Strengthening the pharma supply chain
pharmafile | September 23, 2013 | Feature | Manufacturing and Production, Medical Communications, Research and Development, Sales and Marketing |
Last year’s discovery of fake versions of Roche’s cancer drug Avastin in the US supply chain served as a stark reminder that counterfeit medicines are not just a problem in emerging economies.
While Avastin grabbed the headlines, there is ample evidence that counterfeiting remains a serious threat around the world. Data collated by the Pharmaceutical Security Institute (PSI) in 2012 reveals that Asia accounts for the bulk of pharmaceutical crime incidents at 954 in the year, ahead of Latin America on 381.
What may be surprising is that Europe was only a little behind with 351 incidents, with North America adding 237 to the tally. These figures do not include cases in which patient safety may be threatened not by criminal activity, but by lapses in quality control at the point of manufacture, or during transportation that expose the public to substandard or degraded medicines. That risk is increasing as pharma manufacturers’ outsource production to distant corners of the world, making it harder to manage supply chains.
Regulatory authorities are now responding to this changing operating environment. In 2011, the European Commission adopted the Falsified Medicines Directive (FMD), incorporating a raft of new measures in four key areas, namely supply chain security, safety features on packs, control of ingredients and internet sales.
Earlier this year the EU Commission published its long-awaited EU Good Distribution Practice (GDP) guidelines, updating prior guidance from 1994, to bring it into line with the new FMD requirements, and also to bring the document closer into conformity with the EU’s guidance on Good Manufacturing Practice (GMP).
The guidelines entered into force on 8 September 2013. The responsibility for the product during storage and distribution will remain with the manufacturers up to the point of sale, at which point wholesale dealers take over ownership of the products.
The guidelines make it clear, however, that all those playing a role in the supply chain must comply with these requirements, so service providers such as third-party logistics companies need to develop a solid understanding of the new EU GDP, so they can provide reliable services.
The new guidelines introduce many new requirements, not least of which the extension of their scope to include not only pharmaceutical manufacturers and wholesalers, but also brokers who deal in pharmaceutical products but never actually take physical ownership of the goods.
Their primary focus is on operational processes rather than technical elements and, having been commented on extensively since 2011’s first draft, they held few surprises in their final iteration.
In the case of brokers, sections of the guidelines that relate to the design and operation of facilities are not applicable, but they will be subject to most of the quality-management and record-keeping requirements.
Quality risk management
A principle which permeates the new document is the use of quality risk management systems to set out responsibilities, processes and risk management principles, along with the stricter process on record-keeping and communication to avoid misunderstanding between the supply chain’s various players.
One key element is the section covering requirements for competent personnel “to carry out all the tasks for which the wholesale distributor is responsible”. The primary responsibility lies with the Responsible Persons (RP), and some controversial elements of this requirement have remained in the finalised version despite criticism in the draft stages.
The EC wants this individual to ideally be a qualified pharmacist, as the person appointed to this role “should have appropriate competence and experience as well as knowledge of and training in GDP”.
Commentators pointed out when the draft was published however, that many organisations currently operating in the supply chain have no pharmacist on staff, and while having one is deemed ‘desirable’, there is no information on suitable alternatives.
Questions have also been raised about the requirement for the RP to be ‘continuously contactable’. During the comment period some respondents asked whether it would be acceptable to hire an external contractor for this function, for example, while there remains some confusion about delegation of responsibilities. This is allowed, but the guidance does not say whether the delegated party should have the same level of training as the RP.
There are also changes to the procedures for management of complaints, returns, suspected falsified medicinal products and recalls, as well as new rules for transport designed to reduce the risk of excessive temperature fluctuations, breakage, adulteration and theft.
Sites and temperature control
Wholesalers must have adequate ‘premises, installations and equipment’ so as to ensure proper storage and distribution of medicinal products, and there are also more stringent requirements on the temperature control during shipping.
The label for products must provide adequate information on handling and storage conditions so that shippers can keep within clearly defined limits, and any temperature excursions should be reported to authorities and investigated.
Risk assessment comes to the fore here once again, as shippers should examine delivery routes to guard against any vulnerabilities – such as sitting on the tarmac of an airport for a long spell – with equipment used to monitor temperature serviced and calibrated at least once a year.
Arguably the most controversial element of the guidelines at the draft stages was the introduction of stringent rules for transport hubs, including an upper limit of 24 hours for product to be stored, with many commentators saying that this was unworkable.
Thankfully, the requirement has been relaxed in the finalised version, although it does indicate that “provision should be made to minimise the duration of temporary storage while awaiting the next stage of the transportation route”.
That is rather vague, however, compared to the older standard which set a maximum of 72 hours for storage at a transportation hub, and has led to concerns that the lack of an upper limit could leave room for poor practice. Moreover, no guidance is given on how to oversee temperature, security and cleanliness at transport hubs, which could also lead to some confusion.
Finally the guidance also introduces a requirement for wholesalers to record the batch number of a medicinal product to come into alignment with the FMD, although this will only apply three years after the adoption of a delegated act on safety features, which is not expected to occur until next year. The adoption of the new guidelines has also had knock-on effects for regulators – for example with regard to the inspection of wholesalers and brokers.
In June, an update of the Compilation of Community Procedures on Inspections and Exchange of Information added a new section – called GDP Inspection Procedure – which introduces a maximum time limit of five years between inspections; although it also adds a risk assessment element that allows for shorter gaps between visits.
In addition, it sets out a new certification procedure that sets out three categories of violations – critical, major and other – that would constitute non-compliance. Critical violations could include purchasing products from a non-authorised supplier and failing to meet temperature control requirements for cold-chain medicines.
Other national initiatives
The EU is not acting in isolation on GDP revisions, and the US, China and India are all in the process of updating their own standards for finished medicinal products, while the World Health Organization is revising its Good Trade and Distribution Practices (GTDP) for starting materials, and the EC recently published a draft guideline on GDP for active pharmaceutical ingredients.
Changes in the US have come about as a result of the Food and Drug Administration Safety and Innovation Act of 2012 (FDASIA) – and, more specifically, a section known as ‘Title VII’ which introduces measures such as requiring importers to electronically submit information demonstrating that drugs comply with the Federal Food, Drug and Cosmetic Act before they gain entry to the country.
The proposals – which were reviewed at an advisory committee meeting in July – would also provide for expedited entry for importers who volunteer for compliance programmes, including on-site auditing.
Meanwhile, China published new requirements on Good Supply Practices (GSP) for Pharmaceutical Products in January – which include the need for a comprehensive quality management system including qualified personnel – for pharma manufacturers and distributors, that were due to come into effect in June with a three-year grace period.
The new GSP asks for comprehensive IT systems for companies in the pharma supply chain, with standardised documentation to accompany shipments, while companies operating warehouses will need to operate temperature and humidity auto-monitoring systems with tighter monitoring requirements for cold-chain shipments. Like the EU guidelines it also asks for the responsible person on-site to be a licensed pharmacist.
Finally, India’s Central Drug Standards Control Organization (CDSCO) also released draft guidelines on GDP for pharmaceutical products in January to sit alongside a similar document covering biologics that was published last October.
Once again, the creation of a robust quality control structure with clear allocation of responsibility is at the heart of the guidance, which lays out a framework for procurement, purchasing, storage, distribution, transportation, documentation and record-keeping practices.
