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International Clinical Trials

Touch Point

Almost 30% of scrapped sales at pharmaceutical companies can be attributed to logistics issues (1). As most medical and biological products require a temperature-controlled environment at all stages of manufacturing and distribution, the control of storage and transportation temperatures is vital in maintaining the quality and effectiveness of medicines, and is equally critical for its manufacturers, public health and patient safety.

Good Distribution Practice

In order to maintain the safety, integrity and efficacy of their high-value products and reduce supply chain risks, pharmaceutical manufacturers count on refrigerated fleet operators and shippers to follow the European Commission’s Guidelines on Good Distribution Practice of Medicinal Products for Human Use (GDP) (2).

By some estimates, as many as 70% of products require some type of controlled environment, including those that need to be maintained at a consistent room temperature. For most medical and biological products, the GDP guidelines require a temperature-controlled environment for all stages of manufacturing, shipping and storage. Four stages of qualification are outlined in these guidelines, and they include:

Design Qualification (DQ)

Where the compliance of the design with Good Manufacturing Practice (GMP) should be demonstrated and documented.

Installation Qualification (IQ)

Should be performed on equipment, facilities, utilities or systems, and should include but not be limited to:
  • Verification of the correct installation of components, instrumentation, equipment, pipe work and services against the engineering drawings and specifications
  • Verification of the correct installation against predefined criteria
  • Collection and collation of supplier operating and working instructions and maintenance requirements
  • Calibration of instrumentation
  • Verification of the materials of construction
Operations Qualification (OQ)
Should include but is not limited to the following:
  • Tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed
  • Tests to confirm upper and lower operating limits, and/or worst case conditions
Performance Qualification (PQ)
Should include but is not limited to the following:
  • Tests using production materials, qualified substitutes or simulated product proven to have equivalent behaviour under normal operating conditions with worst-case batch sizes. The frequency of sampling used to confirm process control should be justified
  • Tests should cover the operating range of the intended process, unless documented evidence from the development phases confirming the operational ranges is available (3)
These guidelines should be consulted in order to ensure appropriate procedures are followed, measures are taken to maintain product quality throughout the cold chain, and risks are limited during transport.

Qualification Process

Each refrigerated transport unit used for the transportation of pharmaceutical products needs to go through a qualification process. This process – which is mentioned in Annex 15 of the GMP – can also be applicable for the GDP while qualifying temperaturecontrolled equipment for the transport of pharmaceutical products. Qualification consists of a temperature validation process that maps the temperature performance of the unit operating in the temperature ranges listed below. Temperature sensors are placed in a number of locations throughout the box to identify if there are any hot or cold spots that could affect the transportation of the pharmaceutical products.

It is recommended to conduct the qualification at an accredited laboratory. Once the tests are finalised, it is essential to complete the validation process by preparing adequate documentation, which ensures that the four stages of qualification (DQ, IQ, OQ, and PQ) have been carried out correctly. At this time, a certificate can be provided to prove that the equipment is qualified for pharmaceutical operation.

This extends beyond the transport vehicles used to take bulk pharmaceutical (such as active ingredients) and medical components to the manufacturing facility and finished products from the manufacturing facility to distributors/ wholesalers. It must also ensure compliant delivery to hospitals and pharmacies, as well as supermarkets that sell medicines.

Temperature Regimes

Industry statistics indicate that 25% of vaccines reach their destination in a degraded state because of incorrect shipping, and almost 20% of temperature-sensitive health care products are damaged during transport due to a broken cold chain. Moreover, approximately 0.5% of transported goods are damaged during transport through non-compliance to temperature guidelines (4).

When it comes to transporting pharmaceutical products, there are typically three temperature regimes to ensure they are maintained within required parameters:
  • Under 20°C: typically, products transported for clinical trials should be kept frozen at all times. The cooling compartment should not be allowed to rise any higher than -20°C. The recommended storage handling temperature regime for medicinal shipments such as blood and plasma is -30°C; other products within this temperature regime may be carried at -25°C
  • 2°C to 8°C: medicinal products carried in this temperature regime, such as vaccines and antibodies, should be maintained between this range and not deviate outside of it
  • 15°C to 25°C: products carried in this specified temperature regime, such as APIs or small molecules, should be maintained between this range and not deviate outside of it
Common non-compliance issues include failure to: monitor and/or record storage temperatures; temperature-map warehouses to find hot and cold spots; calibrate temperature monitoring devices or take appropriate action when temperature excursions are noted (5). No wonder leading operators are equipping their fleets with integrated asset management systems that protect shipments by establishing critical controls at all points in the supply chain.

Final Considerations


Preserving cold chain integrity and maintaining product quality is an increasing challenge for pharma companies and their partners in handling and transporting pharmaceutical products globally. As temperature-controlled shipments grow in volume and regulatory requirements change, pharma and biotech manufacturers will need the support of their transportation industry partners to ensure compliance with regulatory requirements and the safety and integrity of their high-value shipments.

Other important factors to consider before or during transport of pharma products are:
  • Load space configuration when the trailer body design is carried out, such as whether or not to include dividing doors, air shoots or a return air bulkhead design
  • The load space should be kept clean at all times, and only cleaning agents that will not affect the cargo should be used
  • To conform to temperature monitoring and recording obligations, the units are required to have on-board temperature recording and monitoring, as well as printed delivery point tickets to prove the temperature integrity of the load space
  • Because the products have to stay within a particular range, both temperature and air management must be controlled within this regime with no deviation allowed or any excursions limited to manufacturer specifications
  • Drivers are required to be trained to show that they can operate the unit within the GDP requirements
  • Regular maintenance and service records should be kept for inspection if needed by pharma companies
  • A calibration check should be completed at least once per year; individual pharma companies may request more checks. A three-point calibration of the sensors is important to ensure that when the unit is operating, it can maintain the load space temperature at the set points as listed above
  • To prevent risk of contamination to sensitive shipments in the compartment, cleaning standards in line with GDP guidelines should be enforced under the guidance of certified service personnel
References
1. Based on estimates from World Health Organization, Parenteral Drug Association and other industry associations
2. Visit: www.ec.europa.eu/health/human-use/good_distribution_ practice/index_en.htm
3. EudraLex ,Volume 4, EU Guidelines for GMP for Medicinal Products for Human and Veterinary Use, Brussels, March 2015
4. Based on estimates from World Health Organization, Parenteral Drug Association and other industry associations
5. Recent review of regulatory inspection findings for UK wholesale distributors

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Essangui Mbaitjongue is Business Development Manager at Thermo King, a manufacturer of transport temperature control solutions for a variety of mobile applications and a brand of Ingersoll Rand. She holds a Master’s degree in International Economics from La Sorbonne, France, and an MBA from the University of Manchester, UK. With more than eight years’ experience in marketing and business development, Essangui is responsible for developing solutions and services that will meet the needs of customers in the transport of pharmaceutical products.
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