STANDING IN THE WAY OF CONTROL:
Simon Clough, managing director of the Formulated Products business unit at Aesica, looks at the guidelines surrounding the manufacture and formulation of Schedule II controlled drugs.
The manufacture of controlled drugs is a vital and necessary part of today's pharmaceuticals industry that looks set to grow substantially over the coming years,. 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 UN, via 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. The markets currently deemed 'closed' are Australia, Argentina, Belgium, Brazil, China, France, Hungary, Iran, Japan, Norway, Portugal, Slovakia, South Africa, Spain, Turkey, the UK and the US. As a result, there is little or no legitimate trade of controlled substances between these countries.
However, even in 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 codeine market can be sourced from anywhere within the EU and the remaining 10% can be sourced from outside, provided that the importer and exporter hold the required licenses.
Regulations
In the USA, the Controlled Substances Act (CSA) of 1970 divides substances with a significant abuse liability into five different 'schedules' according to the levels of control required and governs their legal distribution and use. Schedule I substances, which have no federally accepted medical use, are the most tightly controlled, while Schedule II-V substances include various controlled prescription drugs.
Two federal agencies decide on the scheduling of various drugs and determine which substances are added to or removed from the various schedules: the Drug Enforcement Administration (DEA) and the FDA. However, since Congress initially enacted the CSA, it has the right to schedule substances through legislation and sometimes has.
Schedule II drugs are classed as substances that have high potential for abuse because misuse of them may lead to severe psychological or physical dependence but which have currently accepted medical uses. Among them are 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 by the DEA.
In the UK, the Misuse of Drugs Act 1971 controls 'dangerous or otherwise harmful drugs' that are designated as controlled substances with the primary purpose preventing the misuse of this group of drugs. It does this 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 licence from the Secretary of State.
The medical use of controlled drugs is permitted in the UK 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.
Manufacturing Schedule II drugs
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.
The main discernible differences between a facility manufacturing prescription drugs and facilities used to make Schedule II controlled drugs are the authorisations, licences, quotas and levels of security used to prevent diversion. The US CSA also creates a closed system of distribution for those authorised to handle controlled substances.
The basis of this system is the registration of all those authorised 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 (to LPS 1175 SR4 standard in the UK), an intruder alarm system (to APCO 2000 requirements in the UK), 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.
Systems are also in place to record the movement of all controlled substances (intermediates to final product) imported to and exported from the facility. Employees working with any controlled substances are also scrutinised. They are subject to 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, including, in the UK, a Criminal Records Bureau check. 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 cGMP training protocols.
Once the facility is staffed and secured, a Manufacturing Authorisation and a Controlled Drugs Domestic License is then needed. In the US, 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.
During production, reconciliation reports are forwarded annually to the DEA detailing all materials bought, consumed by testing, sold, converted, rejected and disposed of. All facilities and personnel are subject to additional audits from the DEA to maintain licenses to manufacture, store and distribute controlled drugs.
In the UK, a Controlled Drugs Domestic License is needed, in addition to the Manufacturing and Marketing Authorisations. Pharmaceuticals companies must complete a web-based application to the Home Office, which then sends a compliance inspector to inspect the site. The inspection covers all security measures, systems in place to record the movement of all controlled substances both in terms of import and export.
On a national level, a reconciliation report is forwarded annually to the Home Office detailing all materials bought, consumed, sold, converted, rejected and disposed of. Facilities and personnel are subject to additional Home Office audits to maintain licenses to manufacture, store and distribute controlled drugs.
In both countries, 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 up to three months to complete. 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.
Current market
The global market for the lawful use of controlled drugs is in excess of $21 billion Currently the US is the largest market, with an approximate 63% share of the total in 2009, according to the Newport Database.
While the market is stable, some products have experienced decline over recent years, largely due to the UN's wish to limit the availability of controlled drugs for medical use and promote alternative forms of prescription products. 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%/year, through the development of key specialist APIs, generic products, combination products for the treatment of drug abuse and pain management, particularly as demand for oncology treatments increase. The treatment of addictions and the use of Schedule II controlled drugs in the treatment of the abuse of controlled drugs, legally and illegally, could also drive growth.
In most cases, it is not advisable to withdraw the drug of addiction completely 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 managed through the use of combination products, where the mode of action of the combination drug prevents misuse.
Addiction certainly remains a problem. In 2006 a national survey on prescription opioid abuse estimated that 5.2 million people in the US 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.
It is crucial to strike a detailed 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 pharmaceuticals companies to develop prescription opioid formulations which deter abuse but remain readily accessible for pain management.
Hopefully, 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 API 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 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 API 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 metabolised 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.
Conclusion
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. 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 US, 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.
ENDS
For further information please contact Christina Pounder or Elizabeth Eddy on 01642 584790 or email christina@velvetcommunications.co.uk
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Jeremy Drummond, Business Unit Director – Formulated Products, Aesica Pharmaceuticals, explores the contract manufacturing market, with a focus on the overarching benefits of outsourcing, highlighting the need for unique services that add increased value.
As the contract manufacturing market continues to experience significant growth, increasing numbers of pharmaceutical and biotechnology companies are recognising the benefits of outsourcing their drug manufacturing requirements. Flexibility, swifter commercialisation, minimal capital expenditure and lower scale up costs are the key factors behind the significant contract manufacturing market growth.
The global contract manufacturing market is currently valued at $78billion and looks set to grow by a further 12 per cent over the course of the next two years. While API contract manufacturing remains the largest contributor to the market, the formulated products contract manufacturing and packaging market is steadily increasing and now accounts for $14 billion worth of projects alone.
Time for change
Over the last decade, the face of contract manufacturing has changed significantly and is continually evolving in response to new market trends and demands. It was the generic and specialty pharmaceutical companies who had limited human resources and assets that needed to be conserved to focus on the core competencies of developing new products and effective marketing that originally started the trend. However, larger pharmaceutical companies are now increasingly realising the benefits of outsourcing their manufacturing and packaging requirements, which were traditionally managed in-house.
While the industry has been affected by the recession, the significant changes have being taking place over a much longer period of time. Recently, the most important of these is the realisation by big pharma organisations that their massive infrastructures for development and manufacture are no longer sustainable in an environment when NCE’s are proving harder and harder to bring to market. This has led to many major pharmaceutical companies consolidating. The mergers have starkly highlighted the new companies over-capacity in terms of manufacturing and large overheads, with most big pharma companies now closely evaluating the long-term benefits of their site capabilities. The realisation is that sites have been running at a fraction of their capacity and trying to cover many different technologies with top-heavy overheads.
Pharmaceutical companies have been forced to conduct an extensive assessment and evaluation of their product portfolios as they focus on maintaining their profitability in the absence of new development of blockbuster products. As a result, this has led to old generic products being sold off to generics companies who then look for outsourcing solutions for their manufacturing. However, these generic companies have discovered that many old products are commercially sustainable even in their limited markets. Patients and doctors alike have learnt to trust some long-term therapies in niche areas and seek the assurance of a brand name despite the onslaught of non branded generic products.
As the market evolves, pharma companies are looking to contract manufacturing companies to provide them with specialist technologies and facilities. It is to their benefit that contractors can share the overhead of managing specific suites whether that is for steriles, controlled drugs or high containment. With the increasing number of biopharmaceutical NCE’s there is rapid demand for specialist aseptic filling and lyophilisation facilities. The drivers of much of this innovation, biotechnology companies, look to contract development and manufacturing organisations to provide this first so they can avoid the risks of capital investment. They do not have to factor in time for capital investment into their development programme, which can often delay commercialisation and crucially extend the time to market.
Competitive Growth
Not surprisingly, the growth in demand for contract manufacturing has attracted many players to the market. Many companies have grown through acquisition of plants no longer strategic to big pharma companies and the market place remains very fragmented. There has been some consolidation and yet even the leading companies have only small market shares when compared to their key customers.
One aspect, which is likely to differentiate the companies in the future, is financial stability. This had been highlighted by the recent global financial crisis and a number of contractors have failed to survive the burden of debt they have accumulated in easier times. Those companies that make it to the forefront and remain there will have to be financial sound and sustainably profitable whilst investing to stay ahead of the technological and regulatory trends.
Contract manufacturers are also increasingly broadening their service offering. Initially the trend was to cover development, manufacturing and packing, so they could manage the whole product lifecycle, but more recently companies are adding regulatory advice, supply chain management and artwork support to their host of services in order to set themselves apart from their counterparts.
The benefits of developing products from the clinical stage through to final commercial supply with the same partner are likely to become increasingly attractive to pharma companies. It avoids any duplication and allows the customer to remain with a partner they know and trust throughout the process. A rare differentiator is a contractor such as Aesica that can offer API development and manufacture, alongside that of formulated products. The advantages of coordinated communication that runs in parallel with API development and the resulting formulated product, should not be underestimated as poor communication, typically accounts for a significant number of issues.
A quality proposition
While a clearly defined proposition is essential, it is more important that the capability and expertise of the manufacturer affirms the proposition. As quality agreements can differ from company to company, it is crucial that the record held by the contract manufacturer is fully researched, quantified and qualified. Quality compliance records are vital, as is a history of positive FDA inspections. With the US accounting for over 50 per cent of the global contract manufacturing market, the need to demonstrate compliance with the FDA standard is increasingly important.
The relationship between pharma customer and contract manufacturer is invariably a long-term partnership because of the very significant financial barriers to change. It is a big decision for a customer to move their product to a new contractor, whether it be a generic or a blockbuster. The pharma company wants to be absolutely sure that the contractor will deliver to their expectations and proposals and as a result terms of reference may be subject to several iterations before being agreed. At the heart of any partnership is honesty and integrity and this has to be clear and transparent to both parties from the outset to ensure success.
Once a partnership has been established it is fundamental that contracts are put in place, which while documenting each parties commitments, also allow each party the flexibility to react to the ever changing marketplace and regulatory environment. The contract manufacturer in particular must help their client to negotiate a simple and cost effective path through new regulations and change management by the provision of value additional services.
It is clear that the contract manufacturing and packaging market for formulated products will continue to grow for some period to come. The transformation of pharmaceutical companies from ‘discovery behemoths’ at the end of the twentieth century to nimble and agile sustainable profit generators for the new century is not yet complete and this will continue to be a key driver for demand.
The successful contract manufacturers will be those who can remain financially strong whilst investing to adapt to their customers needs in the light of increased competition from generics and great expectations from patients.
Case study - High containment
As the overarching contract manufacture market grows, so it follows that the manufacture of potent drugs becomes increasingly important. At Aesica we believe that the investment in this marketplace and the technologies associated with delivering such products is increasingly important and as such, we have recently invested in a new containment facility, which will significantly extend our formulation offering in this particular market.
Once completed and operational in May 2011 the facility will enable our team to manufacture potent drugs typically classed as Safebridge category 3. The new facility will also include security measures that will ensure it can manufacture Schedule II controlled drugs such as opiates.
Housed in a purpose built facility at our Queenborough site, the new high containment unit will include suites for granulation, tabletting and blister packing along with the appropriate HVAC and cleaning facilities and will be completely separate from the rest of the site’s facilities to prevent any potential cross-contamination.
As we continue to consolidate and broaden our service proposition, the addition of the high containment facility has enabled us to add yet another dimension to our offer. The evolution of drug development and the use of more potent compounds has made high containment drug manufacturing a key focus for customers outsourcing their products and we are responding quickly to this demand.
With our proven expertise in the production of Formulated Products and APIs, it was a natural progression for us to broaden our reach into this marketplace. Our service offering and capability is the most advanced in the UK and the addition of the new facility will be of huge benefit to all pharmaceutical companies who require potent drug product production.
About Jeremy Drummond
Jeremy has a PhD in Chemistry from the University of Cambridge and a BSc in Biochemistry from the University of Sussex and joined Aesica in November 2008.
He has over 15 years experience in the commercial supply of raw materials and services to the pharmaceutical industry with ISP and Univar. These roles saw Jeremy undertake a variety of tasks including key account management, supply development, marketing communications and business development across the UK and Europe. Prior to this Jeremy was a formulation scientist with Dow and Shell for agrochemicals and pharmaceuticals, where he gained key skills and a broad understanding of the manufacturing industry.
As Aesica’s Business Unit Director – Formulated Products, Jeremy is responsible for the continued growth and strategic direction of Aesica’s formulation business currently centred at its Queenborough site. Under his leadership the formulation business has expanded significantly with a broad range of customers attracted to Aesica as an independent CMO, offering world leading quality standards and services. Jeremy has also been instrumental in expanding the company’s offering in manufacture and packaging to include Schedule II controlled and potent drugs.
ENDS
For further information please contact Christina Pounder or Elizabeth Eddy on 01642 584790 or email christina@velvetcommunications.co.uk
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