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International Clinical Trials
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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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