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Case Study: Meeting Cold Chain Logistics Challenges In Global Clinical Trials (Viewed: 663)
Posted by Gary Hutchinson on June 16, 2016 @ 2:00 pm

First published on June 29, 2016 on Cold Chain IQ – as a contributor, Hutchinson’s column, Global Cold Chain Connections, falls in the Supply Chain & Security category. It can also be viewed at

Highly sensitive cold chain clinical trial products demand operational excellence. Variations in temperature can void a shipment and lead to millions in loss for the manufacturers as well as dramatically raise the costs of the trials. The need for reliable and environmentally controlled cold chain solutions is more critical than ever. Quality cold chain management reduces risk and includes thermal package engineering, data collection / monitoring, and global transportation logistics’ experience to ensure medical treatments maintain their efficacy and safely reach the patient. In addition, during distribution a temperature excursion can also affect the overall data generated for the clinical trial evaluation.

Clinical trial material (CTM) or investigational medicinal products (IMP) are an important part of the early stages of the life science supply chain. As trials are being run on a global scale, in markets with less than ideal infrastructure, there is a dire need for companies to work with specialized cold chain experts to engineer and design innovative distribution processes.

Cold chain failure may lead to: the patient being administered an unsafe product; liability based on compliance infractions; inconsistent data results; or an entire shipment’s product integrity could be rejected by the quality department, resulting in costly delays. 

The industry has progressed from shipping “as usual” to exacting controls on products in-transit with proof of custody at the final destination. Control and documentation for the storage, handling and distribution of temperature-sensitive products is best addressed with comprehensive shipping qualification. 

When biopharmaceutical companies partner with providers and consultants that specialize in the packaging, shipping, distribution, delivery, and monitoring of temperature-sensitive vaccines, clinical trial logistics operations can be streamlined and be more effective for all concerned.

One such example is that of a life-saving CDC-sponsored clinical trial operation for the Ebola vaccination. In April 2015, Daniel “Dan” Littlefield, a co-founder and principal of Modality Solutions, traveled to Sierra Leone, West Africa to provide operational and technical support for the first Ebola outbreak to reach epidemic proportions. Dan trained and worked hand-in-hand with another Modality Solutions project employee, Judy Tempel and local staff at three locations, as well as with our partners FHI360, the CDC and BARDA. The project was funded in whole or in part with Federal funds from the U.S. Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority. 

One such example is that of a life-saving CDC-sponsored clinical trial operation for the Ebola vaccination. In April 2015, Daniel “Dan” Littlefield, a co-founder and principal of Modality Solutions, traveled to Sierra Leone, West Africa to provide operational and technical support for the first Ebola outbreak to reach epidemic proportions. Dan trained and worked hand-in-hand with another Modality Solutions project employee, Judy Tempel and local staff at three locations, as well as with our partners FHI360, the CDC and BARDA. The project was funded in whole or in part with Federal funds from the U.S. Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, Biomedical Advanced Research and Development Authority.

Modality Solutions’ clinical trial operation services include: ongoing monitoring, staff training, data query resolution, drug supply accountability, and regulatory document preparation, review and collection. Every member of our team works to maximize clinical trial performance, clinical excellence, data integrity, and patient safety.

With less than two weeks’ notice, Dan worked to use controlled environment logistics for a very difficult vaccine. He knew he’d be working in a complex Zone 4 emerging market environment. The vaccine had a temperature storage requirement of less than minus 60 degrees Centigrade in a location without a reliable infrastructure of water and electricity.

Dan, an expert in cold chain logistics, with his on-site assembled team, helped coordinate the vaccination of 8,650 healthcare and other frontline workers including: doctors and nurses; cleaning, laboratory, pharmacy, security, and administrative health facility staff; ambulance teams; workers responsible for swabbing deceased people; surveillance teams; and burial workers. In this effort, Dan and his team members were dealing with the potential for issues discussed earlier (namely unsafe product and patient danger) if they did not maintain utmost consistency in their cold chain management.

To assess such risk, Dan initially applied the use of appropriate Six Sigma tools, including statistical analysis, process mapping, and GDP and risk assessment to identify potential issues. When it came to risk analysis, Dan initiated a ground-breaking strategy drawn from his previous experience. Rather than doing the typical Failure Mode Effect Analysis (FMEA), he called for using a Hazard and Operability Analysis (HAZOP). The HAZOP risk analysis focuses on essentials like running water, electricity, and Internet.

Recognizing the limitations early, Dan used his engineering skills to import into the country of Sierra Leone items to build the cold chain. The Ebola vaccine had to be reconstituted, then stored and shipped from the depot to the field sites with monitored refrigerated temperatures the entire time. Using specialized packaging and modern technology, Dan put together a holistic cold chain management approach.  He demonstrated what we talk about as far as integrating the cold chain management system with processes and procedures, risk assessment, modern technologies, training the partner, and packaging qualification. He put it all together very quickly without missing a beat. As a result, no vaccine was lost to temperature excursion.

With the common goal of providing the correct pharmaceutical product safely, clinical supply chain partners have to ensure that items like medications are carefully monitored throughout the supply chain process. Achieving the right conditions through various global conditions, which often change with unexpected weather or problems along the way, requires a deep understanding of not only the regulatory environment of the bio-pharmaceutical market but also the local requirements and at-point options during transport and clinical trials. Handling, storing, and distributing such temperature-sensitive items relies heavily on the individuals who understand the regulations in the big picture and can also meticulously engineer solutions for the product to maintain those standards in complicated or less-than-desirable situations.

It is Never Too Late to Document Your Cold Chain Process Validation Approach (Viewed: 431)
Posted by Gary Hutchinson on May 24, 2016 @ 2:00 pm

Documentation strategy for your cold chain management validation practices has evolved over the last several years. :: continue

A Potential Revolution For Passive Shipper Selection (Viewed: 407)
Posted by Gary Hutchinson on April 1, 2016 @ 2:00 pm

Stability testing outlined in the ICH guidelines primarily addresses the establishment of expiry dating and storage conditions. :: continue

Forecasted Cold Chain Trends for 2016 (Viewed: 408)
Posted by Gary Hutchinson on January 1, 2016 @ 1:00 pm

We are seeing a trend in pharmaceutical manufacturers to start designing their cold chain networks specifically to the drug platform or modality based on therapeutical area. :: continue

A Process Validation Guide for Cold Chain Logistics (Viewed: 634)
Posted by Gary Hutchinson on September 30, 2015 @ 12:00 pm

Process validation for cold chain logistics (packaging, storage, and distribution) is required part of the Common Technical Document (CTD) for any Biologics License Application (BLA) for monoclonal antibodies. :: continue

Dynamic Stability Testing Saves Time and Money in Your Cold Chain (Viewed: 2719)
Posted by Gary Hutchinson on September 15, 2015 @ 1:00 pm

First published on June 15, 2015 on Cold Chain IQ – as a contributor, Hutchinson’s column, Global Cold Chain Connections, falls in the Supply Chain & Security category. Join Cold Chain IQ today to access informative cold chain articles.

By Gary Hutchinson

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.

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 conduct 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.

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 expiry date are being augmented with ‘dynamic’ stability studies for distribution. These distribution stability studies typically stress the drug product formulation is either an extreme ‘real world’ shipment of is a controlled laboratory setting.

The same stability indicating assays used to set expiry date are executed on these ‘stressed’ samples. At each time points, 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.

Without dynamic stability testing for distribution, the manufacturer is left with a difficult choice: either significantly slow down the flow of final drug product to allow critical information to be made available for proper product disposition of potentially compromised drug product or scrap the potentially compromised drug product and reship. Either choice will add significant costs in the logistics network and potentially ration or ‘short’ the supply to patients. Continuous review of potentially compromised drug product during transport could lead to FDA review, review of the manufacturing process, or looking for tighter and tighter logistics controls: all these options are very time consuming and costly.

How should dynamic stability studies be conducted to provide us with the answers to these concerns?
These studies need to be designed and conducted based on expected shipment durations, possible product temperature exposure ranges outside labeled storage conditions, and coupled with other hazards during transport and distribution. The cumulative effects of these hazards on product quality, potency, and efficacy must be determined to the end of shelf life. Most importantly, dynamic stability studies for distribution should show the drug product is not impacted by the following environmental hazards in the controlled-environment logistics network:
• Temperature
• Shock
• Vibration
• Pressure
• Humidity

Paths to degradation of product should be established through dynamic stability testing by defining variables clearly and establishing ranges of acceptable variances to support temperature excursions experienced during transport concurrently with the other environmental hazards listed above. Once these degradation paths are understood, the required shipping conditions, appropriate handling techniques, specialized packaging should be defined and communicated to all parties in the controlled-logistics network, and any required maintenance and monitoring of such procedures. Appropriate means of control (e.g. procedural, visual, marking and labeling, etc.) and monitoring (e.g. data loggers, threshold indicators, time/temperature indicators, etc.) should be implemented once the potential hazards are understood.

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. These effects are hard to predict and have offered continuous challenges for the traditional drug formulation processes. . Understanding the environmental hazards especially to protein formulations that are relatively new but increasingly wide spread, and conducting product testing specifically for the hazards encountered during distribution are the best way to alleviate product quality concerns during transport.

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Why is Pharmaceutical Transportation a Major Concern? (Viewed: 4047)
Posted by Gary Hutchinson on July 28, 2015 @ 4:04 pm

First published on May 11, 2015 on Cold Chain IQ – as a contributor, Hutchinson’s column, Global Cold Chain Connections, falls in the Supply Chain & Security category. Join Cold Chain IQ today to access informative cold chain articles.

By Gary Hutchinson

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 (see chart from US Pharmacopoeia). Distribution systems that deliver pharmaceutical products require special handling based on the conditions clearly indicated in the labeling for the product. The Prescription Drug Marketing Act of 1987 and the ensuing regulations in 21 CFR Part 203, Prescription Drug Marketing, and Part 205, Guidelines for State Licensing of Wholesale Prescription Drug Distributors, provide the necessary regulations and guidance for several legs of the distribution chain for the prescription drug.

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. Current Good Distribution Practices (cGDPs) for the pharmaceutical supply chain have been divided into seven different categories (Stability, Distribution Control Management, Performance Management, Supply Chain Partner Management, Qualification / Validation, Continuous Improvement, and Import / Export Compliance) in PDA Technical Report #52.

Distribution Control Management in a comprehensive cGDP quality system covers the logistics management for final drug product in four key ways:
• Qualifications and training of personnel
• Facilities, material handling, and storage and inventory control
• Non-conformance or exceptions, returns, and product disposition
• Transportation, third-party distribution, and product protection

Maintaining the cGDP quality system for transportation, third-party distribution, and product protection is a difficult challenge because of the distributed nature and contracted third-party relationships found across most modern controlled-environment logistics networks.

Coupled with the increased focus on high-growth 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
• Significant and cumulative hazards to product quality -- temperature with shock, vibration, pressure and humidity

Pharmaceutical products are the most vulnerable during transport. Managing supply chain security risks during transport is important to mitigate the potential loss of revenue and reputation for manufacturers, distributors, and logistics providers. Training to detect and deter potential adulteration or diversion of drug product is needed.

Variances in equipment, material handling, personnel skills, and experience in handling pharmaceuticals for in-transit drug products are important to consider when preparing a validation master plan. These variances make the process validation of the controlled-environment logistics network at a high degree confidence (greater than 95%) difficult, especially when transporting protein-based products. Additional in-transit monitoring, procedural controls, visual indicators, and most importantly stability testing for distribution becomes necessary since validating to a high confidence interval is difficult to achieve.

Stability testing outlined in the ICH guidelines primarily addresses the establishment of expiry dating and storage conditions. The potential product impact in the distribution environment is not addressed. Shock and vibration testing have a role, particularly in the transportation of solution formulations of certain large proteins. Stability testing for distribution is needed: these tests are ‘dynamic’ when compared to current ‘static’ testing per ICH guidelines and should be designed to understand the cumulative and significant hazards to drug quality during transport.

Temperature-sensitive product may exceed long-term storage conditions established by the manufacturer at any time during manufacturing, distribution, and customer handling steps. 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.

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 recommended under ICH guidelines. A gap in understanding exists on protein in solution formulation behavior after exposure to significant and cumulative hazards during transport. This gap should be a cause for concern.

One of the biggest risks to drug product in a controlled-logistics network is the freezing of final drug product. Even the temporary storage of a thermal packaging system into forced-air refrigeration cooler within its qualification time period will most likely cause low temperature exposures and potential freezing. Proper testing of drug products in freeze-thaw conditions for distribution is critical. Most freeze-thaw stability testing does not consider the effect of ‘supercooling’ on solutions.

The suppression of the freeze point or ‘supercooling’ and subsequent ‘flash’ freezing in current freeze-thaw stability testing guarantees a homogenous solid is formed. In the distribution environment, the vibration and shock events inherent in the logistics network practically guarantees freezing of a solution at its freezing point. The frozen solution is rarely homogenous and can be observed as slurry of frozen and liquid solutions. These conditions are detrimental to proteins in solutions because of the risk of increased protein concentration, and how it can cause protein denaturation, aggregation, degradation or inactivation. These conditions are not properly tested by current static stability studies.

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 in a modern logistics network. An integrated process management and product characterization approach using dynamic stability testing for distribution is required to minimize risks to drug product quality during transport.

The risks of not taking an integrated process management or conducting dynamic studies on final drug products can lead to significant compliance and business issues:
• Supply chain security measures across global and contracted third-party logistics networks are required to ensure protection against adulterated and/or counterfeit product and product diversion.
• The confidence interval possible during process validation of complex and highly variable controlled-environment logistics network require either robust product testing specifically for distribution or a significant increase in monitoring and controls and flexibility.
• The environmental hazards in the logistics network and potential impact to product quality at end of shelf life may not be adequately covered in the current product testing approach.

Any cGDP quality system focused on the controlled-environment logistics network will be continually challenged by non-conformances and exception management. This is a characteristic of a modern pharmaceutical logistics network. Dynamic stability testing of the final drug product specifically for distribution is a prerequisite in the development of a modern, world-class pharmaceutical supply chain.

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Pharmaceutical Cold Chain is Complex (Viewed: 1821)
Posted by Gary Hutchinson on May 4, 2015 @ 1:00 pm

First published on April 9, 2015 on Cold Chain IQ – as a contributor, Hutchinson’s column, Global Cold Chain Connections, falls in the Supply Chain & Security category. It can also be viewed at   Join Cold Chain IQ today to access informative cold chain articles.

By Gary Hutchinson

Competing priorities, changing expectations, cost pressures, sustainability initiatives, emerging markets -- these are the challenges facing cold chain management professionals every day. Solutions that deliver value in the supply chain and enhance your regulatory reputation by ensuring compliance, product quality and safety are required every day, around the globe.

Today, engineers and 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:

  • Appropriate expertise and techniques to assess, control and communicate risk as part of an on-going management review process.

  • A lifecycle approach to process validation including design, qualification, and verification.

  • Better integration of product formulation, controlled environment logistics, and packaging design.

  • Innovative, forward-looking quality controls, corrective and preventive actions (CAPAs) strategies, and root cause analyses for once straightforward processes that are highly complex today.

  • The application of technology to achieve greater gains in all areas, including compliance, quality and safety.

Integrate your cold chain management systems.
The appropriate tools, expertise, and experience are critical when coordinating your activities to ensure safety, safeguard quality, maintain regulatory compliance, and prevent falsified, adulterated, and counterfeit product from entering the legal supply chain.

  • Ensure compliance for high-value products in highly-regulated industries.

  • Deliver packaging design and qualification.

  • Conduct transport simulation testing with five environmental hazards – temperature, humidity, shock, vibration, and pressure.

  • Develop transport validation strategies to support global regulatory requirements. Design controlled-environment logistics solutions that ensure product quality during transport.

Get results by focusing on implementation, not just on defining regulatory requirements. A properly integrated cold chain ensures regulatory compliance, product quality, and patient safety by providing a multi-layered approach that combines best practices of process validation, systems qualification and risk assessment with the most applicable monitoring and controls for qualified packaging.

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 ensures control of the distribution chain and consequently maintains the quality and the integrity of products. The seven components are: quality systems; risk management; product stability; qualification / validation; logistics management; partner management; and compliance management.


Quality Systems – The First Pillar
Developing mature quality systems is one of the biggest challenges and one of the most effective tools to manage a world-class cold chain logistics network. Making the systems work for you, and not the other way around, is the key to your success. Quality systems at their best establish, implement, and maintain a set of processes to provide the highest quality service to customers, highest level of effectiveness for management, and most robust compliance approach for regulators. At their worst, they just get in the way -- adding only administrative burden and redundant reviews to an already complex and fast-moving network. I know. I have seen the value of an effective quality system that facilitates continual improvement, and I’ve seen the effects of a nominal one that provides only delays, derailments, and disasters!

An effective guide is needed to conduct a thorough review of your quality management system processes and tools to identify opportunities to provide structure and clarity to assist in the continual improvement of your controlled-environment logistics network. A review of the following elements of your quality systems should ensure these foundational capabilities are in place for your cold chain:

  • Quality Manual, Standards, and SOPs – A review of your quality system structure focused on regulatory requirements, best practices, and ease of use. Match the size and complexity of the activities you are managing to the complexity of your documentation.

  • Good Documentation Practices – Standardized templates, revision controls, and approval signatures are the cornerstones of an effective quality management system. Placing the appropriate practices in place for your technical documents, protocols, and reports are required for a successful audit.

  • NCs and Exception Management – Non-conformances (NCs) and management of exceptions is an uncomfortable reality in a global controlled-environment logistics network. The proper documentation of non-conformances coupled with an effective way to manage and document the exception requires a well-defined and streamlined approach. Coupled with an effective management review, the handling of NCs is a key to continual improvement.

  • CAPA and Change Control – Procedures for implementing corrective and preventative action (CAPA) help analyze processes, operations, records, complaints and other sources of data to confirm root cause and is one of the main roles of quality systems. A robust CAPA process uses appropriate statistical methods to identify trends and reoccurring non-conformances and provides investigational procedures. Controlling change in your organization and identifying a planned approach to CAPA resolution, including effectiveness verification, is necessary to drive continuous improvement.

  • Management Review – Quality systems need management support to enact change. A management review process requires the identification of key performance indicators with process control limits in place to determine when action is required. Along with self-assessments and audits, guideposts for the executive team to understand quality failures, process needs and updates on improvements is an essential feedback loop needed to build into your quality system.

Use these tools to assess your capabilities, create time-bound improvement plans, and mentor your team on the opportunities for improved profitability and efficiency. Conducting a quality systems maturity assessment can lead the way to breakthrough performance.

The New and Improved ISTA Standard 20 v2 (Viewed: 1897)
Posted by Sue Almonpesch on October 24, 2014 @ 12:26 pm

The International Safe Transit Association (ISTA) is a member-driven standards organization. A revised version of ISTA Standard 20 is now available. The original Standard 20 was developed to assist suppliers and users of passive thermal shippers in defining the necessary elements for data packages. When assembled correctly, the data elements are presented in a consistent form by all suppliers and benefit users. They can easily compare their needs with the documented performance of each shipper.

Modality Solutions was proud to play a role in leading ISTA members in the development of Standard 20 v2. Together the team of experts reduced the size and complexity of the original Standard 20. The new version has been simplified, clarified, and streamlined. It benefits both suppliers with an easy to implement approach to documenting shipper qualification.

What Hasn't Changed in Standard 20 v2? The original guiding principle of Standard 20 has not changed. The premise is still the same -- to have an industry standard so that users have a qualified insulated shipper that meets regulatory expectations.

The ISTA Standard 20 v2 process is the same. Some parts are now optional or best practice. User feedback indicated that depending on who qualified a shipper dictated what should be done. Suppliers should not be executing a PQ. End users should perform the PQ. ISTA Standard 20 v2 still incorporates CDER's principles of validation, and Quality By Design is still a key component of the new version.

What Has Changed in Standard 20 v2? Simplified and streamlined the entire program by reducing the size and number of documents in the entire Standard 20 v2 program: Reduced: Total # of docs from 25 to 15; Reduced: From 45 pages to 26 pages; Reduced: Data package examples from 1000 pages to one 17-page manual; Clarified: Protocol templates by moving from an outline format to a table format; Clarified: Thermal sensor locations by creating a table to precisely specify how many and where thermal sensors shall be located in an ISC -- based on the ISC design and payload configuration

Additional Standard 20 v2 Change Highlights: Added flexibility around thermal profiles. Removed qualified air temperature (QAT) to reduce confusion. Parts of the process are now optional depending on who is qualifying an ISC. Now requires a physical test as part of DQ. Clarified that physical testing may take place at an ISTA lab certified to execute ISTA 2B or 3A. Provided clear direction on what to do if a test fails. Removed all company-specific references. Incorporated a process flow diagram to clarify the process flow. Provided more flexibility across the entire Standard to make it easier to use. Tightened up thermal chamber performance requirements so the mean of errors shall not be greater than a (+or-) 1.0°C and no single error greater than a 3.0°C -- providing a more accurate test.

At Modality Solutions we strongly recommend you take advantage of Standard 20 v2. Become an ISTA Member. For more information, visit and/or contact ISTA today at (517) 999-3437.

Brian Wallin, Principal, Modality Solutions,

How to Use USP and ASTM to Evaluate Thermal Test Results (Viewed: 2370)
Posted by on September 30, 2014 @ 11:18 am

To set the stage for this blog post, a thermometer is a device that converts physical changes (of heat) into a numerical value. How to evaluate this value is the topic of this article. 

Rather simple on its face, there seems to be confusion in the application. Look no further than  to the assessment of data from a thermal experiment and the applied results to a specific range. The first thermometers had scales that corresponded to each manufacturer. By 1742 Anders  Celsius proposed a scale with zero at the boiling point and 100 degrees at the freezing point of  water, though the scale that now bears his name has the boiling and freezing points the other way  around.

The USP (United States Pharmacopeia) has definitions of multiple storage temperature conditions.  For instance, a refrigerator “is a cold place in which temperature is thermostatically maintained  between 2° and 8°C degrees.”

Current digital temperature recorders document the history of thermal exposure to the tenths of a degree. Typical thermocouple systems record temperature values to the hundredths of a degree.  What method(s) does one use to compare the measured data with the listed range in a given  standard? The method that follows is based on common methodologies expressed in the USP  general chapters on significant figures and rounding, as well as the ASTM (American Society for  Testing & Materials) Standard E29-13, “Standard Practice for Using Significant Digits in Test Data  to Determine Conformance with Specifications.”

Getting back to the refrigerator reference of a cold place in which temperature is thermostatically  maintained between 2° and 8°C degrees, it should be noted that this is a range commonly used  as an acceptance criteria for passive shippers. When the recorder documents a value of 1.8°C,  is this considered within the specification of “refrigerated?” The USP and ASTM standards agree  that it depends on the specification. The values for USP refrigerated contain one significant digit.  All calculations should use the general rules of retaining significant figures when performing  calculations that summarize or convert values. However, when these calculations are completed,  in order to assess the result, the final calculated value should be rounded to the same number of  significant digits as used by the limit in order to determine whether the test data conforms to the  respective limit. Table 1 contains examples.

Table 1. Illustration of Rounding Numerical Values for Comparison with Requirements

Requirement Observed or Calculated Value Rounded Result Conforms
Limit ≤ 3 ppm  3.5 ppm 4 ppm No
Limit ≤ 3 ppm  3.4 ppm  3 ppm Yes
Limit ≤ 2°C  2.5°C  3°C  No
Limit ≤ 2°C  2.4°C  2°C Yes

Therefore, in the example of USP and the range for refrigerated materials, acceptable unrounded  test values ranging from 1.5° to 8.4°C would be considered conforming to the range of between 2° and 8°C.

I’ve seen countless qualification attempts fail because of a recorded data point that registers 0.1°C  outside of a limit with one significant figure. Hopefully, the references cited within this blog will  find widespread application.

Paul Harber
Modality Solutions

Define Your User Requirements Specifications Upfront to Ensure Success! (Viewed: 2206)
Posted by on January 21, 2014 @ 4:55 pm

Different people have different expectations while developing a drug product shipping solution - for some keeping the final cost low is the most important factor, others measure success by the capability of a shipping solution to keep the drug products within the desired temperature range for the entire expected duration of shipment. Most ask for both!

Defining user requirements is a specification document is an important first step to ensure that everyone involved in a project is working towards achieving the same goal. The packaging is designed and qualified deliver life saving drugs using are variety of modes - air, ground, and even ocean transport - to maintain the safety, quality and effectiveness of the product. User Requirements Specifications (URS) help translate your needs into quantitative and qualitative attributes of a shipping solution that must be met in order to meet the regulatory standards associated with shipping and distribution of drug products. Laying out these requirements upfront also helps customers better understand their own needs and bridge the gaps in their specifications for shipping a product. A few common requirements that must be defined while developing insulated shipping solutions include:

  • Acceptable product temperature range,
  • Allowable thermal exposures based on product stability data,
  • Duration for which the shipping solution is expected to hold the product,
  • Thermal profile against which the shipper will be tested, and
  • Minimum and maximum payload dimensions and the cost of the solution.

It is also important to specify any special constraints that the shipper might be subjected, such as keeping product in a specific orientation and rough physical handling, at the beginning of the project. Keeping the expected date of delivery in mind is also recommended. Taking the time to accurately state and discuss the user requirements not only helps design an effective solution but helps also reduce the cycle time. Too often the design and qualification of a shipper is hampered by poor definition of true user requirements in the beginning of the project. Changes in specifications, additional requirements, and sometimes competing priorities increase shipper cost and design time needlessly.

It is not always possible to meet all user requirements - in such cases, prioritizing becomes crucial. One way of doing this is by classifying the requirements as "high”, "medium” and "low” and working on achieving them in order of decreasing priority. As a project progresses, any changes in the scope of the expected shipping solution should be recorded with corresponding changes in the user requirements. The final solution can be compared against the user requirements to evaluate its effectiveness in delivering what the customer demanded. User requirements guide the development of a cost-effective and regulatory compliant solution from start to the end. 

- Shubhra Kochar, Consulting Engineer

From the Mailbox...When is good enough, good enough? (Viewed: 2375)
Posted by on October 28, 2013 @ 3:20 pm

Since 2003, the regulatory expectation for BLA filings has been to include the process validation in the filing, as you know, distribution is considered part of manufacturing. So you are right, you need to formalize a process, but how?

:: continue

Pharmaceutical Industry Can Learn From the Food Industry on Real Time Monitoring (Viewed: 2021)
Posted by on September 25, 2013 @ 2:40 am

The food industry has been leading the way with many innovations in the cold chain: traceability, visual controls, freshness indicators, etc. Now add real-time environmental monitoring. This technology seems like one of those stories you see about scientist finding a completely new animal that has evolved in isolation on some tropical island! Radically different approach to monitoring that can and should be adopted to the cold chain for biologics, pharmaceuticals, and combination medical devices.

A wireless data system that provides real time temperature monitoring for truck shipments is not really new or particularly revolutionary. What is revolutionary about the their approach to monitoring the cold chain is the technology: fully portable and modular, it does not need to be hard wired or mounted into the trailer nor the power unit. It can simply plug into the 12 volt power source in the cab of the truck!

This real time monitoring technology is great for any company that relies on 3rd party carriers to haul their cold chain biopharmaceuticals. The data loggers attach directly to pallets of product. The devices are similar in size and cost to devices commonly used today. The wireless communications unit in the truck cab collects information from the devices in the trailer and reports to a web portal thru the cell network. The entire 21 CFR part 11 compliant system can be installed in less than 5 minutes. When considering a real time monitoring solution, please remember to examine the functionality of these key features:

- Real time temperature monitoring and GPS tracking
- Real time alerts and notifications sent to voicemail, text, and/or email
- Real time data review on any supported browser or smartphone
- 'Geo-fencing' route alert notifications

This technology is not necessarily new, but simply "discovered” as it used within another industry. There may be further developments that could change the way we monitor clinical sites. Imagine that we could have a record of thermal history from labeling all the way to and including the storage time at the clinical site. I’ll admit its still early, but I look forward to digging into the performance details and sharing more about the applications of this technology and its capability. If you have any questions please give me a call.

Principal, Modality Solutions

Exciting Changes to ISTA Standard 20 - Learn more at 11th Annual IQPC Cold Chain Summit! (Viewed: 1860)
Posted by on September 12, 2013 @ 5:20 pm

Earlier this year the International Safe Transit Association (ISTA) began revising Standard 20 based on feedback from several users on changes they would like to see which would make the standard easier to follow, and less cumbersome. I am happy to report that ISTA Standard 20 version 2 has undergone a massive overhaul to simplify the approach while maintaining the same process and the ideals it was built on: regulatory compliance for the end users, Quality by Design, and CDER’s Guidelines to Validation Principles.

For the past month the ISTA thermal council has been reviewing and providing feedback on the changes, and this past week I got to review those comments for the first time. Overall the comments were very positive and will make Standard 20 even better. The goal of the ISTA thermal council is to have Standard 20 completely revised by the 11th Annual Cold Chain GDP Temperature Management Logistics Conference in Chicago, September 30th to October 4th. It is going to be a tight schedule to get it completely done, but I think this team can do it.

I will be there in Chicago at Modality Solutions' booth for anyone who wants to stop by and chat about the upcoming version 2 of ISTA Standard 20. I’m excited, and I hope you are too! Here are some highlights of the revision to Standard 20:

Simpler - reduced to 25 pages down from the original 45 pages

Integrated - references industry guidelines on insulated shipper qualification: PDA Technical Report 39, ISPE Good Practice Guide: Cold Chain Management

Aligned - templates follow FDA process validation guidance

Effective - Data package examples have been trimmed from almost 1000 pages to a mere 17 pages.

Hope to see a you at the conference!

Brian Wallin Principal, Modality Solutions

Cold Chain Integrity Challenges Biopharmaceutical Industry (Viewed: 2002)
Posted by on September 4, 2013 @ 8:20 pm

The security portion of cold chain integrity can be broadly separated into fixed site security and rolling site security. This is a good logical separation that is also used for force protection and counterterrorism.

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Protein Stability Conference - Biopharmaceutical Industry Discusses Product Transportation Validation (Viewed: 2125)
Posted by on August 15, 2013 @ 4:05 pm

We joined some industry experts to help tackle some of the formulation challenges facing the industry at the annual Protein Stability conference hosted by John Carpenter, Ph.D. University of Colorado, Boulder. The generation of particles in solution has been an industry concern for years. USP requires manufacturers to evaluate and specify limits of particles in solution. The cause of these particles has yet to be defined, but presence of glass particles and filling machines can provide the conditions that predispose a solution to form particles when exposed to the temperature, pressure, shock and vibration in the supply chain. Awareness is growing for the need of additional clinical phase-appropriate tools that will predict the robustness of protein formulation development using Quality by Design (QbD) techniques. Experts debated the appropriateness of “forced degradation” methods past the early formulation development phases.

Two of the largest biotech companies have specially constructed chambers to test the effect of transportation on the formulation candidates. This type of testing, Product Transport Validation, defines a design space for the product that fits into the capabilities of the distribution operations. Distribution operations often cannot support the tight tolerances of the clinical trials and discovery of this mismatch too late delays product launch. The silos are being broken down and formulators and distribution are getting together earlier in the development process with new tools to assure a smooth commercialization process.

Transport Process Validation - Performance Qualification (Part 4 of 4) (Viewed: 2007)
Posted by on August 6, 2013 @ 10:15 pm

All applicable processes will be tested: pack out instructions, training systems, quality agreement and service levels with carriers, receiving procedures, etc. The PQ test will ensure all aspects of the transport process can achieve acceptable..

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Transport Process Validation - Operational Qualification (Part 3 of 4) (Viewed: 1966)
Posted by on July 24, 2013 @ 9:50 pm

Part three of a four part post focuses on the Operational Qualification (OQ) portion of the transport validation process. As discussed in Part Two, conducting a component qualification (CQ) and installation qualification, gives us a well-defined specification of system operational capability and tolerances. OQ plays a critical role in the transport validation process by testing critical parameters of the system/process at expected extremes while confirming that the process is adequate to deliver unadulterated products. It is important to conduct OQ tests in a laboratory to ensure that the product is exposed to the expected extremes within the design space of the transport environment. Testing the 'edges' of your design space is critical to meeting expectations of the FDA and their 'Quality by Design' initiatives. You can’t guarantee that by shipping product in actual 'real world' transport conditions will test your design space. You may not get exposures to desired extreme transport conditions for temperature, pressure, shock/vibration and humidity at one time let alone concurrently!

OQ testing should be conducted using GMP-manufactured product in its final or market formulation or be as close to it as possible. This GMP final formulation includes having the drug product in a qualified primary packaging, which is then placed in a representative qualified secondary packaging along with all the labels. This drug product package should be placed in a qualified insulated shipper container which must be packed as per a well-defined standard operating procedure for pack-out instructions. All materials must be properly pre-conditioned prior to packing and the packing process should try to replicate the real-life scenario as close as possible. Ensuring proper handling and following standard operating procedures will help in getting an accurate performance evaluation of the system under test.

The transport simulation test plan will subject all the qualified components to normal expected extremes in the transport environment using simulated transport. It’s important to note that during actual transport, both the product and packaging are subjected to temperature, vibration, shock, pressure changes, and humidity simultaneously. The combination of these environmental transportation hazards can affect a product uniquely than when exposing the product to these hazards individually. Keeping this in mind, Modality has designed an Advantage Transport Simulation Laboratory that gives you the ability to concurrently simulate these five transportation hazards.

After the completion of transport simulation OQ test, long term stability studies and efficacy tests should be conducted on the product to demonstrate that a dynamic transport environment does not affect the product integrity. The last part of this series will talk about the steps involved in conducting a Performance Qualification, which is last component of the transport validation process.


Transport Process Validation - Component/Installation Qualification (Part 2 of 4) (Viewed: 2187)
Posted by on July 18, 2013 @ 6:15 pm

Part two of this four part post will focus on the Component/Installation Qualification (CQ/IQ) portion of transport validation. In the previous post I listed processes which must be in place and designed to work together to allow the transport process to be validated. How do those processes come together to allow the transport process to be validated?

Robust test standards and test methods must be in place in your quality management system. These test methods can be either a public standard (e.g. ASTM, ISTA, etc.) or be custom developed. Custom developed thermal profiles are a good example. Best practices require you have a data collection methodology, written protocols, and the data package and conclusions summarized in a report that is reviewed by your quality unit representative. Without these basics in place, your custom developed thermal profile may be question or rejected by the regulatory agencies.

We recommend focuses on component qualification for passive thermal shipping systems and installation qualification for active refrigeration systems. Component qualification focuses on gel ice performance and setting specifications and critical-to-quality attributes for the passive shipper. Examples could include R-value, wall thickness, density, or even weight of the packaging for simpler systems. Whatever these attributes are that impact performance, they must be documented in a component specifications. These specifications should also include allowable tolerances and any substitute components that are available.

Installation qualification focuses on confirming manufacturer specifications were followed during installation of the active refrigeration system and all operating parameters are maintained during load testing. Rather than focus on 'thermal mapping' inside a active refrigeration system, a dubious and flawed practice at best, we recommend your IQ focus on component specifications like BTU output, air flow/turn over, and R-value of the walls. This focus on specifications mirrors equipment installation qualification approaches followed in most manufacturing processes more closely than 'thermal mapping' of the inside of a trailer.

Both aspects, component qualification (CQ) and installation qualification (IQ) test critical operational controls, focusing on the key attributes for the type of system to be qualified, and supports robust performance during operational qualification (OQ) of the system.

Having test standards, thermal profiles, and verification shipments for transport lane qualification in place allows an organization to have confidence in the qualification of critical components and equipment delivering product safely to patients. In other words it provides for a robust CQ/IQ test. The CQ/IQ ensures that the system and its components are installed correctly and to the original manufacturer specifications.

The qualification deliverables of an organizations product, primary containers, secondary packaging, insulated shippers, and drug delivery devices all require component specifications. The procedures on how to use and assemble them correctly must be documented as well during CQ/IQ. These CQ/IQ report based on test data and procedures are the deliverables at this stage of transport process validation. They define the design space the systems are capable of operating in and the performance tolerances they can be expected to hold during operation qualification (OQ).

Next week we dive into the operational qualification (OQ) of transport process validation. See you then!


Transport Process Validation - Outlining the Process Steps (Part 1 of 4) (Viewed: 1883)
Posted by on July 9, 2013 @ 8:35 pm

"Cold chain transportation can be validated just like any other process."

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