Life Sciences Logistics Playbook

Transcription

1 Expert planning for a more robust supply chain First Edition QUALITY SYSTEMS & RISK ASSESSMENT PACKAGING & INSULATION QUALIFICATION & VALIDATION LOGISTICS MANAGEMENT VENDOR MANAGEMENT by

2 CONTENTS INTRODUCTION Healthcare Logistics: Leaving nothing to chance CHAPTERS Chapter 1: Integrating Your Cold Chain Management Systems Integrating your cold chain management systems can reduce overall costs, improve sustainability, and improve your regulatory compliance all at the same time. Use these practical tips to assess your level of integration and learn where to start your journey to a better cold chain. Chapter 2: Validating a Cold Chain Master Plan The validation of your distribution processes requires a comprehensive, documented approach. Creating a validation master plan for your logistics processes involves early planning, robust characterization, and qualification of your packaging and other systems, premises, and equipment. 21 Chapter 3: Three Process Qualification Pitfalls and How to Prevent Them Though companies put significant time and effort 28 into their qualification, handoffs and equipment handling/conditioning are risky parts of cold chain shipping, so extra attention must be paid during prework, validation and SOP creation to ensure the process is explicit for the responsible parties. Chapter 4: Ambient Profiles and Qualification Process Choosing the right ambient profile is key to developing an insulated packaging system that will properly manage your temperature-controlled product during transport and distribution. Ambient profiles, which represent the temperatures you expect the shipper to experience during transport (ideally both hot and cold), are used to qualify insulated shippers and set the shipper s design space Chapter 5: Balancing Your Packaging Needs For a given cold chain problem, there are typically several ways that package developers can solve your problem. The fact that there are no one size fits all solutions is both a challenge and an opportunity, because customizing your packaging means you re only paying for shipping services, insulation and refrigerants that meet your needs Chapter 6: Supply Chain Innovation for Growth Supply chain strategies listed here will help you to meet your profit and revenue targets. Plus, this 2015 survey by Frost & Sullivan illuminates the need for effective supply chain strategies in gaining a competitive advantage. Chapter 7: Nine Considerations with Prework and Timing If you fail to plan, then you plan to fail. Cold chain operations are extremely complex, so it s important to invest time in prework and planning to make operations successful. We review some common areas for improvement or misconceptions with regards to timing and prework Chapter 8: Lane FAQs: Characterization, Monitoring and Qualification Ensure patient safety, ensure compliance, and minimize impact. Whether you re shipping to first or third world countries, you must do a proper risk assessment, and you should involve your forwarder and carrier to understand the lane segments Chapter 9: Managing Temperature Excursions Mother Nature, quirky software, electrical surges, schedule changes and mechanical variances may interrupt even the bestlaid product transportation plans. Excursions are unavoidable learn to minimize them. 2 / 105

3 CONTENTS Chapter 10: Perspectives: How Carriers, Forwarders and Manufacturers Can Collaborate to Manage Risk A new approach to lane characterization, quality systems unites the healthcare/pharma manufacturer, the forwarder and the carrier so they all understand each other s challenges and are able to come up with effective solutions Chapter 12: Risk Management and HAZOPs: Tips for Success Learn to rank hazards and ID which are most significant. Use of a risk-based approach is the current best practice 78 to ensure patient safety and optimize risk-reduction strategies. Here is a methodology for risk management that is tailored to controlledenvironment logistics with a risk-assessment technique that is Chapter 11: Technologies to Reduce Your Total Cost Some monitoring and packaging technologies, often incorrectly perceived as prohibitively expensive can provide major efficiency benefits when they re used for the right applications, ultimately saving you time and money. especially well suited to distribution. Chapter 13: Six Ways to Streamline Change Control: Processes for the Real World Some change control processes mean well, but can lead to waste. Change control is a necessary part of any logistics operation for tracking your equipment changes 85 and maintaining safe and efficient operations. But while a change control process is meant to be helpful and keep involved parties in the loop, it can end up wasting valuable personnel and production hours when not tailored to fit your facility. Chapter 14: Accelerating Development with Thermal Modeling No need to prototype with these new techniques. The cold chain industry has embraced thermal modeling to predict package performance prior to running time-consuming chamber tests. Despite decades of widespread use of similar modeling in other industries (automotive, aerospace, etc.), computer 89 modeling of thermal systems in packaging has really flourished in the last six to eight years. Here we ll discuss the technology, how it s helping companies cut packaging development time, and what to look for in a thermal modeling provider. Chapter 15: Eight Key Considerations for Vendor Management Take a common sense approach to vendor selection. 94 Identify candidates on a long list through an RFI (Request for Information), narrow it down to a short list through an RFP (Request for Proposal), and perform due diligence. These 8 steps will make it easy. 3 / 105

4 INTRODUCTION Healthcare Logistics: Cold Enough For You? Keren Sookne, Contributing Editor Traditionally called cold chain logistics (though the cold reference may be a bit limiting), the movement of temperature-controlled products from manufacturer to end-user is typically a complicated operation. It is at once a regulatory, patient safety, brand reputation and profitability matter. The reason for why you need to manage your cold chain operation may be clear, but with new regulations and technologies and so many moving parts, it s the how that many people have trouble with. For our playbook, we reached out to Healthcare Packaging readers along with cold chain industry veterans who provided a great deal of useful information on mitigating risks and streamlining operations. Many of those we spoke to have a unique view in that they ve seen operations at many companies or across many lanes, and told us about the pitfalls they ve seen, from dock mistakes to timing issues, and how to avoid them through proper planning. As companies look beyond the individual costs of containers, we take a look at packaging and service upgrades that can lower the total cost of shipping in the right situations. Another article addresses thermal modeling what it is and how developers are using it to create robust, right-size packaging solutions. 4 / 105

5 INTRODUCTION continued A major theme across the responses was the need for manufacturers and vendors to work together as partners to be successful in transit. We highlight vendor management tips and discuss a collaborative approach between manufacturers, forwarders and carriers that s been helpful in reducing in-transit deviations. Because the cold chain industry is still a relatively new field, there are plenty of areas that haven t necessarily been standardized yet. We go over the process for ambient profile selection and the packaging qualification process, including why an existing profile like the 7E standard may not apply to you. Experts weigh in on lane qualification and best continuous monitoring practices (hint: there s no hard and fast rule). The cost of producing and distributing this playbook has been underwritten by the companies who have sponsored it. We thank them for their support, and we thank you for reading. 5 / 105

6 CONTRIBUTORS The following experts contributed to this playbook John Anderson, VP of Operations Life Science Logistics Paul Harber, Principal Modality Solutions, LLC Craig Simon, President/CEO FedEx Supply Chain Jamie Chasteen, Sr. Product Manager Cold Chain Technologies, Inc Gary Hutchinson, President Modality Solutions, LLC Mark Stein, Packaging Equipment Engineer ProPharma Group Scott Dyvig, Program Manager, Pkg Engineering and Tech Services Jarden Life Sciences Karl Kussow, Manager, Quality and Validation FedEx Custom Critical Robert-Jan van den Bos, Head of Global Logistics AMGEN Tom Grubb, Manager, Cold Chain Strategy American Airlines Ken Maltas, Director of Engineering Sonoco ThermoSafe 6 / 103

7 CHAPTER 1 Integrating Your Cold Chain Management Systems Today s distribution network is increasingly complex and involves many players. Competing priorities, changing expectations, cost pressures, sustainability initiatives, emerging markets these are the challenges facing today s logisticians managing a controlled environment logistics network in the biopharmaceutical industry. Biopharmaceutical manufacturers face economic and regulatory pressures, accelerating costs, technology changes, and the need to constantly adapt their business models. The advent of more widely distributed supply chains and many other influences demand greater investment in tools, expertise and, most importantly, the human capital to succeed with some of the toughest challenges. As a trusted partner within your organization and with partners in your supply chain, you are expected to deliver: Appropriate expertise and techniques to assess, control and communicate risk as part of an on-going management review process. Lifecycle approach to process validation including design, qualification and verification. Better integration of product, quality and design with overall greater industry collaboration. 7 / 105

8 CHAPTER 1 continued Quality controls, corrective and preventive actions (CAPAs) and root cause analyses that were once more straightforward are highly complex today. The use and application of technology to achieve greater gains in all areas, including compliance, quality and safety. It s hard to miss the challenges all around us every day. With the advent of social media and media capture technology, one mistake and EVERYONE knows! Sometimes, we try to ignore the issues or at least avoid them as long as is practical. But at some point, as professionals we rise to the challenge. The question is where and when? Once you commit to a change and integrate your cold chain management systems, everything is different. Everything. Processes, controls and metrics are focused on a community-wide committed vision of success. Conversations are fact-based and datadriven. You are focused and get stuff done. The supercilious takes a back seat to results. Rather than assigning blame, the organization is absorbed in learning, correcting and verifying results. Why integrate your cold chain management systems? A drug can take a variety of paths from the manufacturer to the patient. Most often, the product leaves the manufacturer s direct control and enters a complex system of handoffs. Distribution systems that deliver pharmaceutical products require special handling based on the conditions clearly indicated in the labeling for the product. 8 / 105

9 CHAPTER 1 continued Innovator Generic MFG Shipping Drug Product Distribution REPACKAGER Wholesaler & Distributors Pharmacy Chain Drug Store Government Independent Hospital Pharmacy Clinics Nursing Homes Mail Order Pharmacy MSC Sample Distribution A drug can take a variety of paths from the manufacturer to the patient. This diagram illustrates the complex system of handoffs. Dispensing Doctor Patient Regulatory compliance during transport of pharmaceutical products is not the only concern. The competitive pressures are enormous. Environmentally sensitive biopharmaceutical products generate more than $100 billion of economic activity per year. Manufacturers of proprietary products are driven to get product to market as quickly as possible to maximize their patent exclusivity window, while manufacturers of generics are compelled to keep costs to a minimum. Both are required to maintain a high level of quality of the drugs in their distribution network. The cost of distributing product in the pharmaceutical logistics network is huge. Pharmaceutical Commerce magazine estimates that more than $64 billion in overall pharmaceutical logistics costs was spent in Some $8.4 billion was spent in controlled-environment logistics alone. The specialized logistics for maintaining the quality of products as they are shipped around the world accounts for more than 10% of all biopharmaceutical logistics spending. 9 / 105

10 CHAPTER 1 continued The increasing sales of environmentally sensitive drug products in the pharmaceutical industry will only increase spending in controlled-environment logistics. Already, by 2009, five of the top 10 best-selling pharmaceutical products in the world were biotech-derived large molecules requiring refrigerated storage and handling: Enbrel, Rituxan, Remicade, Epogen/Procrit and Avastin. By 2018, it is estimated that these drugs will comprise seven of the top 10 and 26 of the top 50, with Humira #1 overall. Vaccine sales are growing around 7% per year and sales of blood products such as immunoglobulins are also growing 6-7% or more per year. Most of the growth in dollar sales will be outside North America and Europe expanding the role and potential concerns of drug product quality issues during transportation in the pharmaceutical supply chain. Manufacturers are obligated to include distribution as part of their overall quality system and should be continuously monitored and updated to adhere to industry best practices. A comprehensive cgdp quality system covers the logistics management (i.e. the flow of products, services and related information across the supply chain) for final drug product in four key ways: Qualifications and training of personnel, Facilities, material handling, storage, and inventory control, Non-conformance or exceptions, returns, and product disposition, and Transportation, third-party distribution and product protection. 10 / 105

11 CHAPTER 1 continued The complexity of the logistics network is driven by financially driven choices in manufacturing. Most modern manufacturing networks are global, single-sourced and located in tax-advantaged locations with little local consumption: the transport of final drug product to the initial storage location is typically required. The manufacturer has very little direct control after manufacture and initial storage of finished drug product because most channels of distribution contain wholesalers, distributors, or other intermediaries. Coupled with the increased focus on highgrowth protein products that are environmentally sensitive, the concerns during transportation are heightened for several reasons: Risk of introduction of adulterated and/or counterfeit product and product diversion, Variances in equipment, facilities, skills and experience across locations, and Significant and cumulative hazards to product quality: temperature with shock, vibration, pressure and humidity. The transport of final drug products is one the most difficult tasks in the pharmaceutical supply chain because of the sensitive nature of the product and the complexity of a modern logistics network. Integrated cold chain management systems are required to minimize risks to drug product quality during transport. The benefits of taking an integrated approach can lead to significant compliance and business improvements: 11 / 105

12 CHAPTER 1 continued Supply chain security measures across a global and contracted third-party logistics networks are increased to ensure protection against adulterated and/or counterfeit product and product diversion through effective monitoring and controls. The confidence in process validation of complex and highly variable controlledenvironment logistics network with improved quality systems, risk management, product stability approach, validation master planning, and partner management is greatly improved. Partners are monitored efficiently with enforceable, relevant and scrutinized key performance indicators across the entire cold chain. The concerns during transport are many: the risk of compromised or diverted product in a global-contracted, third-party network allow little direct control, the variables in equipment, facilities, and controls in a global controlled-environment logistics network make consistent handling difficult, and the effects of product temperatures outside of long-term storage recommendations, combined with environmental hazards unique to the transport environment. 12 / 105

13 CHAPTER 1 continued What systems encompass an integrated cold chain management system? A compliant cold chain management system is composed of a variety of components working in concert. An integrated cold chain management system will ensure control of the distribution chain and consequently maintain the quality and the integrity of products. The seven components of this integrated cold chain management system are as follows in the chart below: Quality Systems Risk Management Product Stability Qualification/ Validation Logistics Management Partner Management Compliance Management Quality Manual, Standards, and SOPs Good Documentation Practices NCs and Exception Management CAPA and Change Control Management Review Assessment and Mitigation Planning Plan Design and Documentation Monitoring and Controls Review and Communication Product Protection Supply Chain Integrity Storage Temperature Shipping and Handling Temperature Stability Testing to Support Logistics Stability Budgeting Exposure/Excursion Management Validation Master Planning Design Space/ Characterization Thermal Profiles Transport Lanes Thermal Packaging Active Refrigeration Logistics Process Validation Qualification and Training of Personnel Facilities and Equipment Material Handling, Storage, and Inventory Control Transportation Networks Reverse Logistics/ Product Returns Selection/RFP Quality Agreements Audits and Inspections Monitoring and Controls Key Performance Indicators Subcontractor Management Continuous Improvement Business Review Effectiveness Monitoring Critical-to-Quality Attributes Quality System Maturity Import/Export Emerging Regulations/ Guidance 13 / 105

14 CHAPTER 1 continued In the last 10 years, there has been a transformational change in environmental monitoring technology for today s clinical cold chain. The new modalities being introduced in the oncology therapeutic area, particularly monoclonal antibodies, require a new approach to how we manage, monitor, and inform stakeholders in your clinical supply chain an integrated approach to your cold chain management systems. Now, our cold chain clinical supply chains are moving from reactionary, after the fact data logging to real-time sensor-based logistics networks that adapt to the environment. How do you integrate your cold chain management systems? It s important to integrate your cold chain management systems to better manage outcomes and improve performance in today s increasingly complex controlledenvironment logistics networks. In the balance of this article, I will focus on five of these seven pillars: quality systems, risk management, product stability, qualification and validation, and partner management. Logistics management and continuous improvement are equally important, but many organizations have already optimized their logistics management processes and adopted continuous improvement programs. The greatest impact of integration can be found by focusing on these five areas. Quality Systems The foundation of any integration of your cold chain management systems is based on your quality management systems. Today s modern quality systems have some basic tools that are essential to continuous improvement in your cold chain. Unfortunately, these tools are often not used as effectively as possible by cold chain professionals. 14 / 105

15 CHAPTER 1 continued Non-conformance data is key. However, the focus cannot be just on documenting and resolving each non-conformance. The most importance use of non-conformance data is typically overlooked: trending of the data. The ability of modern quality management systems to collect and collate data must be used to improve the cold chain. Start trending your data along some basic segregations: clinical versus commercial, active versus Modern Quality System Tools passive shipping solutions, Trending of Non-Conformances in Cold Chain and domestic versus Continuous Improvement and Effectiveness Monitoring international shipping lanes. Critical-to-Quality Attributes to Increase Quality System Maturity Look to spot trends in these subdivisions. Then go one step further. Do you have issues in a specific lane? With a specific packaging system? With a specific carrier? Any time we more closely identify the trend in non-conformances, the search for root causes can be timelier, targeted and more effective. This targeted trending of non-conformances is the quickest approach to driving continuous improvement. However, once a correct action is in place, you are not done. Too often, corrective actions are put in place to resolve a trend, but the follow-up is not in place. Any significant trend with a clearly identified root cause should also have a specific time period for monitoring results. Effectiveness monitoring to ensure the trend has been reduced and eliminated is essential to ensuring continuous improvement. 15 / 105

16 CHAPTER 1 continued The third tool in an effective, modern quality management system is the use of critical-to-quality attributes used to improve the maturity level of quality Mitigate systems for your cold chain. These attributes allow all partners in the cold chain to measure the important metrics. And what gets measured gets managed! Evaluate Identifying these attributes, publishing them across the cold chain, and then following up on them in periodic management reviews are necessary to enhancing the maturity of your quality system. Anticipate Risk Management The use of a risk based approach is endorses by the FDA in Section II (p.2) of ICH Q9 Quality Risk Management is the current best practice to ensure patient safety and optimize risk reduction strategies. A methodology for risk management that is tailored to controlled environment logistics coupled with a risk assessment technique that is especially well-suited to distribution is needed to ensure the mitigation of risks in the cold chain. Any risk management approach has three basic components: anticipation of risk through risk assessment, evaluation of risk with qualitative and quantitative tools, and mitigation of risks with various controls and monitoring. 16 / 105

17 CHAPTER 1 continued Stability Testing Stability testing outlined in the ICH guidelines primarily addresses the establishment of expiry dating and storage conditions. Temperature-sensitive product may exceed long-term storage conditions established by the manufacturer at any time during manufacturing, distribution and customer handling steps (e.g. bulk transport, filling and packaging operations, final product distribution operations, end user administration) intentionally (i.e. exposure) or not (i.e. excursion). The allowable time and temperature exposure to ranges outside of the long-term storage conditions for manufacturing is currently justified by using accelerated stability data gathered during static stability studies conducted under ICH guidelines. Study ICH Guidelines Distribution Storage 5oC through shelf life 25oC to point of failure Accelerated Either 25oC/60% RH or 30oC/65% RH for 6 months -20oC ± 5oC for 1 week and 37oC ± 2oC for 1 week However, these accelerated registration (or static) stability studies may be inadequate for the transport process especially when dealing with protein formulations in solution. The accelerated studies are normally terminated without returning samples of the exposed product to normal storage conditions and conducting assay testing to the end of shelf life to confirm product. The cumulative effects of other environmental hazards on product outside long-term storage recommendations are essentially unknown with standard static stability studies as currently recommended under ICH guidelines. 17 / 105

18 CHAPTER 1 continued Master Validation Plan Performance Qualification Operational Qualification (containers AND product) Installation/Component Qualification (Product, Primary Container, Insulated Shippers, Secondary Packaging, Monitoring Devices) Product stability for distribution is a relatively new concept for biopharmaceuticals. Driven by increasing complex regulations, the more typical registration or static stability studies used to set expiration dates are being augmented with dynamic stability studies for distribution. These distribution stability studies typically stress the drug product formulation in either an extreme real world shipment or in controlled laboratory settings. The same stability indicating assays used to set expiry date are executed on these stressed samples. At each time point, the degradation, if any, is compared to the registration stability study. If the degradation pathway is comparable, these studies can show that temperature exposures outside of labeled storage conditions do not have an impact on product quality. These types of studies are powerful in an integrated approach, which allows the operating range of the temperature-controlled network to be significantly broadened reducing costs, increasing service levels, and diminishing non-conformances. Testing Standards (Profiles) 18 / 105

19 CHAPTER 1 continued Qualification and Validation Validation Master Plans (VMPs) have become common practice in the medical device and diagnostic industries for demonstrating that the validation process is under control. A VMP can serve the same purpose for distribution. It identifies the philosophy for how products, processes and facilities supporting the distribution of drug substance and drug product will be validated within the quality system to ensure the suitability of product for forward processing or use by the patient. The VMP demonstrates a structured multi-disciplined approach including product development, quality and distribution operations. It also provides a means to document rationales for validation decisions. Enforceable 1 Relevant 2 Scrutinized 3 Partner Management Comprehensive partner management starts with the selection/rfp process. Early in the honeymoon phase, setting clear expectations of your partners in the cold chain is easiest while both sides are defining the relationship. Manufacturers should clearly set expectations and partner need to understand these expectations to properly evalauate level of effort and pricing. Written Quality Agreements are the best method to clearly articulate these expectations. These agreements are a regulatory requirement for cold chain partners in most regulatory jurisdictions. Without a written quality agreement, it is impossible to properly management your partners. 19 / 105

20 CHAPTER 1 continued Audits and inspections must be conducted on regular and periodic basis. These assessments show that the current monitoring and controls are sufficient and key performance indicators are being managed by your partner. Another key component is managing a complex partner relationship, is understanding their subcontractor management tools and how they are integrated in their overall quality management system. All of these elements must be addressed in a business review with your partners. Unless both sides have a forum to address performance and partner for continous improvement, you risk a stagnant relationship that does adequately address the needs of either party. Our guidelines for business review are simple as 1, 2, 3: actions agreed upon in the business review must be enforceable through a written quality agreement, the key performance indicators must be relevent to process, and they must be scrutizined during audits, inspections and business reviews. 20 / 105

21 CHAPTER 2 Validating a Cold Chain Master Plan Validation Master Plans (VMPs) have become common practice in the medical device and diagnostic industries for demonstrating that the validation process is under control. A dvmp will serve the same purpose for distribution (hence the d in dvmp). It identifies the philosophy for how products, processes and facilities supporting the distribution of drug substance and drug product will be validated within the quality system to ensure the suitability of product for forward processing or use by the patient. The dvmp demonstrates a structured multi-disciplined approach including product development, quality and distribution operations. It also provides a means to document rationales for validation decisions. While not a defined requirement, the omission of a VMP subjects the on-site regulatory investigator(s) to needless frustration. In fact, a recommendation, but not necessarily a requirement, is implied in the 2011 non-binding FDA Guidance for Industry, Process Validation: General Principles and Practices, from section IV, item A. 21 / 105

22 CHAPTER 2 continued We recommend an integrated team approach to process validation that includes expertise from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical chemistry, microbiology, statistics, manufacturing, and quality assurance). Project plans, along with the full support of senior management, are essential elements for success. A dvmp will simplify and standardize validation processes, facilitate continuous improvement, and ensure smooth integration into quality systems, supporting the product life cycle. The scope of this article is to outline the methodology to create a validation master plan for distribution of drug product and drug substance. Also, it suggests a way to incorporate a reference to the dvmp in the Common Technical Document (CTD). Depending on whether you are filing an NDA or BLA, the work described in the plan may have to be completed at the time of submission of the CTD. The initial meetings that set up the filing strategy with the regulatory agencies are the times to discuss your approach and gain agreement on validation activities and timing. Having a dvmp draft with you at these preliminary discussions will help focus the discussion of your validation activities. 22 / 105

23 CHAPTER 2 continued Structure of the dvmp Note that two dvmps should be prepared, one for drug substance and one for drug product. Below are the common elements of both documents. Common elements of a dvmp Item Description Table of Contents Introduction Purpose Scope Responsibilities Approach Definitions and References Summarizes the critical elements in the distribution, including the control and monitoring points. Describes the plan s purpose. Use this as a way to tell the reader how the validation activities relate to each other, as well as how risk assessments drive the criticality of individual validations. Specifically identifies the end points of the exercise. Names the departments with the expected deliverables. Each department will be either a.) Responsible, b.) Accountable, c.) Consulted, or d.) Informed. This is the critical section of the plan. It is where the company will disclose how it will incorporate prior knowledge, validation studies. It should include; Process flow charts that provide a visual representation of the operations along with critical process parameters. User requirements. Validation strategy consider a family approach for multiple units of equipment or shipping systems. An overview of the validation documents (by title) that will be generated as the plan is executed. A list of existing and proposed SOPs that will control the transport of the drug substance/drug product. A list of quality agreements that may be necessary for any work that will be outsourced when the processes become operational. Provides a list of appropriate definitions and references used in the dvmp 23 / 105

24 CHAPTER 2 continued The approach section in the dvmp contains the how-to element in the dvmp. There are three tables, process flow, the process requirements, and testing plan. It begins with a process summary of the user requirement. Within the approach section there will be multiple process flow charts. An example is listed below. Each process flow chart should have a risk assessment attached to determine the process criticality. The level of detail in the risk assessment is proportional to the presumed process risk. Process Flow Chart API Manufacture to Distribution Step Who Description Parameter Target Proven Acceptable Range (PAR) Requirements 1 API manufacturing site 2 Fill-finish site in U.S. 3 Fill-finish site in U.S. Send API to U.S. finishing sites Receive API and place in storage Post fill finish; send bulk drug product to labeling site Transport temperature (air) Transport time Units shipped Method -70ºC 4 days -85ºC to -60ºC NMT 5 days Characterization: Overwrap selection CO 2 effects on ph Max duration for temperature 1 Lot (six 1-L containers and N/A Qualification testing, thermal one ID sample container OQ Insulated shipper/dry ice PQ Put away time CRT 2 hours CRT NMT 4 hours Hold test ; CRT for 4 hours Transport temperature Transport time 2ºC to 8ºC 3 days Refrigerated truck 0ºC to 25ºC NMT 4 days Transport stability; Cycle temperature from 0ºC for 4 days to 20ºC for 4 days. See TOR studies. Verify by temperature monitors per procedure Verify carrier quality agreements effective. Units shipped TBD N/A Method 24 / 105

25 CHAPTER 2 continued Process Flow Chart API Manufacture to Distribution Step Who Description Parameter Target Proven Acceptable Range (PAR) Requirements 4 Labeling Remove bulk drug product from refrigerated storage and label at CRT. 5 Transfer from labeling to distribution Upon lot release; transfer lot to distribution Temperature conditions Time out of refrigeration (TOR) Units to be labeled Method Temperature conditions Transport time 25ºC (max) 25ºC TOR stability studies 72 hrs. 120 hrs. Entire lot N/A Product will be equilibrated to CRT with fans 25ºC (max) 25ºC See requirements step 3. Verify by temperature monitors per procedure 2 hrs. 8 hrs. Units shipped Entire Lot N/A Method Refrigerated truck 6 Distribution Commercial Sale Temperature conditions Transport time Units shipped Method 25ºC (max) 25ºC 20 days 8 days N/A Per orders Refrigerated truck and passive shipper See requirements step 3. Verify by Quality Agreement and Periodic Monitoring 25 / 105

26 CHAPTER 2 continued The user requirements for each component will outline the requirements, and when they will be tested to assure suitability for their intended use. Timing of when these tests will be performed is also helpful to determine necessary resources. User Requirements Table Item # Requirement Acceptance Criteria General Testing Philosophy Requirement Rationale DQ OQ PQ S01 Structural protection The container will protect the flexible bag from punctures, abrasion, etc. Verify the containers provide protection to the flexible bags Processing requirements X S03 Variable volume The container can support a flexible bag filled to L The container will support a flexible bag with a volume of L Processing requirements X S04 Freeze capability The container can withstand temperatures as low as -50ºC Verify the container can undergo five freeze-thaw cycles Processing requirements X S05 Physical handling Container will withstand normal shock and vibration Test container with ISTA 3H Transportation requirement X The test plans provide a link between process and risk. The test plan contains the reference to studies necessary to show that the process contains the requisite monitoring and controls to assure a high level of confidence in maintaining critical quality attributes (CQA). The following table shows how a test plan can itemize the planned studies and the phase appropriate timing of those studies. 26 / 105

27 CHAPTER 2 continued Sample Test Plans Process Link Testing Plan Drug Substance Transport Development Test DQ OQ PQ Document ID (to be filled in and included in dvmp Report) S1 Thaw Study of frozen drug substance X S2 User requirement document complete X S2 Shipper thermal stress testing X S3.1 Shipper physical qualification X X S3.2 Shipper design qualification Define min/max load X S3.3 Shipper min/max thermal qualification; OQ; triplicate testing seasonal extremes X S6.1 Supporting documentation: quality agreement with forwarder X Now, a word about worst case. The concept of worst case was prominent in the 1987 FDA Guidance on Process Validation. In the current 2011 version, the entire concept was dropped. In its place, the emphasis is on the knowledge gained early in the process development that will identify the critical process parameters (CPP). It is up to the firm to determine how controls and monitoring will be arrayed to preserve these CCPs. Process knowledge and risk assessments have replaced the concept of worst case. How does this impact the validation activities? For distribution, it is incumbent on the firm to define the transport environment and how it may affect the products while en route from manufacturing to final destination. The emphasis in the recent updated Validation guidance carry the elements and approaches contained in Quality by Design (QbD). 27 / 105

28 CHAPTER 3 Three Process Qualification Pitfalls and How to Prevent Them Pitfall 1: Disconnects Between Packaging and Dock Operations Scenario A: The packaging management team does not coordinate with the group that manages the dock. A package is brought to the dock and ends up sitting there for hours without temperature control, leading to a temperature excursion. How a package is tested correlates directly to how a package should be handled. In this case, the package was tested in a way that it should have been kept under strict temperature control prior to being picked up by the carrier. Though the company chose a service (temperaturecontrolled truck) and box appropriate to their transportation situation, and had a cold room, they end up with a failure because they did not pay attention to this one step in the loading process. Scenario B: Conversely, a product is packaged and waiting to be picked up on a hot July day. A technician notices the box on the dock and places it in the fridge, thinking that he or she is being helpful, and unknowingly freezes the product. In this scenario the package was designed to be staged at warehouse temperatures prior to pick-up. With biologics, freezing is usually much more harmful to products than heat, and this is a dangerous situation where an employee may not understand the ramifications of their actions, regardless of their careful intent. 28 / 105

29 CHAPTER 3 continued Prevention: Manufacturers must have robust SOPs in place to ensure that proper storage is performed prior to pickup. Even in a domestic move using only one mode of transportation, there are loading and unloading parameters that are often overlooked. Ensure that handoffs are studied extensively in the hazard and operability study (HAZOP) phase, and ask what-if questions to determine possible scenarios. Ensure that time periods and locations during each segment of the transition are explicitly stated. The validation master plan should include analysis and controls for: Duration from the cold room to where product is packaged Point at which the temperature monitor is placed in the package, and start delays Where the package sits, and for how long, while waiting to be loaded into a truck Unloading duration between truck arrival and the destination (next cold room) It goes without saying that personnel must be trained on the allowable time periods at the loading and unloading docks. But companies should also ensure that personnel understand the reasoning behind the procedures, and what happens to the product when wait times are exceeded, or when product is moved to the wrong location. 29 / 105

30 CHAPTER 3 continued Refrigerants must be properly conditioned to manufacturer specifications for each pack-out as detailed in qualification reports. IMAGE: FROM COLD CHAIN TECHNOLOGIES Pitfall 2: Monitor (Pre)Conditioning and Placement Although the packaging SOP is followed to the letter, the temperature monitor for a shipment is pulled from the warehouse and placed in the box. The monitor itself is still warm, and doesn t get down to the product temperature for 30 minutes. When the trend is reviewed, there appears to be an excursion where product was out of range, although the product actually remained within range throughout packaging and placement on the truck. Prevention: Make sure that the SOP includes instruction on how and when to precondition temperature monitors, as well as where to place them in the package. It is a common industry practice to use data loggers that have start delays (typically of 60 minutes) and/or preconditioning of the data logger at the desired temperature prior to packout. Acclimation can take anywhere from 20 to 45 minutes depending on the monitor type and ambient conditions. If a monitor is not preconditioned, a false, and difficult to explain, excursion may appear. It s important to recognize that the reading on a temperature indicator does not correlate directly to the temperature of your product. It is common for monitors to read 8.4 C when the product itself is actually still within C. This is the result of the thermal characteristics of the drug payload itself and its resistance to temperature change versus 30 / 105

31 CHAPTER 3 continued the monitor (which will change temperature more rapidly). Some companies opt to perform rigorous testing to determine the correlation between monitor reading and product temperature. These steps may already be embedded in the plan for companies with years of cold shipping experience, but they re often overlooked in new companies, or those who ship less regularly. Pitfall 3: Refrigerant Conditioning Scenario A: A company has documented that their packaging will adequately protect their product in the shipping lane. An employee removes a full pallet of refrigerants from the freezer and begins pulling off that pallet and packing the shippers according to the SOP. But not all the refrigerants in the pallet have fully frozen, and some boxes are being packed with refrigerants that are too warm. Scenario B: A technician brings a pallet from the freezer to the pack out line, and pulls off that pallet for two and a half hours before taking a lunch break. The technician returns from break and starts packing again. The refrigerants have now been sitting out of the freezer for several hours, and are too warm to be packed. 31 / 105

32 CHAPTER 3 continued Prevention: Packaging qualification is not enough. It s important to qualify the process for your equipment, which includes having a proper process in place to ensure you always use refrigerants that have been properly conditioned. A half-frozen gel pack can have a drastic impact on the performance of the system. Companies need process controls and qualification in place both for initial conditioning of all refrigerants and after the refrigerants are on the shop floor. There need to be clear SOPs that say: How to bring gel packs to the pack out line How they are stored at the pack out line How long they can stay there before being reconditioned (i.e. brought back to the fridge or freezer) Vendors can advise you or provide equipment (such as coolers) to keep refrigerants at a specific temperature for a specific time frame, and even help you write the corresponding SOPs. For example, they may instruct you to state that after a certain number of hours on the floor, the refrigerants that haven t been used must be returned to the fridge or freezer, or marked and held in the freezer for a certain number of days to allow them to get to proper temperature. Companies must look at how refrigerants are staged and used at the line, but also qualify the conditioning process when refrigerants go back to the fridge or freezer, which is different from qualification of the refrigerants when they re delivered to the facility. 32 / 105

33 CHAPTER 4 Ambient Profile Selection and Packaging Qualification Process Choosing the right ambient profile is key to developing an insulated packaging system that will properly manage your temperature-controlled product during transport and distribution. Ambient profiles, which represent the temperatures you expect the shipper to experience during transport (ideally both hot and cold), are used to qualify insulated shippers and set the shipper s design space. * Many companies start with an existing industry profile to have reasonable performance expectations and meet the compliance standards of the FDA (or other regulatory bodies). After one year of operation and data collection, they add their own ambient profiles and retest to make sure the designs are still appropriate, or identify opportunities to improve. Profile choice is critical to the package design, as the more challenging the profile, the more robust and expensive the package. You have to understand the distribution environment through which the package will travel in order to ensure patient safety in a costeffective way. Currently, there is no standard for the development of ambient temperature profiles, which means this step can be a challenge, especially for new companies. There are three options for selecting ambient profiles: 1. Incorporate an existing industry profile (like 7E)* 2. Work with a supplier s profile 3. Develop your own profile 33 / 105

34 CHAPTER 4 continued Whichever route you choose, it s important that the ambient profile you use is based on science and has a statistically useful data set to support it. Development methods range from empirical analyses, where the distribution lanes are mapped and monitored for temperature data and other relevant environmental hazards (i.e. humidity, light, vibration), to theoretical models, where rationale is determined based on geography, historical weather data, or other general information about the distribution environment. Factors to Consider The ambient profile depends on all the conditions that exist in the transportation lane, some of which are choices. Beyond geography, the following factors affect the profile: Transportation lane Handling practices and service level, including temperature control Mode(s) of transport Transportation duration Boundaries of the lane Profile boundaries are extremely important. You have to ask yourself, When will I start the profile? The cold room? When I load the truck? Starting the profile too late or ending the profile early will mean that you miss important activities, like what happens on the dock or the unloading process after the transport company has released it. Though this may seem like 34 / 105

35 CHAPTER 4 continued common sense, companies have created shipping lane profiles and forgotten those parts. To provide the most safety and value, the profile should include the whole shipment, beginning with portions of your activity and ending when the product is safely stored at the delivery site. Temperature Data Collection The subject of how to actually collect temperature data is complicated on its own. Where do you put the data collection devices? How many do you use? As an example, if you ship small parcel one at a time, you might place monitors on the outside on two sides. If you ship full pallets of parcels that aren t separated, then you might put one each on the outside (top and bottom) and one in the middle of the pallet, as they will see vastly different temperatures. There are many possibilities to consider for temperature data collection. Incorporating an Industry or Supplier Profile Several companies have built their own profiles from data they ve gathered in their transport lanes. For those who do not have the funds or know-how to build a science- and data-based thermal qualification profile, there is the International Safe Transit Association (ISTA) 7E thermal qualification profile. Prior to its creation, companies used a variety of standards with varying degrees of accuracy, so the 7E profile was a milestone in establishing some consistency. Ambient temperature profiles must account for temperature variations encountered in all anticipated distribution lanes as temperaturesensitive products travel through various climate zones. The 7E profile was created based on more than 800 shipments and more than 75,000 data points. The protocol, all collected data, and the report supporting the ISTA 7E profile are all available for purchase through ISTA. Guidance on using the profile (including roadmaps and FAQs) is available at the ISTA site. To ensure compliance, it is immensely important that you have the data and science to support the thermal qualification profile you use. The data behind the profile you use will be important during the data analysis 35 / 105

36 CHAPTER 4 continued step for lane qualification. Note: It s important to keep in mind that you cannot assume that a 7E or a vendor profile will work for you without at least a lane review to match to temperatures your product might see. Excursion Monitoring ºC ºC max on the plane ºC min Though 7E is a great starting point for new companies, it does not encompass all shipping scenarios, so it s important to understand when it does and doesn t apply. The study was based on domestic common carrier U.S. shipments from select locations, so you may want to consider other profiles if you are shipping internationally or via a different method domestically. ❶ ❷ ❸ ❹ ❺ ❻ ❼ ❽ *numbers represent stopping points in the lane date/time Currently, the industry lacks a global standard to assess widespread applicability of standard industry temperature profiles. To address the complexities of global distribution, some packaging vendors have developed their own ambient temperature profiles, and they can assist you with determining suitability and customization. Custom Qualification When a company confirms that an industry standard profile is not right for them, it is typically for one of two reasons: 36 / 105

37 CHAPTER 4 continued 1. The industry standard profile is not indicative of their lanes and is not capturing the correct anticipated extremes. An example of this would be a Canadian or Northern U.S. company that cannot use a winter profile based on warmer U.S. climates. In this case, the client needs to create a more stringent ambient temperature profile to ensure product safety in transit. 2. The industry standard could be overly robust for companies that have extensive control of their supply chain in very defined shipping lanes. With enough volume to justify new packaging development, companies in this category can save significant money by designing systems tested against ambient temperature profiles that are specific to their (less severe) lanes because the resulting packaging will be cheaper, as well as smaller and/or lighter. This lowers total cost because it also reduces incoming freight, warehousing, and, most significantly, outgoing freight costs. Note: Custom qualification should be considered early in the evaluation process. But if you re already shipping (using a qualified system like 7E) and you re having failures in the field that cannot be brought under control by working with your logistics provider, this should immediately trigger a custom profile and qualification discussion or the use of an off-the-shelf qualified shipping system tested against a more robust profile. Qualification Process Once the ambient profile is selected, and other key requirements are determined, you can begin the packaging design process, where many different designs will be modeled in computer simulations and tested in environmental chambers. Then you will move on to the qualification steps, summarized here (PDA Technical Report 39 offers specific guidance for qualification). Design Qualification (DQ) After zeroing in on a design with modeling, a DQ is conducted in environmental chambers where n=1 (one sample) of minimum and maximum payloads of each shipper size are tested against hot and cold profiles. Successfully meeting requirements is considered passing the DQ, meaning you have a prototype shipper design that you know works and you intend to move forward with it to commercialization. 37 / 105

38 CHAPTER 4 continued Operational Qualification (OQ) The next step is to tool up production components for the shipper, then test the shipper in environmental chambers in an OQ. This is done with production parts in n=3 (three samples) of minimum and maximum payloads to show repeatability of results. The ISTA Standard 20 provides best practices for developing and testing shippers (thermocouple placement, how often to read temperatures in the chamber, etc.), and includes templates for protocols, reports, and how to present data. Performance Qualification (PQ) The solution has now been qualified in a laboratory environment but there s another step the PQ. In the PQ, shippers are sent with data loggers in mock payloads from the actual origins/distribution centers to a set of destinations representing the overall distribution lanes the client will send product in. Again, n=3 per size and per distribution lane is typically sufficient. It s best to space the shipments out over the course of the peak hot and cold weeks (as opposed to sending all three summer shipments on the same day) to obtain good data. Live shipments producing good results confirm assumptions made in the laboratory were valid and you can expect the systems to perform in the real world. PQ shipments should be made at peak winter and summer months to gage the limits of performance. They should also be sent in consecutive years to verify that no changes took place in the distribution lanes or methods of handling the shipments that will have adverse effects. For example, if a carrier was to change the hub through which it routed packages from Dallas to Detroit, then you could expect the package to see very different ambient temperatures in transit. An ongoing PQ study would highlight such scenarios early on and trigger corrective actions. (See Lane FAQs: page 56, for more information on continuous monitoring). 38 / 105

39 CHAPTER 5 Balancing Your Packaging Needs For a given cold chain problem, there are typically several ways that package developers can solve your problem. The fact that there are no one size fits all solutions is both a challenge and an opportunity, because customizing your packaging means you re only paying for shipping services, insulation and refrigerants that meet your needs. As regulations have increased, healthcare products, including those that weren t shipped with temperature protection in the past, often need temperature control. Regulators are asking more questions how do you know your product doesn t need temperature protection? What if it does? If you don t know, then you have to protect it, and you have to have a plan. Suppliers are there to help find packaging that fits your budget, your requirements, and what s best for your distribution. Ultimately proper package selection is about delivering the lowest total cost, which goes far beyond the cost of the container itself. A more expensive package may allow you to choose ground versus two-day, or save on incoming logistics because it s smaller. 39 / 105

40 CHAPTER 5 continued Stakeholders and Developers One of the keys to choosing packaging efficiently is getting all of the stakeholders and package developers involved early. Many times a company will go through the process with developers, and a new stakeholder comes in and wants to add a restriction. For example, quality management may want controls that procurement doesn t want to pay for. This can cause rework, or the process may even have to start all over again, so it s important that everyone is on same page from the start. QdB Approach and Benefits Quality by Design approach to the problem Benefits and Best Practices Along the way Monitor Qualify Define Design Characterize Additionally, packaging developers can make the process much more streamlined, as they know the questions to ask, know what makes a product work (and what doesn t), and understand the costs and benefits. During package development, many healthcare manufacturers follow Quality by Design (QbD, graphic to the left). It can be extremely beneficial to bring in developers during the Define phase. If a developer starts working on a design before the Define questions have been completely answered, it will likely result in rework. SOURCE: ADAPTED FROM SONOCO THERMOSAFE 40 / 105

41 CHAPTER 5 continued Last Mile Packaging: Case In Point The pharmaceutical industry relies on their sales representatives to educate and provide samples to hospitals and healthcare providers; this, in turn, creates an additional tier of temperaturemanagement complexity. Transporting these drug samples requires a complete Ranking Your Needs When shipping a healthcare product, you have several different needs that must be addressed (see table below). It s best to rank these critical factors during the Define stage in terms of importance. If your company won t ship boxes over a certain weight for safety reasons, then that will help you zero on your packaging options. Once you hit the maximum weight, you may have to use more insulation or more exotic phase change materials to keep products within temperature range. Factors For Team to Consider Performance Needs Regulatory Needs End User Needs Pricing (value) Needs Safety Duration, Temperature, Payload, Ambient Profiles Reference Documents, Available Excursions Packout Configurations:Universal/Seasonal Ease of use, number of components, weight, pack-out time, dimensional, etc. Package cost, freight cost, physical weight vs. dimensional, etc. Ergonomics solution to protect a drug s unique properties. Many of these companies use passive systems, which rely on the user to manually arrange cooling packs each day to create the correct transport temperature. These systems can have variability in their implementation, which continued... Quality Other Tolerances/Testing requirements Sustainability, shipping lanes, return-reuse, conditioning, data monitoring, etc. SOURCE: ADAPTED FROM SONOCO THERMOSAFE Choice of service level and packaging go hand in hand. Most service providers have a variety of service levels and temperature controls next day shipments, service with alerts, etc.). If you choose a service level with more protection from undesired weather temperatures, then you might not need as much package protection. Of course, this 41 / 105

42 CHAPTER 5 continued could cause concern over the quality, safety and efficacy of tvhe drugs before they even get into healthcare providers hands. The importance of the drug samples is one reason why, in 2014, the U.S. Food and Drug Administration recognized the consequences of improper temperature management and updated the Code of Federal Regulations Title 21, which regulates the storage and handling of pharmaceutical samples. Under this revision, pharmaceutical companies are subject to penalties should samples not be kept in temperature-stabilizing conditions. SOURCE: ADAPTED FROM JARDEN LIFE SCIENCES depends on the speed of shipment, ambient temperature profile of the shipping lane, and what controls the carrier supplies en route. Even higher service levels include portions of uncontrolled transit (such as transit from the TC warehouse to the tarmac), so it s extremely important to understand every segment of the package s shipment path when deciding package protection. Conversely, if you choose a more robust active or passive container, this may protect the package from extreme environments and require less temperature-controlled transportation from your carrier. Active Containers Active containers, able adjust to the variables of the distribution system, started off years ago as pallet-sized solutions for bulk transfer, and gradually companies have developed smaller parcel shippers. These containers still face some challenges with availability and trust customers may have concerns about recharging or malfunction but active container companies have built in lots of fail-safes, including audible alarms, visible flashes, and signals if they lose power. These containers can be extremely beneficial in the last mile, ensuring products reach doctors and patients safely. One area where they ve been very successful is in distribution of samples to doctors. These samples have had a reputation for being uncontrolled when it comes to temperature, as a pharmaceutical sales rep might place them in a lunch bag or cooler with gel packs and leave for a long day of appointments. Because the samples are used for evaluation, it s critical that they remain within temperature specifications. With new active container solutions designed to fit in the trunk of a car and plug into 42 / 105

43 CHAPTER 5 continued the cigarette lighter, a sales rep can visit doctors and feel confident that the samples have remained within temperature. This technology also builds trust with doctors, who see that the samples are being protected all the way. Because there are no concerns over leaking gel packs or complicated packouts (it s clear where the payload belongs), some shippers prefer the ease of active containers. If you re able to remain in control of the containers, you can reuse them many times, which makes them an environmentally friendly option. Passive Containers: Insulation and Refrigerants Within the passive packaging sphere, there are various combinations of insulation and refrigerants that may work. Again, this is about making decisions and finding the most cost-effective combination for you, and it might be different for the next customer based on their priorities and product. During the decision-making process, developers help you answer questions like: How much of the problem do you want to solve with insulation (EPS, polyurethane, or vacuum panel boxes)? How much of the problem do you want to solve with phase change materials (PCMs)? What type of PCM do you want to use? 43 / 105

44 CHAPTER 5 continued Last Mile Challenge: Distribution in Africa At present, Africa represents the most difficult logistics path for pharma manufacturers, but with the recent outbreak of Ebola and the ongoing devastation from malaria, it s also the biggest opportunity. It s a tough combination: minimal infrastructure (areas without electricity, lack of airports beyond major hubs), extreme heat, and the need for long shipping durations to reach rural areas, coupled with the demand for vaccines and other pharmaceutical products to protect citizens and prevent pandemics. There has been a lot of work over the last five years to safely transport vaccines to African destinations within acceptable temperature ranges, knowing that it could take two weeks. If you have a 24-hour shipment, you may only need a fairly lightweight, low-cost EPS solution with a water-based PCM. But if you ship your product over a week in harsh temperatures, then it may require a vacuum panel box with a high-tech PCM because that s the only way to get it to the destination safely. An exotic, more sensitive PCM or better insulation can cut package weight and size by up to 50%, but they are both costlier options. There are many great materials and you can solve your problem any number of ways, and it s all about what s important to you. Adjustable Packaging and Shipping Opportunities exist, depending on weather, vendor and shipping lane, to adjust the package or service level you use to save money. If you re able to monitor temperature appropriately, you might be able to reduce temperature controls during times of mild weather (particularly in the fall and spring). Some companies adjust their logistics because they can monitor on a day-to-day or week-by-week basis, while others decide they don t want to adjust because it s too time-consuming or complicated to make logistics decisions and changes on a daily or weekly basis. Talking to your service providers early will help you determine if adjustment is needed. Cold chain companies as well as nonprofits and global healthcare companies, are working on solutions, where active containers will play a major role. continued / 105

45 CHAPTER 5 continued Challenge: Comparing Apples to Oranges A major challenge in the industry is raising awareness that each company s needs are different. A customer may be able to find 10 different packages that will maintain 2-8 C for 48 hours, ranging from simple to complex, and may wonder how an EPS box with a few gel packs and a vacuum panel box with exotic PCMs are both 48-hour solutions. Despite the disparity in cost, they may both be capable (in their own way) because they re designed for different profiles and tested to different standards. Though the industry has developed the 7E profile, it may not necessarily match up to your individual situation. If your lane is very controlled without extreme high and low temperatures, 7E might be a good profile for you, and you may be able to go with packaging that fits that standard. So when you re comparing packaging, understand that your mileage may vary. Though passive systems have typically been more ubiquitous, it would be quite difficult for a passive container to protect the product for the long shipping duration under extreme heat, and keep the weight under a certain amount for logistics. With major organizations like the Bill & Melinda Gates Foundation and the Clinton Foundation working to provide treatment and vaccines for infectious diseases, developers are racing to meet the need with advanced active cold chain solutions. 45 / 105

46 CHAPTER 6 Supply Chain Innovation for Growth A 2015 survey by Frost & Sullivan illuminates the need for effective supply chain strategies in gaining a competitive advantage. the supply chain represents one of the most important yet underappreciated sources of competitive advantage that companies can capitalize on, but only if companies can find the right allies to bring innovative solutions to their customers. Excerpted from Frost & Sullivan s 2015 Improving Profitability, Improving Customer Loyalty, Improving Lives (available here) Historically, healthcare providers have allowed proven operations to function at status quo. Companies sustained margins and incremental revenue with annual price increases and improved efficiencies as business expanded. Day-to-day success was often credited to hardened processes established during periods of consistent year-over-year growth in profit and shareholder value. However, now reimbursements are declining and the buyer has more control. That means more efficient systems are needed to generate improved profits and margins. There is new urgency to improve healthcare supply chains. To achieve success, today s supply chain leader must do more with fewer resources, all while maintaining excellent service levels, drawing down global inventories, and being a good environmental citizen. Focusing on innovation in the supply chain, Frost & Sullivan administered a survey to 39 high-level healthcare products and services executives attending the FedEx 2014 HealthCare Solutions Executive Forum. Companies represented in the survey included manufacturers of pharmaceuticals, biotechnology/tissue, medical devices and clinical diagnostics, as well as distributors and clinical trial executives. 46 / 105

47 CHAPTER 6 continued the most savvy healthcare products companies recognize its greatest potential is in its ability to support top-line growth, market expansion and customer relationships. Frost & Sullivan 22 % Somewhat Important The Importance of Supply Chain 78 % Extremely Important NEARLY 78% say that an effective supply chain will be extremely important to their company s ability to successfully compete. IT COMES AS NO SURPRISE THAT SUPPLY CHAIN AFFECTS PROFITABILITY TARGETS. This list includes the percentage of respondents who ranked supply chain as extremely important to meeting goals in the next three years: Achieving Business Goals Through Supply Chain Multiple responses permitted. Meeting profitability targets 89% Meet top line revenue targets 83% Ensure customer loyalty 78% Maintain regulatory compliance 78% Develop and launch new products 56% Gain market share 56% Expand internationally 50% 47 / 105

48 CHAPTER 6 continued Meeting Cost Pressures Healthcare products and services companies, the providers they serve and the supply chain vendors that connect them are using information to drive efficiencies by rationalizing consumer ordering patterns. This is done by better matching the speed of delivery for a product to when it really needs to be onsite, as opposed to how providers were used to stocking it in the past. Frost & Sullivan 6 % Neutral 33 % Somewhat Important THOUGH THE MAJORITY OF THE ESTIMATED MEDICAL TECHNOLOGY MARKET was derived from sales to developed countries, such as the United States, Japan and Western Europe, Frost & Sullivan reports that growth rates in developing markets are estimated to be higher than those of developed countries. 61 % Extremely Important Market Growth Around the World 6 % Developed Countries (Such as the U.S., Japan and those in Western Europe) % Developing Markets (Such as China, Brazil, India, Russia and Mexico) DECLINING REIMBURSEMENT means that companies must find ways to cut operating costs. The survey shows that 61% say supply chain cost reduction is extremely important in the ability to respond to their customers pricing pressure. 48 / 105

49 CHAPTER 6 continued Top 6 Capabilities Intervention and recovery capabilities Frost & Sullivan believes healthcare products companies can position themselves as solution providers and gain a competitive advantage by seeking supply chain vendors that are leaders in connectivity, experience and technology. Frost & Sullivan Proof of delivery Insulated protection for pallets 24/7 customer support Real-time shipping alerts HEALTHCARE EXECUTIVES said the top capabilities of interest to their customers include these top 6 capabilities Temperature monitoring 49 / 105

50 CHAPTER 7 Nine Considerations for Timing and Prework If you fail to plan, then you plan to fail. Cold chain operations are extremely complex, so it s important to invest time in prework and planning to make operations successful. We review some common areas for improvement or misconceptions with regards to timing and prework. Good Timing 1. Reaching out to vendors early can make a huge difference in achieving goals on time. Vendors have experience solving cold chain problems and may be able to troubleshoot, help identify stakeholders, and get creative with solutions, so manufacturers should take full advantage. Reaching out last-minute is also a problem because vendors have their own timelines and outside contractors as well. The earlier manufacturers communicate their potential timelines, the earlier vendors can start assembling a team and checking for contractor availability. In an A-to-Z timeline, if a vendor is needed for step S but doesn t have an opening then, the whole timeline is thrown off. 50 / 105

51 CHAPTER 7 continued 2. Gathering data for an ambient profile takes one year. Some companies wait to collect data for their ambient profile until just before they need to begin shipping. This is problematic as it takes a year to develop ambient profiles. We discuss this in more depth in the article entitled Ambient Profile Selection and Packaging Qualification Process, page 33. It s critical that companies start data collection before they are ready to redesign their current cold chain shippers. 3. Chamber testing is performed in real-time. Have you considered reverse logistics and returns? The chamber testing process involves programming and running an ambient profile: this is a real-time profile, not an accelerated one. Manufacturers may not realize that simulating a 3-day shipment takes 3 days in the chamber. Prior to the test, there are also preconditioning steps to make sure the frozen gel packs are frozen, the refrigerated product is refrigerated, and that the container is at ambient temperature. On average, preconditioning requires approximately 24 hours, but this can vary depending on product and storage requirements.vv The misconception about length of chamber testing may stem from the fact that there are accelerated testing sequences for other parameters. A vibration profile, for example, is used to simulate 2 days in a truck and can be performed in 45 minutes on a vibration table. 51 / 105

52 CHAPTER 7 continued There s a common analogy in the industry that much like you can t cook a turkey twice as fast by doubling the temperature, you can t speed up chamber testing. It s a real-time test. This is an area that slows people down, as they don t realize it will take months to develop solutions. Prework Tips 4. Invest in validation prework. For a successful validation, manufacturers must understand their system, be clear on client expectations and key metrics before beginning. If a football team hits the field without practicing, they can t expect to be successful it s the same with validation. By writing a test case outside of the formal validation, manufacturers can work out the case and problems prior to the official run. Proper communication and prework help ensure that companies know how their system behaves and apply the proper controls. Examples of prework tasks include: Identifying suitable equipment (with correct specs) and warehouse parameters in the various seasonal climates Temperature mapping to identify hot and cold spots, issues with fans, and to understand the airflow Documenting how to handle cold chain products, and how long can products can be at what temperature (stability data) 52 / 105

53 CHAPTER 7 continued Training handling personnel Having a plan for temperature monitoring (See #3) The details that companies must factor in are available in literature (there are numerous regulations from the global regulatory bodies) but are not always taken into account. If these details are factored in, the protocol will be much more robust with a higher chance of passing. Without the necessary prework, validation may pass, but there is a higher likelihood of issues in future audits, and spending money on repeat work or addendums to the protocol or system in the future. 5. Mitigate validation mistakes with realistic deadlines and contingency timelines. In theory, nearly everyone can agree that rushing leads to mistakes, but in practice, and in the face of deadlines, common sense can be ignored. Every validation is different, but manufacturers are typically under pressure from stockholders, senior management, etc. to meet certain timelines. 53 / 105

54 CHAPTER 7 continued As we mention above, validation is often a serial process where one step waits on the previous. A contractor that can only come in during a certain time frame has the potential to cause major delays, so it s important to be open with management and the team to come up with: A practical timeline Contingency plans It s better to push out a timeline when needed than proceed under duress and cut corners. It will ultimately cost more time and money to haphazardly meet the deadline, than taking the time to properly address deviations during validation. 6. Consider the specifics of temperature monitoring. Some manufacturers are so focused on the finished product that they overlook this step. They re finally ready to ship product and all of a sudden they have a problem that they have to work through because they didn t pay attention to how they were monitoring temperatures. This is especially common in clinical trial products these products are manufactured in small batches under strict timelines, with trials contingent on the arrival of the drug. The operations are typically new, and the personnel may be inexperienced with cold chain logistics as well. If the manufacturer has not made a monitoring plan in terms of temperature (including thermocouple/data logger placement) and chain of custody, they may end up having to discard and start over, which makes a huge impact. 54 / 105

55 CHAPTER 7 continued 7. Take time to educate all departments on what certain restrictions (such as the frequently occurring 2-8 C safety range) mean for logistics. In early meetings, it may be tempting to place heavy restrictions on key parameters. For example, 2-8 C is somewhat the default safety range for manufacturers who aren t sure of their temperature range. Patient safety is of the utmost importance, but that designation may not be necessary. Educate the involved departments on why that designation is so restrictive for shipping. An evaluation can be performed to see if stability testing can help broaden that temperature range. One expert notes that the best practice is to come up with maximum allowable excursion time from testing and stability, and document this in the quality agreement and procedures for worst case. 8. Have a plan for returns. It s helpful to set up a core returns process handled by one group, but understand that each return may be different. Some companies say, We don t do returns, but everyone will have returns at some point because thousands or millions of products are moving quickly through so many hands in the shipping process. Manufacturers must be prepared to deal with scenarios like these: An item that isn t theirs is delivered to their site An item that is theirs is delivered, but to the wrong site 55 / 105

56 CHAPTER 7 continued Product that isn t approved (and should have been) is delivered The ASN or PO for a shipment is incorrect It may be worthwhile to have a regular returns meeting depending on the size of an organization, and call in stakeholders as needed to keep returns cages from overflowing. 9. Consider reverse logistics (as needed). Some companies select reusable packaging (active or passive), but overlook the reverse logistics. Reuse can contribute to a lower carbon footprint (and in some EU countries, avoid waste disposal costs), but a shipper is only reusable if a manufacturer can get it back from the receiver to use it again. In some cases, a medical product may be shipped with several components, of which the customer only uses a few, so the unused components must be returned in a cost-effective way. If selecting reusable solutions, manufacturers must ensure that the packaging is qualified for reuse, and consider return procedures and any prerequisite checks, cleaning steps or refurbishment needed between uses. Reverse logistics have large cost implications and headaches, as they are out of the manufacturer s control in the customer s hands, so budgeting and plans for tracking, receiving and reusing must be considered ahead of time. 56 / 105

57 CHAPTER 8 Lane FAQs: Characterization, Monitoring and Qualification I. Lane Characterization Q: What is lane characterization and which parties are involved? A: Lane characterization includes gathering temperature data and other lane details to assess and mitigate risks. First, you create an overview of all lanes, driven by critical quality attributes (e.g. carrier, layover airport, airline, trucking company, active/passive cold chain) as well as shipment duration and handoffs. Next, you consolidate lanes with similarities and perform characterization for these lanes, including a templated risk assessment, risk mitigation plan, and display the lane specific steps/contacts and lane SOP, in which you also define the controls in place. Whether you re shipping to first or third world countries, you must do a proper risk assessment, and you should involve your forwarder and carrier to understand the lane segments. Optional parties to include: If the destination is a remote area, involving the consignee will help you understand what happens on the ground to assess and mitigate risks. 57 / 105

58 CHAPTER 8 continued If you d like to really be thorough, you can send personnel to observe (but not interfere with) a dummy shipment to see what actually happens as it travels through the lane, goes through customs, etc. With lane details and temperatures, you can determine which lanes are the highest risk (e.g. long shipment distance/duration, the last mile is in a third world country with high fluctuations in temperature, long layovers, or many handoffs). Q: Do I need to test all lanes? Have you considered weather as another element affecting lane risk? A: This is a matter of what level of risk is accepted: some companies choose to use a risk matrix and qualify high-risk lanes, while some prefer to qualify every lane. You may decide that if you have a high volume lane with 100 shipments per year in extreme temperatures, then you don t need to qualify a similar lane that does 1-2 shipments per year, provided that you can justify your decision to regulatory agencies. You may characterize 500 lanes, and find there are commonalities that allow you to consolidate to 50 lane types based on statistics. Be aware that a lane categorized as low-risk might change performance during operation and resemble a more risky lane. This means that you ll have to either adjust your packaging or go back to the forwarder or carrier to discuss what happened and what they can do to return to the relatively low-risk situation. The way you ll find out about these changes is through ongoing quality measures: 58 / 105

59 CHAPTER 8 continued 6 Steps to Lane Qualification Lane qualification is the process of gathering data from your transport lanes on the hazards that are present and converting it into actionable information to support the strategies and decisions about how to manage your cold chain. 1. Select a thermal qualification profile supported by data to qualify your insulated shipper. (See Ambient Profile Selection and Packaging Qualification Process, page 33, for more details.) 2. Execute a lane qualification study. Write a protocol for your data-gathering methods, including: Ship-to and ship-from locations Number of shipments (In the case of ISTA 7E, you should only need to perform between one and seven shipments in any given lane to gather the required amount of data) continued... II. Ongoing Quality Measures Q: What is the requirement for continuous lane monitoring? A: Once you have a successful performance qualification (PQ), you have data that confirms the packaging is suitable for protecting your product though the shipping lane. But after a successful PQ, things can become murky. There isn t a requirement for continuous monitoring, so while one company may not perform continuous monitoring (which is extremely risky) another might perform full lane qualification. Regardless of regulatory requirements, you should practice ongoing quality measures. The world does not stay static after qualification there are thousands of moving parts and handoffs. Handling can change. Environments can change. Customs may place a shipper in a fridge or leave it out on the tarmac; they may not communicate this, or be consistent in their behavior. Monitoring your shipments addresses cost and human health concerns: Without monitoring, you may not be aware that something changed in your distribution lane until there are failures; with monitoring, you greatly increase the chances of capturing the issue and resolving it before an onslaught of failures. With particularly expensive products, the cost of one failure could be more than the cost of continuous performance checks. If you re not monitoring and something has changed, product could be going out of spec without your knowledge. If you re aware of temperature excursions, you can take appropriate corrective actions. 59 / 105

60 CHAPTER 8 continued Time of year to execute the study. Execute your study during seasonal extremes. Instructions for the shipping and receiving sites and instructions for how to get the data back. 3. Assemble a data package, including: Worksheets filled out during lane qualification shipment All temperature recording device data 4. Analyze your data, comparing the data gathered to your profile and its data set. If you can show that the lane qualification data is within ±2 standard deviations, it is within the 95% on a bell-shaped curve that the lane data gathered falls within your design space. Q: How do I determine the frequency of continuous monitoring? A: In the first 12 months of shipping, it s ideal to perform intensified monitoring to capture deviations and areas for improvement in the new lane. How you proceed after this stage is up to you, but experts have two suggestions: Base your frequency on findings from your first year, and the risk assessment. If your shipments internal and external temperatures are within spec, then it s a relatively low-risk lane, and you can reduce frequency (but not stop altogether). Conversely, if there are many temperature excursions or failures in a lane, then monitoring frequency should be increased to gather data, and determine root causes and corrective actions. Perform monitoring during periods with most extremes (risk), because this will provide performance data during the highest risk scenarios. Ensure Patient Saftey Three Key Goals of Qualifying Your Transport Lanes Determine if your qualified shippers can maintain required temperature during transport by gathering data that supports the use of your thermal qualification profiles. 5. Write a lane qualification report summarizing your findings. If remediation is required (typically it is not), common steps include upgrading continued... Ensure Compliance Minimize Business Impact Show that your controlled-environment logistics network is under control. Reduce packaging and shipping costs by using the most appropriate thermal profile. This not only saves money, but is also greener. Less packaging can mean less waste and fuel. 60 / 105

61 CHAPTER 8 continued service level, updating a carrier quality agreement, or finding a new route that falls within the required design space. 6. Verify the effectiveness of any remediation plans if they were required. Execute the lane qualification study again in the appropriate months to verify that the implemented solution has had the intended effect. (One step it does not include is using ambient weather data to determine if your ship-from and ship-to cities are too hot or cold.) Regardless of frequency, you should monitor a statistically relevant portion of shipments (some experts advise approximately 10-15%), whether you choose to send monitors in randomly selected shipments or in the high-risk lanes. Q: Are there other benefits to continuous monitoring? A: The practice also helps you monitor the performance and processes of your forwarders and carriers, to ensure that the actual handling is in alignment with the quality agreement. The agreement may say that the shipment will be refrigerated at Point C, but your monitoring shows that it is not being temperature controlled at that point. Performing quarterly business reviews with carriers and forwarders will give all parties a chance to discuss data and excursions, and corrective actions where necessary. 61 / 105

62 CHAPTER 9 Managing Temperature Excursions The transportation and storage of pharmaceutical products are regulated by Good Manufacturing Practices (GMPs) to ensure that the pharmaceuticals are protected from environmental hazards such as extremes in temperature and humidity. However, Mother Nature, quirky software, electrical surges, schedule changes and mechanical variances may interrupt even the best-laid product transportation plans. When the product is exposed to temperatures outside of its acceptable range, an excursion has occurred, and this event can potentially threaten the integrity of the product, especially if the product is temperature-sensitive. This discussion will look at what to do when an excursion occurs, and how to evaluate its consequences from a quality and regulatory compliance perspective. For the purposes of this article, product can include raw materials and intermediates, bulk drugs, and filled/finished/packaged pharmaceutical and biological products. Likewise, transport encompasses the movement of product both internally (from manufacturing site to manufacturing site) and by external partners such as freight forwarders, trucking companies, and air, ocean, and train carriers. Once the product reaches the first paying customer, such as a wholesaler, pharmacy, or clinical facility, the responsibility for its satisfactory handling is turned over to that entity, which must then ensure the product s integrity through to the patient. 62 / 105

63 CHAPTER 9 continued Temperature specifications: Products are stored according to label storage conditions as registered in the regulatory filing of the product. However, the allowable temperature range during transportation may be wider than the labeled storage conditions when supported by known stability data. This data, or stability profile, paints a time and temperature picture for the safe handling of the product. Materials that are known or suspected to be adversely affected by temperatures outside label storage conditions are known as temperature-sensitive products. Examples include a vaccine labeled for 2 C to 8 C storage that is adversely affected by freezing, or a suppository labeled for storage below 25 C that is adversely affected at temperatures above 37 C. The regulatory organizations at both the sending and receiving locations should agree to any allowable deviations from the label storage conditions, and the supporting data should be appropriately specified in shipping and receiving site procedures. The regulatory filings for the product at both the origin and destination locations should reflect allowable deviations. Where appropriate, the standard operating procedures (SOPs) should document those approved transport temperature conditions. Temperature control: Protecting temperature-sensitive products from temperature excursions requires the use of specialized packaging during storage and transit. This packaging may be passive (such as an insulated container), or active (such as a refrigerated storage unit). The purpose of the protective packaging is to ensure that ambient conditions expected to be encountered in the transport lane do not threaten the product label storage conditions, thereby reducing the risk of product temperature excursions. The responsible quality departments at both the sending and receiving sites must agree on the mechanism to be used for thermal protection of the material while en route. 63 / 105

64 CHAPTER 9 continued Temperature monitoring: The successful performance of thermal packaging can be documented through the use of temperature monitors devices that record and store temperature data. When appropriate, internal distribution should utilize single or multiple temperature monitors to record the transportation temperature of the load. As much as possible, the monitor(s) should capture data that represent either the product itself or the worst-case product exposure, as opposed to monitoring the surrounding space exclusively. The number, type and placement of temperature monitors should be based upon the risk assigned during evaluation of the shipping lane, including consideration of: The thermal sensitivity of the product versus the expected ambient temperatures to be encountered; The duration of transit; The value of the product in the load; The expectation of the sending and receiving sites; Local regulatory requirements; and Product filing requirements. 64 / 105

65 CHAPTER 9 continued If a product has a product stability profile, a temperature monitor should be used to determine if those parameters were met while the material was in transit. Care should be taken to prevent inaccurate readings. In addition to monitoring and storing temperature data during transit, a simpler temperature-indicating device can be used for external distribution to the first paying customer. While this type of device doesn t provide data on the full temperature exposure over time, it indicates whether the product was protected from a specific threshold event, such as freezing. The decision to use a temperature indicating device for external deliveries should be based upon the requirements of the customer and local regulatory agencies, the value and thermal sensitivity of the product, the mechanism used for thermal protection, and the duration of transit to the customer. Reporting and evaluating excursions: Any excursions outside of allowable transport temperature conditions, as defined in the stability profile for the product, should be reported back to the responsible quality person at the release site. The impacted product must be placed under a restricted status either physically or electronically while the quality department determines if the temperature excursion had any potential impact on product integrity. Care should be taken to assure that not only are the chemical attributes of the product intact, but also that the physical and biological/ immunological behavior is unaffected. 65 / 105

66 CHAPTER 9 continued An assessment should be made using the duration of the excursion time and the extent of temperature deviation compared to specific product stability data or stability statements issued by the quality department. Such data may be derived from accelerated and long-term stability studies, forced degradation studies, temperature cycle studies and freeze/thaw studies. Customer reports: In general, temperature excursions reported by customers, such as hospitals or pharmacies, should not be evaluated against stability data if there is a lack of specific time and temperature records. This is because of the potential risk of decisions being made based on unsubstantiated data. However, the quality department may evaluate the excursion where there are sufficient records to substantiate the excursions, and to support a usage or further distribution decision. Additional testing: Depending upon the product, its regulatory filing, and the requirements of the country it is shipping from/to, it may be possible to perform additional testing to determine if the excursion had any impact on product quality. The decision to test, and the conclusions drawn based on test results, should be made by the quality department on a product-by-product and event-by-event basis. Test results should be compared to the original release testing and, using the degradation profile of the product, be extrapolated to the product s expiration date. 66 / 105

67 CHAPTER 9 continued Product disposition: Upon completing an assessment of the excursion s impact on product integrity, the quality department must determine the disposition of the affected product. Partial release may be considered, but only when part of a batch is not impacted by the excursion, and documentation is available to allow clear segregation of that product that has been transported within the defined transit temperature range. Compliance improvement: In addition to the quality assessment, an investigation should take place to determine the root cause of the temperature excursion, and whether preventative actions are warranted. Temperature excursion occurrences should be trended, which may help identify problem areas as well as corrective steps. For examples, trends may be identified with a specific site, carrier, transport lane, day of the week, season, type of thermal protection, or load configuration. The best way to handle temperature excursions during the transportation and storage of pharmaceuticals is with planning and prevention. Developing a detailed standard operating procedure for handling temperature-sensitive products with internal manufacturing departments as well as with any external partners will cut the risk during product movement. Working with experienced materials-handling professionals who can incorporate risk-mitigation activities ahead of time will be the best defense against temperature excursions. 67 / 105

68 CHAPTER 10 Perspectives: How Carriers, Forwarders and Manufacturers Can Collaborate to Manage Risk For the air transportation portion of the temperature-sensitive supply chain, there are typically three partners in a cold chain shipping operation: the healthcare/pharma manufacturer, the forwarder and the carrier. The air freight business model consists of a forwarder selling to commercial customers (healthcare manufacturers, in this case), consolidating massive amounts for freight, and negotiating with carriers to find costeffective air transport. Traditionally, the manufacturer relays information to the forwarder, and the forwarder to the carrier, without direct communication between manufacturer and carrier. This works very well with auto parts, but with temperature-sensitive pharmaceuticals, there s a lot more at stake. Despite best efforts by all three parties, problems can arise from this linear relationship, because it s critical that the manufacturer and carrier understand each other s challenges to come up with effective solutions. We present the perspectives from a healthcare manufacturer and carrier, and discuss how some companies are already benefitting from the collaborative approach. 68 / 105

69 CHAPTER 10 continued Healthcare Manufacturer Pharma Perspective There is a perception that a high percentage of cold chain problems happen in the carrier s possession. There is a sort of black box once the shipment is out the pharma company s hands. They receive news that their product was damaged or late but don t always have visibility into the details, and wonder if the carrier performed per the agreement. Pharma companies have concerns that events like the following will lead to failures during shipping: The forwarder stores the product in a refrigerated cooler, not taking into account that there is a significant amount of dry ice (or other coolant) in the container, and the product temperature can drop below 2 C. Communication and understanding of product needs and transportation capabilities A product is held up entering a country and stored in a customs perishable air freight (PAF) refrigerated cooler, meant for general cargo/foodstuffs and may not be qualified like a manufacturer s pharma-grade cooler. Temperatures can vary widely: if the pallet is placed near the fridge door in Brazil, it might get too warm, but if the pallet is by the condenser in the back of the fridge, it can potentially overcool or freeze. Forwarder Carrier A shipment misses its flight connection leading to a temperature excursion. (Even if it doesn t exceed the acceptable limit, the pharma company wants to understand the contingency processes that will be taken to protect the products.) 69 / 105

70 CHAPTER 10 continued In manufacturing, personnel are used to a certain level of control, operating a safe processing environment within the plant walls. But in logistics, the container may be getting shipped with flowers or computer parts, which could be transported in potentially harsh environmental conditions. Companies may be concerned that as soon as the product is in a box, it s thought of as just a box. So shippers have to choose proper packaging and work with forwarders and carriers to manage protection. (In less developed or small volume economies, general cargo may be the only option, in which case packaging must be robust.) Note: Though each party has regulations it must follow, it s important that pharma companies understand that they are liable for following their products global regulations. Pharma companies must be very aware of their product, and whether there are EHS, U.S. DOT or other special handling protocols. There are rules for the handling of dangerous goods (even batteries are considered dangerous goods, which are present in some medical devices). Also, the consignee s country may have a set of its own regulations. It s important to know the lane, but also the products and the requirements of the lane in terms of handling, waste, etc. This is why it makes sense to involve the carrier early on. They know where the challenges are, and can talk the customer through the detailed process steps, so that risks can be assessed properly. They also have more creativity when it comes to mitigating certain risks because of their experience, and may be able to tailor operations to certain airports or types of transportation. Collaborative Carrier Perspective Carriers understand that manufacturers often have logistics people, but that not all pharma manufacturers recognize the operating environment of an airline. The carrier has one of, if not the most, extreme environments in the logistics chain. Working alongside their forwarder partners, they hope to help manufacturers and forwarders comprehend what a shipment goes through to get from point A to point B. When customers say I need to move passive +2 to +8 C product, there are carriers who handle that, and have trained personnel. But forwarders and manufacturers must know that it s also critical to use the appropriate validated or qualified packaging because temperatures are not always +2 to +8 C during transport to the aircraft. Protection must 70 / 105

71 CHAPTER 10 continued be built in for the ramp, which is where many problems can occur. Customers can start getting into cost versus risk analysis, and see that they can save a lot of money if they don t use expensive, robust packaging. That is a shortsighted view, because the product has to leave the warehouse Controlled Room Temperature (CRT) to go to the aircraft. It s the packaging that helps protect that product while it s moving from the warehouse to the ramp, during loading onto the airplane, flying to the destination, and then traveling into the recovery warehouse. It s important to know what the package will go though. In addition to how a product is packaged and treated, manufacturers have to know the service they re selecting. Unfortunately, there are still some customers shipping pharma products as general cargo, which is a really big problem if risks have not been properly mitigated. On the passive side, general cargo can be pulled to the ramp over three hours before the flight, and staged on the tarmac because numerous steps take place between arrival and departure. At a larger airport such as JFK or Dallas, that waiting time may even be a little longer. Carriers understand that temperature-controlled shipping is costlier, but it s a specialized, value-added process that s been designed to mitigate risks. There are carriers who have spent a tremendous amount of time and money trying to refine cold chain over the last 10 to 15 years. They know that customers are looking for partners who have the experience, training and infrastructure to handle temperaturecontrolled products, and collaborative carriers are making strides to address this by: Developing infrastructure across networks 71 / 105

72 CHAPTER 10 continued Some carriers even include dedicated handling facilities and CRT pharma-dedicated rooms in major hubs for proper temperature control during holds and layovers. They re seeking to minimize risk in the supply chain for customers. They know that if they don t have the right facilities, they might not be considered. Keeping up to date on pharmaceutical regulations Particularly in Europe, there s an increase in regulatory oversight for pharmaceuticals, which is driving the need for increased focus on how the products are handled. The FDA and other regulatory bodies are following suit. The regulations are becoming more demanding, so some carriers are keeping well informed, which is driving productive conversations among all the supply chain participants. Helping with lane characterization during development A Trilateral Approach is Critical When all three parties work together to fully discuss the operational requirements of the product, then each can contribute to quality to meet the needs of the product Some carriers may be able to help during development. For example, a carrier involved in the development phase with the forwarder and manufacturer may be able to talk through various scenarios in development meetings. If responses to potential issues (and communication contacts at each company) are integrated into the SOP ahead of time, the shipping process can be inherently smoother and safer, even upon startup. Collaborative Benefits: A three-pronged approach between manufacturer, forwarder and carrier will improve quality by helping each party understand the product and shipping environments, 72 / 105

73 CHAPTER 10 continued and what each party needs from the other. It s an educational process as much as an operational one that makes it a lot more successful because all three parties can: Understand all the segments of a lane and product requirements to ensure packaging and service level are adequate. Build contingency plans into SOPs. Agree to, and fomalize, roles of responsibility for each. Determine protocol for addressing failures and finding root causes should the need arise. Additionally, forwarders and carriers may see opportunities to standardize processes because of the volume of pharmaceuticals they move, finding common denominators between their different clients. Participation in risk assessment and SOP development also gives carriers an insight into how pharma companies think, which can be beneficial for improving their services. Current Landscape Many companies are very successful with this approach, and in the last five years, it s become much more common. With the collaborative approach, everyone is much more likely to be on the same page. At the end of the day, the business model is still the same, but working together can make pharma manufacturers much more comfortable and allow them to have a good understanding of what s being provided. 73 / 105

74 CHAPTER 11 Technologies to Reduce your Total Cost Vendors are continually working to improve and streamline their offerings. Some seemingly expensive monitoring and packaging technologies can provide major efficiency benefits when they re used for the right applications, ultimately saving you time and money. Active Monitoring for Excursion Management Active monitoring is a robust feature that allows carriers to monitor a shipment s temperature in real-time. Monitoring temperature along with the events of the shipment gives visibility into an excursion as it s happening. Though the service may seem costly, the advantage is that as a deviation starts to occur, the service provider may be able to take remedial action. It can be well worth the investment when compared to the cost of failures in the field, as long as the service provider is able to respond to the real-time information and intervene to avoid discards. As far as volume, some customers choose to monitor a representative sample, while some opt to monitor every box or pallet. This depends on whether the shipment is highly sensitive, and on what service level is selected (if a service level has greater control, customers may need fewer monitors). The important thing is that there are enough monitors to give the manufacturer an accurate picture of the shipment temperature in order to intervene appropriately, which is a function of service level. 74 / 105

75 CHAPTER 11 continued If the carrier sees the product temperature exceed the desired limit in a truck route because of a breakdown or extreme weather, they may be able to send a new truck out or move the product to a temperature-controlled room. In a situation where coolant runs out because of delays in international shipping or customs, and the package begins to fail, the carrier can identify the excursion and intervene to limit it in the manner pre-coordinated by the manufacturer. The excursion is then much shorter than it would have been without real-time monitoring (without intervention, the excursion would have continued until delivery). For companies transporting products like aspirin, this service would be excessive, but it can be extremely cost-effective for biologics and other temperature-sensitive pharma products. For manufacturers that still have a lot of unknowns about a new product (e.g. clinical trial products or manufacturing intermediates), using a service where the carrier can intervene and protect the product can have a particularly tremendous value. High-Tech Packaging for Reduced Costs Good package developers will help manufacturers find the solution that fits their budget, their requirements, and what s best for their distribution lanes. A lot of the discussion in cold chain packaging is about providing the lowest total cost of shipping. It s not always the fact that a container costs a few dollars more than another. Manufacturers must factor in: 75 / 105

76 CHAPTER 11 continued Sustainability in Cold Chain Improving sustainability is important for any industry. But with stringent regulations on temperature, it s a challenge for the cold chain industry as a whole to come up with green solutions while maintaining performance. Experts say they are seeing a push for greener products though, mostly in the form of reusable packaging products, biodegradable materials and shipping strategies that reduce carbon footprint. At present, good materials that can replace EPS in terms of cost-effectively matching that R-value do not exist. So until more biodegradable containers are developed, the greenest solution is often a reusable product. Companies must work to solve reverse logistics to get the packaging back to the packaging site. Insulation: Compared to EPS coolers, some experts find the regulatory compliance for polyurethane to be more difficult than necessary while others say continued... How much it costs to ship the package How much longer they can ship it (i.e. ground versus 2-day), and how much that can save How much money is saved in incoming logistics with a smaller and/or lighter package How much more product fits in a certain package Using a slower method of shipping may justify a more robust package and allow a manufacturer to ship it to more locations. In the past, 48-hour shippers limited many companies to shipping only on Monday, Tuesday or Wednesday. They couldn t send shipments on Thursday or Friday, because they would arrive on Monday, exceeding the 48-hour limit. By improving to a 3-day shipper, companies can ship through Friday, reaping the financial benefits of shipping more days and to more locations, and standardizing shipments. Robust Packaging The pinnacle of insulated containers is the package equipped with vacuum insulated panels (VIP). VIP shippers have, by far, the best R-value when properly assembled and need the least amount of refrigerant inside. Though they are the most costly insulated package, they are the smallest, lightest option, which saves money on logistics costs. VIP shippers also have the added benefit of being reusable (though they are not the only material that is reusable). 76 / 105

77 CHAPTER 11 continued the reusability factor more than makes up for any additional compliance issues. Containers: Active containers are highly reusable. Though they may use dry ice, they do not consume more costly PCMs. Reusable passive systems also reduce waste, and high-end vacuum panel and PCM systems use less material. In either case, it s important to consider the energy required to transport the reusable system back from the customer. Refrigerants: Biodegradable PCMs are being used more frequently. There are also opportunities to use refrigerants in hard plastic bottles, which are reusable and can be more durable. They are more expensive, relatively, but are less prone to leaks than other refrigerant containers. Carbon footprint: as discussed above in Robust Packaging, more expensive VIP shippers can reduce carbon footprint as they are smaller and lighter to ship and store. Refrigerants Cold chain suppliers have started using advanced phase change materials (PCMs) to replace water at different temperatures for more targeted applications. These PCMs have the ability to absorb and release greater amounts of heat, and allow users to take advantage of the latent heat of the PCM versus sensible heat of water in package design. As an example, one gel pack is a formula that phase changes around 20 to 25 C. It s a solid at room temperature, and as it s exposed to heat in the summer, it will start melting and absorb heat in the container to keep products below 25 C. The industry has come up with phase change gels at various temperatures (e.g. 22 C, 5 C, -23 C, and even -50 C). The -50 C gel pack is preferable to using dry ice in some cases, because it does not have the same transportation issues or HAZMAT regulations as dry ice. Ultimately, selecting a more exotic refrigerant may reduce total cost by allowing for a more costeffective packout configuration, or for a slower, cheaper shipment because of increased product protection. There have been incidents where dry ice has come in contact with vials of product inside shippers, leading to contraction of the rubber stopper and CO 2 entering the vials. The CO 2 then warmed the vials, causing the rubber stoppers to go back into place, so manufacturers were unaware of the problem. 77 / 105

78 CHAPTER 12 Risk Management and HAZOPs: Tips for Success Use of a risk-based approach is the current best practice to ensure patient safety and optimize risk-reduction strategies. Here is a methodology for risk management that is tailored to controlled-environment logistics with a risk-assessment technique that is especially well suited to distribution. The main components of risk management are: Initiation, where the need for risk management is determined and the scope of the process is identified Risk Assessment, where hazards and harms are identified and quantified Risk Control, where risk reduction strategies are developed and accountable management accepts the risk level for identified process hazards; and Risk Review, where completed risk management work is used for ongoing monitoring of changes and incidents 78 / 105

79 CHAPTER 12 continued Initiation The first part of risk management is to identify the process to which you intend to apply the principles, including process boundaries. Important questions you must consider are: Will you include shipment of product within manufacturing (from synthesis to formulation, for example)? Will you include shipment of the product from manufacturing to warehouse? Will you include movement of the product after receipt at the wholesaler or distributor (after change in ownership of the product)? How far downstream will you include risk management? Last-mile logistics is a term used to describe pharmaceutical distribution from wholesale/distributor to point of patient use. Note: While it may be tempting to select team members based on their availability for the risk assessment, it s of the utmost importance to choose people with process knowledge and experience, as well as members who can provide data such as key process parameters. More on this subject in Risk Assessment, below. The answers to these questions are normally no, yes, yes and it depends, but accountable management, which is answerable for the results and outcomes of the process, must reach a decision on these boundaries. A risk-management team must be formed to conduct and document the risk-assessment and risk-reduction work. The team should comprise (as a minimum) a subject matter expert, persons knowledgeable about the process, and a team leader/facilitator. The next task is to create a process map that identifies each step in the distribution process, with each product movement as an individual step. A warehouse is normally mapped as six steps: receive, put away, store, pick, pack and ship. The final step in the distribution process 79 / 105

80 CHAPTER 12 continued is transportation. Transportation is usually mapped as a single step unless the movement is complex (customs clearance, multimodal transport, intermediate storage, across multiple shippers). The process map is the basis for the next part of risk management risk assessment. Risk Assessment The next three steps of the risk-management process are collectively called risk assessment. The HAZOP (Hazard Operability Analysis) is a risk-assessment technique based on a theory that assumes that risk events are caused by deviations from the design or operating intentions. Table 1 HAZOP Guide Words, Parameters and Hazards Guide Word Parameter Standard Recognized Hazards Temperature High temperature Pressure Low temperature High Humidity High pressure Low Shock Low pressure Vibration High humidity High shock High vibration Contamination Yes contamination No Theft Yes theft Yes Security No security Delivery No delivery The HAZOP technique uses a systematic approach for hazard identification, which allows for thorough coverage of the potential hazards, without effort wasted on marginal and/or frivolous hazards. The technique creates a list of potential hazards by combining key parameters and guide words (See Table 1). The recommended parameters are: temperature, pressure, humidity, shock, vibration, contamination, theft, security and delivery. For each parameter, the appropriate guide words (high, low, no and yes) are used to create recognized hazards, such as High Temperature, Low Temperature, High Vibration, and Yes Contamination. 80 / 105

81 CHAPTER 12 continued Of course, additional combinations of parameters and guide words can be used as needed based on the distribution process. Table 2 Process Step Hazard Guide Word Sample HAZOP output Parameter Harm Severity Likelihood Chance to Detect Risk Ranking Each hazard and associated harms are analyzed using a qualitative risk ranking (see Table 2), where each of the following is assigned a value of high, medium, or low: Pack Gel ice too cold Low Temperature Patient safety 8 (High) 5 (Medium) 8 (Low) 320 Severity of the hazard Pack Gel ice too warm High Temperature Patient safety 8 (High) 5 (Medium) 8 (Low) 320 Likelihood of occurrence Pack Box not labeled No Delivery Economic 2 (Low) 2 (Low) 5 (Medium) 20 Chance of detection (before the harm occurs) The numerical values are substituted for the qualitative rankings 8 for high, 5 for medium, 2 for low for severity and likelihood of occurrence, but reversed for chance of detection. The ranking of the hazards is then calculated by: Score = [severity] x [likelihood of occurrence] x [chance of detection] The ranked hazards scores will range from 8 (low, low, high) to 512 (high, high, low). 81 / 105

82 CHAPTER 12 continued The final step in the assessment is to take the ranked hazards and determine which are significant. A review of the hazards in rank order will usually result in the team finding a logical break in the ranking. Once the significant hazards have been defined, the next step is risk control, where risk-reduction plans can be developed to address the significant hazards identified in assessment. Risk Control In this section, the risk-management team develops risk-reduction recommendations to apply to hazards that were determined to have unacceptably high risk. In addition, the team must present their findings to accountable management, which will decide if the recommendations will result in a process that meets a level of acceptable risk. Risk reduction is achieved by improving the ability of the distribution process to operate in its design space. The HAZOP technique is very powerful because: Each hazard is documented as a deviation from design intention Each parameter considered in the HAZOP is a critical quality attribute The guide words are used to investigate the deviation from normal operation for each critical quality attribute 82 / 105

83 CHAPTER 12 continued Therefore, risk reduction flows logically by addressing the root cause of the deviation (listed in the hazard column of Table 2) by changing either the severity, likelihood of occurrence, or ability to detect. The use of the hazard information and the risk ranking are critical to making good decisions regarding risk reduction. Hazards identified with a high risk ranking normally have some combination of high likelihood, high severity, and low likelihood of detection. The example in Table 3 illustrates two hazards with high risk rankings. Risk reduction entails implementation of process changes that will reduce the risk by impacting one or more of the risk categories. Process Step Hazard Table 3. Risk-Reduction Plan Risk Ranking Implementation of a gel management SOP with temperature checks for frozen gels therefore reduces the risk of product damage. Note that the risk-reduction plan directly applied to the hazard (frozen gels too cold or too warm) addresses the deviation from the quality critical attribute. The risk-reduction plans would normally include responsibility and timing to ensure their completion. No risk-reduction recommendation is needed for the hazard of box not labeled ; risk-reduction plans should Risk-Reduction Recommendation be commensurate with the level of risk. Pack Pack Pack Gel ice too cold Gel ice too warm Box not labeled Implement gel management SOP with temperature checks on frozen gels used for pack out. Implement gel management SOP with temperature checks on frozen gels used for pack out. N/A none needed Once risk-reduction recommendations have been identified and documented, the next step is risk acceptance. It is the responsibility of accountable management to review and accept the identified risks and the risk-reduction plan for each. The HAZOP 83 / 105

84 CHAPTER 12 continued document should be used as a basis for discussion of all the identified hazards and agreement that the risk-reduction recommendations address those with unacceptable levels of risk. If there are some risks that need additional risk reduction, accountable management should direct the risk-management team to develop additional recommendations. Risk Review Risk review is the final step in the process. The documentation from the risk-management work is evergreen; the full HAZOP document represents a comprehensive description of the controlled-environment logistics process with analysis of hazards, risks, harms and risk reduction. It should be used: As a basis for periodic risk-management reviews; As a tool for failure investigations; As a tool to assist in change management; and As a means to share information about risk. 84 / 105

85 CHAPTER 13 Six Ways to Streamline Change Control: Real World Processes Change control is a necessary part of any logistics operation for tracking your equipment changes and maintaining safe and efficient operations. But while a change control process is meant to be helpful and keep involved parties in the loop, it can end up wasting valuable personnel and production hours when not tailored to fit your facility. 1. Keeping it Reasonable The change control process is a tool intended to help you track and document changes, not a system to prevent you from making improvements to your equipment. If the process is too burdensome, people may spend nearly as much time trying to justify bypassing a change control form as they would actually filling it out. The definition of like for like or criticality can become amazingly flexible, so it s important to keep the process and the document user-friendly. 2. Focusing on Direct Impact One way to keep things user-friendly is to minimize the signature requirements. Seemingly small checkboxes can add up to a significant waste of time in chasing people down for approval for example, it may not be necessary for microbiology to sign off on a program change to a shipper coding machine. Small adjustments like reducing signature requirements can make it easier for the change initiator to complete the actual 85 / 105

86 CHAPTER 13 continued work so that production can move forward, with the added benefit that people who are not directly impacted do not waste their time. If fewer people need to sign the change control form, the initiator may be able to get signatures one-on-one without waiting for a change control meeting. To reduce signature requirements, it s wise to consider who is directly impacted by the change, and consider consolidating responsibilities (e.g. deciding that quality can also sign for validation in certain cases). 3. Minimizing Meetings Consider whether a regularly scheduled change control review meeting is truly necessary. Frequently, key people are busy and unable to attend, which defers the change discussion until the next meeting and postpones the actual change. This is particularly wasteful in the case of small changes. It may be more beneficial for your company to have meetings about changes that affect multiple departments on an as-needed basis. If you prefer to use meetings, consider designating a person who will call or text each change initiator to come to the meeting when their turn to speak is coming up. 4. Streamlining, Without Overlooking Though reducing signatures can save time, it s important to have maintenance and engineering groups involved in any material changes right from the start. Marketing or purchasing departments may make minor changes to a component or material, only to find that when it reaches the shop floor, the existing equipment can t handle the change, or it causes other problems downstream. Technical groups can help figure out ways to make packages run with new materials, or at worst, start working on parts or modifications to accommodate the new item by the time it arrives. 86 / 105

87 CHAPTER 13 continued Example 1: A company packages a pharma product in a 3 ml vial. The marketing department introduces a 3.5 ml vial, without letting the production or engineering departments know. When the new vials arrive, the machinery is not able to handle the 3.5 ml vial, which causes downtime while the technical groups modify the equipment. Example 2: In an attempt to save money, a purchasing department selects a cheaper cardstock, but the new product has different characteristics than the previous product. The new packaging causes jams and requires continuous retuning of the packaging machine, leading to downtime that exceeds the new product savings. 5. Using Templates Templates for common changes can be beneficial, but there must be a set of strict guidelines in place ahead of time to determine which templates fit which specific scenarios. If there are two templates, where both call for validation, but one also calls for drawings and an SOP update, people might try to push for the template with fewer requirements when the latter is appropriate. 6. Handling Handoffs Not all changes happen during the day shift. One expert suggested that it might be helpful to appoint an off-hours employee with signature authority in order to move changes forward on nights and weekends. Controls can be put in place so that the product is not released until the next business day, when the change control document is routed to all parties. For lower risk and less complex changes, appointing and training an off-shift representative can really help to increase efficiency. 87 / 105

88 CHAPTER 13 continued The Big Picture Though the change initiator s primary concern is to make the change and move the process forward, they should be sure to listen to personnel in the affected departments and understand their concerns about adverse events stemming from the change. Part of the document should include a comment section where the initiator can explain what measures will be taken to prevent adverse issues brought up by the affected personnel. Keep in mind that the change control process is there to serve you and provide guidelines for processing and packaging. It s meant to be used as a tool and not as a hindrance. It must be used correctly to ensure that operations are safe, compliant and efficient, but it provides the most value when it is reasonable and user-friendly. 88 / 105

89 CHAPTER 14 Accelerating Development with Thermal Modeling The cold chain industry has embraced thermal modeling to predict package performance prior to running time-consuming chamber tests. Despite decades of widespread use of similar modeling in other industries (automotive, aerospace, etc.), computer modeling of thermal systems in packaging has really flourished in the last six to eight years. Here we ll discuss the technology, how it s helping companies cut packaging development time, and what to look for in a thermal modeling provider. Advanced thermal modeling techniques incorporating Computational Fluid Dynamics (CFD) and Finite Element Analysis (FEA) are allowing companies to design more efficient shipping solutions in a much shorter development cycle. Thermal Modeling Explained Thermal modeling is a simulation tool that uses CAD drawings, thermal data and fundamental heat transfer equations to predict how a package will perform in a given ambient temperature profile. The technique allows engineers to draw a 3D model of a package and test it in a virtual chamber in a computer, providing a map of temperatures throughout the box for the duration of the shipment. SOURCE: COLD CHAIN TECHNOLOGIES 89 / 105

90 CHAPTER 14 continued Probe Your Vendor: 5 Important Questions to Ask Your Packaging Designer With pharmaceutical products, it s critical that packaging is properly qualified. Not all thermal modeling services are created equally a computer model is only as good as the data behind it so vendors must truly understand their materials and phase change curves to create useful simulations. A model with textbook numbers may give a directional prediction, but to achieve accuracy of ±10% and make good decisions, a model needs highly specific data. Designers should be able to answer the following questions about their thermal modeling process: 1. How did you build your modeling system? 2. Where did you get your data? This complex modeling combines conduction and convection (and, if needed, radiation) inside and outside of the box. Engineers can study how those factors interact with each other inside the container, analyzing air movement in the box, as well as heat transfer between two objects next to each other. In their analysis, engineers are tasked with modeling parameters such as: Empty space in a container Part interfaces Dunnage used to hold product in place The ambient profile ramps and soaks Insulation characteristics Phase change material characteristics Engineers create a 3D representation of the system and divide the 3D model into small increments for analysis. Analyzing the package system with the simulation software requires significant computing power. Package design companies have invested significant time and effort in development by bringing in experts and validating the technology against real chamber tests. continued / 105

91 CHAPTER 14 continued 3. How have you qualified your data? 4. Do you know your phase change curves? 5. Is your correlation data accurate do you verify the data coming out of the model with a chamber test? Some companies verify their model with a chamber test before moving forward, or warn the customer if verification is not completed. If a model doesn t predict as well as expected, a designer may adjust the model, because that s ultimately less time-consuming than starting over if the prediction doesn t work. Efficiency Benefits Cold chain design is an iterative process, which is why computers are so helpful. To perform chamber testing, prototype samples are created, an ambient profile is programmed into an environmental chamber, and the test is run. It s a real-time profile so it cannot be accelerated, i.e. simulating a 3-day shipment takes three days in the chamber. Every change in the system design requires another 3-day test. Using thermal modeling is much faster for development because prototypes aren t needed and iterations can happen in hours rather than days. A prototype, chamber testing and a quote may take six weeks, while computerized design, thermal modeling and a quote may only take half that time. Engineers are able to design packaging in the computer, make changes if temperatures are hotter or colder than expected, and instantly precondition and run subsequent iterations to test designs in a shorter period of time. Now companies don t need to build prototypes to test in the chamber until they re fairly confident that they have a passing solution. Guess-and-check chamber testing has been replaced with science and heat transfer formulas on a computer, so a 9-month development process in chambers may only require five months with modeling. 91 / 105

92 CHAPTER 14 continued Comparison & Timelines Yes Yes START Concept Design Educated guessing Reference past designs New Prototype Needed? No Custom Prototype Tooling ($) Samples ($) Testing Order samples ($) Test Preporation Assembly Chamber tests Analysis Review data with customer Redesign Passing? No Qualification 3x testing Repeatable & Validated cgmp report package FINISH Production 1 Week 24 Weeks 12 Weeks VS START Concept Simulation Simulation chamber testing Increased confidence Prototype Tooling (<$) Samples (<$) Testing Confirm model < Physical tests Analysis Review data with customer Qualification 3x testing Repeatable & Validated cgmp report package FINISH Production 1 Week 8 Weeks 12 Weeks SOURCE: GRAPHICAL REPRESENTATION ADAPTED FROM MATERIAL FROM SONOCO THERMOSAFE 92 / 105

93 CHAPTER 14 continued Though thermal modeling is not yet being used for the entire design qualification, some healthcare companies are starting to accept modeling runs for parts of the qualification to eliminate certain tests. Typically, package qualification includes testing of the minimum and maximum loads, at the highest and lowest temperatures with probes in the worst-case locations in the box. Companies may opt to model the minimum load and then chamber test the maximum load, or probe many locations in the model, but chamber test only the two worst-case probe locations. Limitations Improving thermal model accuracy is still a challenge in the industry. When a company builds a computer model of a complex system, they have to make judgments about how much detail to put in. The more detailed the model, the longer it takes to develop, and the longer each solving iteration will take. If some of the detail is reduced to arrive at a quicker answer, then companies must understand how the accuracy is affected. At present, some companies are able to predict performance with 85-90% accuracy, and this is expected to increase as companies develop the tool further. 93 / 105

94 CHAPTER 15 Snapshot: Eight Key Considerations for Vendor Management Taking your business global can be very intimidating, especially for small organizations that may be relatively new to the market. Going global requires in-depth knowledge of: Medical device and pharmaceutical regulations around the world, Restrictions and licenses required for imports, and Establishing a distribution process to ship and bill to end-users in each country. Working with experienced providers can help guide you through global trade requirements. While much of cold chain vendor selection is similar to vendor selection in other industries, there are some key performance indicators and steps that cold chain manufacturers should pay extra attention to. 94 / 105

95 CHAPTER 15 continued 1. Vendor Selection Take a common sense approach to vendor selection. Identify candidates on a long list through an RFI (Request for Information), narrow it down to a short list through an RFP (Request for Proposal), and perform due diligence, which should include: Templated scorecard for selection Formal quality audit Finance checks or D&B report Reference checks (which help to really see how much work a vendor did for a customer and how happy they were with the final result) Typically, it s wise to look for vendors with: Segregation of duty: A quality department that reports to site or global quality (as opposed to operations) so they are separate from operations influence. Deviation management: A good nonconformance and CAPA system. 95 / 105

96 CHAPTER 15 continued 2. Spotlight on Tailoring SOPs for Third Parties Though it s important to set global standards, don t try to implement a rigid one-sizefits-all approach. Allow local sites or regions to operate within those processes and select their own carriers/local heroes: vendors that are a good fit for their business. Tailor SOPs in such a way that you can approve the use of third party packages based on risk, a review of qualification and performance package, and use intensified monitoring in first 12 months, with regularly scheduled reviews. Some companies have had success with qualifying packaging locally for in-market distribution. In the case of passive containers, local packaging tends to be very successful for handling those environmental temperatures. You need a process for how to review (1) quality, (2) performance data and (3) how they re managed. There is a bit of risk in having a big portfolio of approved shipping containers, but the performance is typically very strong because they use proven technology for their specific region. 3. Vendor Onboarding This includes training, product awareness, and a company overview for operations personnel. 4. Vendor management Most healthcare companies see their contract service providers as an extension of their own operation, and they conduct routine audits to validate continued compliance with regulations. When you visit your service providers for audits, be prepared to ask questions about supplier management, customer complaints, document control practices and training, along with observing warehouse processes and the effectiveness of training. 96 / 105

97 CHAPTER 15 continued Your quality agreement should include acceptance criteria, and all critical quality attributes related to product handling, storage, shipping, protection, as well as process requirements like staff qualification and when/how/who to inform of various deviations (including recalls). It should also include to local GDP regulations, need for licenses (if applicable), and any additional requirements specific to your manufacturing company. The management specifics will vary based on each product, company and service. Some companies visit vendors once a year, or inspect data weekly or monthly. Some want to be contacted only if there s an excursion, while some opt to see trend data daily or weekly, even if it s in spec. The latter may be part of an audit response, i.e. if there s a CAPA, the company must continuously monitor temperature or parameter in question. Additionally, use activity-based costing where applicable and be careful with exclusivity or volume commitments. Hold vendors accountable for performance and cost. 97 / 105

98 CHAPTER 15 continued 5. Vendor Offboarding This is often forgotten, but it does happen and it s best to be prepared. You perform the due diligence and training when selecting and onboarding vendors, but you must have a process for ending a vendor relationship, as well. This will differ depending on the agreement specifics, but ensure you have a process for details like: Ending contracts Paying outstanding invoices Meeting document retention requirements Paying applicable local fees IT updates 6. Key Performance Indicators In cold chain shipping, key performance indicators are primarily related to product temperature, damaged/lost cargo (infrequently including vibration control) and OTIF (on time in full). There are different failure modes within the OTIF metric of successful delivery: there can be missed connections, mistaken warehouses, late delivery by the carrier, etc. But what you won t see immediately are temperature excursions unless you re using near realtime, en-route temperature monitoring. A delivery may appear to be successful, having 98 / 105

99 CHAPTER 15 continued been received on time by the consignee, until they remove the temperature logger, read the data and see that there has been an excursion. In cases like these, you must analyze the logistics and segmentation (e.g. product was in flight from X to Y, inland transportation from Y to Z). Once you define the section where the excursion occurred, you can look for the root cause for the excursion, either in the environment or in a technical issue with the packaging. For this reason, the metric of temperature excursions can be defined by the TE rate: number of temperature excursions divided by the number of monitored orders. This can give a good indication of how temperature control is being improved by the vendor. However, it s important to be cautious about comparing data between separate systems or carriers. Care should be taken that the comparison is using data that is equivalent: using temperature data that is captured in the same way, with monitors placed in similar locations. For example, data from temperature monitors dipped in solution should not be compared to data from monitors inside a product package, monitors in the air of the controlled temperature space, or monitors in the return-air within the TCU. 7. Security Security is always a concern with pharmaceutical products. This important issue goes beyond financial loss product control is a patient safety and regulatory issue, and loss can be an immediately reportable deviation. The FDA has been increasing its focus on chain of custody (preventing unknown tampering, diversion/theft) and anticounterfeiting, and recently implemented the Drug Supply Chain Security Act (DSCSA) in the U.S. 99 / 105

100 CHAPTER 15 continued With rapidly changing security regulations and services, keeping up-to-date may seem difficult. But third party logistics (3PL) providers can help you meet regulatory requirements by offering valuable assistance to capture and return critical data from transactions. Some 3PL providers work to stay ahead of data format changes, including how data will be incorporated. An older labeling system may have used traditional catalog numbers, and included other fields on the label. Requirements for UDI compliance or serialization may add new layers of complexity, but may also give companies an opportunity for greater efficiency such as converting to bar codes to capture more detail in a single scan. 8. Spotlight on Personnel We tend to focus a lot on stats, profits, KPIs, etc., but personnel cannot be overlooked. Look for companies that uphold standards outside of the hard numbers, including company culture. For example, how does your 3PL treat the people that work there? Do they treat their employees the way you would in your own operation? Do they provide in-depth training for the team members on the floor? When you visit the warehouse are there often apologies that a person is new so they don t know all of the procedures? People make logistics operations hum that s important whether they are full-time, part-time, or even a temporary worker. The right mix of training, development and useful technology will deliver results. Over time, you ll see this reflected in the stats, KPIs and profitability. Investing in personnel is one of the best investments a company will ever make, so it s an important part of your provider evaluation. 100 / 105

101 VENDOR RESOURCES END-TO-END SOLUTIONS 29 Everett Street, Holliston, MA p: e: Mission The primary mission at Cold Chain Technologies is to be the expert that organizations turn to for effective and reliable controlled-temperature distribution solutions for all segments of the life science supply chain. Our goal is to continue to design and deliver innovative and costeffective solutions which meet the high quality, performance and regulatory expectations of the life science industry. Cold Chain Technologies considers our customers, suppliers and employees to be mission-critical partners and treats them with respect, responsiveness, fairness and flexibility. Products Confidently ship your critical therapies with KoolTemp and Koolit compliant thermal solutions. Our innovative product family includes: KoolTemp GTS Pre-Qualified Solutions Protection of virtually any size payload from single dose to multiple pallets through high performance shipping systems qualified in our ISTA-certified, cgmp-compliant lab. KoolTemp PUR Polyurethane Solutions Superior, extended temperature control even under extreme weather conditions. KoolTemp EPS Molded and Panel Sheet Insulated Containers Lightweight, recyclable Expanded Polystyrene (EPS) in a variety of styles and thicknesses. Koolit Refrigerants A variety of reusable, longlasting gel packs, foam bricks, and gel bottles known for their superior performance. Koolit Advanced PCM Refrigerants Innovative phase change material (PCMs) formulations that provide exceptional protection against hot and cold temperature extremes. Temperature Indicators and Loggers Single and dual-temperature models for short or longterm applications, with specific or programmable temperature. 101 / 105

102 VENDOR RESOURCES Complete Compliance. Total Confidence. Many of today s important discoveries life-saving drugs, vaccines and other derived therapies can be destroyed during transit by exposure to temperatures that are too hot or too cold. After spending huge sums on R&D and production, pharmaceutical, biotech, healthcare, medical device, and nutraceutical companies all face the same dilemma: How can we protect our temperature-sensitive products and meet government regulations? In every case, organizations can turn to Cold Chain Technologies to solve this sometimes confusing and difficult challenge. We understand that there are many ways to solve the problem. It s our objective to always provide the most effective, efficient, easy to-use solution at the lowest total cost. Every Cold Chain solution begins with the same foundation the real-world needs of customers. Our talented, experienced professionals understand the challenges your product will face once it leaves your facility. And they work closely with you to ensure that those challenges are met. We apply unrivaled industry engineering expertise at every stage of our customer relationships, from needs analysis to product selection to support services. Furthermore, our customer teams are multi-disciplinary, so you can be certain you re working with people who have experience throughout the cold chain. Whether you re looking for immediate delivery of a stock product or the development of a customized system, we can provide a cost-efficient solution to meet your needs. Services We offer a wide range of services that simplify adherence, including pack-out training, onsite assessment, conditioning services, and more. Our leading technical services includes: KoolDesigns Thermal Modeling Thermal Packaging Design Thermal Packaging Qualification Ambient Temperature Profile Analysis Educational Seminars Cold Chain Best Practice GAP Analysis Inventory & Logistics Management Return/Reuse Refurbishment Service With over 45+ years of experience in the cold chain, Cold Chain Technologies designs and manufactures the industry s smartest thermal packaging solutions inside and out. Stay connected with Cold Chain Technologies: 102 / 105

103 VENDOR RESOURCES 3930 N. Ventura Dr. Suite 450, Arlington Heights, IL p: e: ABOUT US Sonoco ThermoSafe, a unit of Sonoco (NYSE:SON), is the leading global provider of temperature assurance packaging for the safe and efficient transport of pharmaceuticals, biologics, vaccines and other temperature sensitive products. Our shipping solutions mitigate risk for our customers and ensure product efficacy throughout the extremes of a supply chain. With operations in North America, South America, Europe and Asia, Sonoco ThermoSafe has a vast product offering featuring industry-leading technology that encompasses refrigerated, frozen or controlled room temperature applications. In addition, Sonoco ThermoSafe s ISC Labs design and testing services deliver individualized and innovative packaging solutions along with qualification and validation services to meet all regulatory requirements. The Broadest Range of Temperature Assurance Packaging Our portfolio includes an extensive array of pre-qualified and readyengineered solutions for refrigerated, frozen or controlled room temperature shipping applications. Additionally, our vast selection of payload sizes and shipping durations ensure we will meet your unique requirements for parcel and bulk shipments. 103 / 105

104 VENDOR RESOURCES Custom Designs to Meet Your Needs Sonoco ThermoSafe s ISCLabs has been a leader in innovative design and testing services within the temperature assurance packaging industry for 26+ years. Our cutting edge thermal modeling capabilities enable rapid development of highly optimized custom solutions. Our modular ready-engineered platforms allow for hundreds of configurations using standard components resulting in short development times and cost optimization. Our thermal testing is accompanied by distribution testing to prove that each solution not only maintains temperature control, but withstands the rigors of distribution. Material Neutrality We have the largest platform of products manufactured in house which allows us to take a material neutral approach to our design and development processes. This includes the manufacturing and/ or supply capability for Expanded Polystyrene (EPS), Polyurethane (PUR), Vacuum Insulated Panels (VIPs), as well as patented hybrid insulating technologies. Our manufacturing capability for water based gels, bricks, and advanced phase change materials (PCMs) provides flexibility to design products that result in the lowest total cost of ownership. Advanced sustainable technology PureTemp Our PureTemp phase change materials are patented natural vegetable based phase change materials which were developed under 5 years of research sponsored by the National Science Foundation and Department of Defense. PureTemp is engineered to react to a precise temperature, from -40 to 37 C, and to operate in a very narrow temperature range. PureTemp PCMs are the industry s only USDA Bio Preferred phase change material. These patented phase change materials are made from natural sources such as palm oil, palm kernel oil, rapeseed oil, coconut oil and soybean oil. They are nontoxic and biodegradable. Global manufacturing redundancy At Sonoco ThermoSafe, we pride ourselves in our ability to confidently and efficiently supply our customers. We have 14 manufacturing plants in the US and Europe as well as warehouse and distribution capabilities in South America and Asia.. To ensure the highest quality of products, our plants operate in compliance with cgmp standards. We are the only company in the industry that is vertically integrated and manufactures both insulation and refrigerants across the U.S. and Europe. Further, we can leverage Sonoco s strong and expansive network of 340+ manufacturing facilities to stock Sonoco ThermoSafe products near our customers international locations. 104 / 105