Manufacturing oral solid dosage (OSD) forms of controlled substances presents a distinct set of regulatory, operational, and logistical challenges not typically encountered in the production of other drug types. While the FDA provides broad regulatory oversight to ensure that all drugs, controlled or otherwise, are safe and effective, the Drug Enforcement Administration (DEA) focuses specifically on diversion control. This means every controlled substance entering or exiting a registered facility must be carefully tracked and accounted for at every stage.
LGM Pharma brings decades of experience in the production and management of controlled substances. In the sections below, we will explore key considerations such as substance handling, security protocols, operational planning, and the additional space requirements associated with manufacturing oral solid doses.
Planning for Oral Solid Doses Development Success
Initiating a development project involving a controlled substance like OSDs requires thorough planning that addresses regulatory requirements.
The first step is determining which DEA schedule the substance will fall under, whether I, II, or the less stringent requirements of Schedule III-V substance. Schedule I and II substances, in addition to List I substances like pseudoephedrine, require submission of a quota request to the DEA to obtain permission to receive the active pharmaceutical ingredient (API). Approval times vary, ranging from a couple of weeks to several months, and until the DEA grants this, a drug manufacturer cannot receive the API.
Storage capacity is another critical consideration. Schedule I and II substances such as codeine or hydrocodone require the highest level of security, including vault storage, while Schedule III-V substances may be stored in secured cages. When evaluating a new project, a CMO must assess whether it has adequate secured storage capacity to accommodate the projected drug volume.
LGM has assessed its facilities to ensure that we have adequate storage for our anticipated production volumes. Our Texas manufacturing facility has secure cage storage for large volumes of Schedule III-V liquid and semi-solid products. Solid oral dosage forms (capsules and tablets) are manufactured at our California facility.. The California site can handle moderate volumes of Schedule I-II products in addition to secure cage storage for large volumes of Schedule III-V liquid and semi-solid products.
Understanding the Oral Solid Dosage Form Regulatory Challenges
The primary focus of the DEA in regulating facilities working with controlled substances is diversion control. In short, the agency requires full accountability for every gram of a controlled substance from receipt to final disposition, whether it was incorporated into the finished drug product, retained as in-process material, or destroyed as waste. Having a locked down system of inventory control is paramount to maintaining DEA compliance.
During a typical DEA inspection, the agency will usually select one or two lots of controlled substance and require complete traceability, including every use, waste record, and sample. Any significant discrepancies could indicate poor security or inadequate accountability procedures.
To meet security and accountability requirements, LGM considers each step in the manufacturing process. These considerations include the need for multiple weighing checkpoints to help us account for material lost in equipment or to manufacturing processes. We also track concentration changes during production, as the API starts at 100% purity and is gradually diluted to the final potency of the final drug product. LGM currently manufactures products in which the controlled substance constitutes 2.5% to 80% of the formula weight. Each step requires a stringent reconciliation of waste, losses,, and samples accounting for the concentration of controlled substance in the product at that processing step.
Schedule I and II substances and products, and List 1 chemicals (pseudoephedrine), demand the highest level of security, including vault storage and restricted access. Lower-schedule materials (III–V) may be stored in secured cages, but they are still tightly controlled.
For controlled substance manufacturing, in addition to needing DEA-compliant vaults and cages for substance storage, LGM’s sites have a designated employee that acts as a DEA liaison. These liaisons are vital to the oversight of the storage and handling of these substances. DEA liaisons are present during the weighing of controlled substances and are responsible for delivering the material to the manufacturing room. during the weighing of controlled and responsible for delivering They will remain on site to oversee the production processes and then ensure that the material is returned to the vault or cage at the end of each day. Depending on the schedule of the drug, the DEA liaison may remain in the manufacturing facility for the entire day to monitor sampling, waste collection and product movements to ensure a high level of accountability.
Work with a Trusted CDMO Partner
While many CDMOs can handle basic manufacturing, working with controlled substances requires a higher standard of discipline, transparency, and regulatory alignment. At LGM Pharma, we have maintained an excellent reputation with the DEA via a commitment to effectively managing all the tasks needed to stay compliant with current regulations. Our processes are documented, traceable, and defensible—not only for the DEA, but also to meet FDA expectations.
With decades of experience in controlled substance development, we are able to proactively navigate quota requests, anticipate operational challenges, and avoid common pitfalls that less experienced partners often overlook.
To learn more about our team of controlled substance experts and our ability to manage large and small projects, contact us today.
