error. However, we have been treating diabetes with insulin by vial and syringe for 100 years or so and have accommodated to that more hazardous agent. Vial and syringe delivery has multiple advantages including lower cost than auto injection devices and more importantly the ability to manage dosage, both amount and timing in a much more individualized manner depending on clinical response. This is especially important for an agent with extremely common and significant non-fatal adverse effects that are very dosage and timing dependent. It's my opinion that cheaper and more flexible GLP-1 RA availability, such as from good quality compounding pharmacies, would allow thoughtful doctors and their patients to make much more widespread use of these dramatically effective agents. However, this would demand more rather than less doctor-patient interaction which is what I fear might be happening with the TV advertised online entities.
Excuse my ignorance, but do compounders work to CGMP? Only you comment "I get the med from a compounding pharmacy which I think is good quality" How sure are you on the quality? Has FDA reviewed the CMC details of a compounded drug, as is that case with a licensed drug?
Actually, I started getting the semaglutide there during the shortage a couple of years back. At that time there were no additives and there were no FDA restrictions that I was aware of. The pharmacy I use has been in business for a number of years in the Naples FL area, part of a consortium. The pharmacists are qualified and I discussed the agent with one of the main ones. Thus far the med has been effective and side effects only minor as far as I can see so I have no reason to believe that it's not legitimate. And then what's the alternative? The use I'm making of it is not a standard indication although I have considerable expertise in this area and am very comfortable with the process. I could prescribe the med off label and pay out of pocket but the cost is prohibitive. Furthermore, the injector device is limiting as to dose unless you do the click counting technique but then you wind up using the drug past its expiration date. One last point, and perhaps you can help me on this if you have pharmaceutical knowledge. The question I have is the source of the agent for the compounding pharmacy. Do they access it somehow from the same source as the pharmaceutical company? I'd be interested to know.
Thank you so much for such a considered reply. If I can begin with the description of a 'branded drug.' As well as being a brand, the companies selling them are Product License Holders (PLHs). That means they would have to have submitted an NDA to the FDA to get their drug approved for sale (BLA if it were a biologic). There is a globally harmonized template for submitting the data relating to the entire drug development program, known as the electronic Common Technical Document, devised by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). https://www.ich.org/
The eCTD comprises three modules:
Module 3: Chemistry, Manufacturing & Controls (the entire supply chain from beginning to end).
Module 4: Safety study reports
Module 5: Clinical study reports
Here is the eCTD on the FDA website: https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-technical-document-ectd
This document is confidential between the FDA and the NDA/BLA applicant.
So, in answer to your question "Do they access it somehow from the same source as the pharmaceutical company? I'd be interested to know."
Ergo, a compounder will not know the source of any active agent, nor the excipients (non-active ingredients) used to formulate the product into a final dosage form.
As well as this, the Product License Holder is governed by the 1938 Food, Drug, and Cosmetic Act: https://www.fda.gov/about-fda/histories-product-regulation/1938-food-drug-and-cosmetic-act and CFR Title 21, the FDA portion of the Code of Federal Regulations.
The obligations are legally binding under CFR Title 21. In particular, pharmacovigilance - here is a link to the referring documentation:
https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-314/subpart-B/section-314.80
As far as I know, and you will be far more familiar with compounders in the U.S. than I am, these safeguards to not apply to compounders, but I am very happy to be corrected.
Thanks again for your comment, regards, Hedley
Actually, forget about the previous question unless you're inclined to comment. I had a long discussion with GEMINI about the matter and think I'm pretty well informed. Mr. GEMINI is pretty much on the side of the pharmaceutical companies but I think I gave him something to think about. :)
Thanks for all that. Hate to be a bother but do you know? - Is the actual semaglutide molecule or solution manufactured in-house somewhere in a NovoNordisc factory or does some third party make it so that it might be available to others to distribute and sell than the actual developer company. I.e. where do the compounders get the agent from? Do they make it themselves? Where did they get it when it was in short supply from Novo?
No bother at all. So, Novo holdings (part of Novo Nordisk) acquired Catalent Pharma Solutions (world's 2nd biggest CDMO), in December 2024. The rationale is that Novo would have control of the supply chain, and capacity, for its GLP-1 products. Prior to that Novo Nordisk had no in-house manufacturing capability. Lilly still has no in-house manufacturing capability, which is interesting.
This is the score on compounding:
How compounders source the “agent”
Under U.S. federal compounding law, outsourcers and 503A/503B pharmacies are expected to source active pharmaceutical ingredients from FDA‑registered facilities, i.e. conventional API manufacturers rather than making the molecule in‑house. Industry commentary from the Alliance for Pharmacy Compounding and NPR notes that semaglutide API, for example, is produced in factories around the world and that compounders “use some of the same FDA‑registered facilities that the drug manufacturers use.”
In practice that means compounders buy API (often peptide powder) from registered suppliers, then do only the downstream compounding step (dissolving, formulation, filling) under their own license. They are not running full GMP peptide synthesis plants; they sit at the tail end of the value chain, more like a small‑scale secondary manufacturer than a primary producer.
Hope this helps.
Last question I promise. Is it possible for good legitimate compounders to do due diligence to make sure that the API they're using is good quality, unadulterated, and effective, essentially the same as what the pharmaceutical companies are providing.
One final comment, as a 40+ year veteran of the pharmaceutical industry and author of 2 supply chain books for Hoboken-based academic published Wiley - if a drug is not FDA approved via the NDA/BLA route, safety of the supply chain (based upon submitted Chemistry, Manufacturing & Controls data) has not been assessed a competent authority. Neither is there a pharmacovigilance process in place to collect data on adverse events. Hope that is helpful also.
I just want to say thank you both for this back and forth questioning and answering. I have had the same questions as Dr. Perry. Mr. Rees, I want to make sure I understand what you are saying. Are you saying that as long as the compounding pharmacy has the designation as a 503A/503B pharmacy, they SHOULD be using the same molecule as the brand name?
Whenever someone -- usually an elite Wellness Wonder bitch starts to sigh and say, " Do we know about the long term effects of Ozempic, etc."
I stop them and say: 70% of the population won't have a long term. Anyone who is trying to stop the use from the branded version or the compounded one is worried the public will walk form their diets and dopey exercise and endless life style hacks like Get up at 5;00AM!!
What do you, Vinay, think of the ethics of not paying the pharmaceutical companies, who own the patents?
Is there any requirement for the product license holders to run phase 4 studies?
"bodega reta" That's too funny. Walk in to my bodega and ask for some chopped cheese and reta.
Feta? No....Reta.
LOL.
Having said that...anything that Medical establishment recommends....I'll stay away. I learned my lesson with C19 vax.
Compounding has an important but should also have a limited role in healthcare. It can help when a patient needs a medicine that is not available in the needed strength, formulation, or dosage form.
Approved medicines are developed with heavy research costs, are subject to extensive requirements for clinical evidence, manufacturing cmc, regulatory review, and ongoing safety monitoring.
This usual procedure help ensure that patients receive medicines that are safe, effective, and consistently produced. Furthermore hopefully innovative.
When affordability becomes a concern, the focus should be on working with pharmaceutical companies, regulators, and healthcare systems to make approved medicines more accessible and affordable, rather than lowering quality requirements and using compounded alternatives as a substitute.
In my view this can weaken incentives for innovation and investing and bypasses established quality requirements.
Furthermore No one will ever know if the compounded products have more or less adverse advents since compounders are not controlled by the same rules for safety monitoring.
Lastly the future innovative drugs will not be done by compounders ..
Nice comment, agree…
I write a fair amount of Zepbound through Lilly Direct. I always write for the 15 mg/0.5 ml bottles. As long as the patient orders the 4 vials every 6 weeks, they pay $450 for them (they have to remember to click that they don't want the supplies Lilly ships with the vials, because they charge for that and they ship the 1 ml syringes and this makes it hard to use lower doses). I instruct my patients to purchase 0.5 ml syringes at a pharmacy (or through Amazon). I start them at 0.1 ml weekly for however long they feel works for them. They can titrate up or down by 0.1 ml increments weekly depending on their results and potential side effects. Obviously, if they eventually end up on the 15 mg weekly, the out-of-pocket costs get to that $450 monthly. But I have found that the vast majority of my patients don't need the 15 mg dose. I instruct my patients to call me with any questions (I do concierge - I don't charge as much as some of the other local concierge practices - so they all have my cell phone. I understand it would be much harder to do this if a provider has 100's of patients on it). I am not concerned about them puncturing the same vial multiple times. As Dr. Perry pointed out, we have been doing this with insulin for decades.
Once a patient reaches their goal weight, we start tapering down not only the dose, but also the dosing interval.
I tell them that they will accumulate extra boxes of 4 vials since they are making the vials last longer. They need to watch the expiration dates and do "first in first out". They will eventually accumulate more vials than they are going through so they will not need to order at 6 weeks. If that happens, their next order does go to $600. But it drops back to the $450 once they get back on the 6-week schedule (I hope that makes sense).
I do not like my patients using the compounded products. A lot of the time they are paying the provider (usually an online company) not only for the medication, but for the membership. They get very little counseling. And since it is compounded, a lot of the pharmacies do not show how many mg of semaglutide or tirzepatide is actually in the syringe that has been drawn up for them.
The Alabama Board of Medical Examiners recently banned any medical professional from
prescribing peptides despite having no evidence of risks or adverse events.