When it comes to analyzing logistics processes, cold chain — or more correctly, management of a temperature-controlled supply chain for drugs and other healthcare products — has fallen pretty far down on the list of priorities. What with all the last-minute anxiety an organization faces attending a new product launch, expediting a backorder or coordinating a clinical trial, “just do what you need to do to get it there” is a common phrase that spills down through the chain of command, eventually landing in the lap of some poor but dutiful soul in the shipping department. Before you know it, bad habits, poor procedures and unnecessary expenses become the modus operandi and they are routinely ingrained so deeply that little is done to correct deficiencies or improve processes. I have seen this scenario played out many times by many companies over the years; indeed, I have fallen victim to it myself. 

Here then, based on my industry experience, are the seven most common cold chain distribution mistakes organizations make that can put products, patients and profits at risk. Not all of them may apply to you, but no one in the supply chain is immune. See how many you recognize within your organization.

1. Arriving Too Late to the Dance

Transportation and logistics, particularly of time- and temperature-sensitive drug products, is often an afterthought. Experienced organizations with a strong history in temperature-control supply chain have learned that upfront resource investment pays big dividends. Consider it preventive maintenance. Whether the entity is a drug innovator, a contract manufacturer, a wholesale distributor, or a logistics or transportation service provider, the starting point for most successful organizations involved in this niche specialty requires a project management team that recognizes and includes someone well versed in all aspects of transportation and logistics of temperature-sensitive products, including regulatory compliance. They are often called “cold-chain experts” and whether they are on the corporate payroll or hired guns, they can be worth their weight in gold. These individuals are often empowered by a company with the authority to manage, delegate or consult to key personnel and departments on the procedures and processes necessary to meet both operational constraints and regulatory parameters. They are the movers and shakers of the industry. Their network and sphere of influence can be extensive, as they frequently present case studies and best practices at conferences and can often be found involved with other key outside associations.

2. Chronic Underachievement

There is a general rule among regulatory authorities worldwide: if you didn’t document it, then you didn’t do it. The Medicines and Healthcare products Regulatory Agency (MHRA) in Great Britain, for example, indicated that out of 277 inspections conducted in the UK in 2009, there were 631 critical and major deficiencies related to GMP. A whopping 79% of all violations were attributed to just three things: 30% to temperature conditions, 25% to quality management systems and 24% to documentation. A mere 5% of deficiencies were related to actual drug manufacture.¹

The numbers speak for themselves: making the stuff is pretty routine and generally well controlled. Getting it out the door, through the supply chain and into the hands of the patient is woefully anemic and suggests a lack of knowledge and understanding within the industry and highlights the amount of education and training throughout the supply chain that still needs to occur.

3. You Can’t Buy Tiffany Diamonds in a Wal-Mart Box

Any way you look at it, qualified packaging is expensive. It is only a matter of time before the use of unqualified packaging that insufficiently protects the drug product against the detrimental effects of temperature exposure will lead directly to a product recall, patient injury or worse. The importance of packaging and logistics are frequently underestimated and undervalued. There is a tendency to cut corners here because packaging and cost for transport are expensed items and are rarely figured into the fully burdened cost of drug manufacture. Wholesalers, who regularly operate on razor-thin margins, are constantly looking to trim costs out of their products and many get by with what they can. Clinical trial operations, on the other hand, lean toward big budgets for packaging and transportation costs. As they ramp up their investigations they tend to be overprotective of their temperature-sensitive blockbusters-in-waiting and are not shy about incorporating expensive, high performance packaging and expedited forwarding services. Their risk-averse approach seeks to minimize temperature variability so as to not cloud or skew the data that could potentially jeopardize an already expensive trial and threaten to delay a product launch.

These three entities each have a different take on qualified packaging. Drug manufacturers (often the holder of the market authorization) have ultimate responsibility for the drug. Many biological drug manufacturers have invested heavily in their packaging and logistics to document and support the common practice of international and multi-stage, multi-site manufacturing processes, maintain their market share in an increasingly competitive market, and to protect their brand. Custom qualified packaging and the documented qualification package supporting its use does not come fast or cheap. One can expect to burn three to six months and invest $25,000-50,000 for each package configuration. But “proper fit” packaging, while expensive, provides an exceedingly high level of confidence against temperature abuse that can adversely affect the drug product. Even a modest biological drug like Actemra, with $428 million in sales for 2010 (50th on Contract Pharma’s Top 50 Biopharma sales for that year), brings in more than a million dollars a day. Lose sales or share for one day and that $50,000 doesn’t look like a bad investment at all. A million dollars a day can buy a lot of qualified packaging! Whether the choice is active or passive controlled temperature packaging, a well-documented DQ/OQ/PQ validation process, as outlined in the PDA Technical Report No. 39, has become the expected regulatory norm. Clinical Trial operators who do not have time to design, develop and implement custom packaging often opt for a “pre-qualified” packaging solution — a robust and often over-engineered behemoth that enables them to ship under tightly controlled temperature ranges against a wide variety of environmental and logistical challenges. Wholesalers sometimes look to drug manufacturers for recommendations, as they are very price sensitive and even the slightest change to packaging and transport expenses can have a profound effect on their P&L.

4. Sketchy, Vague or Non-Existent Quality Agreements 

Nearly all new regulations and guidance documents to emerge worldwide in the last few years have made a notable reference to Quality Agreements. They can go by several names, like service level agreements or service contracts. Regardless of nomenclature, they all have one thing in common — they document (there’s that word again) and define the responsibilities of the parties involved. The proposed language set forth in the definitions section of USP General Chapter Good Storage and Shipping Practices, edition 37 (4) of the Pharmacopeial Forum (and available for your industry comments until September 30, 2011), echoes that of the IATA Perishable Cargo Regulations Chapter 17: “A Service Level Agreement or Contract is a negotiated, documented agreement between the customer and service provider that defines the common understanding about materials or service, quality specifications, responsibilities, guarantees, and communication mechanisms.” Their scope often outlines minimum requirements, performance monitoring and reporting, problem management, escalation procedures, compensation information and remedial action. It is incumbent upon the customer to have quality agreements in place with the appropriate service provider. A drug manufacturing company is not likely to have a Quality Agreement in place with a specific air carrier, for instance, since one rarely deals with the other directly for the transport of products. But such an agreement should be in place with the responsible global freight forwarding agent that is responsible for both sides of that supply chain segment. So while a regulator may not ask a drug shipper for its agreement with an air carrier, it is the shippers’ responsibility to document that all such agreements are in place.

5. Reliance on Tribal Knowledge 

In 1992 I temperature-mapped an extensive set of U.S. domestic overnight distribution lanes for a major pharmaceutical manufacturer. Ten years later I repeated the exact same study for the same company, using the same integrator, and got an entirely different result. The temperature extremes and averages were within a much narrower band and the standard deviations recorded for the data were considerably less the second time around than they were the first. After some additional confirmation tests and analysis I concluded that the differences were not the result of seasonal variation or global temperature change, but rather a vast improvement in operational efficiencies! (And 10 years on, I’ll bet it has changed yet again.)

The point is this: in the span of 10 years and completely out of view from its clients, the service provider evolved, becoming much more proficient at what it does because, to the provider, if a package wasn’t moving, neither was the money. The second study revealed that the packages moved through its system with greater speed, accuracy and efficiency, minimizing exposure to adverse temperature events. This was the evidence I needed to confirm a package redesign resulting in a significant cost savings for the pharmaceutical company while exposing the product to no additional risk.

It should be noted and it is often argued, that even though the healthcare industry relies heavily on a spate of service providers to move its products to the same general destinations, not all operations are the same and not all service providers are created equal. 

When it comes to understanding your distribution environment and defending your packaging and logistics decisions in a regulatory audit, nothing stands up better than your own data.

6. Lack of Monitoring

This is a dicey one. Monitoring — any monitoring, whether it’s data logging, mapping, benchmarking or KPI tracking — has one common element: it exposes your vulnerabilities. This is actually a good thing! The problem for those with unhealthy cold chains is that they don’t always recognize that, or worse yet, intentionally choose to not to know. 

For once a gap is documented (here we go again), the organization is obligated to fix it and fixing it costs time and money. Some choose to keep their heads in the sand over such matters, as if the problem will not be noticed or will magically go away. That’s not just risky; it’s reckless and irresponsible. 

Any regulatory agency worth its salt would rather see an organization identify a gap and put a plan in place to close it, rather than see it deliberately ignored or discover the gap for you. Trust me, you don’t want to be on the receiving end of that. Such folly has crippled more than one company — it’s even driven some out of business.

Conscientious companies use monitoring as a tool for continuous improvement: music to the ears of a regulatory agency. Monitoring is the hallmark of a strong Quality Management Program and ever-increasing regulatory demands.

7. Ignorance and Arrogance

It’s difficult to say which is worse: not knowing or not caring. There is no excuse for either. Still, there exist companies that believe they are too small or too big for the regulations to apply to them. There are those dodge their responsibility, who scour the language of best practices, guidance and regulation in search of ambiguity and loopholes while ignoring the intent. And there remain the disingenuous — driven more by profit than process. 

The industry has come along way in the past few years, but there remains much to be done. USP’s draft of General Chapter contains a curious and forward-looking conclusion statement that stresses a shared responsibility and optimistically envisions a future of nearing perfection. 

I like this idea and hope it becomes part of the final document (scheduled for approval in December of 2012). It states:

The practices and processes set forth in this general information chapter apply to storage and distribution as part of the life-cycle management of drug products. All involved should ensure the product to its point of use, creating a contiguous supply network that is collaborative and emphasizes preventive measures to protect drug product quality. The increase in global processes coupled with products requiring special environmental controls highlights the need for a strong QM program. QM should provide the foundation for maintaining the storage and distribution practices in a continual improvement program and part of an overall management system review by each entity, as appropriate, in the supply chain. 

It is equally important to stay current and be adaptive to change as new solutions evolve (e.g., proactive approaches to implement strategies such as track and trace technologies, industry standards, and on-demand visible technologies). Pharmaceutical scientists will create new technologies to meet world needs. These new technologies should be considered in developing strategies for good distribution practices, controls, and procedures.

Amen. 

Reference

1. Holloway, I., MHRA Observations and Guidance for Conducting Regulatory Compliant Cold Chain Operations, presentation at IQPC Cold Chain Global Forum, 21 September, 2010, Philadelphia, PA

Kevin O’Donnell is a senior partner at Exelsius Cold Chain Management – U.S. He serves as chair for the International Air Transport Association (IATA) Time & Temperature Task Force, is a member of the USP Expert Committee on Packaging, Storage and Distribution, and is a temporary advisor to the WHO. He blogs at www.coolerheadsblog.com. He can be reached at [email protected].