It is never too early to develop your formulation
I have breathed thirty years in life-sciences, pharmaceutical entrepreneurship and small startup companies, and my ambition in this chat is to help and guide my friends and colleagues in the first step in pharmaceutical development. If you are a corporate employee, please do not continue reading, honestly, it is not for you.
Dear reader, you have a new idea, a new concept, a new product or new molecule you are rushing to raise money to prove your idea. Let’s call it the “VENTURE”. Evidencing your idea is your one and sole target for now and whether you are sure about route of administration or about mechanism of activity, or not, you have to pay special attention to your formulation development.
At this stage, you can’t be entirely sure if it really works in the real world, but, you believe in your “VENTURE” value, and you are eager to perform significant proof of principle, in order to raise a lot of money that will bring you to Phase II clinical study. Successful Phase II clinical study is considered a significant milestone and exit point for your investors and a bargain for the big pharma to join you or buy you out.
Is it critical to invest time / money in formulation development at this early stage of your entrepreneurship?
So the question is when and how much to invest in formulation development, since you have so many critical activities, synthesis, chemical analysis, IP, all sucking your limited resources and time, why the hell do I need to spend any time on formulation development now? Yes, the 1 million $ question, number one, please be patient, soon you will meet number two.
Throughout my professional career as a formulation scientist, I have encountered numerous cases when great scientists had brilliant ideas, and made exceptional scientific progress in treating diseases, with proof of principle, in-vitro, pre-clinical in-vivo and even in human study proof of concept or Phase II, and then suddenly realized they were not aware of the significance of “formulation development”. They have postponed the pharmaceutical development, done too little in analytical methods, stability and proper formulation that will support a successful regulatory path. This is typical of the thriving startup environment in the Israel and other life sciences entrepreneurship, although this situation is changing now. We currently see more mature managers in bio life sciences in Israel at early stage.
I was involved in numerous not so successful startups, and a couple with success stories, even in a NASDAQ IPO and profitable M&A, (very personal, indeed) so I have a strategy perspective on formulation and pharmaceutical development, and I am eager to share it with you.
I am meeting new startups on a regular basis; I thrive to help even with short punch line advice. Sometime, when I encounter a great game-changer startup, and the formulation is a big challenge for me and I believe I can design the proper delivery system that will be innovative, I join such startup`s efforts and try to contribute as much as I can to their (our) success.
Analytical method development.
There is no way to perform formulation development without proper analytical methods. What is proper analytical methods? Analytical method development are expensive, so what is “proper” for the various development stage? Again, another 1 million $? So now we have two 1 million $ questions on the table. Both analytical methods development and formulation development are going hand in hand and both should never be under-estimated.
Tips on regulatory development
The regulatory authorities will review if the data you provide for pre-clinical studies, specifically safety toxicology data, are for the same entity drug product that you claim for. In other words, it is your responsibility to provide data on identity and purity and stability of your product. It is accepted and normal that the drug substance and drug product are changing through the development, since you gain experience and data on your product and production process and you improve, so it is your obligation to prove and provide on each tested item, the identity, purity and assay. For this, you need GOOD/SATISFACTORY analytical methods in place, that are reliable, verified (as a minimum descriminatory) and as is sometimes required in the pharmaceutical development process, validated. Well, nice words, how much is “verified” or “good acceptable science” and when exactly do I need to perform the expensive validation step. Sorry colleagues and friends, the regulatory guidelines are vague in many critical places and the industry standard in not in your hands. You need to hire many experts to help you navigate the regulatory path. It is like a sentence in the law court. The law is there but interpretation is huge, and you will get as many interpretations as the number of consultants you listen to. Where is the gold-path? My advice to you is that the GOLD-PATH is your common sense and judgment after listening to the consultants; you have to pave your own way with your common sense.
What is formulation development?
I will not go into definitions, since what you have to know is that your recently invented molecule, repurposing idea, etc., has to be well delivered into the desired target organ with the best formulation. What is the “best formulation”? It is one that is fully compatible with your molecule, and may even contribute to stabilizing it, and that contributes to the optimal and desired pharmacokinetic profile for intended use.
Please keep in mind, there is not any “inactive ingredients”. What we, the formulators call is excipients or functional ingredients, since ingredients may have profound effect on stability and bio distribution and that pharmacopoeia monographs are the minimum entry level and you have to provide the unique and extra pharmacopoeial specifications to serve your specific and unique drug product.
So when to start the formulation development?
Many times scientists approach me, make me a formulation! Please? I have a new extract from a newly identified herb from south Papua New Guinea or I have synthetized a new molecule that alleviates psoriasis better than steroids. We have placed it on few rats skin and results are promising, so my advice to them is have your new entity mixed with any simplest (cheapest) body lotion from your close by pharmacy the same morning of experimental day, and after it will works for you with scientific publication quality data, you are invited to come back to me. I will also be happy to help you mix them if you feel not confident about it. Well guess what, 95% do not show up again.
Now to be more somber, after you have decided that your newly invented “VENTURE”, really works in some model and you are fully ready to start investing your life into the adventure and dedicate your full attention and resources, you are then ready to assess the need for formulation development.
Nice words, Doron, please do not fool around with me, how do we do this?
Very simple, 1st start with Target Product Profile (TPP) and then make a short and critical risk assessment for your “VENTURE”. I have drafted a list for you my friend, attached herein, please ask yourself;
A) TPP - Start with a thorough written TPP thinking and working file. Well, too much work for you now, when you are so tight with time and money. It is not me, it is the FDA recommendation and it really will help you dramatically, if you have not done this yet, from my experience, do not start any project without a lot of thinking on your TPP. You will be surprised and you will be much more knowledgeable about your “VENTURE”, finally. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm080593.pdf
B) List of critical questions
1. Do I know how to identify and define “VENTURE ITEM” properties, content and purity?
2. Do I have clear synthesis and production process that is repeatable in small scale?
3. Is my “VENTURE ITEM” soluble in water or oils and is it free flowing or is it stable in various conditions? For example, influence of pH or temperature on stability.
4. What are the optional delivery systems for intended route of administration?
5. Is your “VENTURE ITEM” have specific crystalline state or molecular conformations and is it stable accordingly?
Bring all this information together to the formulation scientist for his/her opinion. Your mutual goal is to identify risks points and challenges. Start with designing the simplest formulation as possible, a direct compressed tablet for oral delivery, and expand to novel drug delivery systems if you wish or anticipate influencing absorption or targeting or solving critical risk points, you have identified in the process we have just gone through.
QBD, Factorial design
I am using factorial design for formulation development for over twenty-five years. I have been successful to resolve some formulation hurdles where others have failed, that is my claim of fame, and in some cases also in significantly shorter time, nice milestone payments, (the personal point). At those times, two decades ago, factorial design was a “project” with statisticians and experts, however, these days it is so handy, you cannot compromise. http://www.fda.gov/downloads/Drugs/.../Guidances/ucm073507.pdf
Challenges in formulation development, drug delivery system
There are many. The most important in my understanding is how to target a drug to reach its activity site and spare the other body organs, not just in cancer but think on regular antibiotics that is prescribed for ear or throat infection, and when you calculate what fraction of the dose really reaches the target organ, you end up with homeopathic figures. Think about targeting antibiotics or steroids preferably to the desired organ. That will be great advantage to the patient, spare huge future complications, and improve quality of life for million of patients. This is something I have been engaged in recent years and striving to solve some of these “holy-grail” challenges. Well, the simple tasks have been cracked; we now face the complicated great ones, we have to join forces in order to gain success.
In summary or take home message
I admire your scientific achievements, your understanding in molecular biology and/or gene discovery, since I am not a biologist and I believe your fundamental work is the heart of human progress. I know you rely on many consulting experts to transform your discoveries into beneficial treatment to many suffering patients. Please do not ignore or under estimate the analytical method development and the pharmaceutical regulatory path and formulation development, at least understand the challenge and the hurdles and make smart decisions, I hope my blog will help you in this task.
Last issue, indeed?
Between us, I did not “instruct” you on the HOW-MUCH formulation development you should do at any stage of your development. I believe that the formulation is an integral part of and build into your “VENTURE” invention, in one way or other, so you have done some work, even solubilizing a small molecule in saline and adjusting for pH and osmolarity, and taking into consideration its sterility. In some cases it may be fine and even sufficient performance for you to take to Phase II.