Manufacturing Controlled Substances

Close to three years ago, when we announced our capabilities for controlled substance development and manufacturing, we had no idea just how great demand would become for Contract Development & Manufacturing Organization (CDMO) services in this space. 

By putting in place the infrastructure, processes and expertise to manufacture controlled substances and becoming registered with the Drug Enforcement Administration (DEA), we’re meeting the growing demand for new molecules that make use of the medical value of controlled substances. We now have three cGMP suites equipped to produce them.

While the manufacture of all new chemical entities (NCEs) and Active Pharmaceutical Ingredients (APIs) takes stringent requirements and follow all of the same steps, manufacturing controlled substances takes some of those requirements to a whole new level of quality control, in order to comply with state and federal regulations.

A New Level of Compliance Requirements

What actually makes a substance a controlled one?  According to the U.S. FDA, it needs to have an accepted medical use for treatment in the United States, along with a likelihood of causing dependence when abused. Most prescriptions for chronic conditions, such as high blood pressure or high cholesterol, asthma or diabetes, are non-controlled. In contrast to them, controlled substances are medications that can cause physical and mental dependence, and the manufacturing, possession and use of these medications is regulated by law. Some examples of controlled substances include opioid pain medications like Vicodin, or ADHD medications such as Adderall.

The Controlled Substances Act

Put into law in 1970 by Congress, the Controlled Substances Act (CSA) has been used by U.S. law enforcement to decrease drug abuse and dependence among Americans by regulating the production, sale, purchase and use of many drugs. This act gives authority to the DEA to monitor and control the use of substances, both legal and illegal. Because of the many differences between the various categories of controlled substances, consider the following: Schedule 1 drugs have no medical value and high potential for abuse, while schedule 2 through 5 substances all have some medical value but differ in ranking depending on their potential for abuse.

European countries also follow similar guidelines regarding the designation of controlled substances and their classification. These guidelines were based on United Nations Conventions of 1961, 1971 and 1988, controlling and supervising the legitimate scientific or medical use of controlled substances, while taking into account the particular risks to public or individual health.

Seqens CDMO N.A. has approval to develop products that fall in the Schedule 2 through 5 range in the U.S. To put that into context, Schedule I substances, include drugs such as heroin, while Schedule 2 includes methadone or oxycodone; and schedule 5 includes cough preparations, such as Robitussin.

What’s Different in the Manufacture of Controlled Substances?

As mentioned above, manufacturing controlled substances is similar to manufacturing other chemicals, but requires extra diligence in in two key areas:

1. Quality Control. Conforming to Current Good Manufacturing Practices (cGMP), highly specific processes must be put in place to ensure heightened quality control of the compound you are developing. AT Seqens, one of our core pillars has always been an unwavering commitment to ensuring quality in everything we do – from cleanroom operations, to calibration of instruments and preventative maintenance in utilities systems, and we’ve built processes and controls that help us meet our own strict standards, as well as industry regulations. This commitment to quality goes up exponentially when it comes to controlled substances.

• Security.  This is one of the most critical areas for manufacturing controlled substances. Contract Manufacturing Organizations (CMOs) must revamp their entire processes and physical features to ensure specific security requirements are met.  For example, employees working in any function within the kilo lab or plant must have thorough background checks, as well as secure restricted access permission for entry into facilities, and cameras in all entry ways.

How Do You Pick the Right CDMO?

Pharmaceutical companies that look to outsource the development and manufacture of DEA controlled substances need a partner that is equipped to perform cGMP processes, as well as more specific requirements to ensure proper management of risk throughout the manufacturing process. So how do you know you’re selecting a CDMO equipped to handle your controlled substance project? It involves asking the following five questions:

1. What type of compliance system is in place? It’s important that your CDMO has a robust compliance system in place for handling schedule 2-through 5 controlled substances and that they have a clear understanding, as well as a strong track record of meeting all regulatory requirements
2. Do you have a good relationship with the DEA? It’s necessary that your CDMO is registered with the DEA, but it’s also important that they have a good working relationship with the agency.  You should inquire about its history with DEA inspections, and what type of a working relationship it has with it.
3. How do you handle raw materials from overseas? It’s important if you are getting raw materials or chemicals from suppliers outside the U.S., to ask if your CDMO has an established system for handling international sales or shipments, including necessary import permits, DEA Form 236, etc.
4. Do you have comprehensive controls in place?  Make sure your CDMO has comprehensive controls in place for manufacturing, handling and storing products, that are clearly understood and adhered to by every employee of the company. These controls include environmental, laboratory, security, materials handling and training.
5. Do use QRM tools?  An effective quality risk management (QRM) approach to the manufacture of controlled substances can ensure the high quality of the drug product to the patient by providing a proactive means to identify and control potential quality issues during development and manufacturing. 

Despite the increasing attention that controlled substances get when it comes to their abuse and mistreatment, they also provide effective treatment for a variety of conditions when used correctly according to their intended purpose. It pays to do your homework when choosing a CDMO so that you can select a partner that can help you bring these critical drugs to market safely and effectively.

About the Author

Ed is President & CEO of SEQENS North America (formerly PCI Synthesis). He serves as a co-chair of the New England CRO/CMO Council and sits on the Industrial Advisory Board for the Department of Chemical Engineering at UMass, Amherst. Ed is also a long standing member of the American Chemical Society and advises the Bulk Pharmaceutical Task Force of the Society of Chemical Manufacturer’s and Affiliates (SOCMA)...

Do you have questions? Talk to Ed.