Manufacturing Controlled Drugs
Guidelines for manufacture & formulation of Schedule II drugs
The manufacture of controlled drugs is a vital and necessary part of today’s pharmaceutical industry that looks set to grow substantially over the coming years, both in the U.S. and abroad. Understandably, control of goods in this market requires an appropriate set of stringent rules and regulations, which manufacturers and distributors alike must adhere to.
Manufacturing and transporting controlled drugs must be closely monitored, and the process is controlled globally, by the United Nations. The UN discharges its duties through the International Narcotics Control Board (INCB), an independent and quasi-judicial monitoring body. National governments then decide how they will administer and control the manufacture, distribution, import and export of scheduled materials. Many governments share and subsequently adopt similar controls and protocols.
Several countries have adequate domestic sources of narcotics and are therefore inaccessible, or closed, to foreign manufacturers. Currently the list of markets deemed closed consists of Australia, Argentina, Belgium, Brazil, China, France, Hungary, Iran, Japan, Norway, Portugal, Slovakia, South Africa, Spain, Turkey, the UK and the U.S. As a result there is little or no legitimate trade of controlled substances between these countries.
However, even in what are considered closed markets, it is possible for individual governments to review the status of the market and choose to open their borders for specific drugs and, within that, specific quantities. For example, in the UK, 90% of the total UK Codeine market can be sourced from anywhere within the EU, and the remaining 10% can be sourced from outside the EU, provided the importer and exporter hold the required licenses.
In the U.S., the Controlled Substances Act of 1970 (CSA) divides substances requiring regulation into schedules. These schedules govern the legal distribution and use of substances with a significant abuse liability. Controlled substances are classified into five different schedules according to different levels of required control, with Schedule I substances being the most tightly controlled (and reserved for drugs with no federally accepted medical use), through Schedule V substances that require lower levels of control as the potential for abuse is lower. Schedule II – V controlled substances include within the schedule, prescription drugs (controlled drugs). There are two federal agencies that decide on the scheduling of various drugs. These are the Drug Enforcement Administration (DEA) and the Food and Drug Administration (FDA). These two bodies determine which substances are added to or removed from the various schedules. However, since the CSA was enacted by the U.S. Congress, that body has the right to schedule substances via legislation.
Schedule II drugs are classed as substances that have high potential for abuse, but which have currently accepted medical use. However, misuse of these drugs may lead to severe psychological or physical dependence. Drugs in this category include Cocaine, Fentanyl, Opiates, Methadone, Morphine and Amphetamines. Even proper administration must be properly controlled since potency and dosage vary widely within the schedule. For example, Fentanyl is approximately 80 times more potent than Morphine, yet both are classed as Schedule II.1
Manufacturing Schedule II Control Drugs
The main discernable differences between a facility manufacturing prescription drugs and facilities used to make Schedule II controlled drugs are the authorizations, licenses, quotas, and levels of security used to prevent diversion. The CSA also creates a closed system of distribution for those authorized to handle controlled substances. The foundation of this system is the registration of all those authorized by the DEA to handle controlled substances. All individuals and firms that are registered are required to complete and maintain accurate inventories and records of all transactions involving controlled substances, as well as security for the storage of controlled substances.
Facility security requirements include many barriers between the controlled drug and the external environment. The list includes perimeter fences and gates with detector activated surveillance, fortified external walls and doors, an intruder alarm system, CCTV cameras, demountable safes for storage at all stages of manufacture, and strictly controlled access to production and storage areas with multiple levels of authentication. There are also systems in place to record the movement of all controlled substances (intermediates to final product) imported to, and exported from, the facility.
In addition to the site requirements, employees are also scrutinized. Personnel working with any controlled substances are subject to criminal background checks, random searches, auditing of their movements by electronic access control, and many standard operating procedures that cover procedural security. Candidates are screened for any disciplinary operational record relating to ethical or criminal activities. Once hired, operators must then complete a rigid training program covering the rules and regulations relating to the manufacture of controlled substances in addition to the current Good Manufacturing Practice (cGMP) training protocols.
Once the facility is staffed and secured, a Manufacturing Authorization and a Controlled Drugs Domestic License is then needed. Companies must complete an application to the DEA, which is then followed by an assessment of the site by an inspector to ensure the site has all appropriate security measures in place. There is also a review against the national quotas for each individual compound to ensure manufacture of surplus does not occur. This entire process is comprehensive and can take as long as three months to complete.
Finally, during production, reconciliation reports are forwarded annually to the DEA detailing all materials bought, consumed by testing, sold, converted, rejected and disposed of. While the disposal of controlled drugs is routine, it must be conducted under strict supervision, where a registered person must witness the destruction via incineration at an approved waste disposal facility before signing a witness statement to that effect. And all facilities and personnel are subject to additional audits from the DEA to maintain licenses to manufacture, store and distribute controlled drugs.
The market for the lawful use of controlled drugs is in excess of $21 billion worldwide. Currently the U.S. is the largest segment, with an approximate 63% share of the global market for controlled drugs.2
While the market is stable, some products have experienced decline over recent years, largely due to the desire of the UN to limit the availability of controlled drugs for medical use and promote other forms of prescription products as alternatives. Therapeutic treatments for conditions such as insomnia and anxiety are readily available and do not have the same propensity for abuse. However, pain relief and addiction treatments retain strong demand for controlled drugs.
Growth in the current Schedule II drug market is estimated at 6% per annum, through the development of key specialist APIs, generic products, combination products for the treatment of drug abuse, and pain management, particularly as we see the demand for oncology treatments increase. Growth in this sector should also arise from the treatment of addictions and the use of Schedule II controlled drugs in the treatment of the abuse of controlled drugs, legally and illegally, as in most cases it is not advisable to completely withdraw the drug of addiction but to replace it with a similar, less addictive drug from the schedule. The key here is for the substitute drugs themselves not to be abused or to be used in conjunction with the illegal drugs to produce a stronger reaction. This issue is being managed through the use of combination products, where the mode of action of the combination drug prevents misuse.
And addiction remains a problem. In 2006 a national survey on prescription opioid abuse estimated that 5.2 million people in the U.S. used pain relievers in a non-medical way and for the first time, prescription opioids surpassed marijuana as the drug most often associated with drug initiation.3 It is crucial to strike a balance between making prescription opioid medications available for pain relief and preventing these medications from being abused.
Taking into consideration the potential of abuse, the burden has been placed on pharmaceutical companies to develop prescription opioid formulations, which deter abuse but remain readily accessible for pain management. It is hoped that the development of abuse deterrent formulations (ADFs) will decrease levels of abuse of prescription opioid medications. Various types of ADFs are currently being developed, each with a unique mechanism to prevent abusers' attempts to manipulate the drug so that the active ingredient is immediately available or made available through different methods of administration such as injection or smoking. Whether or not the ADF is successful in practice depends on various factors including the pharmacokinetic profile of the drug, the features of the drug formulation that make it attractive or unattractive for abuse, the type of drug abuser, the progression of the abuser’s addiction pathway, and the abuser’s social environment — all of which play a role in the abuse of prescription opioids and what methods are used to abuse these drugs.
Some ADFs employ physical barriers that resist common methods of tampering used by abusers, typically crushing the pill, and subjecting the powder to various manipulations in order to extract the active ingredient and used through intravenous, snorting, and oral routes of administration. ADFs also employ combinations with antagonists to mitigate the effect of immediately ingesting an entire dose, while others incorporate an aversive stimulus, such as niacin or capsaicin, which produces an uncomfortable physical sensation in the taker if the product is tampered with prior to ingestion. Even the drug itself may be manufactured as a pro-drug, which has to be metabolized to an active form upon ingestion to produce a pharmacological effect.
It is clear that the maximum impact of these ADFs will most likely not be seen until, at the very least, most of the opioid analgesics prescribed are ADFs. And although ADFs are developed with the goal of decreasing abuse of prescription opioids though alternate routes of administration, they have little impact on those who prefer to abuse these drugs by taking the drug intact.
For the foreseeable future there will always be a need across the globe for the manufacture of controlled drugs, as they are vital in the treatment of pain and addiction. And the recent increase in abuse deterrent formulations will continue to support market growth. It is therefore essential that companies continue to invest in the manufacturing base for distribution throughout the U.S., and for export to countries that do not have facilities to manufacture their own. Obviously with this in mind, governments need to act in concert to ensure that there is a real balance between supply from responsible manufacturers through to legitimate public demand.
1 www.justice.gov/dea/concern/fentanyl.html - United States
2 Newport Database 2009 sales
3 SAMSHA2006 National Survey on Drug Use & Health: National Results. Rockville, MD: Substance Abuse Mental Health Services Administration; 200
Scott Silaika is director, business development, for Aesica Pharmaceuticals, a UK-based supplier of APIs, formulations andcustom synthesis solutions. He can be reached at firstname.lastname@example.org.