How Good Distribution Practices Help Ensure Pharmaceutical Quality

As the FDA increases regulations to ensure consumer protections, expectations for pharmaceutical quality are playing a greater role for all stakeholders in the supply chain, from manufacturers and suppliers to pharmacies and clinics. Patients in need of medications rightfully expect that their prescriptions will be safe and effective, since consumers are unable to detect contamination in drugs as they might, say in food, through sight, smell, or touch. More than ever, the industry must take responsibility to increase visibility in the supply chain and improve relationships among all entities involved in distribution.

Of course, managing the quality of medications and vaccines during distribution presents many challenges. Each product has its own different shelf life and storage requirements. On top of that, the various kinds of dosage – injectables, syrups, tablets – require different environmental conditions and therefore cannot be handled with general rules. That’s why formalized Good Distribution Practices (GDP) have significant importance for the pharmaceutical industry.

FDA Current Good Manufacturing Practices (CGMP)

What fundamentally drives the need for a GDP program? Not surprisingly, the Food and Drug Administration. The FDA’s main regulatory standard ensuring quality is the Current Good Manufacturing Practices (CGMP) regulation for human pharmaceuticals. These regulations appear in several parts of Title 21 in the Code of Federal Regulations (CFR), which interprets the Federal Food, Drug, and Cosmetic Act and related statutes.

The FDA carefully monitors compliance with CGMP minimum requirements for the methods, facilities, and controls used in manufacturing, processing, packing, and distributing drug products. Adherence to the regulations ensures the identity, strength, quality, and purity of drugs by requiring that all stakeholders along the supply chain adequately control their operations.

According to the FDA, pharmaceutical distribution best practices start with a quality management system to prevent instances of contamination, mix-ups, deviations, failures, and errors. These formal controls help to ensure that drug products meet FDA quality standards. Keep in mind that CGMP regulations are the minimum requirement.

The flexibility in these regulations allows companies to use new technologies and innovative approaches to achieve higher quality through continuous improvement. Accordingly, the "C" in CGMP stands for "current," encouraging companies to use monitoring solutions that are the most up-to-date. Equipment that was "top-of-the-line" a decade ago may be inadequate by today's standards.

USP Good Distribution Practices (GDP)

U.S. Pharmacopeia (USP) is a key source for pharmaceutical Good Distribution Practices (GDP) applicable to all people and organizations involved in any aspect of the storage and distribution of pharmaceutical products – from the receipt of raw materials at manufacturing plants to the final shipment of finished drugs to the end user.

The key stakeholders include:

• Manufacturers of drug products for human use
• Laboratory operations
• Distribution companies involved in automobile, rail, sea, and air services
• Importers and exporters
• Packaging and repackaging operations
• Third-party logistics providers, freight forwarders, and consolidators
• Mail distributors including the U.S. Postal Service (USPS) and other expedited shipping services
• Retail, compounding, specialty, mail order, hospital, and nursing home pharmacies
• Professional healthcare offices dispensing or administering the drug product

Three core tenants of good distribution practices (GDP). Source: https://foodrugint.com/good-distribution-practices-gdp/

Quality Management Systems (QMS)

USP provides recommendations for a quality management system (QMS) that is the foundation of a good GDP program. A robust QMS includes several sub-systems for managing risk, documentation, storage, transport, and temperature. A QMS acts as the architecture of GDP. First and foremost, it should build on the foundations of the FDA's CGMP. Beyond that, it should be tailored to the specific needs of your operation, and at most, aspire for excellence, rather than mere competence.

There’s no point in adopting processes and procedures related to GDP without putting a QMS in place. All it takes is a single company to neglect implementing a formal system to measure and monitor processes and procedures, to put at risk the efficiency, integrity and cost-effectiveness of the entire supply chain.

Risk Management

Think of risk management as the strategies you create that guide how you build your QMS. That means ensuring your organization’s best interests are served by adhering to proper practices, controls, and procedures, including but not limited to:

• The nature of your drug products
• Distribution requirements on the container label
• Incidents of exposure to adverse environmental conditions
• Number of stages and receipts in the supply chain
• Manufacturer’s written instructions
• Drugs at risk from freezing or elevated temperatures (vaccines, insulin, and biological products)

Examples of common risks include:

• Temperature excursions that cause melting or freezing
• Loss of container integrity during transit
• Exposure to humidity leading to product degradation

Documentation Management

Good documentation practices should be incorporated into your QMS. Documentation should include standard operating procedures, corporate policies, and protocols that delineate the elements of the QMS. For purposes of training and employee compliance, all procedures should be broken out into written steps needed to complete a process and ensure consistent outcomes.

The following should be documented:

• How and when a product should be moved from one transport container or vehicle to another
• How products are handled when equipment malfunctions or distribution is delayed
• How to communicate with the necessary parties

All records and documents should be maintained in accordance with a traceable records-retention program and should be made available upon request to regulatory agencies. In particular, all deviations from proper protocol should be logged and recorded to ensure that subsequent investigations have access to all relevant data.

Storage Management

Good storage management identifies all of the facilities requiring the implementation of adequate controls for drug storage, including:

• Manufacturer warehouses
• Contractor warehouses
• Wholesale distribution warehouses
• Mail order or retail pharmacy storage areas
• Hospital or nursing home pharmacy storage areas
• Border Customs storage areas

For each of these locations, one or all of the following processes should be accounted for depending on the facility’s specific operations:

• Receiving: bringing a drug product into a facility
• Transferring: moving a drug product internally within a facility or into or out of a vehicle
• Storing and holding: maintaining temporary possession of a drug product in the supply chain process, during which no movement of the product will occur

Storage in Buildings and Facilities

Buildings and facilities used for warehousing, storage, and holding of drug products should conform to the following standards:

• Drug product temperatures must be maintained as defined on the product label.
• Storage areas should be of adequate size for their intended use to prevent overcrowding.
• The facility should be designed to control environmental conditions where necessary and be easy to clean.
• Storage should provide for the segregation of approved, quarantined, rejected, returned, or recalled drug products.

Receiving and Transferring Drug Products

Storage includes time spent at the receiving bay area, where products can quickly react to ambient conditions. When drug products arrive at the warehouse loading docks, they should be transferred immediately to a designated storage environment to ensure minimal time outside specified storage conditions. Receiving docks should also be clean and protect deliveries from inclement weather during unloading.

Refrigerators and Freezers

Refrigerators and freezers used to store drug products must maintain temperatures defined on the product label. Typically, a refrigeration unit specification is set to 5° with an allowable range of ±3° to store products labeled 2°–8°. Freezer temperatures may vary and typically range from −25° to −10°.

Products should be organized in refrigerator and freezer units to allow adequate air flow between them. The units themselves should be positioned in the facility so that they’re not subjected to environmental extremes of heat or cold that could affect their performance.

In large commercial units such as walk-in cold rooms, a suitable number of temperature-recording devices should be installed to record and monitor temperatures. Each smaller unit should use digital devices to log and track temperatures within its interior.

Transportation Management

Transport is the movement within the supply chain between distribution facilities by trucks, trains, aircraft, sea vessels, mail delivery vehicles, emergency medical vehicles, and industry representative automobiles. Communication within the supply chain should be coordinated to determine proper timing for drug products to be transported and received, taking into account holiday schedules, weekends, and other forms of interruption.

Pharmaceutical manufacturers should use packaging that best protects the drug product during transport, taking into account seasonal temperature differences and the routes and modes of transport. The type, size, location, and amount of temperature stabilizers required to protect the product should be based on documented studies of specific distribution environments the drug will encounter along the supply chain. Accordingly, environmental conditions should be measured continuously with digital monitoring equipment.

The pharmaceutical distribution process. Source: https://www.bsigroup.com/en-IN/gdp-for-pharmaceutical/

Temperature Management

Temperature is one of the most important environmental conditions to control. Temperatures should be tracked using a system of calibrated monitoring devices that include an alert mechanism if preset temperature ranges are breached, as well as a data logger to record and hold scheduled temperature readings.

Before implementing a monitoring system, each unit of storage (e.g., facility, vehicle, shipping container, refrigerator, freezer) used during distribution operations should undergo a professional temperature mapping to define thermal risks. This protocol helps determine the number of temperature monitoring devices that should be installed in any three-dimensional storage area to comply with product requirements. Temperature stability and uniformity are carefully measured in each direction and axis – top-to-bottom, left-to-right, front-to- back – where products are stored.

Temperature mapping should also account for:

• Maximum and minimum loads to capture temperature variability resulting from variations in temperature mass of the payload.
• Performance of equipment under extreme scenarios including door-open, door-close, and equipment failure
• Performance of storage facilities, transport vehicles, and containers during periods of expected hot and cold weather
• Correlations between ambient conditions and potential thermal risks inside the controlled space (which should be documented once identified)

Drug products should not be stored in areas where a thermal risk has been identified, which should be clearly labeled to ensure they are not used.

The Importance of Continuous Improvement

As a temperature mapping indicates, an independent assessment of compliance against USP GDP guidance is the most effective way to establish that your QMS aligns with FDA CGMP requirements. The increase in global processes coupled with products requiring special environmental controls highlights the need for total supply chain integrity. Continuous improvement is therefore essential in an ever-changing distribution environment under increasing regulatory scrutiny.

Establishing and following GDP need not be complex. Your QMS should be appropriate to the size and intricacies of your company to keep it comprehensible. As new solutions evolve, consider those technologies that will best implement your strategies as part of an ongoing, flexible continuous improvement program.

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