PDA TR39 药品冷链指南

Technical Report No. 39 Cold Chain Guidance for Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products Through the Transportation Environment PDA Journal of Pharmaceutical Science and Technology September/October 2005 Supplement Volume 59 No. S-3 PDA Technical Report No. 39 Cold Chain Guidance for Medicinal Products: Maintaining the Quality of Temperature- Sensitive Medicinal Products Through the Transportation Environment PDA Cold Chain Management Task Force Rafik H. Bishara, Ph.D., Eli Lilly and Company—ret. (Chair and contact person) Jim Antonopoulos, sanofi pasteur Mari Bakken, Abbott Laboratories Daniel Colton, Genentech Inc. Laura Fontan, Human Genome Sciences Derrick Gallagher, Sanofi-Aventis Paul Harber, Eli Lilly and Company Kelly Klien, Wyeth Chris Landauer, Eli Lilly and Compnay Teresa Lucas, Eli Lilly and Company Sarvang Mishra, Wyeth Kevin O’Donnell, Abbott Laboratories Oumer Salim, Wyeth Jeff Seeley, Merck & Co., Inc. Bob Seevers, Ph.D., Eli Lilly and Company Edward G. Smith, Ph.D., Wyeth Douglas Staruk, Wyeth Donald Wilson, Amgen Inc. Cold Chain Guidance for Medicinal Products Technical Report No. 39 Supplement Vol. 59, No. S-3 September/October 2005 © 2005 by PDA TECHNICAL REPORT # 39: COLD CHAIN GUIDANCE FOR MEDICINAL PRODUCTS: MAINTAINING THE QUALITY OF TEMPERATURE-SENSITIVE MEDICINAL PRODUCTS THROUGH THE TRANSPORTATION ENVIRONMENT Table of Contents I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . 2 ● Purpose of Document . . . . . . . . . . . . . . . . . . . . 2 ● Scope of Document . . . . . . . . . . . . . . . . . . . . . 2 ● Process Flow Diagram . . . . . . . . . . . . . . . . . . . 3 II. PRINCIPLES OF QUALIFICATION FOR TRANSPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 III. PRODUCT STABILITY PROFILE . . . . . . . . . . 4 IV. TRANSPORTATION PROCESS FLOW CON- SIDERATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . 5 ● Temperature Profiles for Use in Qualification . . . 5 ● Packaging Components . . . . . . . . . . . . . . . . . . 5 V. DESIGN AND DEVELOPMENT . . . . . . . . . . . 6 ● Develop Functional Requirements Docu- ments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 ● Component Specification . . . . . . . . . . . . . . . . . 6 ● Design Testing . . . . . . . . . . . . . . . . . . . . . . . . . 6 VI. QUALIFICATION TESTING ● Operational Qualification (OQ) Testing . . . . 7 ● Performance Qualification (PQ) Testing . . . . 8 VII. PROCESS IMPLEMENTATION AND TRAINING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 VIII. QUALITY SYSTEMS . . . . . . . . . . . . . . . . . . . . . 8 ● Auditing and Process Assessment . . . . . . . . . 8 ● Regulatory . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 IX. REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 X. GLOSSARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 XI. APPENDIX . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 1Vol. 59, No. S-3, September/October 2005 This document should be considered as a guide; it is not intended to establish any mandatory or implied standard. I. Introduction Medicinal products requiring controlled temperature storage should be transported by appropriately special- ized means to ensure product quality is not adversely affected during transport. These products may be shipped outside of their respective label storage conditions pro- vided stability data exist demonstrating that product qual- ity is not affected. This document presents a design approach to develop specialized packages and systems that will protect tem- perature-sensitive products during transport. The design approach is comprised of three elements. These elements are (1) Identification of Requirements, (2) Development, and (3) Implementation. The distribution environment can vary greatly, especially when transporting medicinal products between climatic zones. Seasonal changes, mode of transportation, and regional regulations and capabilities are also variables that must be considered within the transportation envi- ronment. These variables should be evaluated on a case- by-case basis. Global regulatory expectations and compendial standards regarding good storage and shipping practices and time, temperature, and humidity monitoring devices have been put forth by WHO, EU, Canada, and USP. Purpose The purpose of this document is to provide guidance to industry on the essential principles and practices of trans- porting temperature-sensitive medicinal products through the transportation environment. This process is com- monly referred to as “cold chain.” This guidance has necessarily been written at a high level. As befits a guidance document, it enunciates the what without pro- viding prescriptive detail on the how. Scope The process defined in this document is for thermally controlled transportation of medicinal products. The same principles may also be applicable for intermediates, active pharmaceutical ingredients (APIs), and diagnostic products that require thermally controlled transportation. The level of guidance provided herein should allow firms to develop their own processes and also be aligned with CDER’s General Principles of Process Validation as adapted in this guidance: ● Component Qualification (CQ) X Establishing confidence that ancillary com- ponents are capable of consistently operat- ing within established limits and tolerances ● Operating Qualification (OQ) X Establishing confidence that the process is effective and reproducible ● Performance Qualification (PQ) X Establishing confidence through appropriate testing that the product produced by a spec- ified process meets all release requirements for functionality The above principles may be used to reliably qualify the cold chain distribution process. Even a qualified process is subject to change over time. Therefore, periodic and appropriate monitoring is recommended. The frequency and type of monitoring will be based on the specific conditions of a given distribution process. The diagram in Figure 1 shows an overview of the medicinal cold chain management process flow. II. Principles of Qualification for Transport The principles of qualification for the transport of tem- perature-sensitive medicinal products closely follow es- tablished guidelines and regulations for qualifying the manufacture of these same products. These include ● Development of specifications, processes, systems, and components ● Written procedures ● Approved protocols and reports ● Justified test methods and acceptance criteria ● Qualification testing that challenges “anticipated ex- tremes” 2 PDA Journal of Pharmaceutical Science and Technology Figure 1 3Vol. 59, No. S-3, September/October 2005 ● Ongoing monitoring or periodic evaluation ● Change control Medicinal products are transported in a commercial en- vironment as opposed to a controlled laboratory environ- ment. Therefore, factors such as unforeseen transport events and the weather affect the actual conditions a specific shipment may encounter. These factors should be considered when designing test protocols and in under- standing “anticipated extreme” challenges. III. Product Stability Profile Medicinal products must be transported in a manner that ensures products will be maintained within an acceptable temperature range. This range may differ from the con- ditions specified for long-term storage and is determined by performing product temperature-excursion studies. The objective of this section is to outline studies for evaluating the impact of temperature excursions on prod- uct stability that may occur during transport of medicinal products. Figure 2 shows the basic principles of the proposed studies. These studies will expose medicinal products to temper- ature conditions both within and outside of long-term storage conditions. 1. Long-term stability study—ICH Q1A 2. Accelerated stability study—ICH Q1A 3. Temperature excursion study—FDA 1998 Draft Sta- bility Guidance (see Appendix, Tables I to IV). The idea is to evaluate stability data from long-term and accelerated stability studies, temperature-excursion stud- ies, and/or thermal cycling studies to predict the impact of temperature excursions on medicinal product quality during the transportation process. An example of a com- prehensive study design for a refrigerated product to generate sufficient stability data to determine the poten- tial effect of temperature excursion on product quality is presented in Table V. In this example, the product has three strengths; in addition to long-term and accelerated stability data, a bracketing approach is used in which the high and low strengths are also tested under freezing conditions, at 40°C, and under temperature cycling con- ditions. Other study designs may be used as appropriate. Table VI is an example of compiling the results of the stability studies from the example protocol shown in Table V. This then would serve as a guide to the type and extent of temperature excursions that would be supported by the stability data for this example product. Transpor- tation stability study results from Table V have been used to write the Transportation Control Strategy document shown in Table VI. The stability data support the tem- perature excursions for the time periods indicated. Note: a table such as Table VI must be constructed for each product based on product-specific stability data. The process described covers newer products for which ICH stability data are available. Pre-ICH Guidance prod- ucts will need to be assessed on a case-by-case basis. Figure 2 Proposed Stability Studies 4 PDA Journal of Pharmaceutical Science and Technology A Note on Storage Temperature vs. Distribution Tem- perature: Storage temperatures of drug products are relatively constant, and stability studies intended to sup- port storage conditions take into account expected vari- ations of storage temperatures; thus drug products in- tended for storage at 20°C are tested at 25°C. It is not possible to control the temperature of product in the same way during the distribution process; therefore additional studies at extreme temperatures (e.g., elevated or freezing temperatures) must be performed. Long-term storage or label storage temperatures may be different from short- term shipping/distribution temperatures. IV. Transportation Process Flow Considerations Development of Temperature Profiles for Use in Qualification Studies In order to perform qualification studies of controlled temperature shipping packages and systems, it is typi- cally necessary to conduct laboratory testing to thermally challenge the packages and systems. These tests should be conducted using environmental temperature profiles that are typical of the conditions that the package will encounter during a shipment. In order to develop the testing profiles, the shipper should consider a number of factors, including but not limited to ● Temperature conditions at origin and destination points ● Seasonal temperatures (winter vs. summer) ● Transport routes and modes (overnight air, ground, international, etc.) ● Total duration of transit ● Duration and location of various handling/stopover points along routes ● Product handling and logistics at various handling/ stopover points along routes Whenever possible, environmental profiles should be based on realistic expectations of transport temperatures, which are developed using scientifically sound criteria. This may be done using field-testing (monitoring) of actual shipments, review of historical environmental data, review of published standards (i.e., ISTA 7D), or by other means. Profiles should include anticipated extreme conditions in order to challenge the effectiveness of the cold chain package or system, whenever possible. Anticipated extremes in ambient temperatures to which the product may be exposed are sometimes referred to as “sum- mer” and “winter” or “hot” and “cold” temperature profiles. Where actual historical temperature data in transportation is not available, the scenarios may be defined by calendar months or actual temperatures at product origin, product destination, along the transport route, and at transportation hubs (as applicable). Sound rationale should be provided for the process used in developing temperature profiles used in transport qualification testing. Packaging A container/closure system can be comprised of one or multiple packaging components. The container closure sys- tem refers to the sum of the packaging components that together contain and protect the dosage form or drug product. Container/closure system components are divided into two types: primary and secondary. A primary packaging component is one that is or may be in direct contact with the dosage form. Some examples of primary components are vials, syringes, bottles, rubber closures, and container or closure liners. A secondary component is one that is not, nor will be, in direct contact with the dosage form. Some secondary packaging components are stopper over- seals, overwraps, cartons, and container labels. A market package includes the container closure system, any associated components (e.g., dosing cups, droppers), and external packaging (e.g., cartons, shrink wrap). The market package is the unit provided to a pharmacist, hospital, or retail customer upon purchase but does not include packaging used solely for transportation (e.g., corrugated boxes or insulated containers). Shipment under cold chain controls may be required for both market packages and any precursors to the market package such as APIs, intermediates, excipients, bulk-packaged drug products, or packages of multiple units of the labeled or unlabeled drug product in its container closure system (e.g., vial or syringes). It is important to identify the container closure system because it is the entity that must be temper- ature-controlled during the transport process. Packaging must be identified to determine the amount of thermal mass that must be temperature-controlled. The greater the thermal mass, the less reactive it is to ambient temperature variation. The purpose of secondary packaging is to identify, pro- tect, market, and communicate information about the product. Examples of secondary packaging include la- bels, cartons, and trays. The materials and components 5Vol. 59, No. S-3, September/October 2005 selected for the secondary package may affect the design of the transportation container and/or system. Secondary packaging must be identified to determine the minimum and maximum product loads that can be placed within the transportation container. Secondary packaging also determines the number of primary packages that can be placed within it. The more empty space within the second- ary package not utilized by the thermal mass of the product, the more difficult it is to control the system thermally. V. Design and Development Functional Requirements Document The functional requirements document is the summary of the Identification of Requirements process step. The pur- pose of this step is to document the critical parameters of the product, packaging, and transport system previously iden- tified in Sections I through IV. Critical parameters include ● Transportation (e.g., duration, mode(s), route(s)) ● Product stability (e.g., temperature range established) ● Packaging (e.g., bulk or finished goods) Component Specification (CS) This section of the guidance outlines general principles that apply to product impact components for the transport process. Product impact components are those that may reasonably be expected to have a direct effect on the performance of a transportation system. Examples of product impact components include insulated containers and refrigerants. The component specification establishes confidence that components are capable of consistently performing within established limits and tolerances. A specification should be generated to outline component requirements as applicable. This specification may in- clude, but is not limited to ● Material requirements ● Mechanical requirements ● Dimensional requirements ● Printing requirements ● Storage requirements ● Sampling requirements ● Weight requirements ● Calibration limits ● Fragility limits ● Shock and vibration limits ● Insulation requirements Design Testing Design testing should be performed prior to qualification testing. Design testing is performed to ensure that func- tional requirements are met by the proposed package or system. Design testing process parameters typically in- clude, but are not limited to ● Process duration ● Quantity, temperature conditioning, and location of refrigerant ● Type of insulating material ● Minimum and maximum thermal mass The outcome of design testing assures a high confidence for successful operational qualification (OQ) of a specific package or system. The results of design testing should be formally documented in a report. Design testing is illustrated in Figure 3. VI. Qualification Testing: Operational Qualification (OQ) and Performance Qualification (PQ) A Note on Qualification vs. Validation: Qualification is documented testing that demonstrates with a high degree of assurance that a specific process will meet its pre- determined acceptance criteria. Validation is documented testing, performed under highly controlled conditions, that demonstrates that a process consistently produces a result meeting pre-determined acceptance criteria. There- fore, transportation processes can be qualified rather than validated, since it is not possible to control, in the real world, all the parameters that could affect the transpor- tation process (e.g., weather, customs and traffic delays, mechanical failures, etc.). Even a qualified process is subject to change over time. Therefore, periodic and appropriate monitoring is recommended. The frequency 6 PDA Journal of Pharmaceutical Science and Technology and type of monitoring will be based on the specific conditions of a given distribution process. OQ/PQ must be performed using the designated transport configuration to provide assurance that product quality is maintained during transport. Qualification testing and results should be documented in a formal report. The OQ and PQ protocols, test plans, or SOPs should contain at a minimum the ● Testing objective ● Scope ● Materials description ● Equipment description and calibration information ● Critical quality attributes ● Critical performance parameters ● Test methods and rationale ● Acceptance criteria Qualification Protocol Formal qualification testing should always be performed under a pre-approved protocol, test plan, or SOP. Testing typically consists of OQ and PQ testing. OQ Testing Testing may be performed using temperature-controlled environments (i.e., temperature chambers) or actual ship- ments at ambient temperatures (i.e., field testing), as appropriate, based on the projected transportation chan- nel. The testing should reflect actual transportation load conditions and configurations, and it should capture ex- pected extremes anticipated. Product or approved representative material may be used in qualification testing. Rationale for using approved representative material should be included in the quali- fication protocol. All packaging components used in testing should be approved for use. Calibrated temperature monitors should be placed di- rectly in contact with the product or representative product, if possible, to collect temperature data. Suf- ficient positions within the load should be monitored to get representative temperature data on variances that may be inherent to the load packing, load configura- tion, or manner of transport. OQ testing should include but is n