Demand for controlled substance active pharmaceutical ingredients (APIs) has increased rapidly in recent years not least because these products have considerable potential to address unmet patient needs, particularly in therapeutic areas such as depression, PTSD, addiction and pain management. However, stringent regulations surrounding the development and manufacture of controlled substances can create challenges for companies. This has led to many firms choosing to outsource this work to contract development and manufacturing organizations (CDMOs) which have the experience and license approvals required to allow them to handle controlled substance APIs.

The controlled substances market:increasing demand
Controlled substances were historically highly stigmatized, primarily as a result of the opioid epidemic, meaning the use of controlled substances was historically not considered good practice. The negative perception of these substances led to many studies during the 1950s and 1960s being abandoned or simply not being used to their full potential. However, recent years have seen a change in mindset studies are now starting to explore the potential therapeutic uses of controlled drugs in more depth, and the industry is keen to encourage new approaches around applying controlled substance APIs to meet market demand for new treatments. For example, “An ethical exploration of barriers to research on controlled drugs”¹ discusses the application of controlled products to address chronic pain and HIV/AIDS.

The controlled substances market was valued at $64 billion globally in 2018 and is expected to reach a CAGR of 7% during the forecast period 2019-2027.² Many controlled substances are also being considered in other therapeutic areas, such as in the treatment of PTSD, addiction, pain management and depression and the approval of products for indications such as ADHD or depression is expected to continue to drive the global controlled substances market. In addition, the oncology market is continuing to grow and explore the use of these products. As such it’s likely that demand for controlled substance products will also continue to develop in this area as well.

Navigating stringent regulations
The market for controlled substances has experienced considerable growth driven by increased demand for alternative therapies and regulatory changes, such as the Controlled Drugs Supervision of Management and Use Regulation 2013. Despite this, a limited number of companies can manufacture and formulate the required APIs, primarily as a result of licensing issues. This has led to an ongoing debate around whether legislation and control measures associated with controlled drugs are slowing down progress and limiting the inclusion of these substances in medicines.

Firms that manufacture controlled substance APIs in the UK must have specific measures in place. These measures must be deemed sufficient by the UK Home Office and are often costly to implement, demand in-depth knowledge of compliance requirements surrounding controlled substance manufacture. Substance classification ranges from schedule I-V, with I regarded as the highest risk of abuse or harm and V regarded as the lowest; requirements for control measures vary depending on the substance classification. For example, the Sterling site had many of these controls in place before beginning to work with controlled substance APIs, but additional investment was made to obtain the Schedule I license.

Benefits of outsourcing
CDMOs can often offer considerable advantages to smaller organizations that are looking to outsource controlled substance API requirements due to quality control measures, existing licenses and the comprehensive expertise they can provide. CDMOs often possess knowledge of regulations and can prove a strong track record of working with controlled substances, which is essential when ensuring the compliant handling of APIs and accelerating products from development to commercialization.

Enlisting a third-party provider can be beneficial to companies when entering highly regulated markets such as the UK and US. Using native CDMOs can allow companies to sidestep import restrictions, allowing a native CDMO to manufacture APIs in the required locations before shipping the product to its destination.

Key considerations to ensure success
Batch size is one of the key issues linked to the manufacture of many controlled substances. Low dosing requirements and small batch sizes mean that firms must carry out thorough analytical sampling and stability samples. As such, many CDMOs with flexible manufacturing capabilities and experience with small batches are well equipped to cater to low dose APIs used in controlled substance products such as orphan drugs and some cytotoxics.

The transportation of controlled substance products must also be considered; companies that transport these products must obtain a license and ensure specific measures are in place to prevent loss or theft of these products.

Final thought
The potential of controlled substance APIs in areas such as psychiatric disorders, pain management, and addiction treatment is beginning to be explored further as the industry mindset towards controlled substances continues to adapt. Manufacturers choosing to outsource these projects to experienced CDMOs can benefit from advantages such as cost reductions, import/export assistance and previous experience of regulatory compliance. Firms can also leverage their relationships with CDMOs to enter and develop a presence in tightly regulated markets such as the US and UK, rather than investing time, resources and capital into buying or refitting their own facilities to meet regulatory requirements. 

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849133/
2. https://www.marketresearchhub.com/pr/controlled-substance-market.html
3. https://www.pharmoutsourcing.com/Featured-Articles/335913-Experience-and-Expertise-Facilitate-Controlled-Substance-Manufacturing/

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Mike Gibson is R&D Director at Sterling Pharma Solutions. Mike has over 18 years’ experience in the pharmaceutical industry having held various roles including synthetic chemist, head of key accounts and product manager. As the R&D director at Sterling he is responsible for the running of the development center in the UK and overseeing the chemistry and technology activities on site. He is also responsible for the new product introduction team and supporting the delivery of customer projects. He holds an MA in Chemistry from Oxford University.