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Chain Challenge: Part 1 of 2


During the distribution of pharmaceutical products, many of the errors that occur are avoidable – often resulting from a lack of understanding of the distribution process. Using a risk-based approach will not only meet current regulatory expectations and requirements, but will also help create a quality system that is both effective and efficient.

A general view of the pharmaceutical industry is that the supply chain is not treated as an integrated system, and that there is a poor understanding of what is critical to product safety and what isn’t. The factors that are critical to product safety are often neglected because they are: not being assessed to establish the level of risk; not managed so as to reduce the risk to an acceptable level; and not monitored to demonstrate continued compliance. The result is a piecemeal approach where decisions are based on opinion rather than science. Indeed, other industries are equally guilty of this approach – though many do a lot better in spite of it.

The Integrated Supply Chain

Much comment has been made recently about ‘the last mile’, suggesting that this is where failures are most likely to occur – particularly those related to temperature control. While the last mile is critical to maintaining product (and hence patient) safety, loss of control at any other part of the supply chain can have equally disastrous effects. In fact, experience suggests that many temperature excursions occur before the product has left the manufacturing site. The pharmaceutical supply chain is just that – a chain – and we all know that a chain is only as strong as its weakest link.

A compliant supply chain is one where all of the stages are properly and fully understood and the necessary provisions are made to protect the product. While this may sound somewhat onerous, it should not be if the right methodology is used. Managing the supply chain following a piecemeal approach, often with one or more stages outsourced, but without proper control of the contractor, is an accident waiting to happen.

Regulatory Encouragement

Since the FDA published cGMPs for the 21st Century: A Risk Based Approach in 2004, the pharmaceutical industry has been encouraged to understand their processes and the risk to product safety presented at the various stages (1). Aimed at pharmaceutical manufacturers, the report is equally applicable to pharmaceutical distributors.

The above initiative also spawned additional documents in the FDA’s Guidance for Industry series; PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance (2004); Quality Systems Approach to Pharmaceutical CGMP Regulations (2006) and Process Validation – General Principles and Practices (2011) (2-4). Again, although written for manufacturing operations, much of the content is directly applicable to distribution. GDP is, after all, simply an extension of GMP.

The FDA took the lead in introducing the pharmaceutical industry to new ways of thinking and addressing the effective (and efficient) management of quality (where quality equates to patient safety). However, other global regulators, particularly the European Commission, have not been slow to adopt a similar approach. Various updates and additional text have appeared in the EU Rules and Guidance – much of it based around ICH Q8 (Pharmaceutical Development), Q9 (Quality Risk Management), and Q10 (Pharmaceutical Quality System) (5-7).

Critical and Non-Critical Activities

The industry has been slow to adopt a risk-based approach to quality, but those organisations that have done so demonstrate far better control and compliance – and benefit from reduced complexity and cost. Where there is minimal or no impact on product safety, no action is necessary; but where there is an identifiable risk, appropriate action must be taken.

Knowing which aspects of a process are critical to product safety is not a matter of chance or guesswork. There are various methodologies for assessing risk, though Failure Mode and Effect Analysis (FMEA) appears to be an industry favourite.

The obvious danger of not understanding which aspects of the supply chain are critical to product quality is that critical elements get missed. The often-overlooked cost of this is that work on non-critical aspects absorbs a huge and unnecessary amount of time and resource. Increasingly, regulatory inspectors require companies to demonstrate that they understand their processes, and the associated risks, and have taken the appropriate action to manage the risks to an acceptable level.

Assessing Risk

When assessing risk, ICH Q9 identifies the risk model as a three-stage process, as outlined in Figure 1.

FMEA – A Bit of History

FMEAs have been around for a very long time. Before any documented format was developed, most inventors and process experts would try to anticipate what could go wrong with a design or process before it was developed. The trial and error alternative was both costly and time-consuming. FMEAs were introduced formally in the late 1940s, with the publication of the Military Standard 1629. Used for aerospace/rocket development, the FMEA and the more detailed Failure Mode, Effects and Criticality Analysis (FMECA) were helpful in avoiding errors on small sample sizes of costly rocket technology (yes, it is rocket science, but it’s not difficult!) (8)

The use of FMEA was encouraged in the 1960s for space product development and served well with getting a man on the moon. Ford Motor Company reintroduced FMEA in the late 1970s for safety and regulatory consideration after the disastrous ‘Pinto’ affair. Ford Motor Company also used FMEAs effectively for production improvement as well as design improvement. FMEA is one of a number of methodologies that may be used to assess risk; there is no obligation to use it, the only requirement is that some assessment platform is used. The basic methodology is shared with the various other tools and techniques.

FMEA – A Simple Tool

FMEA considers the failures that could occur in a process and assesses:

􀁏 The severity of the failure on product quality (the impact on the end user)
􀁏 The frequency of the occurrence of the failure
􀁏 The ability to detect the failure should it occur

Each of these considerations can be given a score according to a pre-determined scale and the scores multiplied together to create a Risk Priority Number (RPN). The scores derived from each of the potential failures can then be prioritised and appropriate action taken to reduce the risk to an acceptable level. Failure modes that generate a low score can often be ignored.

‘High’, ‘medium’ and ‘low’ is not recommended as there is insufficient separation between the scores. The scoring system presented in Failure Modes Effects Analysis – FMEA Methodology & Application by Gadekal Reddy is particularly suited to the needs of most clients (9).

Applying a Risk-Based Approach in Distribution

Once the process is fully and properly understood in terms of which aspects have a direct impact on product quality, the quality system can be managed effectively and efficiently. In particular, the results of the risk analysis should be used to manage the following aspects:

  • Creation of SOPs – areas that are critical must be covered by SOPs to an appropriate level of detail, whereas activities that have little or no impact on product safety do not require the same level of detail or may simply be included in documentation outside the regulated GDP quality system
  • Training – staff should be fully trained on tasks that are shown to be critical to product quality. The effectiveness of the training should be clearly demonstrated
  • Audits – activities that are known to be critical to product safety should be included in audits and self-inspections
  • Designing transport routes – by understanding and quantifying the potential risks during transport, alternatives can be evaluated and those providing the best protection for the product can be chosen. This is particularly important when transporting temperaturesensitive products
  • Validation – the cost of validation can be significant in terms of the time and resources it can consume. With a proper understanding of the risks associated with the process, validation activities can be aligned accordingly
  • Cost – people often forget that businesses exist to make money, so there is no harm in using risk-based approach to avoid exposure to financial loss

Though, to a large extent, the application of a risk-based approach to the above should be self-evident, validation is a topic that might benefit from further comment.

Validation

Validation is defined by the FDA as: “The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Process validation involves a series of activities taking place over the life cycle of the product and process” (4).

Fundamental to successful validation is a proper understanding of the process being validated and the collection and analysis of data that accurately represents the actual process. It should be clear that understanding the process includes understanding which aspects are critical to product safety and the extent of their impact. This is used to plan validation activities. The other key aspect of validation is that quality data is generated, collected and analysed using real product (possibly placebo), real packaging and subjected to the temperate profile of the actual transport route. The notion that pre-validated packaging can be bought off the shelf and used without further qualification is incorrect.

Conclusion

Pharmaceutical distributors are at the end of a complex and expensive process. By the time that a product reaches the distributor, the quality is as good as it will ever be. There is nothing that the distributor can do to improve the quality, but there are many opportunities to cause damage. When the product has temperature-sensitivity (all do to a greater or lesser extent) the opportunities for harm are far more numerous and the effect of damage often irreversible. Having a full and proper understanding of the supply chain not only satisfies the regulator, but helps create a quality system that is both effective and efficient. It’s as easy to over-comply as it is to under-comply and each will end up costing money. The smart companies manage their compliance systems so as to achieve the right level of product protection at the lowest cost.

References

  1. cGMPs for the 21st Century – A Risk Based Approach, Final Report, US Food and Drug Administration, September 2004
  2. Guidance for Industry: PAT – A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, US Food and Drug Administration, September 2004
  3. Guidance for Industry: Quality Systems Approach to Pharmaceutical CGMP Regulations, US Food and Drug Administration, September 2004
  4. 4. Guidance for Industry: Process Validation: General Principles and Practices, US Food and Drug Administration, January 2011
  5. Pharmaceutical Development, Q8(R2), International Conference on Harmonisation, August 2009
  6. Quality Risk Management Q9, International Conference on Harmonisation, November 2005
  7. Pharmaceutical Quality System Q10, International Conference on Harmonisation, June 2008 8. MIL-STD-1629A: Procedures for Performing Failure Modes, Effects and Criticality Analysis, US Department of Defense, November 1980 9. Failure Modes Effects Analysis – FMEA Methodology & Application, Gadekal Reddy, PQRI Workshop: Risk Management in Solid Dosage Form Manufacture, Jan/Feb 2005

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Robert J Hayes (BSc, CEng, FIMechE, FIET) has worked in the Pharmaceutical Industry for 30 years. His experience includes production and engineering management, new product development, factory design, supply chain management, validation and a variety of support functions. Bob is Vice Chair of the Pharmaceutical Technical Activities Committee of the Institution of Mechanical Engineers (London). His principal areas of expertise include quality systems and quality improvement strategies, risk management methodologies, manufacturing systems, operational improvement methodologies and lean manufacturing.
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