Pharma By Air: Equipment Qualification and Route Risk Assessment

• TEVA Pharmaceutical Industries Ltd.
• Merck
• Eli Lilly and Company

Abstract

Aviation and pharmaceutical industries are both highly regulated industries that had a long way in communicating and consolidating the quality requirements with realistic capabilities. In the past 10 years considerable steps were taken to bring both industries together and to understand each other's drivers. PDA’s Pharmaceutical Cold Chain Interest Group (PCCIG) together with the International Air Transport Association (IATA) played an important role in this process. Understanding the transportation industry, and its relationships and responsibilities provided all involved stakeholders with an opportunity to work on quality driven shipping solutions. This article briefly reviews regulatory requirements related to distribution of medicinal products with the highlight on transport risk assessment and equipment qualification requirements. Insights into an air freight route risk assessment and methodology are provided as well.

Key words

Air freight, critical quality attributes, critical process parameters, route approval process and equipment qualifications, risk assessments, stakeholders.

Introduction

Global air freight industry contributes with 0.5% of global world trade in volume but raises at the same time up to 35% of its value or $6.4 trillion according to Air Transport Action Group (ATAG).¹ Managing the transportation of temperature controlled products (refrigerated and frozen) will total $12.6 Billion in 2016 of the total of $78.8 Billion pharma logistics market.² By 2020, this will grow to $16.7 Billion for cold chain logistics and to $77.1 Billion for the non-cold chain. Pharmaceuticals shipped as air cargo are expected to double to 12% from 2013 till 2018 compared to a share of 6% recorded from 2008 till 2013. At the same time the share of air cargo in global pharmaceutical transport decreased from 17% in year 2000 to 11% recorded in 2013.³ Thus pharmaceuticals shipped by air are rising in value while declining in weight, while ocean freight as a first alternative, is gaining volume in both low as well as typically high value pharmaceuticals such as vaccines.⁴

To ensure that quality, safety and efficacy of pharmaceutical products are kept on the radar of all involved supply chain stakeholders, regulatory agencies around the globe introduced Good Distribution Practices (GDP). Here qualification of shipping systems is a regulatory requirement.⁶ This requirement is derived from the need for enhanced visibility in the supply chain starting with the active pharmaceutical ingredient (API) being received for production to the last mile of distribution of finished product. Enhanced visibility in shipping lanes enables better control over engaged stakeholders and shipping processes and systems. This is reached through an efficient communication platform established to improve service level and to maintain product quality.

In recent years, qualifications of defined handling and shipping processes for Time and Temperature Sensitive Pharmaceutical Products (TTSPP) became a focus of IATA. In 2007 IATA issued an industry manual called Perishable Cargo Regulations (PCR). Three years later a new Chapter 17 for TTSPPs was introduced and in 2014 the first edition of Temperature Controlled Regulations was published. Both documents provide minimum standards for all involved airfreight stakeholders, including shippers, to be followed when handling and transporting TTSPPs.⁵

Regulatory Background

Many governmental and non-governmental organizations like the European Commission, U.S. Pharmacopeial Convention (USP), Parenteral Drug Association (PDA), World Health Organization (WHO) and The International Air Transport Association (IATA) published in the last years numerous guidelines and technical reports on GDP. They provide guidance and requirements towards route risk assessment and qualification of equipment and processes, quality risk management, quality management systems, deviation management, change control, training, roles and responsibilities and more in the distribution of medicinal products. The main purposes of these guidances and requirements are to minimize risk and to maintain the medicinal product integrity including quality, safety and efficacy through the supply chain to the end user. European Commission document, EC 2013/C 343/01 states that for temperature sensitive products use of qualified equipment; thermal packaging, temperature controlled containers or temperature controlled vehicles is required.6 World Health Organization Technical report series, No. 961, Annex 9, published in 2011 indicates the requirement for qualification of active and passive shipping systems. It also indicates the requirement to use qualified trucks.⁷

Highlights related to risk assessment and qualifications in transportation from the USP General Chapter <1079>, Good Storage and Shipping Practices, could be summarized as a requirement to use vehicles designated to provide appropriate temperature range for the product being shipped and that seasonal temperature mapping is performed with typical loads on the vehicles.⁸ The European Commission’s Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use in Annex 15: Qualification and Validation, under Chapter 6, indicates requirements for defined transport routes, risk assessments in transportation for identification of variables (delays or monitoring failure) and continuous monitoring, unless otherwise justified.⁹ The execution of risk assessments in the temperature-controlled distribution of phar- maceuticals, biological medical products and medical devices is clearly described in PDA Technical Report 58.¹⁰ Here it is stated that by applying risk management, risk-based decisions are made to:

• Preserve the quality, safety and efficacy of the product
• Understand the distribution process
• Reduce risk
• Understand residual risk
• Improve the effectiveness of the process

Medicinal products are shipped via various modes of transport including road, ocean, air and sometimes rail or the combination thereof (multimodal transport) to deliver it to the next step in the supply chain. Each mode of transport has its own challenges, opportunities and risk towards the medicinal product. The choice for a transport mode depends on various factors including but not limited to:

• Product characteristics
• Packaging solutions
• Size and value of the shipment
• Shipping cost
• Total expected transit time
• Stock availability on the market
• Required speed of product delivery

Once a transport mode is chosen, then the product characteristics will determine other requirements towards the shipment. For example, the product stability, physical appearance, and value have a great impact on the shipping model selection in relation to thermal and physical protection, and security of medicinal products. These requirements are important as for each shipment two basic questions should be answered by the consignee upon receipt:

1. Is the right medicinal product delivered in the right quantity, at the right place and at the right time without physical damage?
2. Are the medicinal product quality, safety and efficacy maintained during the shipment?

In order to answer both questions with “Yes”, quality-risk management systems should be in place in the supply chain, involved stakeholders should be qualified, and shipping systems should be transparent and defined.

Medicinal products are shipped as loose cartons or on pallets with or without active or passive thermal protection systems depending on the product requirements. Each thermal protection system should be (pre-)qualified prior to its use for a shipment in order to mitigate risk. In addition it should be temperature monitored, unless otherwise justified. By comparing the shipping temperature with the product requirements, one can determine whether the product quality, safety and efficacy are maintained during the shipment. Packaging should protect the medicinal product against other factors such as humidity, light, oxygen and sterility where applicable, and it should be tested and qualified against the product requirements and international standards prior being shipped.

Qualification

EU GDP defines Qualification as “Action of proving that any equipment works correctly and actually leads to the expected results.”⁶ PDA Technical Reports offer extensive insight into the qualifications arena.^11,12 Starting from definitions of Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ) to best industry practices approach in qualification preparation, subject definition and methodology application.¹¹ DQ is the documented verification that the proposed design of equipment or system is suitable for the intended use. IQ is the documented verification that the equipment or system as installed complies with defined user requirements and manufacturer specifications, while OQ is the documented verification that the equipment or system operates/performs according to its intended use as defined in user requirements and manufacturer specifications. Finally, PQ represents the documented verification that the equipment or system when used in accordance with its user requirements, manufacturer specifications and purpose, per- forms according to the declared requirements and specifications.

Qualified distribution systems may include:

• Validation and thermal performance qualifications.
• Continuous temperature monitoring by calibrated monitors (continuous verification).
• Retrospective qualification of shipping system using historical data.
• Operational and performance shipping studies using loading profiles and expected ambient extreme conditions.
• Testing on both active and passive shipping systems.
• Three dimensional temperature mapping for facilities, vehicles, shipping containers, refrigerators, freezers, and other confirmed shipping systems.
• Representative sample (of the same fleet) approach for road and/or ocean transport vehicles.

In terms of air freight, a comprehensive route risk assessment exercise might be brought in correlation with equipment qualification and where a detailed defined route together with the critical process milestones results in a tailor made solution set to keep the product integrity preserved throughout the shipping process. The combination of route risk assessment and planned equipment qualification in air freight is from here defined as verification of transport or air freight route approval process.

Quality and Risk Management Principles

Quality management system aspects related to air freight shipping could be summarized under Critical Quality Attributes (CQA) and Critical Process Parameters (CPP):

• CQA’s are those related to product integrity such as temperature and humidity conditions, shock, vibrations and damage during transportation.
• CPP’s reflect expectations related on the service provided such as pickup on time, flown as booked, delivered on time, and accompanied with relevant documentation. Those quality objectives are process inputs for air freight process design.

Quality objective considerations are not only those related to the product integrity and attributes but also those linked to process assets planning and resources utilization. The regulatory environment relevant for the process definition is evaluated during the process design phase. Process output is evaluated against defined quality objectives or customer requirements by setting measurements to prove its efficiency. Handling or transport process typically comprises of one or more sub-processes reflecting in more detail product requirements and specifications. As an example, handling of a medicinal product shipment in an airport might be a sub-process of a general cargo or pharma service handling process but might also comprise of physical and documentary handling sub-processes. Process composition depends on the stakeholder services related to handling and transportation. The same principle applies when differentiating activities based on product characteristics and required infrastructure or handling equipment. Each activity in the process requires detailed definition and documented description. Roles and responsibility are defined on the activity level and documented in a matrix. Definition of process milestones or critical control points is an important step in process design. Those are particularly important at responsibility transfer points, where two stakeholders are interacting in the process. Agreed and documented communication protocols are crucial for seamless transition from one process step or a milestone to another where responsibility over the process step changes owner (responsible stakeholder).

Failure to meet quality and business objectives represents a risk. Risk management principles and definition are preferably predefined in a policy. Risk is being defined in different ways while one of the most frequent definitions describes risk as a likelihood of future events and their impact on project, process or objective. This simple formulation can be further developed by extending evaluation of impact to other factors like threat, vulnerability, consequences and resistance of the project or process subjected to evaluation. In general, risk management aspects are defined first following definition of risk factors and criteria according to a documented policy.

Process work breakdown structure represents process decomposition to activity level. Risk assessments are then applied on each activity considered critical for the process functionality. Different risk assessment methodologies could be applied on process milestones. Some of those are typical for certain industries and are more frequently applied. Others might be used in combination with one to another. Understanding process character and objectives is important when deciding on applicable method. Selected method should be documented.

Verification of Transport

Verification of a transport process comprises of risk assessment and documented testing of each single activity in the technological process in order to confirm and document process compatibility and efficiency with the defined conditions and shipping requirements.

Risk assessment subjects may equally be standard technological processes defined to address main requirements for handling of general cargo shipments, or specially designed technological processes set to address the special handling requirements derived from the product characteristics, regulatory expectations (GDP) or manufacturer instructions. Development of a Quality Assurance Plan is thus required as part of a quality management system. Elements of Quality Assurance Plan are shown in Figure 1.¹³

 Figure 1. Quality Assurance Plan components.

The level of qualification is determined by the risk assessment results. The basic rule of less visibility equals more risks is a fundamental approach in defining qualification subject and applicable qualification methodology. Defined shipping temperature regime based on the label storage conditions might influence the complexity of the shipping route risk assessment. IATA defined following temperature regimes:⁵

• +2 °C to +8 °C
• +2 °C to +15 °C
• +2 °C to +25 °C
• +15 °C to +25 °C
• Keep frozen (-20 °C)
• Do not freeze

Compliance requires the understanding of shipping and distribution processes and its risks and their potential impact on the product integrity. Typical air freight route risk assessment for shipping time and temperature sensitive pharmaceutical products is comprised of risk assessment on identified critical control points, involved stakeholders, handling and manipulation infrastructure, equipment, and operational and performance qualification of the equipment intended for use. Design route qualification could be exceptionally performed in cases where the route and all its components are designed in collaboration with the shipper, which is a rare case. Instead, airlines like airports are undertaking steps to reduce identified risks in their handling and transportation processes to address requirements derived from product characteristics and shipper needs.

Air Freight Industry Initiatives

Ever since the shipper community expressed their concerns related to air freight transport visibility and traceability, IATA started to raise awareness of industry capabilities in terms of shipping time and temperature sensitive products. The main concerns under-lined by the shipping community could be highlighted by the number of involved stakeholders using handling agents, airport warehouse operators and carriers per single route and consequently, the number of critical process milestones. Handling and in transit storage facilities play an important role since, according to Air Cargo News, 90% of the transit time in air freight is spent on waiting to be moved. At the same time 50% of temperature excursions occur during airline or airport tendering for cargo, according to IATA Director General and CEO, Tony Tyler.¹⁴ To address these and other identified challenges in the air freight industry, in August 2014, IATA launched a qualification program under the title: Center of Excellence for Independent Validators (CEIV). The program was designed to target airlines, ground handling companies, freight forwarders, road transport companies, distributors and airports. The main objective of the CEIV program is to enhance industry readiness to deal with growing expectations from pharmaceutical manufacturers thus bringing back the confidence and potentially volumes the industry lost to ocean freight. The ambitious program was designed to harmonize efforts in understanding and provide answers to the rising regulatory environment in the pharma supply chain and to provide global and consistent cer-tification program with high compliance standards. The quality of the program has been acknowledged by the pharmaceutical manufacturing industry as well as regulatory agencies such as the Belgian Federal Agency for Medicines and Health Products (FAMHP) which endorsed CEIV product in November 2014.³ All CEIV validated stakeholders will be published on IATA website.

Air Freight Route Approval Process

While the IATA initiative in harmonizing the air freight industry is in progress, understanding of regulatory and shipper community expectations is gaining momentum by all partners of the supply chain. Shippers are striving to increase visibility and traceability in their air freight transport solutions. According to EU GDP, risk assessment of delivery routes should be used to determine where temperature controls are required.6 For temperature-sensitive products, qualified equipment (e.g. thermal packaging, temperature-controlled containers or temperature-controlled vehicles) should be used to ensure correct transport conditions are maintained between the manufacturer, wholesale distributor and customer. If temperature-controlled vehicles are used, the temperature monitoring equipment used during transport should be maintained and calibrated at regular intervals. Temperature mapping under representative conditions should be carried out and should take into account seasonal variations. Besides the fact that route risk assessment is a regulatory requirement (e.g. EU GDP), enhancing overall visibility in supply chain preserves product integrity and overall safety. The air freight route approval process is comprised of three main groups of activities:¹⁵

• Pre-approval activities consisting of route risk assessment, qualification protocol definition for selected equipment, DQ, IQ, and OQ of thermal protection systems and documentation of qualification process.
• Equipment performance qualification process comprised of definition of information flows, shipping process monitoring, corrective activities and irregularity handling for cases deviating from the process.
• Approval process comprised of data collection and analysis, equipment qualification approval and new knowledge gathering. Final route approval should be documented. Training may be performed on risk assessment exercise and reported latter on.

The risk assessment exercise as a part of the selected route approval may consist of the following activities:

• Route (trip duration), origin, transit and final destination airport (new route or re-qualification)
• Quality, service level and costs evaluation (availability of temperature records from the temperature controlled trucks is important for multimodal routes)
• Logistics service provider and/or carrier evaluation (new, existing, used by another affiliate within the company)
• Experience with supplier (handling irregularities, root cause analysis, corrective and preventive action - CAPA response time and handling)
• Role of logistic service provider (LSP) and their level of support

The risk assessment exercise starts with pro-cess definition followed by dividing it to an activity level. Each stakeholder involved in the route approval process should be made aware of its role and responsibilities from the approval preparation to risk assessment data evaluation.

Overall preparation for approval process consists of activities summarized in the following highlights:

• Define risk assessment protocol scope, application, responsibility matrix, primary and secondary goals
• Identify involved stakeholders like carriers and LSPs
• Define responsible persons on shipper and consignee side, internally and externally
• Define route details with multimodal transport considerations
• Prepare schedules
• Define and describe roles and respon-sibilities for all stakeholders involved
• Prepare check list and define check points on critical control points or milestones
• Define security elements like procedure for handling seals where applicable

Risk assessment and selected equipment performance qualification process is a main event in route approval process and it is compromised of the following highlights:

• Maintain information flow (shipment advance notice in defined form and distribution protocol)
• Continuous monitoring, role of involved stakeholder needs to be defined in advance
• Irregularity handling procedure activation and backup plan is required in case of irregularity

Key elements of an air freight route approval exercise for shipping medicinal products are shown in Figure 2.¹⁵ To define critical control points or process milestones, a risk assessment exercise is required together with the LSP and the carrier involved to define zones of responsibility, responsibility transition points and detailed activities schedule. The basic rule for critical milestone definition is less access to an activity, less visibility and control hence the higher risk in the process.

 Figure 2. Main elements of air freight route approval exercise.

Typically, critical milestones of an airfreight route could be summarized in groups depending on the stakeholder involved. The matrix above indicates standard group of activities grouped per stakeholder involved.

Risk assessment data mainly include the check list records and records from the temperature measuring and recording devices attached to shipment, are evaluated against defined assessment criteria. The route approval report will be composed of the results of the evaluation and acceptance criteria matrix.

Table 1. Example Activities of Stakeholders.

Multimodal shipping routes combining road segments and air freight routes is the most complex shipping environment due to a number of stakeholders involved, different types of transport vehicles, exposures to environmental conditions during regular tarmac time operations and overall capabilities of aircraft in maintaining a defined temperature regime during flight. For road transportation, part positions in the trailer close to truck door might have an impact on the level of recorded temperatures and it has been proven to be temperature deviation sensitive. Cargo hold load configuration may have an impact on temperature distribution especially for loads in the cargo hold door zones. Handling, manipulation and storage at transit airport within the set temperature regime represents a challenge as well. Tarmac operations and handling time is an area of highest risks hence most of temperature excursions from a defined shipping temperature regime might occur during this process milestone. Handling and manipulation activities on passenger airports could take up to three times longer than on a predominately cargo airports. Temperature excursions were recorded in cases where the aircraft parking position was a far distance from the carrier inbound cargo terminal. Those were caused by the long towing time. Last out (from the warehouse) – last loaded (on an aircraft) ensures appropriate storage under temperature controlled conditions to the largest possible extent but also loading position close to the compartment door which was found more sensitive to temperature deviations during flight.

Discussion

If thermal protection systems, packaging and equipment are tested and qualified for a medicinal product prior to a shipment and temperature monitoring during the shipment is in place, should each air freight route be approved? If yes, what should the approval process comprise of? The first step in determining which of the air freight routes should be subjected to the approval process is to perform a volume and product characteristics risk assessment. This exercise will enable identification of priorities in route analysis and approval process. Once priorities are identified, stakeholder screening process is a next step. This activity enables further process decomposition which includes infrastructure and attached processes evaluation at origin, transit point(s) and final destination. Different risk assessment methodologies could be applied. Two primary principles of quality risk management are:¹⁶

• The evaluation of the risk to quality should be based on scientific knowledge and ultimately link to the protection of the patient; and
• The level of effort, formality and documentation of the quality risk management process should be commensurate with the level of risk.

A responsible person will evaluate the most appropriate methodology to perform the exercise. One of the methodologies frequently used is a Failure Mode and Effects Analysis (FMEA). A producer’s design and operational qualification documentation for active, semi-active or passive equipment should be the subject of risk assessment on the intended use. Scientific knowledge, industry best practices as offered in PDA's Technical Reports for example and data on environmental conditions, transit times and industry qualification initiatives (such as IATA CEIV) should be accounted for in the defined air freight route approval process.

Conclusion

Risk assessments on critical control points in transportation of temperature sensitive medicinal products are part of Quality Management Systems and requirements stipulated in a majority of regulatory guidance documents. Maintaining product integrity and process performance could be considered as two main quality objectives communicated as expectations towards the air freight industry.

Shipping route risk assessment is a regulatory requirement according to GDP. The route approval process is comprised of a route risk assessment which includes a comprehensive system, evaluation of direct service providers (contract acceptors), their infrastructure (warehouses) if used in shipping and processes designed for shipping medicinal products.

A qualification CEIV program designed by IATA enhances overall industry efforts in harmonizing expectations and offering uniformed best practices in the field of qualifications in air freight. Combining a CEIV program with air freight route approval process designed by the pharmaceutical industry supports all involved stakeholders reaching a new compliance level. Connecting different CEIV validated stakeholders in a route approval process exercise would present a concrete step forward in harmonizing pharmaceutical industry expectations with the air freight industry's realistic capabilities.

References

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Disclaimer: The content and the views expressed in this document are the result of a consensus achieved by the authors and are not necessarily views of the organizations they present or represented.

Zvonimir Majic PhD, is a Director of a Global Quality Logistics in TEVA Pharmaceutical Industries Ltd. ([email protected])

Erik J. van Asselt, PhD, is a Senior Specialist QA at Merck, Sharp & Dohme (MSD)" and Leader of the Parenteral Drug Association (PDA) Pharmaceutical Cold Chain Interest Group (PCCIG), EU Branch. ([email protected])

Rafik H. Bishara PhD, is a Technical Advisor, (Retired) Director, Quality Knowledge Management and Technical Support, Eli Lilly and Company. ([email protected]).