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European Pharmaceutical Contractor

Securing the Supply Chain

Rüdiger Lomb of World Courier makes a case for the urgent need for qualified transportation providers in global clinical research

According to a recent study conducted by the UK-based Medicines and Healthcare Products Regulatory Agency (MHRA), a staggering 43 per cent of critical and major product deficiencies are related to ineffective temperature control and monitoring during storage and transportation (1). Similarly the World Health Organization (WHO) has maintained that 25 per cent of all vaccine products arrive at their final destination in a degraded state (2). Most GDP deficiencies are caused by: a lack of, or inadequately written procedures; general cold storage issues involving temperature control and monitoring; cold chain transportation; or unauthorised activity.

Given the high cost of conducting global clinical trials and the even higher cost of failure, regulatory agencies and pharmaceutical companies alike now demand that every party involved in the pharmaceutical supply chain – transportation and logistics providers included – conform to GxP guidelines.

WHAT IS GxP?

Pharmaceutical ‘good practice’ embraces a variety of different processes and oversight mechanisms that apply to each sequential stage within the supply chain. Good manufacturing practice (GMP), for instance, pertains specifically to the production and control of marketed and investigational products during the manufacturing process, while good storage practice (GSP) and good distribution practice (GDP) deal with the appropriate storage and distribution of pharmaceutical products. All are guided by good clinical practice (GCP), or ethical clinical trial conduct. These conventions have been designed and are accepted by the industry as the international standards for ensuring public health and safety as it relates to product quality.

In recent years international regulatory agencies have worked diligently to eliminate any inherent ‘weak links’ in the supply chain and now routinely extend their guidance documents to cover all individuals or companies involved in any aspect of pharmaceutical product handling including transport, storage and distribution. For a list of the key international guidelines currently in effect as products move off the factory floor, see ‘Good Practice International Guidelines’.

Good Practice International Guidelines
  • WHO’s Guide to Good Storage Practices for Pharmaceuticals: intended for those involved in the storage, transportation and distribution of pharmaceuticals. This document is closely linked to other existing guides (for example, GMP) and supplements them by describing the special measures considered appropriate for the storage and transportation of pharmaceuticals
  • WHO’s Good Distribution Practices for Pharmaceutical Products: A comprehensive guidance document that applies to all persons and companies involved in any aspect of the distribution of pharmaceutical products
  • FDA’s cGMP/21 CFR 211: this document outlines general GMP rules for manufacture, control, storage and distribution
  • US Pharmacopeia (USP) 1079 Good Storage and Shipping Practices: This document provides general guidance concerning the storing, distributing and shipping of pharmacopoeial preparations, outlining (among other requirements) storage in warehouses, pharmacies, trucks, shipping docks and other locations, as well as the distribution and shipment of pharmacopoeial articles
  • Canada’s Guidelines for Temperature Control of Drug Products during Storage and Transportation: This guide states that every activity in the distribution of drugs should be carried out according to the principles of GMP, good storage and distribution practices, and applies to all persons and companies involved in the storage and transportation of drug products
  • Ireland’s Guide to Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products and Active Substances: this document provides guidance for manufacturers, wholesalers, transporters of human medicinal products and API manufacturers in Ireland in relation to conditions for cold storage/cold chain and controlled temperature storage and distribution
  • EU’s Guidelines on Good Distribution Practice of Medicinal Products for Human Use (94/C 63/03): this document outlines handling conditions that must be observed during both storage and transportation as well as requirements for personnel, documentation, premises and equipment, deliveries, returns and self-inspections 

Several of these guidelines – including those issued by Health Canada, USP and the EU – are currently under review. Others such as WHO’s Good Distribution Guidelines were recently updated, underscoring the dynamic nature of the regulatory process and the diversity and complexity of today’s pharmaceutical supply chain as compared to the past.

NEED FOR PROFESSIONAL PARTNERS

Even with these guidelines in place, pharmaceutical practitioners can still face enormous uncertainty once clinical trial materials leave their control unless they are working with a proven GxP-compliant logistics provider.

The application of regulations in the real world presents a tremendous challenge, particularly given the highly complex nature of today’s temperature-sensitive pharmaceutical supply chain. Clinical studies are now routinely outsourced to multiple and often difficult countries where fragile infrastructures cannot ensure efficient transit times. Researchers may also be dealing with multiple time zones, extreme climates, lengthy protocol approvals and import timelines, language barriers and local unfamiliarity with the clinical trial process, among other variables. Without experienced in-country partners, it can be extremely difficult to harmonise the goals of the regulated with those of the regulators – that is, to ensure the smooth flow of materials to and from the research sites (the goal of the pharmaceutical community) without compromising product integrity (the goal of the regulatory agencies).

As a result, enforcement of global GxP compliance throughout the entire pharmaceutical supply chain has become more critical than ever, as evidenced by the current environment of increased regulatory scrutiny – a trend that is expected to intensify. In recent months, for instance, the FDA has stepped up its efforts to identify regulatory offenders, issuing a series of warning letters for noncompliance. Similarly the Health Sciences Authority (HSA) in Singapore is currently transitioning to revised quality standards which will become compulsory in February 2011.

IDENTIFYING QUALIFIED SUPPLIERS

As a matter of course, transportation providers have increasingly gravitated towards the pharmaceutical industry over the past two decades, attracted by the geographical scope and long-term nature of clinical trials. Biological specimens once routinely shipped on dry ice have, over time, given way to the temperaturecontrolled transport of bulk investigational drugs and ancillary supplies that necessitate ever more sophisticated handling and increasingly stringent regulatory scrutiny. Clinical trials formerly conducted in developed nations with well established infrastructures have been moved further afield to some of the most challenging locations in the world in terms of climate, services, education and facilities. Given the number of variables potentially at play within a single clinical trial, it can no longer be assumed that every supplier can manage every type of shipment to every location, regardless of their claims.

What are the key considerations in choosing a transport or logistics supplier? How can you be assured that the supplier of choice has adequate experience and resources to manage the project? How can you ensure that quality guidelines in place at the point of origin extend, without compromise, throughout the entire length of the supply chain to each investigator site? How confident are you that highvalue products and supplies will be appropriately managed during periods when they are not in your possession? Pharmaceutical practitioners are advised to review the following qualifications of preferred suppliers in each individual country associated with the trial.

GxP Compliance
In today’s exacting regulatory environment, GxP compliance is the cornerstone of responsible pharmaceutical research and development. Virtually every international regulatory agency now calls for GxP compliance throughout the entire length of the supply chain, applying its criteria to all parties (individuals and organisations) involved in any aspect of the pharmaceutical product distribution cycle including transport, storage and distribution. Ultimately it is the responsibility of the pharmaceutical company to ensure that its suppliers comply with all applicable regulations. The penalty for non-compliance is severe and may include warnings, fines, declined new drug applications, and loss of partnerships and professional reputation.

Working with a fully-integrated GxP-compliant transport, storage and distribution supplier ensures that the high quality standards demanded by industry are met, assures compliance with all current regulatory and ethical requirements, significantly reduces the number of parties involved in the supply chain and decreases risk. GxP compliance also ensures that all consignments are handled in accordance with documented SOPs and with a view to minimising delays and safeguarding the integrity of materials during transit. Only a GxPcompliant service provider can deliver true process control to the pharmaceutical industry, ensure the integrity and stability of investigational drugs and biological samples used globally, guarantee the availability of independently verifiable data, and support the industry’s need to successfully qualify suppliers and subcontractors participating in their supply chain. A GxP-compliant provider guarantees full accountability, transparency and a documented chain of responsibility including the ability to take corrective actions when required.

An Established Network
In order to effectively establish and monitor GxP standards on a worldwide basis, qualified service providers must have strong and well-established local representation in all site locations associated with the clinical trial, not only in selected countries or cities. Local company-owned offices afford greater control on the ground including a higher degree of specialisation due to the comprehensive and consistent training of staff; a sharing of common goals, communications and technology; networkwide adherence to standard operating procedures; and the ability to respond to problems and inquiries in a timely fashion, in the same language and within the same time zone. Some transport companies routinely sub-contract site work to thirdparty suppliers and manage operations remotely from Europe or the US in a bid to reduce costs. Over time this strategy invariably leads to communications errors, loss of control, compromised integrity of supplies or samples, and a flawed chain of responsibility. Only a well-established network can successfully manage the dayto- day application of systems and processes in every required location – both well established and especially in new growth markets. The alternative of quick-fix ‘bolt on’ solutions in select locations is not sustainable in the long-term, nor can it provide the legitimate verifiable control data required by regulators.

Local Expertise
Qualified service providers should also be able to demonstrate a thorough understanding of local regulations, the protocol approval process, import timelines, and customs procedures and facilities – a capability that is particularly important in emerging markets where public agencies may not be easily accessible or formal procedures well documented. As local authorities may lack specific clinical trials knowledge, be dealing with increasing workloads and limited resources, or be hampered by language barriers, it is crucial to have experienced in-country partners working on your behalf. As a rule, conducting clinical trials in emerging markets requires additional planning and extended timelines when compared with most standard markets. A qualified supplier should be seen as a partner in the process, bringing valuable insight and expertise to the planning process and acting as an effective resource in remote locations. Once the trial is underway, its operatives should ensure that all proper import and export permits are in order, facilitate clearance, assist with and resolve customs, temperature-control or local delivery issues, and facilitate any required drug returns.

Packaging Expertise
Depending on the design of the clinical trial, packaging requirements will vary according to temperature requirements. Consignments may need to be shipped in liquid nitrogen (-196°C), on dry ice (-80°C), frozen (-25°C to -10°C), cold (2°C to 8°C), cool (8°C to 15°C), controlled room temperature (CRT) (15°C to 25°C), or ‘ambient’. There may be specific instructions such as ‘do not store/ship over/under xx°C’. Depending on the expected length of time in transit and the external temperatures at origin, destination and throughout transit, packaging configurations will vary. A qualified supplier should be able to make packaging recommendations suitable for each shipment and provide the appropriate packaging solutions. They should also be prepared to monitor temperatures both in transit and during warehousing to the degree necessary, replenish refrigerants as needed en route, and independently set and manage any required temperature monitoring devices.

CONCLUSION

Although the transport and storage of investigational drugs and supplies represents only a small part of the overall quality equation, pharmaceutical companies who take proactive steps to secure their supply chains now may well eliminate unnecessary risk and regulatory exposure later on.

Before choosing a supplier, know that GxP guidelines are applicable to all parties involved in the supply chain including transportation providers, that compliance will be enforced by regulatory authorities, and that the pharmaceutical company is ultimately responsible for non-compliance anywhere within its supply chain. Each study is different and must be approached methodically to ensure optimum results. While the shipper must set the priorities, he or she will also need to rely heavily on the off-site expertise of others. There is no ‘cookie-cutter’ approach to clinical research, so it is recommended that pharmaceutical practitioners select their service providers with care.

References

  1. Taylor J, (MHRA), Regulatory Expectations, IQPC Cool Chain 2008, Brussels, Belgium
  2. Black AE, Logistics in Cold Chain Management, quoting WHO

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Rüdiger Lomb is Global Director, Quality & Technical Compliance for the World Courier group of companies. Since joining World Courier in 2008, Rüdiger has brought his considerable technical expertise to bear on shaping and refining the company’s quality assurance programme. He was formerly Group Head and Director of the Global Logistics Clinical Supplies Division for Bayer Schering Pharma AG in Germany, where he was responsible for the auditing and qualification of depot and transportation service providers. Rüdiger is a licensed pharmacist and holds a PhD in Pharmaceutical Biochemistry. 
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