Good Storage and Distribution Practice (GSP/GDP), cold chain safety and validation

Good Storage and Distribution Practice (GSP/GDP), cold chain safety and validation

2020-08-05T09:18:18+00:00July 7th, 2020|

Background

Good Storage Practice (GSP) and Good Distribution Practice (GDP) describe human, veterinary and investigational drug substance and drug product supply chain procedures and standards for assurance of the biological/pharmaceutical product identity, strength, purity, efficacy and quality after storage, transportation and distribution operations up to the point of use, i.e, to the point where the patient or end-user receives the product.

GSP and GDP in the biological/pharmaceutical products supply chain are receiving more focus from regulatory authorities lately, and are areas which have been included in recent GMP audits.

As pharmaceutical and biotechnology industry operations became globalized (due to manufacturers’ interest in keeping low production costs), more APIs/DSs (active pharmaceutical ingredient/drug substance) and drug products are being manufactured in one region and then transported/imported/exported to other regions worldwide. As a result, supply chain safety, validation and GSP and GDP have become much more critical and relevant. Uncontrolled or unsafe supply chain steps my lead to huge risks related to product safety and quality that can easily lead to product recalls or risks to patients’ health.

GSP and GDP is a broad topic, and relevant to entities involved in pharmaceutical and biotechnology product handling, storage and distribution, such as manufacturers, contractors, repackaging companies, wholesalers, distributors, hospitals, mail delivery and distribution companies, retail pharmacies, logistics companies, freight companies, and others.

GSP and GDP management, safety and validation should cover warehouses, intermediate/temporary storage and transportation areas, operation vehicles, transportation cabins, aircraft, containers, trucks/automobiles/emergency vehicles, rail cars, ships, etc.

Pharmaceutical/biological products should be kept within the pre-defined controlled environmental conditions, as written on the API/DS or product label, throughout the entire supply chain. Supply chain environmental conditions to which pharmaceutical/biological products are exposed can vary greatly, especially when transporting products between different climate zones. Seasonal changes, mode of transportation, regional regulation and capabilities are also variables that must be considered within the supply chain environment and should be controlled as much as possible. These variables should be evaluated on a case-by-case basis, and risks should be analyzed as part of a risk assessment procedure. Suitable storage and distribution equipment, packaging and facilities should be used to minimize the effect of external environmental conditions on the API/product identity, strength, purity, efficacy, quality and safety.

According to GDP requirements, all relevant entities along the entire pharmaceutical supply chain must assure that product handling, storage, transportation and distribution controls are applied appropriately for temperature, relative humidity, light, oxygen and other relevant environmental conditions, and that adequate control and monitoring of these conditions should be established and validated to assure product identity, strength, purity, efficacy, quality and safety.

Temperature- and relative-humidity-controlled transportation of products require the use of special temperature and relative humidity handling and equipment during storage, transport and distribution. Products may be shipped outside their official storage conditions only based on approved stability data or other scientific/technical justifications (such as Mean Kinetic Temperature or other relevant parameters) which demonstrate that product quality will not be adversely affected from the time of product manufacturing until it arrives at the wholesaler.

GSP and GDP are further detailed in USP 1079, PDA technical reports, ISPE and other documents.

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Glossary

  • First Expiration, First out (FEFO) – Inventory control methodology that assures material/product with the shortest remaining shelf life will be distributed/used first.
  • Logistic Service Providers (LSP/3PLs) – Freight forwarders and brokers that assist product transportation but may not physically touch the product.
  • Mean Kinetic Temperature (MKT) – A single derived temperature , which if maintained over a defined period, would afford the same thermal challenge to a pharmaceutical product as would have been experienced over the range of both higher and lower temperatures for an equivalent defined period (ICH, Q1A).
  • Transportation service provider – Company that physically transport the product.
  • Validation Master Plan (VMP) – Approved plan that documents rational for the approach to validation, defines the validation scope and lists all systems and their validation status.
  • Verified Accredited Wholesale Distributors (VAWD) – An accreditation governed by the U.S national Association of Boards of Pharmacy for pharmaceutical wholesale distribution facilities indicating they are in compliance with state and federal laws.

Procedure

According to PDA technical report No. 52, Good Distribution Practice includes seven different categories:

  • Stability

Stability studies data will be collected, analyzed and used in order to determine the required conditions for safe storage, transportation and distribution of the product.

  • Storage conditions

In case specific storage conditions for the Pharmaceutical/Medical product are required, it should be defined on the product label. Storage or cargo areas should be designed and equipped properly in order to maintain these conditions within the defined limits. These areas should be validated and relevant storage parameters should be mapped through the entire storage area. Moreover, conditions should be constantly monitored using an appropriate calibrated instrumentation. Specifically for temperature monitoring, the calibrated temperature data logger should indicate and record when, for how long and what was the temperature at the exact time period it was out of the defined allowable temperature limits. The effect of deviation on product quality will be using product stability data and characteristics/parameters such as MKT. Storage conditions should be monitored and controlled in the entire storage area/warehouse volume and not only in adjacent to the floor level. Data loggers and other monitoring devices should be located in the worst case locations identified in the Validation stage (warmest, high humidity etc.). Data loggers should technically allow continuous monitoring as well as alarms generation in cases of the monitored parameter deviations (outside the limits) were monitored.

As part of Computerized System Validation, data loggers and other monitoring, alarm systems and software should be Qualified / Validated and comply the GAMP, Annex 11 and 21CFR part 11 standards.

In cases of out of range storage and/or transportation conditions, a deviation should be reported to the manufacturer immediately and until deviation closure, the product should be kept in “hold” and should not released to the market. The deviation should be investigated for root cause, corrective actions implementation and the potential product impact should be assessed. Moreover, as part of CAPA process, preventive actions should be considered as well.

  • Shipping conditions

Pharmaceutical and Biological products should be transported in such a way that will maintain and control the environmental conditions that the product is subjected to as well as other conditions that may affect product quality and safety. Shipping conditions should be monitored continuously through all shipping routes, unless it was validated under supply chain Validation. The shipping conditions may differ from the product long term recommended storage conditions, for a limited time periods during shipment, based on excursion, forced degradation, freeze-thaw, accelerated and long term stability studies results and other challenging studies in order to assure no impact on product quality during shipment. Product impact should be assessed for shipping conditions (single as well as cumulative excursion) during the storage, shipment and distribution process.

  • Stability testing to support distribution

Primary and secondary Pharmaceutical/Biological/Medical product packaging should be designed in such a way that will protect the product from mechanical and environmental conditions impact in addition to product identification and other relevant information that suppose to be printed/labeled on product packaging. Product packaging type and material should be designed considering several issues including transportation mode, conditions, routes and destination (for example: for cold chain it is recommended to use non-paper labels). In case specific storage conditions are required, the packaging type and design should support maintaining the required conditions through the whole supply chain including during product handling, storage, transportation and distribution activities. In addition, the Pharmaceutical/Biological/Medical product packaging should be validated after Risk Assessment completion. Allowable time period for product handling, storage, transportation, repackaging and distribution exposure outside the storage conditions specified on product label will be based on the product stability data. These ‘out of range’ time periods and conditions should be monitored, controlled, documented, investigated and justified.

  • Distribution control management

Distribution control management purpose is to define the required process and controls in order to assure product safety, identity, quality, integrity and tractability through the entire supply chain life cycle. “Track & Trace” methodology should be implemented as part of supply chain control. Every packaging configuration of the product, from primary package to the shipment pallet should be aggregated and identified using bar-codes (visible and non-visible).

  • Qualification and training of personnel

Employees, logistics service providers and contractors who were hired for Pharmaceutical, Medical and Biological product supply chain, need to be trained and qualified for their job in addition to background check. Controlled documents such as policies and SOPs should be written and trained for all supply chain functions and relevant personnel in the manufacturer company and related companies, service providers and contractors.  In cases of narcotic and hazardous products/material handling, storage, transportation and distribution- dedicated SOP’s and training should be implemented and documented, in addition to securities pro-active actions required for narcotic material handling, storage and distribution. Training program, requirements, frequency and documentation should be based on Good Manufacturing Practice standards and principles.

Validation

  • Equipment, facility and packaging Validation

Warehouse, storage equipment, containers, packaging, vehicles and other system which may have an impact on product quality or GMP should be qualified including Design Qualification, Installation Qualification, Operational Qualification and Performance Qualification.

  • Computerized system and software validation

Warehouse computerized system and software for inventory management, monitoring, alarms, track & trace and others should be validated according to 21CFRpart 11, GAMP and Annex 11 standards. For more information refer to article: Computerized System Validation

  • Validation scope

Qualification and Validation for the facility, equipment, utilities,software and computerized systems should be completed before using it for product/material storage and distribution.

The validation activities scope may vary from one facility to another. Below examples for recommended qualification and validation stages:

  • URS (User Requirements Specifications)
  • Validation Plan
  • Risk Assessment
  • DR (Design Review)
  • DQ (Design Qualification)
  • IQ (Installation Qualification)
  • OQ (Operational Qualification) including Passive shipping systems
  • PQ (Performance Qualification) including Active shipping
  • Ambient temperature profile
  • Computerized System and software Validation
  • Monitoring and alarm software Validation
  • Facility Qualification
  • Warehouse management system Validation

Material handling

Material and product handling procedures should be clearly defined and cover all relevant aspects. SOPs should define all areas including (but not limited to) delivery, receipt, storage, transportation, shipment and distribution. Conditions and procedures for receiving and shipping areas, where the product is not stored for long time period but may subject the product to non-controlled environment, should be clearly defined. Product’s status determination and quarantine procedures should be defined and implemented.

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Storage and inventory control

Product’s relevant data such as product name, batch number, expiry date, storage location, storage conditions, product status, bar-code and others should be tracked, traced and recorded using validated software/system and relevant SOP’s. Procedures and software should be Qualified/Validated covering inventory, product status control and in-transit storage. These systems will be secured and include environmental control, monitoring, GPS technology based products track & Trace systems and alarms.

Transportation

Pharmaceutical, Biological and Medical products should be transported keeping product identification, safety, purity (contamination and cross contamination), security (spillage, breakage and theft), stability, packaging/labeling and pest controlled in addition to stable ambient conditions (temperature, light, humidity, oxygen etc.). Products that require controlled storage conditions will be transported with appropriate controls and monitoring. In cases where a specific parameter is out of the defined range, the relevant personnel should be alert immediately to avoid low quality or unsafe product reaching the wholesalers. Transportation duration will not exceed the transportation time covered under Shipment Validation.

Transportation loading pattern and configuration will not exceed the transportation load under tested as part of the Shipping Validation.

Existing transportation routes should be covered under Shipment Validation worst case tested as part of the Validation.Every new route and/or changes in existing routes will be verified to meet the Validation. In case not covered, the Validation should be repeated as part of the Change Control procedure.

Refrigerators and freezers and other containers for coolants storage to be used in cold chain transportation should be properly designed for the specific transportation route, conditions and climate of the transportation region should be validated. Validation should include summer time and winter time validations.

Temperature controlled products for international shipments should be labeled properly and according to the IATA regulatory requirements.

Product shipment conditions (usually temperature) may differ from the long term product stability data and are usually based on Mean Kinetic Temperature values, accelerate stability, temperature cycling, temperature excursion and transportation studies that were performed on the product, usually in the product development stages. In these studies, product is exposed to shipment conditions outside the defined long term storage conditions submitted for approval, in order to predict and control the potential impact of “extreme” storage and transportation conditions excursion on product quality, purity, identity and safety.

Vehicles and containers used for product storage, transportation and distribution should supply the required environmental conditions, package & label integrity and contamination prevention through all transportation stages and routes including loading, unloading and transportation.

Vehicles Validation should be performed in the entire cabin volume where product can be stored. Based on Validation results, the vehicles calibrated monitoring sensors should be located in the worst case location identified as part of the Validation stage. Moreover, vehicles should be inspected and documented for cleanness, malfunction, visual inspection, control parameters and set points routinely prior to product loading and transportation.

Product disposition, protection and returns

  • Medical, Pharmaceutical and Biological products and materials can be distributed to qualified suppliers sites only. Usually, product and materials will be distributed according to FEFO (first expiry first out) methodology.
  • Quality System, GMP (Good Manufacturing Practice), GSP (Good Storage Practice) and GDP (Good Distribution Practice) implementation are essential in order to ensure products are handled, stored, transported and distributed in an appropriate manner that does not impact or deprecate product quality and safety and protect it from environmental conditions outside the defined range such as chemical, light, humidity, oxygen, temperature, pest infestation and other adverse influences that can potentially cause chemical, microbial contamination, degradation or physical damage. Moreover, warehouse, vehicle, containers, packaging etc. should be clean and free from dirt, dust and pests. Adequate precautions should be taken in order to avoid spillage, breakage and even harm the packaging (or peel product label) that can attracts microorganisms, cause cross contamination and mix up.
  • Any shipped returned Medical/Biological/Pharmaceutical product must be evaluated in accordance with return procedures and return management policies in order to determine if the material/product quality and safety were kept and the product is eligible for restocking. In case of unclear product status or missing data, the product/material must be destroyed. Product/material can be returned and restocked only if it is clear after detailed investigation that the returned product/material quality was maintained.

Cold chain returns should be destroyed anyway.

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Management duties

  • Exception management

Product and quality non-conformities should be routinely reported, investigated, tracked and analyzed using risk based approach, CAPA (for more information refer to article Corrective And Preventive Actions – CAPA system), complaints management, product holds/release, recall policy etc.

  • Performance management

Quality System performance should be monitored, reviewed and assessed periodically. Opportunities for continuous improvement should always be identified, documented and implemented.

  • Performance management and reporting

Performance reports should be generated and reviewed periodically in order to track performance, monitor trends and identify areas of potential improvements to be implemented.

  •  Self inspections

Quality Assurance management is obligated according to GMP principles for supply chain partners third party GMP, GSP and GDP audits and other quality inspections) . Audits will be performed periodically. Summary of observations should be documented, discussed and relevant mitigation activities should be implemented based on Change Control and CAPA methodologies (for more information refer to article Corrective And Preventive Actions – CAPA system)

  • Management review meetings

Quality Management System reviews should be performed on regular basis and should cover issues such as improvements opportunities, internal audits, performance, non-conformity status, CAPA, customer complaints, product status, Change Control etc.

  • Supply chain partner management

The Quality System of supply chain partners, logistics service providers and outsourcing companies is critical for product safety and quality. Most of the Pharmaceutical and Medical companies cannot complete the entire supply chain duties, with no supply chain partners, contractors, logistic service providers and outsourcing companies. The manufacturer should emphasis the requirements detailed below in order keep low risks level at his supply chain:

  • Partner selection

Logistics service providers, outsourcing companies and partners should be evaluated for their GSP, GDP, GMP capabilities and compliance prior to contract establishment. The preferred partner should maintain a Quality System including sufficient qualified personnel. A partner selection procedure should include GSP, GDP and GMP audits that will assess the Quality Management System level. These audits should include transportation safety records, regulatory certificates, policies and procedures, vehicles and equipment, securities, calibrations, validation and qualification, training etc. In several cases, the manufacturer, who usually is well known with Quality System regulatory requirements, should support the partner implementing the required improvements to achieve the desired level.

  •  Quality audits

Services agreements and quality agreements should be established with the supplier chain partner, logistics service providers and outsourcing companies. Quality System reviews, inspections and audits frequencies should be defined in these agreements.  Quality System reviews, inspections and audits will be performed by the quality department of the manufacturer or by external consultants and should be appropriately documented in order to enable mitigation activities reporting, implementation and effectiveness follow ups.

  • Quality agreements

Quality agreements should be signed between manufacturer and other logistics service suppliers, partners and contractors before starting working together. These agreements enforce these partners to follow the quality and other GMP, GSP and GDP standards that were established and to keep high transparency level in front of the manufacturer in cases of deviations and other observation were detected and specifically in cases that it may affect product quality and safety.

  • Business review meeting

Business review meetings should take place routinely and will cover areas such as deviations, malfunctions, quality audits results, performance, CAPA, product recall/returns, new products storage and distribution requirements, Change Control and opportunities/recommendations for improvement.

  • Continuous improvement

As part of the GSP and GDP principles, the quality of the stored, shipped and distributed Medical product is a dynamic process and therefore continuous improvement methodology should be kept through the whole life cycle of the process. Continuous improvement should include (but not limited to) the following principles:

  • Industry trends –  Monitoring, documentation, analysis and investigations
  • Regulatory trends- Review, analysis and implementation
  • Re-qualification – Periodically Qualification and Validation for the equipment, vehicles, warehouse, computerized systems, software and other related system that may have an impact on the supply chain quality and safety.
  • Import/export compliance

As part of Medical/Biological/Pharmaceutical import/export compliance, the following activities should be implemented:

  • Regulation
  • Custom release
  • Documentation control
  • Product Track & Trace
  • Parameters monitoring

GSP and GDP implementation tips

Good Storage and Distribution Practices implementation should include the stages detailed below:

  •  Product characteristics related to storage and distribution conditions
  • Risk Assessment
  • Determining proper storage, handling and distribution practices including writing and training relevant policies and procedures.
  • Communicating storage and distribution practices through the entire supply chain including quality agreements, audits, service agreements, technical agreements etc.
  • Product stability data and other relevant information and data available for deviation investigation.

Quality Management System should establish program that will cover areas such as:

  • Storage Management system that manage warehouse and storage control.
  • Distribution Management system that manage transportation and distribution control
  • Environmental Management system that manage and monitoring controlled climate conditions control relevant parameters
  • Risk Management system that identify, analyze and control exposure to adverse conditions and other potential risks that the product/material is exposed to through the entire supply chain including vibration, packaging, container closure integrity, inversion, high risk products etc.

Biochem has been advising biomedical companies for more than 13 years.
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