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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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March 13, 2013

Who to Manufacture an API?

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Posted by Derek

Here's a very practical question indeed, sent in by a reader:

After a few weeks of trying to run down a possible API manufacturer for our molecule, I am stuck. We have a straightforward proven synthesis of a 300 weight lipid and need only 10 kg for our trials. Any readers have suggestions? Alternately, we will do it ourselves and find someone to help us with the documentation. Suggestions that way, too?

That's worth asking: who's your go-to for things like this, a reliable contract supplier for high-quality material with all the documentation? I'll say up front that I don't know who's been contacted already, or why the search has been as difficult as it has, but I'll see if I can get more details. Suggestions welcome in the comments. . .

Update: this post has generated a lot of very sound advice. Anyone who's approaching this stage for the first time (as my correspondent clearly is) is looking at a significant expenditure for something that could make or break a small research effort. I'm putting this note up for people who find this post in future searches - read the comments; you'll be glad you did.

Comments (67) + TrackBacks (0) | Category: Drug Development


COMMENTS

1. NoDrugsNoJobs on March 13, 2013 11:38 AM writes...

There should be no shortage of CROs who would take this on!!!!

I'll do my part and say Cambridge Major in Milwaukee Wisconsin is very good!

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2. Nicholas Tesla on March 13, 2013 11:47 AM writes...

I would suggest Catalent for contract API manufacture - likely the branch in KY.

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3. Bob Forner on March 13, 2013 12:03 PM writes...

I work with Cedarburg Hauser, another Wisconsin based CMO. We've taken customers from pre-IND to NDA and have a few commercial products so we are well versed in the necessary documentation.

Our website is linked through my name, I can also be contacted directly.

Bob Forner
Cedarburg Hauser Pharmaceuticals
bob.forner@cedarburghauser.com
262-376-1670 x 117

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4. Ed on March 13, 2013 12:06 PM writes...

surely you mean "Whom to manufacture....?". Tsk!

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5. simpl on March 13, 2013 12:09 PM writes...

Our supplier list is well-guarded by development chemists and purchasing, and differs for every API and/or its precursors. Since I am not involved enough to reveal any secrets, I could split it up for you into a)chemical specialists, like BASF, b) one of the many API research/production contractors, and c) here, lipid specialists (Unilever?). Pick one or two with plenty of experience, especially if you can't afford delays.

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6. fat old man on March 13, 2013 12:14 PM writes...

Sounds like this person has no experience in GMP manufacturing, I suggest they use a 3rd party like Davos (not to give them a plug, other readers may know equally good companies) that will match client/CRO characteristics, you want a company that has experience with the chemistry, the scale, GMP compliance, and potential future scaleup. I do not suggest they do it themselves, that is a recipe for disaster when they file an IND. They need 'only' 10 kg? Seems like a lot for Phase 1, and what have they been using for their animal studies? You want the impurity profile qualified before you make the Phase 1 drug product. I hope they are thinking ahead.

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7. Rob on March 13, 2013 12:15 PM writes...

You could look through the list of Socma members - http://www.socmachemicaldirectory.com/socma-marketplace-directory?quicktabs_directory_qt=1#quicktabs-directory_qt

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8. NH_chem on March 13, 2013 12:55 PM writes...

This best advice is to seek advice from those in the industry. Ask friends at other companies who they use. SOCMA is a joke since it is basically a way to get on a list but does not help CMOs from overseas.

I see good luck with companies that are both in the US and Europe. I like companies that own their own facilities in China and run them with their own people. I don't trust India and know I am not alone.

There are only a handful of CMOs in the US and a great number in Europe. Look for expertise to make a choice. HIPO materials can be made at a variety of places. Basic organic chemistry can be made at many places. Specialties, fro example the ability to make chiral materials with/from amino acids, reduces the field to some very good companies.

It is really a matter of choice.

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9. C. K. Lau on March 13, 2013 1:03 PM writes...

I am the R&D manger for Delmar Chemical Inc. located in Montreal. We have been in business for 70 years and we major in API development and manufacturing. We are a completely GMP facility. We have been inspected by FDA in 2009 and 2012 with no 483s. We are owned by FIS, one of the largest API manufacturing company in Europe. We will be quite happy to discuss your need.
C. K

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10. processchemist on March 13, 2013 1:11 PM writes...

"We have a straightforward proven synthesis of a 300 weight lipid "

Sure. Official tox already performed? With a fast scale up of the "straightforward proven synthesis"?
INDA application already filed? The first impression is that they need a GOOD project manager, before going from a CMO to another asking for something like "a 50 l rotavap working in a GMP environmnet for drug substance isolation" (no jokes, I heard this kind of request).
Sorry for the bitterness, but years ago my job was really fascinating, years ago....

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11. milkshake on March 13, 2013 1:24 PM writes...

ChemCon in Freiburg, Germany. They have a large GMP facility and are willing to scale up reactions that use problematic solvents and hazardous reagents (ethyl ether, phosgene - you name it), from kilos and up. They are very solid and meticulous about everything and they are pleasant to work with. Not the cheapest ones but well worth it.

(I have no interest in ChemCon, we just used them twice in the past, my colleagues went there to assist with the process methodology transfer and loved those German guys)

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12. YetAnotherChemist on March 13, 2013 1:47 PM writes...

Try Irix..plenty of good experience with them.

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13. Curt F. on March 13, 2013 2:02 PM writes...

@4. Ed:

surely you mean "Whom to manufacture....?". Tsk!

That wording is incorrect unless the goal is to manufacture people.

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14. Ted on March 13, 2013 2:11 PM writes...

Fat old man is right, the request itself sounds like they have no experience.

GMP manufacturing is not a matter of "assembling the documentation." It is about putting quality systems in place that allow a loose process to meet FDA guidelines. There is no expectation that everything be understood in phase 1 work, but there is an expectation that you have SOPs, training documentation, auditing procedures, etc... that demonstrate that you have control. Unskilled clients waste a lot of money trying to control the wrong things.

They're probably having trouble finding a partner because they have unrealistic expectations. In this environment, there are custom manufacturers falling all over themselves trying to score business. At my former employer (they quit the API business in 2012 because they felt the margins are too small and the business is too competitive...), we won >90% on repeat customers, but only 5 - 10% of new project bids.

Sorry, but I'm not giving references to my former competitors. But I am calling BS on the basic premise.

Did they even know to attend Informex?

-t

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15. Hap on March 13, 2013 2:14 PM writes...

I think "who" is used to refer to the subject of a dependent clause, and "whom" is used to refer to the object of a dependent clause - hence, Curt F.'s comment. "Who" seems to be OK.

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16. barney featherson on March 13, 2013 2:44 PM writes...

I have been waiting for this question since I, as an American process chemist, was laid off. Since every American process chemist has been laid off since 2008 and replaced with highly inferior chinese and indian chemists, I knew this would happen. Good luck finding a competent contract manufacturer in the USA because they have adopted the coolie mentality of the 1840's where you hire poorly qualified workers because they are cheap. Beware of buying any generic medicines from anywhere because they are made by crappy chinese and indian chemists. I have seen the batch records and C of A's from these countries-complete falsifications. Examples are heparin, milk, baby toys and many more. It is time to stop this. Start hiring people who are qualified-get the HR people out of the hiring process. No more H1B visas, there are plenty of qualified Americans with scruples who can be hired. The pharmaceutical company model now is not to make any new drugs because it costs 10 years and $1B to market a product. So instead they hire crappy chinese and indian chemists for 50 cts on the dollar because it is a tax write off. Result-American unemployment. Let's get real.

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17. Ed on March 13, 2013 2:59 PM writes...

Well, to further the grammar debate .... :-)

I understand that you use "whom" rather than "who" when it does not refer to the object of the verb (in this case API and manufacture)....but rather is an object in itself. Anyway, back to GSK bashing.

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18. Toad on March 13, 2013 3:05 PM writes...

I've been in the same boat as the questioner.

If you don't have experience or expertise, hire someone with it. There are hundreds of CROs that will say they can do this, and many of them are good. But you need to be able to ask the right questions and get the right information so you don't get a bad one, or have something show up down the line that can cause problems. The regulatory and development world is much different.

I'm sure management just wants the compound, but you need to convince them they have to do this right. Not difficult, but it can be really bad if you don't make sure certain things are done right from the start.

If you don't know what an FDA Form 483 is, then get help.

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19. Bob Forner on March 13, 2013 3:08 PM writes...

@barney featherson . While I understand your frustration, I'm not sure your statement that CMOs in the US are hiring poorly qualified workers is correct. At least at Cedarburg Hauser, we have hired a number of highly qualified chemists from industry. Many of these chemists were process chemists who were laid off and took the opportunity to stay in the midwest and come to Cedarburg Hauser.

We are actually looking to hire a couple of analytical chemists (both entry level and senior level). Feel free to drop me a line at my email address above. I know you're a process chemist and this probably isn't a great fit, but just throwing it out there.

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20. Virgil on March 13, 2013 3:32 PM writes...

If it's a lipid, then a good bet would be Avanti Polar Lipids in Birmingham AL. They're well known in academia for providing very high quality lipids, especially reactive ones (way better than the stuff sold by Cayman et al.)

No affiliation, just I've used their products ever since I was in grad' school in the mid '90s and haven't been disappointed yet.

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21. David Formerly Known as a Chemist on March 13, 2013 3:44 PM writes...

Just by the nature of the question this looks like it's going to end sadly. The person who posed this question sounds like they're doing this for the first time and doesn't realize how many traps are laid out for him/her. My suggestion would be for this person to engage a consultant, perhaps one of the experienced laid-off process chemists reading your blog, who can help out with CRO due diligence and make sure everything that needs to be done actually gets done. Good GMP facilities, good batch records, appropriate analytical in-process and release methods, release specs, closure/container systems, API stability studies, etc. This takes experience and if the person asking the question has little, he/she needs to find some before flushing somewhere near a million dollars (which is what this will likely cost in the end). I did this for years as part of a CRO and by using CROs. It's much more complicated that just making a molecule and filling out some documentation.

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22. Anonymous on March 13, 2013 4:15 PM writes...

Hire a CMC expert, ask the right questions, visit the sites and then decide who to quality as your CMO Vendor

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23. Helical_Investor on March 13, 2013 4:31 PM writes...

I'll give a couple of shoutouts. Contracting with contract manufacturing organizations (CMOs), and other CMC/regulatory, is the basis of my day job.

First, you note this is to be an API, so I presume you are looking to manufacture this for preclinical toxicology testing and eventually clinical use (I'll cross my fingers for you). You do not want to do this yourself! It will need to be GMP (eventually) for use in clinic, and it is a good idea for the tox testing as well.

Get a hold of the annual Contract Pharma 'Corporate Capabilities and Contract Services directory'. Or search it here: http://www.contractpharma.com/csd/categories
Look under the manufacturing categories, as there are many specialties. You probably want someone with lipid experience. Especially if your product is not a nice stable easy to work with solid? There are some trade shows worth attending, though you missed Informex and Contract Pharma's own show is a bit shy on API CMOs (not what I was looking for last I attended, so maybe it was just me).

You are going to want both an API/drug substance CMO and a then eventually (for clinical use) a formulator/fill&finish/drug product CMO. Make yourself a punchlist for what you want in a manufacturer, interview at least five, send a proposal for a quote to at least two (three). Don't send a proposal request until you really know what you want and have talked through the process with some manufacturers and a CMC consultant (use your own, not theirs). Project management is critically important for working with a CMO or CRO, on both sides.

Accept that manufacturing and contracting are processes. Leave room (as in time and money) for process development. Rarely ever does lab scale and processes translate to 10 kg and higher.

Zz

P.S. I note you had a response from a CMO, Bob @ #3. For what it is worth, I have been and am a satisfied customer of CedarburgHauser.

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24. Anonymous on March 13, 2013 4:50 PM writes...

You use "who" when you are referring to the subject of a clause and "whom" when you are referring to the object of a clause.

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25. Anonymous on March 13, 2013 5:54 PM writes...

I used a UK company called Onyx. Ask for Denise Browser, she is very good. I they do perform cGMP synthesis.

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26. CMCguy on March 13, 2013 6:00 PM writes...

I too have been doing this for many years and know directly or indirectly all the CMOs listed above plus know there are several others that could likely do the job. Although expect most CMOs are probably capable it comes down to good fit for your particular project and company. #23 HI is right on target of good approach and starting place and general factors on how to address: do good due diligence. As he noted Informex was a couple months ago and believe there may be a searchable database of exhibitors (http://www.informex.com/en/informex-usa/attend/2013-exhibitor-list). Would search a few key words as needed (Lipid, GMPs, ID special chemistry/reaction type used, do you lyophilize?). Many on Informex and Contract Pharma lists could be off-shore (and a few could be worth checking out) so if that is restriction can eliminate but once narrowed down to a few can look for website or contact them directly. If possible advance to CDA then RFP/quotes can help define would would be a good match.

A CMC consultant or Brokers like Davos could also be of value to guide the process but again need to investigate and interact to see if will provide what is really desired.

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27. Anonymous on March 13, 2013 6:00 PM writes...

@16 which school taught you to capitalize only American and not other civilizations

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28. rtw on March 13, 2013 6:38 PM writes...

I have to agree with 21. David Formerly Known as a Chemist. He needs a consultant/PM. A good recommendation would would make would be these guys for someone that has never gone through the process before. They match CRO's to clients and act as PM's and go betweens. LOTS of experience rolled into the organization. Give a look at the following link.

http://www.idscbiotechnetwork.com/

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29. rtw on March 13, 2013 7:11 PM writes...

I have too many "woulds" in there and didn't notice. Anyway it should read: "A Good recommendation I would make would be...."

Sorry

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30. CMC chemist on March 13, 2013 7:16 PM writes...

@21 you nailed it

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31. Anonymous on March 13, 2013 7:29 PM writes...

Follow the advice by Helical Investor@23 and the process has been very well outlined for a starter

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32. Anonymous on March 13, 2013 8:53 PM writes...

Anyone but Almac. Totally incompetent.

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33. Derek on March 14, 2013 12:32 AM writes...

Institute For Therapeutics Discovery & development University of Minnesot - Dr Vadim Gurvich
www.itdd.umn.edu

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34. Cymantrene on March 14, 2013 3:31 AM writes...

I agree with above opinions that first of all you need a good GMP consultant, and also one for scale up-manufacturing. They are headaches - and not for the fainthearted.
Anyway, we at UbichemPharma do cGMP manufacturing from grams to hundred kilograms (we even do GMP-manufacturing of (radio)isotop-labelled compounds). We did it successfully for totally unexperienced customers too, and also coped with lipids as well.
www.ubichempharma.com

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35. simpl on March 14, 2013 3:44 AM writes...

I love this thread: it contains many lifetimes of hopes, disappointments and wisdom. It contains warnings, appropriate cynicism and real help.
A topic shimmers in the background: since the FDA got into GMP for APIs in the '70s, is there any research into what has changed? There could be higher quality, different errors, less rework, new careers, more paper, less job satisfaction, chemistry leaving the US, and others.

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36. utbiotech on March 14, 2013 4:32 AM writes...

So many CROs in China, We can do it..

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37. utbiotech on March 14, 2013 4:33 AM writes...

So many CROs in China, We can do it..utbiotech.com

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38. newnickname on March 14, 2013 4:55 AM writes...

I have contracted small scale custom syntheses but I have never been close to contracting cGMP manufacturing of APIs in the past (but I hope we'll get there soon). One of my fears, even just with requesting quotes on something like this, is confidentiality and tech transfer. To get reliable quotes, OP will have to convey all details of their "straightforward proven synthesis" to several companies but only one (hedge your bets: two?) CMO will get the contract. Meanwhile, your valuable, detailed methods are floating around. I have also heard horror stories of Chinese and Indian companies making improper use of such IP. Any suggestions or precautions to take? ("Due diligence: don't disclose anything to companies with tainted reputations."?)

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39. Orchid on March 14, 2013 5:53 AM writes...

I work for Scynexis in Durham, NC. We have a fair amount of experience with difficult lipid chemistry. We have a fully qualified and inspected GMP/GLP facility with no 483's. Contact Clare Murray at clare.murray@scynexis.com.

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40. milkshake on March 14, 2013 6:29 AM writes...

@newnick: I think you are mildly paranoid, perhaps because of a past bad experience with some foreign CROs - but your advice is incorrect because a new API is very different business from a non-proprietary building block/reagent scale-up or a generic API manufacture (where the only business advantage you often have is the manufacturing process trade secrets.)

If you don't have a composition of matter or at least method of a disease treatment patent coverage, keeping your manufacturing method for your new API top secret is not going to make a difference. If on the other hand someone in Asia learns how to make your molecule but you do have a good patent coverage, he wont be able to scoop you.

In this case I would be more concerned about other kinds of possible sketchy behavior that could screw up your clinical trial timing if it turns out that your supposedly GMP-made material has problems or the paperwork was not in order

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41. mamid on March 14, 2013 7:37 AM writes...

You might also contact Zambon Group.

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42. fat old man on March 14, 2013 10:29 AM writes...

at the risk of beating a dead horse, I'll expand on what a couple of the better informed people said above: do these people have any idea what it takes to make a GMP batch of API or drug product? This has to be done prospectively, you can't make it GMP after the fact. Have they ever seen a CMC section or read a guidance? I encourage them to start reading, they are easy to find on the FDA/ICH sites. There are guidances on GMP (Q7), impurities (Q3), analytical methods (Q2), specifications (Q6), and even how to write a CMC section (M4). Oh, and have they evaluated their structures for 'DNA reactive impurities'? If not, they will have to control any hits to 1.5 µg/day (there are somewhat higher levels allowed for clinical trials, see ICH M7.). If they don't know what I'm writing about I doubt any direct contact with a CRO will help them, they need a consultant to be their project manager.

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43. Anon on March 14, 2013 12:00 PM writes...

14, 21 & 42 are correct--the cGMP part is often (I would even say "usually") much more complicated and expensive than the scale of the synthesis, formulation compounding, fill & finish.

If I were selecting a PM for this, I would look for someone with, ideally, previous experience at the FDA; failing that, someone with decades of GMP manufacturing experience. Probably several someones really, because you'll want someone with the QA background to judge the quality systems, a facilities/process engineer to be sure that the CMO's facilities can handle your synthesis (many promise they can, then you find out a year later that they can't, it's not fun), and maybe a regulatory person specializing in due diligence who (subordinate clause!) knows enough people in the industry to know which ones pull the most shenanigans.

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44. Richard on March 14, 2013 1:37 PM writes...

Thanks to everyone here for the comments and suggestions. Outsourcing has been the goal from day one. The links here however give me some renewed confidence in finding the right group. It seemed from the blank walls we were running into that we would have to do this in-house and the use of the word 'documentation' was done for brevity. Also I wanted to show the comments to some of my partners who have a breezy sort of life and assume all things are a paint by number book regarding the FDA process. So far we haven't stepped in anything.

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45. Richard on March 14, 2013 1:42 PM writes...

Follow-up API questions for the commenters:

We can produce our API from either a natural source with a millennia of human consumption history or through the synthetic routes. As a practical matter, there would never be enough of the natural compound available should the product get approval. The FDA process is simplified with the natural compound compared to the synthetic derived – or no difference? Assume both at 99%+ - does it all come down to impurities? If approved by the FDA using a natural source what happens with the available synthetic – any ideas on what the FDA thinking would be on further testing of the synthetic?

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46. okemist on March 14, 2013 3:56 PM writes...

Hi Derek, I would like to throw my company: Aptuit in to the ring of consideration. We have experience from beginning to commercial (see Aegerion story in this month's C&En) and very good systems in place.

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47. fat old man on March 14, 2013 4:38 PM writes...

OK, don't mean to hog the board but I did have some experience with this, millennia of human consumption has no relevance to toxicological qualification of impurities of the drug substance you intend to dose to human subjects. You will need to identify and qualify impurities above a certain level depending on dose (either 0.05% or 0.15%, read ICH Q3 for drug substance) level determined using a validated analytical method (validated for linearity, precision, specificity, detection limit.....) in 2 animal species. Those studies usually took my project teams 6 mo to a year to complete. It doesn't matter if the process is through chemistry or bugs, rules are the same. 99+% may sound impressive to you, to me that leaves a lot of room for big impurities.

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48. CMC chemist on March 14, 2013 5:24 PM writes...

If you change the method of manufacture, the drug substance may end up with different impurity profile and new tox qualification study may be needed. Going from natural to synthetic obviously brings in completely different set of impurities.

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49. fat old man on March 14, 2013 6:44 PM writes...

as a point of clarification, the tox qualification studies I mentioned as in 2 species were in conjunction with the IND-enabling studies to determine Phase 1 dosing. If you change the method of manufacturing and have to qualify new impurities we used to do that with a single species, 2-4 weeks in life, but about 6 months for a complete study with a report suitable for filing.

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50. CMCguy on March 14, 2013 9:40 PM writes...

Natural or synthetic is not necessarily a big consideration to get into clinic early on so lean towards what ever works easiest and cheapest early you can go with. If must switch later the point about impurity profile variation is critical (and tox implications) but typically can be handled as project continues. This does point to a major component of eval of CMOS that a couple people already noted: Make sure they have strong Analytical group/resources, again with experience direct with class of molecules you have, as ultimately everything depends on their work- I would probably say the same for QA, although there again need some one on your team that can adequately judge QA systems (however too often can be fooled by what looks good on paper and find later by frustration does not work well in practice).

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51. CMCguy on March 14, 2013 11:29 PM writes...

One additional comment on that could knock out natural source as it does make a huge difference if from Animal or Vegetable due to BSE/TSE concerns therefore if your lipid raw material comes from animals (i.e. stearic acid from cattle) it will make the task harder to get through regulators. Another reason to hire someone experienced to aid with such issues.

http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003700.pdf

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52. John Devlin on March 15, 2013 1:14 AM writes...

Hi, I work with a LOT of small biotechs in Australia giving them advice in scale up and manufacture. I work with Indian, US based and European manufacturers-working for you the client and not the manufacturer. If you need some help drop me an email

John Devlin
www.devchem.com.au

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