Pharmaceuticals-How Are They Produced?

I thought I would talk a little about pharmaceuticals. Chances are you take some, know someone who takes them, and have all complained about their prices. This past semester, I took a pharmaceutical chemistry class taught by scientists from Gilead, and I must say it was very enlightening. I thought I would share some of the lessons I learned and some of the key problems that face those charged with making these chemicals that many people depend on.

Let's start with a poignant news story. What would you do if you were suddenly unable to get a hold of a medication that you require? When a company decides to stop producing a compound, what can be done? Is that right or wrong? How should medications be priced? These are questions that are very difficult to answer.

To understand a little bit about the complexity of the issues with the pharmaceutical industry I think it is first important to understand how these medications are produced. I know I found it eye opening. Guess how long it takes to produce a drug? 0-5 yrs? 5-10 yrs? 10-15 yrs? 15-20 yrs? If you guessed 15-20 yrs, then you would be correct. It takes 20 years and (as of 2008) $1.7 billion to develop a SINGLE drug. 

The timeline:

Discovery/Preclinical Trials

Time: 1-3 years

In this time, the company will begin by identifying a medical need, such as anti-HIV medications, and then study that disease to determine where drugs can target the disease and the possible interactions of the drug. This is where potential contenders for a drug are determined. This amounts to some 30 000 chemical compounds will be screened! These preclinical trials will involve pharmacodynamics and pharmacokinetics.

Pharmacodynamics: studies how a drug interacts with a target-this is the impact of the drug on the body. Is the drug going to do what is was intended to do? Is it going to do something else? 

Pharmacokinetics: this is how a drug is transported to the target-this is really looking at the impact of the body on the drug. This looks at four things: absorption, distribution, metabolism, and excretion. Remember, your body is one self contained complex chemical reactor. I think one excellent example of the importance of studying this effect is the notorious thalidomide. There are two versions of thalidomide: R and S. One is an anti-emetic (R) while the other causes birth defects (S). Yes it is possible to separate the two and give a person only the version that DOES NOT cause birth defects; however, once in the body, the drug is inter-converted to the other form (a process called racemisation).

Any potential drug will be screened for toxicity using two species: one rodent and one non-rodent. They will be tested for single and repeated dosing. They will be tested by various delivery methods. (Side note: a 14-day rat trial costs $250 000.)

During this time, chemists will be answering the questions of: can the drug be made? How many steps (hint: more steps, more costly, more trouble)? What are the yields (not all chemical conversions give 100% yield-actually very few give 100%)? Is chemical manufacturing possible, feasible, and affordable? 

After all of this, about 100-200 of the 30 000 compounds will make it on to the next step. 

Safety Review

Time: about 30 days 

This is where the pharmaceutical company is trying to get approval from human clinical trials. All of the information gleaned in the preclinical trials must be presented to the regulatory bodies, including the synthetic routes for production. This is also the time that a company will take out a patent on a compound (a process in the tens of thousands of dollars for each one). 

Clinical Trial: Phases 1, 2, 3:

Time: 2-10 years

This is where the human trials begin. 

Phase 1: 

- 10-100 volunteers

- months to 1 year

- involves "proof of concept" and determines whether the drug is adequate, safe, tolerable. 

- 50-70% of the compounds (that made it to clinical trial) will be abandoned. 

Phase 2:

- 50-500 patients 

- 2 years

- 60% of the compounds (that made it to phase 2) will be abandoned

Phase 3:

- 500-2000 patients

- 3-5 years

- only 4-10% of compounds will succeed

Approval:

Time: up to 7 years

This is the stage where regulatory bodies determine if a drug is safe enough and effective enough to sell to the population. 

Now if you have been keeping track, we are about 15 years from when the patent was filed to the point that the drug can be sold. A patent is only good for 20 years; therefore, a company only has about 5 years to recover the cost of the production. This also means that drugs that are currently hitting the market were just getting out of preclinical trials in 1996.

During this time, optimisation is ongoing to make the manufacturing process safer, cheaper, and more efficient. However, if the process is changed too much, it may mean that a company will need to refile their drug for approval. 

There is lots of interesting chemistry in pharmaceutical production. I think I will leave that for another entry, but if you have found this interesting, please check out these course notes for reference material.