The Guidelines for qualification of cold chain transportation for biological drugs in Brazil

The Guidelines for qualification of cold chain transportation for biological drugs in Brazil : 작성자, 카테고리, 작성일, 조회수, 원문,출처, 정보 제공
작성자	임이슬	카테고리	전문가 인사이트
작성일	2017-10-20	조회수	4,647
원문
출처

글 Priscilla Viana Palhano Lima: GPKOL위원

세부 전문분야 및 컨설팅 내용

Regulatory affairs: Register of products in ANVISA, including the obtaining of necessary license and certificates
GMP: Prepare the company for Sanitary Inspection to obtain the Brazilian GMP (CBPF), and other required certificates

Abstract

This manuscript has as main objective to guide the activities of qualification of transport of active biological inputs, bulk biological in their primary packaging and finished biological products, establishing minimum requirements necessary to be observed for this purpose. The main focus is the foreign companies that wish to export their products to Brazil.

1. Introduction

Biological drugs are often composed of highly complex protein molecules whose biological activity is dependent on their structural integrity. Both chemical and physical instability can contribute to a loss of activity. Chemical instability arises from a change in covalent bonds, whereas physical instability originates when non-covalent forces, which maintain the secondary and tertiary structures of proteins, are disrupted. Physical instability can be minimized with special care in storage and transportation. Normally, to avoid physical instability, these products are kept under controlled temperature.

The cold chain encompasses all storage and transportation facilities, necessary for the embarkation of product requiring refrigeration, from the manufacturer to the end user.

A major concern of the pharmaceutical industry and regulatory authorities is to ensure that drugs are delivered to patients without compromising their therapeutic properties. An increasing number of therapeutic products developed by the biologicals industry (vaccines, biotechnology, among others) require temperature controlled forms of transport. Delays are often encountered during transport, placing product quality at risk when transport times and temperature control can not be maintained. In these cases, the product may undergo a temperature excursion.

The adverse thermal effect on the protein structure may vary from product to product. Some vaccines, for example, are not resistant to freezing while other classes of vaccine remain stable. Generally, lyophilized products are not adversely affected by freezing.

The effect of high or low temperatures on the physical and chemical stability of the medicaments is well known. However, elevated temperatures may also cause an adverse effect on some formulations, for example, the separation of emulsions and sedimentation of active principles in suspensions.

For organic products, storage and transport temperatures are extremely important for the maintenance of the quality of the product throughout its useful life. Although the storage conditions are relatively constant, the delivery environment can vary widely, especially when a drug is transported between different climatic zones. Significant variations also occur depending on the time of year.

In a simple way, the transport chain involves direct shipment from the manufacturer to the customer or end user. In its most complex form, the transport chain involves different storage and transit locations, including airports, ports, warehouses, and different transportation methods. All these variables have a major influence on the transport chain.

To minimize temperature fluctuations during transport, special care must be taken. The main tool used for this purpose is to qualify the cold chain transport systems. The main objective of the qualification is to demonstrate the robustness of the transport systems used, leading to a reduction in temperature excursions, which may occur during transportation.

2. Main Subject

a. LEGAL BASE

Currently, Brazilian legislation for the registration of biological products, RDC No. 55/2010, requires companies to present validation of the transport chain. For this validation of transport, it is necessary to send a qualification of operation and performance of the systems for the international and national transportation of the product, the biological product for the product, the intermediate biological product, the biological product in its primary enterprise, the biological product The diluent and the adjuvant.

The pillars of the qualification of transport systems are a qualification operation and a performance qualification of the system are used for the transportation of biological products. In addition to having the appropriately qualified transport system, according to the stability characteristics of the product, all transport of a biological product must be continuously monitored during the import process for the maintenance of the transport temperature.

These requirements are not defined in paragraph 1 of RDC 38/2010, which amend paragraphs 5 and 6 of article 3 of the RDC no. 234/2005. The importing company has constant temperature records of the transport chain, which prove that the product has been kept within the pre-established transport and transportation conditions. Temperature logs allow you to identify the product name, batch number, time, and send and receive data.

b. VALIDATION X QUALIFICATION

The terms validation and qualification have been used interchangeably by the cold chain industry. In this guideline, the concepts of qualification and validation defined in RDC nº 17/2010 are adopted. The qualification comprises the set of actions taken to attest and document that any facilities, systems and equipment are properly installed and / or function correctly and lead to the expected results.

Validation is a documented act that attests that any procedure, process, equipment, material, activity or system actually and consistently leads to the expected results. In addition, the term validation is used for processes, methods and systems for which conditions can be controlled in the real world. Therefore, transport processes can be qualified rather than validated, since it is not possible to control in the real world all the parameters that can affect the transport process (eg. weather conditions, customs and traffic delays, Mechanical, etc.).

While the qualification procedure is used to provide with a high degree of assurance the result that the process is reproducible under predetermined variable ranges, validation is used to describe how a system will behave under highly controlled conditions. Although RDC No. 55/2010 uses the term "transport validation", in this guideline the term "transport qualification" will be used, based on the justification described above.

c. GENERAL CONSIDERATION

All persons and companies involved in transport activities have a responsibility to ensure that adequate conditions of transport are maintained, from the departure of the manufacturing company to delivery to the final customer. The transport of organic products must be done in a way that does not adversely affect their quality, always avoiding temperature excursions. The temperature at which the biological product is to be transported is that which ensures the maintenance of product quality, as evidenced by the long-term stability study presented. Transport should not be performed in situations other than those demonstrated in the approved long-term stability study.

The company may anticipate temperature excursions throughout the transport, for limited times, provided that it has performed stress stability studies, which support the intended excursions. The transport of biological product means all the activities necessary to send the product of the manufacturing company to its final destination, such as clinics, hospitals, distributors, among other establishments.

In the case of imported products, this activity also includes the transportation of the exporting company to the importing company. The transport of the active biological material, biological product in bulk or biological product in its primary packaging is defined by all transport activities required to send the product from a manufacturing site to the place responsible for manufacturing the subsequent step.

The most appropriate transport systems should be chosen to protect the products from the most extreme temperature conditions which may occur throughout the year on the transport route to be qualified. The transport process must not compromise the integrity and quality of the products.

The drawings of the packaging material and of the transport system must be adequate to prevent physical harm to the medicinal product during carriage as well as possible contamination. As recommended by RDC No. 55/2010, for registration purposes, the qualification of the transportation procedures is mainly understood by the steps of qualification of operation and performance qualification of the transportation system to be used.

In addition to having the appropriately qualified transport chain, all imports of a biological product must be monitored for the maintenance of the storage temperature. In addition, it is recommended to monitor the temperature during transportation of biological products in national territory.

d. TEMPERATURE MONITORS

Electronic temperature monitors are equipment capable of storing data for long periods, creating continuous history for issuing non-editable daily reports. The data sampling interval is adjusted by the user as needed. Temperature monitors should be periodically calibrated to ensure they will operate within the manufacturer's specifications. Monitors should never be used without proper calibration or overdue calibration. The monitors should be located as close as possible to the product as tested in the qualifications.

Electronic instruments, calibrated in the range of use, must be used with a minimum accuracy of ± 0,5ºC and minimum resolution of 0,1ºC. All monitors must be able to record the temperature at each time interval. For this purpose, electronic data loggers are usually used.

In the qualification process, the number of temperature monitors to be used will depend on the size of the load and they should be positioned carefully to ensure that in all parts of the load the temperature remains acceptable. The number of temperature monitors to be used during routine transport shall be determined on the basis of the results obtained in the operating and performance ratings.

Chemical monitors have their working principle based on changing the color or appearance of the indicator, through an induced chemical reaction or phase change, attesting the exposure of the product to temperatures outside established conservation limits. However, these monitors do not allow data collection and hence its history. In general, they do not accurately show the accumulation of exposure time at a given temperature. Therefore, chemical temperature monitors should not be used for the purpose described in this guide.

Some examples of monitoring devices for comparing benefits are described in Table 1.

Table 1. Examples of monitoring devices for comparison of benefits.

e. TRANSPORTATION SYSTEMS

The type of transport system to be used shall be decided according to the size of the cargo, the nature of the product and the risk posed by exposure to high and low temperatures, temperature fluctuations and the time of exposure of the system to adverse conditions .

The systems used for the packaging of products that require maintenance of a certain temperature during transportation can be divided into two groups: active systems and passive systems.

Active systems are those with active temperature control, such as refrigerated containers for air and sea transportation and refrigerated trucks. These systems are thermostatically controlled and typically use fans, dry ice or an electrical cooling system and are powered by an external power source. They are systems that use electricity or another fuel source to maintain a controlled temperature environment within the insulated system under thermostatic regulation.

Passive systems are those without active temperature control, such as thermally insulated containers, made of polystyrene or polyurethane, with refrigerant material. They are systems capable of maintaining a certain temperature range within an isolated system without thermostatic regulation.

f. USER REQUIREMENTS (ROUTES, TEMPERATURE PROFILE, TIME)

User Requirements Specification (URS) is a document that should define the requirements in a detailed and consistent way to meet a qualification project, describing what you want to accomplish with it. These requirements must be written from the user's point of view, without defining its functionality. Approval of this document should be attributed to those responsible for Quality and / or Distribution. At the discretion of the company, this information may be included in the design of the study or qualification of operation.

I) REQUIREMENTS FOR AN URS

I.1) CHARACTERIZATION OF ROUTES

Route is the detailed mapping of the origin to the destination, considering all the logistical nodes and the transport type (s), as well as the time of each step. The characterization of the routes is one of the necessary elements, together with the other logistic elements for the definition of the temperature profile. And this will serve to develop the transportation system and to conduct the qualification tests.

I.2) VERIFICATION OF ENVIRONMENTAL CONDITIONS

Considering the origin, destination (customers) and / or the main logistical nodes, the environmental conditions for each period defined for the temperature profile (eg summer and winter) are checked. For this, it can be based on some survey carried out by the company, or use official meteorological sources.

I.3) DEFINITION OF THE WORST CASE

In addition to environmental conditions, the worst case definition should also take into account the route (duration, distance) and transport steps (as shown in table 2). The worst case conditions can be used to contemplate less critical routes.

I.4) DEFINING THE TEMPERATURE PROFILE

With the times of each step and maximum and minimum temperatures, for the different periods, the temperature profile is defined. It is recommended to display this result graphically.

The definition of the ERU, including the temperature profile, is required for the qualification tests. Each organization or company must define its temperature profile, since the characteristics mentioned above vary according to the route used.

Temperature profiles can be defined by reviewing environmental history data, taking into account the following parameters:

- Temperatures of origin, destination and along transport routes (places of loading and unloading);
- Seasonal temperatures (summer and winter);
- Duration, temperature and location of the various points of handling and stopping along the routes (airport / port, intermediate storage).

Other necessary information, such as time and distance between cities, duration of flights and temperatures (maximum and minimum) in the various cities where deliveries are made, can be obtained from official sources (Instituto Nacional de Meteorologia, Infraero, among others) or Field data.

Historical route temperature data should be considered in order to assess the uniformity of the maximum and minimum temperatures recorded and avoid misunderstandings arising from an assessment based on point data.

Table 2. Examples of Temperature Profile (Summer).

Picture 1. Summer route: 4hs at 25°C / 16hs at 35°C / 16hs at 25°C / 12 hs at 40°C.

The same rationale should be used to define the temperature profile of the winter route.

a. QUALIFICATIONS OF THE TRANSPORT SYSTEM:

The RDC No. 17/2010 defines qualification as being the set of actions taken to attest and document that any facilities, systems and equipment are properly installed and / or function properly and lead to the expected results. All qualifications must always be carried out following a pre-approved protocol. This protocol should be well detailed, describing the types of transport (air, sea, land, etc.) required during the entire route and specifying the conditions under which it occurs (refrigerated truck, for example) and for how long. There should be a description of the storage of the cargo and the auxiliary materials (refrigerant, for example) within the transport system used.

The presentation of photos and diagrams can be a useful tool in understanding the configuration of materials within the transport system. The type of refrigerant used must be informed, as well as its location on the transport system and the quantity to be used. The selection of the refrigerant must be made with criteria.

In some cases, such as when a product is denaturated by freezing, direct contact of the refrigerant material with the product should be avoided using appropriate barriers for this purpose. The use of refrigerant material should not adversely affect the quality of the product and its primary and secondary packaging.

The company should detail how summer, winter and mixed profiles were determined, according to user requirements. The historical weather conditions of the route can serve as a basis for this assessment.

It is recommended that the company keep in its files the calibration certificates of the temperature monitoring devices, informing the date of the last and the next calibration. The location and justification for positioning these devices in the transport system should be reported.

The qualification protocols for transport systems may vary according to the type of transport system chosen. In general, passive systems are more susceptible to thermal variations than active transport systems. However, the qualifications must be completed in both cases.

The acceptance criteria for each qualification protocol must be established. The particularities of each system must be observed. For example, for an active energy dependent system, behavior against a power outage must be tested.

The results obtained during the qualifications should be described in the form of a report. This report should not be limited to presenting the results; They should be widely discussed, using bibliographical references wherever possible.

In the case of transport systems, three types of qualification are usually carried out: design, operation and performance. Design qualification is not required by RDC No. 55/2010. However, where appropriate, companies may submit it together with the transport qualification documentation.

It is recommended that protocols and reports be issued for each step, and the next step can only be initiated after completion and approval of the previous step. For example, Performance Qualification tests may only be initiated after the issuance and approval of the Performance Qualification report.

The maintenance of the "qualified" status should be done through periodic evaluation. A requalification may be necessary when a change is made to an item that has an impact on the qualified system, such as the type, quantity and position of the refrigerant elements, significant alteration of the route, modification of the minimum and maximum loads, Transportation, as well as other relevant modifications.

I) DESIGN QUALIFICATION
Design qualification is performed to ensure that the functional requirements of the proposed transport system are met. This qualification must be performed prior to the operation and performance qualifications.

The parameters evaluated in a drawing qualification usually include:
• duration of the process;
• defined ambient temperature profile;
• location and amount of refrigerant or air conditioning system;
• load configuration in the transport system;
• location of the equipment responsible for monitoring the temperature;
• type of transport system used (isolated or not, passive or active);
• minimum and maximum thermal mass.
A well-conducted design qualification with satisfactory results guarantees high confidence for the qualification of operation.

II) QUALIFICATION OF OPERATION

According to RDC No. 17/2010, an operating qualification is the set of operations that establish, under specified conditions, that the system or subsystem operates as expected, in all operational ranges considered.

The qualification of operation is a simulation of the worst conditions that can happen in a real transport. Testing should be performed in temperature controlled environments, such as in climate chambers.

When it is not possible or applicable to perform the qualification of operation in temperature controlled environments, such as for some active systems and refrigerated trucks, the company should provide a technical justification and the rational of the chosen approach.

This qualification can be carried out with the product or with representative samples of the product, provided that the thermal mass is preserved. Racionals with the worst case can be used to justify that a qualification contemplates other products, as long as justified by the thermal mass. For example, when the product to be transported is a lyophilized vial powder, empty vials may be representative.

Where the transport is relative to vials containing a certain content of injectable solution, bottles filled with placebo or water may be representative, provided the packaged volume is representative of the product volume. Specifically for active systems, the qualification of operation can be performed with the minimum thermal mass configuration and a higher volumetric occupation of the container space, which represents the configuration of the airflow with greater interruption, this scenario being considered a worse case.

Therefore, the operating qualification of the active systems can be independent product. This qualification can be carried out simulating the worst conditions expected for the actual transport, so as to have a safe range for any unforeseen events that may occur during transportation. The company must demonstrate that the transport system is able to maintain the storage temperature of the product, without any temperature excursion, in each tested situation, for a time superior to that anticipated for the actual transport.

In case the company plans a temperature excursion in the qualification protocol, it must inform the maximum time and temperature at which the product can be exposed without compromising its quality, according to the specifications approved in the registration. In these situations, the stress stability studies completed should be presented, as recommended by RDC No. 50/2011, in order to support the proposed temperature excursions.

Sufficient temperature recorders shall be used for the mapping of the qualifying transport system. In this way, the company evaluates the critical points of the transport system, which are more susceptible to temperature variations, justifying the choice of the points to be monitored in the performance qualification and during the actual transport.

The worst case loads should be challenged because the amount of thermal mass may influence the maintenance of the internal temperature. The external temperature must be monitored, so that the most critical temperature situations of the route to be used are simulated. For example, in the case of an import from the northern hemisphere, winter is usually stricter than summer and the reverse occurs for the southern hemisphere.

Therefore, in order to send cargo from the northern hemisphere to Brazil, the winter profile should be similar to that of the country of origin, and the summer profile should be based on the highest temperatures at this time of the year in Brazil.

The company can still test a mixed profile, considering a part of the time in the winter condition and another part of the time in the summer condition, simulating the worst case, which is the shipping during the months of December to March. It is recommended to record the temperatures (both external and internal) within a maximum interval of 30 minutes, for purposes of this qualification. If transportation and opening and closing activities of the transport system are required during transport, as well as the replacement of refrigerant material, these should be included in the qualification protocol.

A sufficient number of tests should be performed to ensure the robustness of the results. Normally, three simulations in each scenario (load and external temperature profile) is the number recommended for the elaboration of the protocol of the operation qualification. Vibration and shock tests can be planned as additional assessments for the qualification of operation of the transport system

III) PERFORMANCE QUALIFICATION

As recommended by RDC No. 17/2010, a performance rating is the documented verification that the equipment or system performs consistent and reproducible performance, according to defined parameters and specifications, for extended periods. Therefore, the performance qualification of a transportation system consists of consecutive shipments of the product (or representative samples of the product) under real conditions to demonstrate that the process is effective and reproducible.

Typically, the qualification is performed using load configurations typical of the product itself. In some situations, the company will be able to carry out the different transports foreseen by the qualification protocol with different loading configurations, to verify if in real conditions, the temperature is controlled in worst case loads. It is recommended that shipments be made with the product itself.

However, when this is not possible, shipments can be made with representative samples of the product, just as it is for the qualification of operation. When possible, shipments for the purposes of this qualification should occur at the time of year where the route temperature is most critical.

Internal temperature monitors should be located at those points rated as most critical during operation and design qualifications, according to system volume and amount of load. The external temperature must also be monitored throughout the transport by at least one monitor.

According to ASTM 3103 Standard Test Method for Thermal Insulation Performance of Distribution Packages, data logging intervals are recommended for 10-30 minutes at both temperatures. The type, number, size, location and quantity and conditions of conditioning of the refrigerant used in this qualification shall be the same as those used in the operating and design qualifications.

A sufficient number of tests should be performed to ensure the robustness of the results. Normally, three submissions is the minimum number considered and recommended for the elaboration of the protocol of performance qualification.

If temperature excursions occur during this qualification, the company must justify and present the completed stress stability studies, as recommended by RDC No. 50/2011, in order to withstand the observed temperature excursions.

h. TEMPERATURE EXCURSIONS

A temperature excursion is a deviation from the approved storage conditions for a product for a certain period of time, either during storage or transport. Temperature excursions should always be avoided, due to the stability characteristics of the proteins against the thermal effect.

For example, temperatures below 0 ° C can lead to freezing which, even for a short time, can irreversibly denature some proteins, leading to a significant loss of effectiveness.

The same phenomenon can also occur with exposure to temperatures above the conservation care. Despite all the care that must be taken during transportation so that the storage temperature is always maintained, sometimes temperature excursions can occur for short periods of time.

All temperature excursions should be immediately and thoroughly investigated. The difficulty in evaluating a temperature excursion is to ensure that a particular excursion will not be able to change the quality of the product throughout its useful life as determined by the shelf life. A brief discussion of some concepts currently used for this assessment is made below

I) MEDIUM KINETIC TEMPERATURE (MKT)

The average kinetic temperature is a calculated fixed temperature, which simulates the effect of temperature variations over a given period of time. The average kinetic temperature is higher than the average temperature and takes into account the Arrhenius equation.

The average kinetic temperature may also be defined as a single calculated temperature where the total amount of degradation over a given period of time is equal to the sum of the individual degradations that may occur at various temperatures.

It expresses the cumulative thermal stress experienced by a product at different temperatures during storage and distribution. However, there are restrictions on the use of MKT.

MKT should be applied only in cases where scientific data related to the thermal stability of the product in question used to establish conservation care allow temperature excursions between 25 ° C and 30 ° C. It is only applicable for products stored at room temperature, with approved conservation care of 15 ° C to 30 ° C. It is not suitable for products that require storage at low temperatures, such as 2 ° C to 8 ° C, for example.

MKT can not be used to compensate for precarious temperature control or absence of temperature control during transport of a medicinal product.

II) ACCELERATED STABILITY STUDY

According to DRC No. 50/2011, accelerated stability studies are studies designed to accelerate the chemical, biological or physical changes of a pharmaceutical product under forced storage conditions. The temperature used is higher than that used in the long-term stability study.

This type of study demonstrates the consequences of a certain temperature on the quality characteristics of a product. However, these studies alone do not serve to demonstrate the impact of a temperature on the quality of a product by the end of the shelf-life. It is a model based only on meeting the specifications for the product at the established times. Only an accelerated stability study is not enough to support temperature excursion evaluations.

III) STRESS STABILITY STUDY

As defined by DRC No. 50/2011, this study is designed to evaluate the impact of short exposures on conditions other than those stated on the product label, which may occur during transport and / or storage. Each stress condition imposed on the product may lead to a certain level of degradation, affecting its quality. Temperature excursions near the storage temperature may affect the product minimally; However, any other stress condition can significantly affect its quality.

As stress conditions are tested and the study continues to be conducted under long-term conditions until the expiration date, this type of approach is able to assess the impact of temperature excursions on product quality. It evaluates the cumulative effect of temperature excursions on product quality.
Currently, this study is required to support the evaluation of possible temperature excursions.

3. Conclusion

This article tried to address the main points to be considered by international companies for cold chain validations requested by ANVISA. However, although different issues have been addressed, many specific points must be analyzed due to the different environmental and bureaucratic conditions found in different countries of the world.

It is fundamental to know, monitor, control and document the activities of storage, distribution and transportation of products sensitive to temperature, always seeking the optimization of the cold chain.

Brazil is a country with several critical factors for the transport of temperature-sensitive medicines, such as wide climatic variation and territorial extent of continental proportions, together with the difficulties inherent in transportation, such as the decentralization of services, the volume of goods circulation, the type of transportation Modal, among other factors.

For these reasons there is great ease in breaking the links of the cold chain and a vulnerability in not guaranteeing the quality and safety of the products in the logistics operations.

References :

Agência Nacional de Vigilância Sanitária – Anvisa. Guide to the Qualification of Transport of Biological Products. MEDICINES - GUIDE nº 02, version 02, of April 11, 2017

Profile :

Priscilla Viana Palhano Lima was Manager of Regulatory Affairs and Special Projects of the Brazilian public laboratory. He was directly in charge of the legal compliance of technology transfers with foreign companies from France, Poland, the United States and South Korea. He has experience in dossier analysis and elaboration of Partnership for Productive Development projects for the Ministry of Health. She is currently a consultant Regulatory Affairs and organizations of Partnership Projects for Productive Development for the Ministry of Health. Priscilla is the founder of the Argo Consulting company that promotes consulting in the areas of regulatory affairs, business development, international partnerships and technology transfers in partnership with MM Assessoria Industrial company.

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The Guidelines for qualification of cold chain transportation for biological drugs in Brazil

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