Why Doesn’t Sashimi Taste as Good at Home?

Understanding the Importance of Cold Chain Management in Pharmaceutical Distribution

Introduction: Cold Chain in Daily Life

Have you ever noticed that sashimi purchased from a supermarket and eaten at home doesn’t taste as good as the sashimi served at a sushi restaurant? One of the main causes of this difference lies in the “disruption of the cold chain.”

Fresh fish such as tuna is strictly maintained under cold chain (temperature control) management to ensure its quality from the moment fishermen catch it until it reaches the fish market shelves. By being refrigerated or frozen immediately after landing and maintaining the appropriate temperature throughout the distribution process, freshness and quality are preserved.

However, what about how consumers handle it after shopping? In many cases, purchased fish is simply placed in a bag and carried home, even under the scorching sun. Especially during summer, the temperature inside the bag rises rapidly during the 30 minutes to 1 hour from shopping to returning home. During this time, the carefully maintained cold chain is broken.

Ideally, one should use an insulated bag, place ice or ice packs inside to prevent the cold chain from breaking, and quickly return home. However, many consumers do not sufficiently recognize the importance of temperature control during this final “last mile.”

This everyday experience applies exactly the same to pharmaceutical supply. In the pharmaceutical industry, an international standard called “GDP Guidelines” has been established, requiring that quality equivalent to that at the time of manufacture be maintained throughout all processes from the manufacturing site to the patient’s hands.

What is GDP (Good Distribution Practice) Guidelines?

Definition and Purpose of GDP

GDP (Good Distribution Practice) refers to standards for appropriate pharmaceutical distribution, establishing quality assurance standards throughout the entire distribution process from when pharmaceuticals leave the manufacturing site, through wholesalers, medical institutions, and pharmacies, until they reach patients’ hands.

In Japan, the “Pharmaceutical Good Distribution Practice (GDP) Guidelines” were issued by the Ministry of Health, Labour and Welfare on December 28, 2018. These guidelines were developed based on the PIC/S (Pharmaceutical Inspection Co-operation Scheme) GDP Guidelines, taking into account the actual conditions of pharmaceutical distribution in Japan, prevention of counterfeit pharmaceutical infiltration, and systems for detecting questionable quality pharmaceuticals.

Background of GDP Guideline Development

The development of GDP Guidelines was based on several important factors.

First, there is the increasing complexity of pharmaceutical distribution routes. With globalization, supply chains from raw material procurement to manufacturing and distribution have expanded internationally, with more stakeholders involved. This complexity increases the risk of quality control gaps.

Second, the 2017 “Harvoni counterfeit product distribution case” had a significant impact. In this incident, counterfeit hepatitis C treatment drugs infiltrated legitimate distribution channels and were discovered just before reaching patients. Fortunately, no health damage occurred because patients who noticed abnormalities did not take the medication, but the incident greatly undermined trust in pharmaceutical distribution safety.

Third is ensuring international harmonization. Japan joined PIC/S in July 2014, necessitating alignment with international GDP standards. In fact, the government already stated in the “Pharmaceutical Industry Strengthening Comprehensive Strategy” formulated in 2015 that it would consider developing domestic GDP standards in accordance with PIC/S GDP.

Objectives of GDP Guidelines

The GDP Guidelines aim to achieve the following objectives:

1. Maintaining Pharmaceutical Integrity: Ensuring that pharmaceutical quality is maintained without deterioration from when pharmaceuticals are shipped from manufacturing sites until they reach patients’ hands. Preventing quality deterioration due to temperature changes, damage from impact, degradation from light, etc.
2. Prevention of Counterfeit Pharmaceutical Infiltration: Thoroughly implementing qualification assessment of business partners, document management, and traceability assurance to prevent counterfeit pharmaceuticals from infiltrating legitimate distribution channels.
3. Quality Assurance During Distribution: Maintaining GMP standard quality established by manufacturers during the distribution process and reliably delivering it to patients.
4. Ensuring International Harmonization: Achieving consistency with PIC/S GMP Guidelines and improving reliability in international pharmaceutical distribution.

Scope of Application of GDP Guidelines

These guidelines apply to pharmaceutical procurement, storage, and supply operations from market shipment to delivery to pharmacies, pharmaceutical sales businesses, and medical institutions. Target pharmaceuticals include all “pharmaceuticals” under the Pharmaceutical and Medical Device Act, including prescription pharmaceuticals, in vitro diagnostic pharmaceuticals (IVD), and over-the-counter pharmaceuticals (OTC).

Main target businesses are as follows:

• Pharmaceutical manufacturing and marketing authorization holders
• Pharmaceutical wholesale distributors
• Pharmaceutical warehouse operators
• Pharmaceutical transportation companies
• Other businesses involved in pharmaceutical distribution

Relationship Between GDP and GMP

While GMP is responsible for quality control in the “manufacturing process,” GDP is responsible for quality control in the “distribution process.” By combining both, consistent quality assurance from pharmaceutical manufacturing to patient supply is achieved from upstream to downstream.

GDP is positioned as complementing the quality assurance standards required in GMP manufacturing, aiming to maintain product quality established at manufacturing sites during the distribution process.

Key Requirements of GDP Guidelines

Quality Management

Wholesale distributors must maintain a quality system that defines responsibilities, processes, and risk management principles related to their operations. All distribution operation procedures must be clearly defined and systematically reviewed.

The scope of the quality system also applies to management and review of all outsourced operations related to pharmaceutical procurement, storage, and transportation. Quality risk management must be incorporated, including evaluation of contractor operational capabilities, documentation and storage, and verification of pharmaceutical sales business permits.

Personnel

An appropriate number of qualified personnel must be assigned and training must be provided. In particular, a person responsible for GDP Guidelines compliance must be appointed, and this person must have knowledge of the guidelines, receive necessary training, and possess appropriate capabilities and experience.

Facilities and Equipment

All equipment affecting pharmaceutical storage and distribution must be designed, installed, maintained, and cleaned according to standards appropriate for their respective purposes. Storage facilities must ensure appropriate environmental conditions (temperature, humidity, cleanliness, etc.) to maintain pharmaceutical quality.

Temperature control is particularly important. Equipment used for controlling or monitoring environments where pharmaceuticals are stored must be calibrated at intervals determined based on risk and required accuracy. Calibration must be traceable to national measurement standards.

Appropriate alarm systems must be provided to issue warnings when deviations from predetermined storage conditions occur. Alarm levels must be appropriately set, and alarms must be regularly inspected to ensure proper functionality.

Document Management

Standard Operating Procedures (SOPs) must be created and documented for all distribution operations. Records must be accurate, tamper-proof, and stored for appropriate periods.

Particularly important documents include:

• Procurement and sales records
• Temperature management records
• Deviation reports
• Change control records
• Regular quality review records
• Business partner qualification assessment records

Supplier Management

It is necessary to confirm that pharmaceutical suppliers comply with these guidelines and have obtained pharmaceutical sales business permits. When starting new transactions with new suppliers, qualification assessment must be performed.

Supplier evaluation should consider the following items:

• Status of permits and certifications
• Status of quality system development
• Past transaction records
• History of quality problems
• Supply stability

Actual Temperature Control in Pharmaceutical Distribution

Importance of Temperature Control

Pharmaceuticals obtain manufacturing and marketing authorization from the Ministry of Health, Labour and Welfare for each item, and storage temperatures are specified in the authorization. Based on this, they are typically stored in the following temperature categories:

• Room temperature storage: 1-30°C (more strictly, 15-25°C is recommended)
• Cold storage: 2-8°C
• Frozen storage: -20°C or below
• Ultra-low temperature storage: -70°C or below (some biopharmaceuticals, vaccines, etc.)

When pharmaceuticals deviate from specified control temperatures, significant impact on quality may occur. In addition to chemical problems such as decomposition of the active ingredient itself and decrease in content, physical and chemical effects may occur due to temperature abnormalities, such as cracking, chipping, or discoloration of tablets, phase separation of ointments and creams, or turbidity or precipitation of injectables.

Biopharmaceuticals, antibody drugs, nucleic acid drugs, and vaccines, which have been increasingly developed in recent years, often have low thermal stability, making strict temperature control essential. The requirement for -75°C storage for some mRNA vaccines against COVID-19 is still fresh in memory.

Temperature Mapping and Temperature Monitoring

GDP Guidelines specify temperature control as follows:

Temperature Mapping Temperature mapping must be conducted under representative conditions before using storage areas. Temperature mapping involves installing temperature loggers at multiple points within spaces such as warehouses or transport containers and analyzing measurement data over a certain period. This allows understanding of temperature distribution characteristics within the space and identification of hot spots (high-temperature areas) and cold spots (low-temperature areas).

Temperature Monitoring Temperature monitoring equipment (e.g., data loggers) must be installed at appropriate locations according to temperature mapping results. Temperature must be constantly monitored, and when preset temperatures are exceeded, the alarm system must promptly notify responsible personnel.

However, simplified temperature control may be acceptable for small facilities of several square meters.

Response to Temperature Excursions

Response when temperature excursions occur is one of the important requirements in GDP Guidelines.

Short-term Temporary Excursions In many companies’ SOPs, short-term (e.g., within 30 minutes) temporary excursions may be acceptable based on risk assessment. However, even when such excursions occur, records must always be kept and impact assessments must be conducted.

Serious Temperature Excursions When long-term temperature excursions or temperature excursions significantly exceeding acceptable ranges occur, the following responses are necessary:

1. Immediately implement corrective actions (temperature restoration)
2. Isolate affected pharmaceuticals
3. Investigate root causes
4. Evaluate impact on quality
5. Promptly contact manufacturing and marketing authorization holders
6. Make recall decisions as necessary
7. Implement preventive measures
8. Document all processes

Actual Conditions and Issues in Shipping Management at Manufacturing Sites

Temperature Control at Truck Yards

Due to the nature of my work, I have opportunities to audit many pharmaceutical manufacturing sites. During these audits, I always check the handling of products at shipping truck yards.

A commonly observed case is where products are brought out to the truck yard and arranged just before the expected arrival time of trucks. At first glance, this may seem like efficient operation. By bringing products out in advance, loading can start promptly as soon as trucks arrive.

Of course, in many companies’ SOPs, short-term (e.g., within 30 minutes) temporary excursions are often permitted based on risk assessment. During the process from temperature-controlled areas within manufacturing sites to shipping areas and loading onto trucks, it is somewhat unavoidable that products are temporarily placed outside controlled temperature ranges.

Risk Blind Spots

However, there are significant risk blind spots here.

Trucks do not necessarily arrive at the same time every day. Various factors such as traffic congestion, accidents, bad weather, and truck breakdowns can delay truck arrival. Especially considering recent labor shortages in the logistics industry and increasing natural disasters, such risks are not small.

Is the lead time from when products are brought to the truck yard until they are actually loaded onto trucks being measured? Even for room-temperature-controlled pharmaceuticals, exceeding 30°C under scorching summer sun is undesirable. Storage temperatures specified in manufacturing and marketing authorization typically state “room temperature (1-30°C)” or “30°C or below,” but from a quality perspective, it is desirable to maintain as low and constant a temperature as possible.

In some cases, when truck arrival is significantly delayed and products are exposed to scorching sun for extended periods, the cold chain may be broken. Particularly for pharmaceuticals requiring cold storage (2-8°C), even if placed in insulated containers, there is a risk of temperature rise during long waiting periods.

Points for Improvement

Improvement measures for this problem include the following:

1. Real-time Temperature Monitoring: Install temperature loggers in truck yards and monitor temperature in real time. Link with alarm systems to immediately notify personnel when temperature excursions occur.
2. Lead Time Recording and Analysis: Record all time from when products are brought to truck yards until loading and analyze regularly. When abnormally long waiting times occur, investigate causes and implement preventive measures.
3. Installation of Refrigeration Equipment: Install refrigeration equipment (air curtains, simple refrigerators, etc.) in truck yards to store products awaiting loading at appropriate temperatures.
4. Precise Management of Truck Arrival Times: Utilize GPS tracking systems to accurately determine truck arrival times. Adjust product delivery timing according to actual arrival times.
5. Clarification of Temperature Excursion Response Procedures: Clearly define response procedures when temperature excursions occur and inform all personnel. Prepare tools and formats for impact assessment.
6. Regular Audits and Reviews: Regularly audit temperature control conditions at truck yards and identify problems. Continuously consider improvement opportunities in management reviews.

Case Study of Temperature Control in Clinical Trial Drug Distribution

Peculiarities of Clinical Trial Drug Distribution

Clinical trial drugs are pharmaceuticals under development that have not yet obtained manufacturing and marketing authorization, and their handling requires particularly careful management. Clinical trial drug distribution is strictly regulated by GCP Ministerial Ordinance (Ministerial Ordinance on Standards for Conducting Clinical Trials of Pharmaceuticals), and thorough quality control is mandatory.

Main requirements for clinical trial drug distribution are as follows:

• Strict adherence to storage conditions described in clinical trial drug management procedures
• Temperature monitoring during distribution and data recording
• Prompt response when temperature excursions occur
• Use of appropriate transport containers and packaging materials
• Documentation of distribution routes and traceability assurance

Problem Case of Data Logger Non-Use

In a certain clinical trial that I experienced, the following problem occurred.

During midsummer, when distributing clinical trial drugs to medical institutions, the delivery company did not include a data logger (temperature recorder) in the packaging.

These clinical trial drugs were transported by dedicated temperature-controlled trucks. In the delivery company’s SOP, dedicated trucks were equipped with systems recording the entire vehicle temperature, which was normally considered sufficient. Indeed, temperature excursions likely did not occur during transportation.

However, there was a serious problem here.

Because individual data loggers were not installed inside the clinical trial drug packaging, there was no evidence that the clinical trial drugs themselves were actually kept at appropriate temperatures.

Why Evidence is Important

One of the basic principles of GCP is the idea that “what is not recorded is the same as what was not done.” This is the principle that no matter how appropriately operations were conducted, without objective evidence (records) proving it, it will not be recognized as having been conducted in audits or inspections.

The following problems arose in this case:

1. Lack of Quality Assurance: Unable to prove that clinical trial drugs were distributed at appropriate temperatures
2. Difficulty Explaining to Regulatory Authorities: Unable to present evidence showing appropriateness of temperature control in GCP inspections
3. Questions About Data Reliability: Reliability of clinical trial data itself may be questioned
4. Protocol Deviation: Possible violation of clinical trial protocols and clinical trial drug management procedures

Corrective and Preventive Actions

After this problem was discovered, the following corrective and preventive actions were implemented:

Corrective Actions

1. Conducted detailed investigation of relevant distribution
2. Cross-referenced vehicle temperature records with distribution records to evaluate possibility of temperature excursions
3. Promptly reported to clinical trial sponsors and principal investigators
4. Conducted impact assessment and determined whether clinical trial continuation was appropriate
5. Created deviation reports and shared with relevant parties

Preventive Actions

1. Revision of clinical trial drug distribution procedures: Made installation of individual data loggers inside packaging mandatory for all clinical trial drug distributions
2. Establishment of data logger calibration management procedures: Conducted calibration traceable to national measurement standards
3. Review of contract terms with delivery companies: Clarified temperature monitoring requirements
4. Re-qualification assessment of delivery companies: Confirmed compliance with GCP and GDP requirements
5. Implementation of training: Conducted training on importance of temperature control for all clinical trial personnel
6. Creation of checklists: Specified data logger installation as pre-distribution confirmation item

Best Practices in Clinical Trial Drug Distribution

The following best practices in clinical trial drug distribution were established based on lessons learned from this case:

Before Distribution

• Identification of clinical trial drugs requiring temperature control
• Selection of appropriate packaging materials and refrigerants
• Preparation and operational verification of calibrated data loggers
• Confirmation of distribution routes and required time
• Agreement on distribution conditions with delivery companies

During Distribution

• Real-time temperature monitoring (when possible)
• Monitoring of distribution status via GPS tracking
• Establishment of emergency contact systems

After Distribution

• Prompt collection of temperature data from data loggers
• Analysis and evaluation of temperature records
• Confirmation of presence or absence of temperature excursions
• Creation and storage of distribution records
• Regular reviews and continuous improvement

Consideration for the World Outside Manufacturing Sites

Gap Between Inside and Outside Manufacturing Sites

Within pharmaceutical manufacturing sites, strict rules are established based on GMP, and quality is thoroughly controlled. Advanced quality assurance systems are constructed in all aspects, including temperature and humidity control of manufacturing environments, cleanliness control, cross-contamination prevention, validation, deviation management, and change control.

However, the moment products leave the manufacturing site gates, their management is entrusted to other businesses (delivery companies, warehouse operators, wholesalers, etc.). A significant gap may exist here.

Even pharmaceuticals perfectly manufactured within manufacturing sites, if quality is compromised during the distribution process, may no longer meet approved quality when they reach patients’ hands. This means that GMP efforts may be wasted.

Responsibility Across the Entire Supply Chain

Pharmaceutical quality assurance does not end at manufacturing site gates. Consistent quality assurance is necessary until products reach patients’ hands and are actually taken.

Based on this recognition, GDP Guidelines require the following responsibilities of manufacturing and marketing authorization holders:

1. Contractor Management: Conduct qualification assessments of contractors such as delivery companies and warehouse operators, and conduct regular audits
2. Quality Agreement Execution: Execute quality agreements with contractors clarifying responsibility sharing for quality, communication methods, and responses during excursions
3. Training: Provide necessary training to contractor personnel
4. Continuous Monitoring: Continuously monitor contractor operations and promptly demand corrective actions when problems occur
5. Regular Reviews: Regularly review quality performance across the entire supply chain and identify improvement opportunities

Commonly Overlooked Risks

Commonly overlooked risks in the world outside manufacturing sites include:

Risks During Transportation

• Delays due to traffic congestion or accidents
• Temperature rise inside vehicles during summer (enclosed vehicle interiors can exceed 50°C)
• Freezing risk during winter
• Damage from vibration or impact
• Deterioration from ultraviolet light
• Long-term storage inside vehicles when recipients are absent

Risks During Storage

• Temperature unevenness in warehouses (hot spots and cold spots)
• Air conditioning equipment failure
• Power outages
• Temperature changes due to seasonal variations
• Expiration due to inventory stagnation
• Mix-up with other products

Risks During Handling

• Inappropriate stacking
• Dropping
• Poor repackaging after opening
• Label peeling or contamination
• Mixing of products from different temperature zones

Risk assessment must be conducted for these risks and appropriate control measures must be implemented.

Challenges in GDP Guideline Implementation

Issue of Legal Binding Force

Japan’s GDP Guidelines are positioned as “guidelines” and do not have legal binding force. This means they are guidelines that companies should voluntarily adopt.

Therefore, the following challenges exist:

1. Temperature Differences in Efforts: Large differences may occur in effort levels between companies
2. Investment Priorities: Investment priorities may be lower because they are not legal obligations
3. Audit Limitations: Mandatory audits by regulatory authorities are not conducted

On the other hand, precisely because they are voluntary efforts, there is also an advantage that each company can respond flexibly according to its own circumstances.

Challenges for Small and Medium-Sized Enterprises

Fully meeting GDP Guideline requirements may require considerable investment in some cases. Implementation of temperature monitoring systems, warehouse facility renovations, purchase and calibration of data loggers, SOP development, training implementation, etc., require many resources.

For small and medium-sized wholesalers and delivery companies, these investments may be a significant burden. However, cases are increasing where large manufacturing and marketing authorization holders and wholesalers request GDP compliance as a condition for continuing transactions, making response increasingly unavoidable.

Ensuring International Harmonization

While Japan’s GDP Guidelines are based on PIC/S GMP Guidelines, they are not completely identical. Parts consider domestic circumstances, and for internationally distributed pharmaceuticals, multiple GDP requirements may need to be met.

Particularly for clinical trial drugs and imported/exported pharmaceuticals, systems must be constructed to simultaneously meet multiple countries’ GDP requirements, which is a challenge.

Future Prospects and Recommendations

Utilization of Digital Technology

In the future, utilization of digital technology is expected to become increasingly important in GDP implementation.

IoT (Internet of Things) Temperature Monitoring

• Cloud-based temperature monitoring systems
• Real-time alert functions
• Automatic recording and reporting
• Predictive maintenance through big data analysis

Blockchain Technology

• Ensuring transparency of distribution routes
• Strengthening counterfeit pharmaceutical countermeasures
• Improving traceability
• Preventing tampering

AI (Artificial Intelligence) Utilization

• Predicting temperature excursion risks
• Selecting optimal distribution routes
• Optimizing inventory management
• Automating anomaly detection

Industry-Wide Efforts

Cooperation across the entire industry, not just individual company efforts, is essential for enhancing GDP effectiveness.

Establishment of Industry Standards

• Standardization of temperature monitoring methods
• Unification of data logger specifications
• Commonization of evaluation criteria during temperature excursions
• Sharing of best practices

Enhancement of Training

• Provision of training programs by industry organizations
• Establishment of certification systems
• Development of e-learning content
• Regular follow-up

Promotion of Information Sharing

• Sharing of counterfeit pharmaceutical information
• Sharing of quality problem cases (in anonymized form)
• Commendation and dissemination of excellent examples

Expectations for Regulatory Authorities

In the future, the following responses are expected from regulatory authorities:

1. Continuous Guideline Revision: Regular reviews based on international trends and technological progress
2. Enhancement of Q&A: Providing clear answers to practical questions
3. Strengthened Monitoring: Investigation and guidance when serious quality problems occur
4. Introduction of Good Examples: Introducing cases of companies implementing excellent efforts
5. SME Support: Consideration of support measures for small and medium-sized enterprises with limited resources

Conclusion

Let us return to the sashimi example at the beginning. Due to temperature control failure during the “last mile” from shopping to home, delicious sashimi is ruined. This is exactly the same for pharmaceuticals.

Even pharmaceuticals strictly managed within manufacturing sites and manufactured at high quality, if quality is compromised during the distribution process, approved quality can no longer be guaranteed when they reach patients’ hands. In some cases, it may even cause reduced effectiveness or safety problems.

GDP Guidelines are important standards for preventing such problems and reliably delivering manufacturing-time quality to patients’ hands. The essence of the guidelines is to extend consideration to “the world outside manufacturing sites” and ensure quality across the entire supply chain.

Even if rules are established within manufacturing sites and quality is strictly managed, cases where consideration does not extend to the world outside manufacturing sites are often seen. As actual cases such as waiting time at truck yards and data logger non-use during clinical trial drug distribution show, there are many easily overlooked risks.

What is important is to always keep in mind the principle that “without evidence, non-deviation cannot be proven.” Leaving objective evidence such as temperature records by data loggers, lead time measurements, and detailed records during excursions is the basis of quality assurance.

All stakeholders involved in the pharmaceutical industry need to share the mission of reliably delivering product quality established by GMP to patients’ hands through GDP. Responsibility does not end at manufacturing site gates; consistent quality assurance responsibility must be held until the moment patients take pharmaceuticals.

This is not merely a matter of regulatory compliance, but a matter related to the fundamental mission of those involved in pharmaceuticals: protecting patients’ lives and health.