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Pharmaceutical Manufacturing and Packing Sourcer

Keeping Control

Simon Clough at Aesica Pharmaceuticals considers the guidelines surrounding the manufacture and formulation of Schedule 2 controlled drugs

The manufacture and formulation of controlled drugs is a vital and necessary part of the pharmaceutical industry today and looks set to grow substantially over the coming years. Understandably, growth in such a complex market requires a detailed set of stringent rules and regulations, which manufacturers and distributors alike must adhere to.

Manufacturing and transporting controlled drugs must be closely monitored – a process which is managed globally by the United Nations. The UN discharges its duties through the International Narcotics Control Board (INCB), an independent and quasi-judicial monitoring body. Although it is left to national governments to decide how they will administer and control the import and export of scheduled materials, many governments share and subsequently adopt controls and protocols.

Several countries have adequate domestic sources of narcotics and are therefore inaccessible 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, UK and the US. As a result there is little or no legal trade of controlled substances between these countries.

Although they are considered closed markets, it is possible for individual governments to review the status of the market as they have in the past, and choose to open their borders for specific drugs and, within that, specific quantities. For example, in the UK, 90 per cent of the total UK Codeine market can be sourced from anywhere within the EU, provided the supplier and receiver have the appropriate licenses and the remaining 10 per cent can be sourced from outside the EU, again provided the importer and exporter hold the required licenses.

MANUFACTURING SCHEDULE 2 CONTROLLED DRUGS

The main discernable differences between a facility manufacturing Schedule 2 controlled drugs and facilities used to make prescription drugs are in the levels of security. These include perimeter fences and gates with detector activated surveillance, external doors to standard LPS 1175 SR4, an intruder alarm system conforming to ACPO 2000 requirements, CCTV cameras, demountable safes for storage, strictly controlled access to areas, CRB checks on personnel, random searches, electronic access control system with audit trail and standard operating procedures to cover procedural security, as well as a reconciliation report forwarded annually to the Home Office detailing all materials bought, consumed, sold, converted, rejected and disposed of. Furthermore, facilities and personnel are subject to additional audits from the 89 Home Office to maintain licenses to manufacture, store and distribute controlled drugs.

The Misuse of Drugs Act 1971 controls ‘dangerous or otherwise harmful drugs’ that are designated as controlled substances. The primary purpose of this legislation is to prevent the misuse of this group of drugs, which is achieved by imposing a total prohibition on the possession, supply, manufacture, import or export of controlled drugs with the exception of those permitted by regulations or by license from the Secretary of State. The medical use of controlled drugs is permitted through the Misuse of Drugs Regulations 2001 and subsequent amendments. These Regulations define the classes of person authorised to supply and possess controlled drugs, while acting in their professional capacity and lay down the conditions under which these activities may be carried out.

The Controlled Substances Act of 1970 divided substances requiring regulation into schedules. These schedules govern the legal distribution and use of most substances with a significant abuse liability. Controlled drugs are classified into five different schedules according to different levels of control, with Schedule 1 being the most tightly controlled schedule and Schedule 5 the least controlled.

Schedule 2 drugs are classed as substances that have high potential for abuse, but which have currently accepted medical use. However, misuse of the drugs within the Schedule 2 category may lead to severe psychological or physical dependence. Drugs in this category include cocaine, fentanyl, opiates, methadone, morphine and amphetamines. All drugs within the schedule vary in potency – for example, fentanyl is approximately 80 times more potent than morphine, yet both are classed as Schedule 2.

To manufacture Schedule 2 drugs, in addition to a Manufacturing Authorisation and relevant Marketing Authorisation, a Controlled Drugs Domestic License is needed. Pharmaceutical companies must complete a web-based application to the Home Office, which is then followed by an inspection of the site by a Home Office compliance inspector. The site must have appropriate security measures in place, which include secure storage facilities, restrictive access to production and storage areas, CCTV monitoring, perimeter fencing, an on-site security presence and a criminal charge audit of all staff. In addition, systems should be in place to record the movement of all controlled substances both in terms of import and export. There is also a review against the national quotas for individual compounds to ensure a surplus does not occur. This process is comprehensive and can take up to three months to complete.

As noted earlier, security surrounding controlled drugs is paramount and is the key differentiator in terms of guidelines for their manufacture and formulation. Controlled drugs are manufactured using the same technologies as prescription medicines and, as such, share the same processes and stages of manufacture. The difference lies in the reconciliation of all materials used, converted and rejected during the process, which is significantly tighter for controlled drugs.

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.

SECURITY IN DETAIL

Initial screening takes place through CRB checks – current and prospective operators must fulfil a set of strict criteria which includes a clean disciplinary operational record relating to ethical or criminal activities. Operators must then complete a rigid training programme covering the rules and regulations relating to the manufacture of controlled substances, in addition to the normal good manufacturing practice (GMP) training protocols.

The facility must have several security barriers in force between the controlled drug and external environments. These would typically include perimeter fencing, permanent security surveillance, CCTV cameras, key pad/key card access control to production areas, as well as a demountable safe to store the product at all stages of manufacture.

CURRENT MARKET

The market for the lawful use of controlled drugs is in excess of $21bn worldwide (source Newport Database 2009 sales) with the US being the largest player with approximately 63 per cent share of the global market, and the UK holding an eight per cent share.

While the market is stable it has experienced a slight decline over recent years, largely due to the desire for the United Nations 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, steroids, pain relief and addiction treatments retain strong demand for controlled drugs.

The estimated growth in the Schedule 2 drug market is positive with a predicted six per cent increase per annum, through the development of key specialist APIs, generic products and, as previously noted, combination products for the treatment of drug abuse.

Further and continued growth is expected in pain management, particularly as we see the demand for oncology treatments increase. However, the real growth in this sector should arise from the treatment of addictions and the use of Schedule 2 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.

CONCLUSION

For the foreseeable future there will always be a need in this country for the manufacture of Schedule 2 controlled drugs. They are vital in the treatment of addiction and, while the current import and export procedures are in place, it is essential that the UK continues to manufacture these substances for distribution throughout the UK and export to countries that allow import of controlled drugs, but do not have the facilities to manufacture their own.


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Simon Clough is New Business Introduction Director at Aesica Pharmaceuticals. He has recently moved to Aesica’s head office, having been the Site Operations Director at their Queenborough site from 2007 to 2010. At Queenborough he delivered a site expense reduction of £8 million (24 per cent) in two and a half years. Before joining Aesica, Simon held a variety of roles within Abbott’s Operations for UK Formulated Products division and prior to this he worked for GSK within Quality, Supply Chain, Third Party Management & Operations for Formulated Products. He has a BSc (Hons) in Applied Chemistry from Nottingham, and is a registered Qualified Person, having satisfied the permanent provisions of 2001/83/EC and 2001/82/EC in 2007. He is also a member of the Royal Society of Chemistry (MRSC).
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Simon Clough
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