Controlled substance manufacturing: Navigating API chemistry and security protocols
Section overview
- Meeting growing demand for controlled substance manufacturing
- What are controlled substances classifications?
- Choosing the right CDMO for controlled substance manufacturing
- Controlled substance infrastructure: Handling controlled substances within a closed system
- Integrated chain of custody for controlled substances
- Audit-ready by design: Ensuring compliance for controlled substance handling
- Integrated regulatory support
- Seamless scale-up of controlled substances from development to commercial manufacturing
- Deep API chemistry expertise for controlled substances
- Choose a trusted CDMO for controlled substances
- How to prepare a controlled substance CDMO inquiry
Meeting growing demand for controlled substance manufacturing
The global pipeline of therapies targeting the central nervous system (CNS) is expanding at a remarkable pace. According to Citeline, there was a 14.7% growth rate in the start of Phase I–III trials for CNS indications, the second highest across all therapeutic areas. This increase is being driven, in part, by sustained R&D investment in pain management, depression, and Alzheimer's disease. Highlighting the scale of unmet need, the World Health Organization (WHO) ranks neurological conditions as the leading cause of ill health and disability worldwide.
While much of the focus in the CNS space is on compounds that fall under controlled substance classifications, the supply chain supporting these programs is relatively constrained. Controlled substances require manufacturers to hold specific government-issued licenses, maintain documented security systems, and undergo periodic regulatory inspections by national authorities. As a result of these high barriers to entry, pharmaceutical companies often rely on experienced contract development and manufacturing organizations (CDMOs) for their controlled substances programs.
Relatively few CDMOs bring all of the necessary capabilities together for developing and manufacturing controlled substances; as such, selecting the right partner is a critical strategic decision.
What are controlled substances classifications?
Controlled substances are regulated compounds with recognized potential for abuse, dependence, or misuse. Regulatory classifications differ by country with each nation maintaining its own legal framework governing which substances require special licensing, how they must be stored, and how they may be transferred across borders.
In the United States, the Drug Enforcement Administration (DEA) classifies controlled substances into five schedules under the Controlled Substances Act (CSA); the DEA classification is the most widely recognized around the world. Switzerland, where one of our Small Molecule CDMO site is located, operates under its own federal narcotics legislation set by Bundesamt für Gesundheit (BAG) and administered by Swissmedic. The site also operates under full GMP and is licensed to produce APIs. While the categorizations differ across countries, the core principle is that manufacturers, distributors, and handlers of controlled substances must be licensed by national authorities before they can legally produce or ship these compounds.
Choosing the right CDMO for controlled substance manufacturing
Given the complexity of controlled substances, selecting a CDMO requires careful evaluation across both compliance and technical dimensions.
In addition to holding the appropriate licenses, a controlled substance CDMO must demonstrate a clear understanding of regulatory requirements, including import/export controls and audit expectations. Security infrastructure and chain of custody systems should be robust, well-documented, and proven through inspections.
At the same time, specialized technical capabilities are essential. The CDMO should have demonstrated expertise in API development, including synthetic chemistry, purification, and analytical methods, as well as the ability to scale processes efficiently.
This page describes the capabilities of our controlled substances CDMO in Schaffhausen, Switzerland, a stable regulatory environment. The site combines a team with deep expertise in synthetic chemistry and global regulatory requirements in the area of API development and manufacturing, with specialized security systems and licenses. Together, these capabilities enable customers to advance their programs with confidence, quality, and speed, from early development through commercial-scale production.
Controlled substance infrastructure: Handling controlled substances within a closed system
Regulatory agencies worldwide require that controlled substances be handled within a "closed system", a traceable, documented chain of custody in which every gram of material is accounted for from supplier receipt through production, quality control, and final shipment or waste disposal. At our Schaffhausen site, this system has been built, audited, and refined over decades to ensure full traceability and prevent diversion. At this site, we can manufacture for and export to any geography when the receiving party is authorized and regulated by the authorities governing the site’s licensed activities. All exports and imports are carried out under approved licenses and permits aligned with international trade and narcotics conventions.
This approach governs the entire manufacturing lifecycle from raw material receipt through production and final shipment. The site holds the necessary licenses for controlled substances, issued by Swiss authorities, and has robust internal systems to control access, track materials, and document every transaction.
The CDMO team also has extensive experience managing the complexities of international supply. For each shipment, import and export licenses are coordinated to meet country-specific requirements, helping to minimize delays and facilitate global distribution.
Comprehensive record-keeping is embedded into daily operations. Every movement of material is documented, verified, and retained in accordance with regulatory expectations, supporting full transparency and audit readiness.
Integrated chain of custody for controlled substances
A closed system requires a fully secure and documented chain of custody across all stages, from incoming goods to final reconciliation. Robust systems ensure that the location, status, and disposition of all controlled materials are continuously known. This integrated approach is used at our Schaffhausen site to guarantee full traceability, operational control, and regulatory compliance throughout the lifecycle of every substance.
The chain of custody includes the following elements:
Incoming goods and secure storage
Controlled materials are received and stored in restricted-access areas under tightly managed key and access control systems. Only authorized personnel are permitted to handle incoming substances, ensuring secure custody from the point of receipt. Clear ownership and accountability are established immediately upon entry into the facility.
Production transfer and manufacturing
As materials move into production, each transfer between manufacturing steps is tightly controlled and documented. Highly regulated internal procedures ensure that movement of controlled substances through manufacturing is fully traceable. Each inter-departmental material handover is tracked using proven procedures. This ensures that chain-of-custody is maintained at every stage of processing.
QC vaults and in-house analytics
Samples collected for release testing and stability studies are transferred to Quality Control under the same chain of custody protocol. QC maintains two dedicated, secured vault areas, one large vault with controlled access for storage, and individual locked cases within the laboratory to secure samples during brief periods such as analyst breaks. All analytical work is performed in-house, eliminating the need to ship controlled substance samples to third-parties and avoiding the regulatory complexity and security risk that off-site transfers would entail.
Waste management and disposal
Controlled substances are managed through secure, approved waste handling processes that encompass internal transport, documentation, and disposal via authorized channels. Every step is designed to ensure compliant handling and ensure material traceability.
Export and certified delivery
When materials are released for export or external delivery, they are handled under certified and compliant logistics procedures. Chain-of-custody documentation accompanies all shipments, ensuring full traceability from site to destination and adherence to applicable regulatory requirements.
Annual mass balance and reconciliation
Reconciliation processes are conducted to account for all controlled materials on an annual basis and communicated to Swissmedic. Mass balance reviews confirm that all inputs, outputs, and waste streams are fully documented and reconciled. The mass balance for all controlled materials are submitted to the Swissmedic on a yearly basis. This ensures complete transparency, full legal compliance, and ongoing process integrity.
Audit-ready by design: Ensuring compliance for controlled substance handling
Audit readiness in controlled substance manufacturing requires a fully integrated compliance framework that includes accountability, transparency, and regulatory expertise into every aspect of operations.
- Swissmedic licensing
The Schaffhausen site operates under established Swissmedic licenses for controlled substances, ensuring that all activities meet stringent national legal requirements from the outset. - Controlled substance inspections
The facility is regularly subject to inspections by regulatory authorities, confirming adherence to applicable controlled substance laws and GMP standards. These inspections reinforce a culture of continuous compliance and operational transparency. - Continuous documentation to Swissmedic
Ongoing communication and documentation are maintained with Swissmedic, including required reporting on controlled substance handling, inventory, and manufacturing activities. - Responsible person system
A defined Responsible Person (RP) framework ensures clear accountability for controlled substance oversight. Designated RPs are responsible for legal compliance across handling, documentation, and regulatory interactions. - Internal self-inspection program
In addition to external audits, a robust internal self-inspection program is in place to proactively identify and address compliance risks. This continuous monitoring strengthens audit readiness and supports consistent quality standards. - Import/export license management
The CDMO team manages all import and export licensing requirements for controlled substances, ensuring compliant cross-border movement. This includes coordination of permits, documentation, and certified delivery processes.
Integrated regulatory support
The CDMO team provides comprehensive regulatory support to efficiently advance controlled substance programs, working closely with customers to prepare detailed documentation for regulatory submissions, including descriptions of the API, manufacturing processes, controls, and analytical methods.
This support extends to Common Technical Document (CTD) sections, as well as data packages for Drug Master Files (DMFs) and Active Substance Master Files (ASMFs). By aligning documentation with global regulatory expectations from the outset, the burden on customers is reduced and the risk of delays during review is minimized, helping to keep programs on track from development through commercialization.
Seamless scale-up of controlled substances from development to commercial manufacturing
The Schaffhausen facility is equipped to support controlled substance programs across the full development lifecycle, from early-phase production to commercial supply.
The site offers the flexibility to manufacture small-scale GMP batches for clinical development, typically in the range of 1–5 kg, and to scale processes to commercial volumes of up to ~ 60 kg per batch.
Deep API chemistry expertise for controlled substances
The Schaffhausen site can develop and manufacture a wide range of controlled substances including those covered by Swissmedic schedules a, b, c, and f, which overlap, in large part, with substances categorized as DEA Schedule II-IV. The combination of this broad license and deep expertise in API chemistry enables the development of scalable synthetic routes, optimized yields, and robust GMP batch production.
Controlled substances span a wide range of molecular structures and synthetic approaches, requiring tailored process development strategies for each program.
Our process chemists develop and optimize synthetic routes tailored to each molecule. For controlled substances, we work exclusively with synthetic and semi-synthetic pathways. We apply chemical transformations to generate even highly complex APIs with chiral centers and parenteral APIs. We also offer advanced hydrogenation capabilities, a specialized high-pressure reaction technology expanding the range of chemical transformations available in route design.
We excel in handling difficult-to-filter APIs, which can be characterized by poor particle size distribution and, by extension, difficult-to-control API particle size. These challenges are overcome using a combination of crystallization development and particle engineering, supported by in-house analytical support teams and enabled by precision milling equipment. Fully integrated, on-site analytical capabilities eliminate the need for external testing, enabling faster decision-making and greater efficiency throughout development and manufacturing. By reducing the risk of off-site shipments, this integration also simplifies the chain of custody, which is beneficial when manufacturing controlled substances.
Choose a trusted CDMO for controlled substances
Our controlled substance CDMO capabilities bring together the critical elements required for success:
- Dedicated licenses for both API GMP production and controlled substances, supporting a broad range of global programs.
- Established security and chain of custody systems that ensure safe, compliant handling at every stage.
- Deep expertise in small molecule API development, enabling a wide range of chemical transformations and process optimization strategies.
- In-house analytics eliminate the need to send samples to an outside testing organization.
- Regular inspections by authorities such as Swissmedic, reinforcing quality and audit readiness in a stable regulatory environment.
- Integrated regulatory support to help navigate complexity and advance global submissions.
By combining these capabilities within a single, experienced team, pharmaceutical companies can more effectively navigate complexity with confidence, advancing controlled substance programs efficiently from development through commercialization, with full compliance.
Substance schedule and classification
What DEA schedule or equivalent national classification is required? This will determine the licensing requirements that must be in place on both the import and export destinations.
Synthetic pathway
Do you require a fully synthetic route, a semi-synthetic approach, or have a defined process you wish to transfer?
Bill of material
Will there be key starting materials and intermediates, including any that may themselves be classified as controlled substances or restricted in supply? This allows for procurement feasibility assessment early in the evaluation.
Launch country
In which countries your finished product will be marketed or used? This determines the import licensing process and the export licensing the CDMO must obtain from their country-specific authority.
Molecule class
Define the molecule class, molecular weight, key physical and chemical properties, known impurity profile, and any specific formulation or particle size requirements for the API. This helps match your molecule to the right equipment and process platform.
Documentation and phase
Know the clinical or commercial phase, existing process documentation (if any), regulatory submissions in progress or planned, and any requirements for DMF/ASMF filing. Early clarity on the regulatory strategy helps to correctly structure CDMO support and plan for capacity.