How Drugs Are Made

Drugs are biological or chemical substances that have a biochemical or physiological effect on the body. They can be either single compounds or a combination of many different compounds. While pharmaceutical companies intend for medications to be highly beneficial, they can lead to harmful side effects for certain individuals.

Even the most basic medications are developed over an extended period of time. The drug development timeline is typically around 10-15 years with costs that often exceed $500 million and can approach $1 billion. The following is an in-depth guide on how drugs are made.

Discovery and Initial Research

The first stage of the drug development process begins with discovery and initial research. There are many ways that research into a new drug can begin. For instance, researchers may discover new insights into a specific disease that allows them to create a medication that will reverse or stop the harmful effects that this disease causes.

Research can also be performed by conducting numerous tests of molecular compounds in order to identify potential positive effects against various diseases. Researchers may discover that existing medications or treatments have beneficial effects that were otherwise unanticipated.

Many modern medications are developed because of the introduction of new technologies. For instance, researchers can precisely deliver medications to certain areas in the body. It’s also possible to alter genetic material with the right technologies.

In the earliest stage of development, it’s possible for thousands of different compounds to be candidates for future development into a medical treatment. However, the early testing that occurs immediately afterward results in only a small selection of these compounds being studied any further.

Preclinical Testing

The next stage in the drug development process involves preclinical testing, which is used to identify the best method to create a drug for its intended use. The purpose of this testing is to determine how drugs are absorbed before being broken down and removed from the body.

Preclinical testing goes further than the initial hypotheses that were tested when researchers first discovered the viability of a drug during the discovery and research stage of this process. There are times when a drug will be modified in order to enhance the properties and characteristics in small ways that might result in a more effective drug.

All of the results that are taken from pre-clinical testing will be used to identify how to formulate the drug, which means that now is when the researchers will determine if the drug is best used as a pill, spray, cream, or injection. Some additional factors that will be tested at this point include:

• The optimal dosage
• The possible side effects
• How the compound affects various groups of people
• The effectiveness when compared to similar medications
• How the medication interacts with other treatments and drugs

As mentioned previously, hundreds or thousands of compounds are narrowed down to a few ideal candidate drugs before clinical research begins. The drugs can then be sent to the necessary regulatory authorities. If the drug is approved, clinical development can begin.

Before a drug is tested in individuals, researchers will need to identify if it has the potential for severe harm, which is referred to as toxicity. The FDA requires all researchers to adhere to good laboratory practices (GLP) during preclinical testing. These regulations set requirements for:

• Personnel
• Study conduct
• Facilities
• Written protocols
• Equipment
• Study reports
• Operating procedures
• Quality assurance oversight

In most cases, preclinical studies aren’t too extensive. However, they will provide useful information on toxicity levels and proper dosing requirements. Once the preclinical testing has taken place, researchers will review their findings to determine if the drug can be tested in people.

Clinical Trials

Preclinical research is designed to answer some of the more basic questions surrounding the safety of a drug. However, it can’t be used as a substitute for testing within the human body. Clinical research involves trials that occur in people. Once developers create the clinical study, they’ll set goals on what they would like to achieve during all stages of clinical research.

Researchers create clinical trials that answer specific questions that were brought up during the research stage. These trials adhere to a specific study plan, which is referred to as a protocol. The study plan is developed by the drug manufacturer or researcher. Before clinical trials start, researchers will look at previous details about the medication in order to set clear objectives. They will then decide:

• How many individuals will take part in the study
• Who qualifies for the study
• How long the study is expected to last
• How the drug is administered to patients
• What dosage each patient will receive
• If there will be some type of control group to limit any research bias
• When and what assessments will eventually be conducted
• What types of data will be gathered
• How the gathered data will be analyzed

Clinical trials usually involve four phases, which include everything from small-scale studies to large-scale studies. During phase one of these studies, around 20-100 individuals will participate. These people can be either healthy volunteers or individuals who currently have the condition or disease that the medication is expected to treat. Phase one usually lasts for several months. Nearly 70% of all drugs move to phase two.

The second phase of clinical trials typically involves several hundred study participants, all of whom will have the condition or disease that the medication is designed to treat. This stage of clinical trials can last anywhere from a few months to two years depending on the severity of the disease. The purpose of this study is to research the effectiveness of the drug and the possible side effects. Around 33% of drugs in phase two will move on to phase three.

The third phase involves testing of anywhere from 300-3,000 volunteers who are suffering from the condition or disease. These studies can last for upwards of one-to-four years. Around 25% of drugs in this stage will move to the fourth and final stage.

Phase four involves several thousand volunteers, all of whom will have the condition or disease. The purpose of this study is to make sure that the medication is safe and effective. Drug sponsors or developers will need to submit the Investigational New Drug Application to the FDA before they can start clinical research. In this application, the developer will need to provide:

• Clinical protocols for all studies that will be performed
• Manufacturing information
• Toxicity information and study data from previous animal testing
• Data from previous human research
• Information pertaining to the investigation

During the drug development process, the developers can request assistance from the FDA at all stages. While the FDA provides comprehensive technical assistance, developers don’t need to use the suggestions provided by the FDA.

However, the clinical trials will need to safeguard all participants and meet various federal standards. The FDA review team that looks at the clinical trial application includes many different specialists with unique responsibilities. These specialists include:

• Project manager
• Statistician
• Medical officer
• Pharmacologist
• Pharmakineticist
• Microbiologist
• Chemist

FDA Approval

New drugs applications tell the entire story of a medication. The purpose of this application is to show that a new medication is safe and has proven to be effective for the intended use. Drug developers will need to provide every piece of information that was gathered during preclinical and clinical testing when they send in a new drug application to the FDA. This information includes:

• Safety updates
• Potential labeling
• Patent information
• Drug abuse information
• Review board compliance details
• Directions for how to use the drug

After the FDA is given the NDA, the review team will determine if the document includes all of the necessary information. It it does, the review team then has around 6-10 months to make a final decision on approving or rejecting the drug.

All members of the review team will conduct their own review of the information that pertains to them and their chosen field. For instance, the statistician reviews all clinical data. FDA inspectors often travel to sites of clinical studies to perform inspections.

At the end of the review process, the project manager will gather all individual reviews and combine them into an “action package”, which is the record that the entire FDA will receive. The team will then provide a recommendation, after which an FDA official makes their final decision.

Mass Production

The drug manufacturing process involves the industrial-scale creation of drugs by pharmaceutical companies. This process can be separated into four distinct stages, which include milling, coating, granulation, and tablet pressing. The amount of time it takes for a drug to be mass produced depends on the type of drug and scale of operations.

Quality Control and Monitoring

While clinical trials offer relevant information on the effectiveness and safety of a drug, no pharmaceutical company has all of the information required to determine the safety of a medication when it’s approved.

Limitations are present, which is why companies must perform quality control and monitoring in the months and years after the drug has entered the marketplace. The FDA will receive any reports of issues with the drug. Depending on the side effects, the FDA can add extra information to the drug packaging.

FDA officials will perform regular inspections of drug manufacturing centers throughout the U.S. or in other countries depending on where the drug is manufactured. While manufacturers are sometimes informed of these inspections, they can be unannounced. While many of these inspections are routine, some occur as the result of a concern that has been raised. The FDA can choose to close a facility if the minimal standards for good manufacturer practice aren’t met.

Keep in mind that the FDA also regulates how prescription drugs are advertised and promoted. Developers are restricted from marketing unapproved product uses. It’s also essential that advertisements aren’t false or misleading. They need to include verifiable information about the drug’s side effects, prescribing details, and effectiveness.

When a drug has been approved for marketing, it will be patent-protected, which means that the company behind the product is the only one that can market it. After the patent has expired, it’s possible for other manufacturers to develop a generic version of the same drug. Generic drugs will need to have the same:

• Intended use
• Dosage form
• Safety
• Strength
• Performance characteristics
• Quality

Since generic drugs are similar to ones that are already on the market, clinical trials aren’t necessary. However, bio-equivalence studies must still be performed.

When it comes to product monitoring, the FDA is currently creating a national surveillance system to identify safety issues. This system is set to use electronic health databases to perform real-time monitoring of approved medical products. This technology will supplement the post-market safety assessment tools that the FDA already uses.

Conclusion

One of the main reasons why modern medications are so expensive is because of the considerable research and testing that must be performed over a period of 10-15 years. Every year, hundreds of potential drugs are taken through the initial stages of drug development only to find that they are ineffective or produce too many side effects. However, the presence of such strict regulations surrounding this process means that the chances of harmful drugs entering the market are low.

References

1. https://www.fda.gov/patients/learn-about-drug-and-device-approvals/drug-development-process
2. https://pharmaceutical-journal.com/article/feature/drug-development-the-journey-of-a-medicine-from-lab-to-shelf
3. https://www.yourgenome.org/facts/how-are-drugs-designed-and-developed/