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Pharmaceutical Manufacturing and Packing Sourcer

The Consistent Global Quality Challenge

Delivery of the right drugs and devices takes on particular significance in the world of clinical trials, where the link between time and cost is especially sensitive. So how exactly do you deliver a consistent global quality network within the clinical trials supply chain?

The pharmaceutical industry and, consequently, the R&D arena, saw significant developments in quality management in 2010, including the end of the UK Medicines and Healthcare products Regulatory Agency (MHRA) grace period in quality risk management (QRM) and the focus on maintaining ambient product stability within the supply chain. These focused regulatory controls, coupled with a tough economic climate,have manifested potentially conflicting demands, resulting in a renewed vigour for cost reduction and service enhancement, without compromising the need to deliver consistent and visible global quality standards within R&D. Another challenge, springing from a multitude of acquisitions within the pharmaceutical industry, has led to companies operating via multiple facilities and systems, therefore, organisations have undertaken strategic reviews, leading to revised clinical trials logistics networks. In general, there has been movement away from the legacy affiliate networks towards a redesign, creating a dynamic supply chain which can weather the patient demographic trends and regulatory requirements.This shift has seen companies migrate towards one of the following strategies: 
  • Outsourcing studies on a global basis to specialist partners managing discrete activities (such as medical logistics, medication packaging, and blinding and IVR system provisions) 
  • Regional or global outsourcing of business to specialist logistics providers as dedicated or shared user warehousing.This currently includes medication and ancillaries, but could be extended to include all outbound (lab kits, investigational products, ancillaries, report forms and investigator manuals) and long-term storage (frozen samples) items
  • Outsourcing of all services to clinical research organisations, who then outsource to specialist providers within particular countries and regions where they have no logistics facilities 
  • In sourcing clinical trials activities to local affiliates, maintaining all business internally but providing little true measure of the logistics element of conducting the clinical trial (1)
All of the aforementioned strategies have one common challenge: how to ensure globally consistent quality processes while maintaining the five key characteristics of safety, identity, strength, purity and quality (SISPQ) within the clinical trials supply chain, where the majority of depot networks consist of a hybrid of in-house and partner depots, which are located in geographies governed by different regulatory authorities (2).The focus must remain on the six Cs that underpin quality with the healthcare industry, as laid out in Figure 1 (3).

Quintessentially, the six Cs represent the concept of building blocks within a global clinical trials supply chain. Breaking them down further, they involve facilities and equipment (including compliance), people,processes, systems (including QRM) and transportation – all underpinned by a robust quality management system,business continuity plan and communication.Communication is a pertinent point in such a global industry,where large organisations often have regional functional silos.Resulting from this, internal barriers to sharing best practise and developing a consistent quality approach have unintentionally been created.

Facilities and Equipment
Domestic facilities, whether they are inhouse, managed or from a partner, need to provide the same level of quality as the global or regional facilities.Activities undertaken in-house that fall into the quality management system category to ensure self-audit and validation (including installation, operational and performance qualification) are achieved and maintained via the validation master plan.However, compliance of activities in managed or partner facilities can only be achieved via a robust supplier qualification process, an ongoing supplier management process, proactive project management and communication during project setup.

Focusing on the robust supplier qualification process, all parties within a supply chain should comply with the manufacturer’s specifications (‘baseline’ requirements).Technical activities are stipulated and agreed contractually within technical agreements, but the challenge is how to ensure this contractual obligation is maintained until patient dosing; especially if services are subcontracted in geographies where local legislation takes precedence over the ‘baseline’ requirement.Some key activities which assist with this are as follows: 
Having a basic understanding of the local regulatory requirements of any supplier facility.This is certainly being made more achievable by the ICH E6: GCP consolidated guideline, as well as the PIC/S,where 39 country regulatory authorities, together with WHO and EMA,are working to harmonise GMP Standards (4) 
Identification of the gaps between the local regulatory and ‘baseline’ requirements.Within the supply chain, this is often the gap between the local regulations and the contractual obligations outlined in the technical agreement between a third party, such as a logistics service provider (LSP),and the manufacturer 
Auditing the supplier/affiliate against the identified gaps, in addition to the supplier technical agreement and local regulatory requirements 
Where possible, a global quality team should undertake the audit of such internal and external facilities, in order to ensure a consistent standard is achieved – this also enables best practice to be shared across the depot network

People and Systems
Consideration of the people involved in the trial supply should focus more specifically on project management, which is such a pinnacle role within the clinical trial environment.Often this is the main route of communication between the manufacturer, functions and facilities,be they outsourced or in-house. If project management itself is an outsourced activity, often via a CRO or LSP, then it is paramount that the project manager is as well-versed in the technical requirements agreed between contracted parties as the responsible person and quality function.

IT systems and interfaces (EDI flows) with other manufacturers and/or supplier systems require validation in accordance with GAMP 5 guidelines and GMP requirements, specifically EU Annex 11 and 21 CFR Part 11.These primarily focus on patient safety, which assists in delivering compliance. In addition, the integration of Warehouse Management Systems (WMS) and courier systems is key to ensuring global visibility within the supply chain, which is so essential to the temperature assurance/lead-time management within the supply chain.

Processes and QMS
Ultimately, standard operating procedures (SOPs) and work instructions are vital elements in the delivery of a consistent global quality network within the clinical trials supply chain. In addition, the content and effectiveness of such procedures are the foundations upon which the ‘people’ segment of the overall quality and compliance jigsaw is built.The replication and effectiveness review of SOPs should be attainable in a depot network and supply chain built through organic growth. Where managed or partner facilities are critical links in the supply chain, the aim should be to have high-level global SOPs which supplier facilities either already adhere to (this can be assessed via supplier qualification and the audit process) or their current work instruction can sit under to deliver the key quality and business elements. In all instances the effectiveness of SOPs should be ascertained by regular training, test activities and monitoring, which can be done via annual internal audit of SOPs.

Quality Management System
The key elements of a quality management system,irrespective of geography, are corrective action and preventive action (CAPA), change control, document control (including validation and calibration management), training, internal audit programmes,QRM and, ultimately, an effectiveness review of the QMS via data trending and management review.

Temperature Control
The need for maintaining the temperature of investigational medicinal product (IMP) in transit became even more essential in 2010, with the QA function of many pharmaceutical companies driving the shift towards utilising ambient passive temperature-controlled packing media for both primary and secondary shipments (inter depot and investigator shipments respectively). Due to climatic temperature variations, a high percentage of companies are utilising temperature monitors in parallel to passive packaging media,hence providing ultimate visibility and a subsequent audit trail throughout the supply chain. Ultimately, this shift tips the scales in favour of quality, but can have a budgetary impact. It should be noted that local sourcing of passive temperaturecontrolled media, utilising the clinical trials supply depot network, can counteract some of the additional costs incurred.

Quality Risk Management
In recent years, the pharmaceutical industry has adopted a risk based approach to quality management with the introduction of ICHQ9 in 2006, and more recently the FDA Q9, as well as Annex 20 to the EU guideline on GMP.The aim of this quality risk management approach is to proactively identify and undertake a scientific evaluation to control potential quality risk issues during the product life cycle, further ensuring the patient receives a high quality product.Many organisations have been undertaking elements of QRM within standard processes and existing QMS (for example CAPA and internal audit). However, it is clear that the formalised risk management plan, tools, report and clear lines of ownership deliver the objective of further enhancing the quality of the product.

Even though the quality risk assessment framework approach should be consistent, the tool – and subsequently the quantification required – should be proportional to the level of the specific risk. Some of the tools outlined in ICH Q9 and in Annex 20 to the EU guidelines on GMP are: 
  • Process risks:where potentially failure mode and effect analysis, hazard analysis and critical control points, process mapping and flow charts could be the best tools to utilise 
  • Product risks:where flow charts and fault tree analysis might be the best options
While facilities within the supply chain may maintain multiple quality management systems, it is advantageous to utilise the replicable framework of QRM throughout the depot network to ensure the consistency of this approach,and determine whether any mitigant identified is owned at the respective country/depot level. However, it is accepted that any managed or partner depots will need to be assessed for QRM effectiveness during supplier qualification and auditing.

Business Continuity Planning
Alongside QRM there should also be a comprehensive business continuity plan (BCP) in place to manage the recovery or continuation of business activities in the event of disruption, in order to safeguard patient safety and supply.The BCP should apply to all regions, countries and sites, irrespective of function, and should establish the basic principles and framework necessary to ensure emergency response, resumption, restoration and,ultimately, permanent recovery of services during such events. It should be recognised that such events could be local, regional or global in nature, so the BCP framework should be adopted by all links within a supply chain.

Conclusion
The shipping lead time,patient demographics and local customs procedures will always drive the necessity for a clinical trials depot network. International bodies have the vision of harmonisation, which will undoubtedly provide an easier platform on which to build and deliver consistent quality standards. In the interim it is recognised that there are disparities between current regulations;however, high quality facilities, processes,data, risk management and people – which sit under the umbrella of the six Cs of quality within healthcare – are key to delivering a consistent level of quality compliance within clinical trials supply chains.

References
  1. Blamey J and Tierney C, DHL Exel Supply Chain white paper: Global Clinical Trial Logistics Operations; challenges and responses, 2007
  2. Vesper JL, Focus on compliance – so what are GMPs, anyway? BioProcess Int 1(2): pp24-29, 2003
  3. Global Department of Quality Assurance and Regulatory Affairs, DHL Life Sciences and healthcare rules and guidance 2010/2011
  4. www.picscheme.org


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Suzanne Parish graduated in 2001 with a BSc in Physics with Biomedical Physics, and has worked for DHL since 2003. Suzanne has worked in Operations and Quality and Project Management, both within DHL’s Healthcare and Retail sectors. Suzanne is currently responsible for the delivery of DHL’s Clinical Trial Logistics Global Quality Strategy.
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