NOT FOR DISTRIBUTION GMP IN PRACTICE REGULATORY EXPECTATIONS FOR THE PHARMACEUTICAL INDUSTRY FOURTH EDITION. James L. Vesper James L.

Transcription

1 GMP IN PRACTICE REGULATORY EXPECTATIONS FOR THE PHARMACEUTICAL INDUSTRY FOURTH EDITION James L. Vesper

2 ISBN: Copyright 2011 by James L. Vesper. All rights reserved. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Where a product trademark, registration mark, or other protected mark is made in the text, ownership of the mark remains with the lawful owner of the mark. No claim, intentional or otherwise, is made by reference to any such marks in the book. At the time of printing, all web site links referenced functioned, however PDA and DHI cannot guarantee the accuracy of the information or that the listed web sites will not move or delete information. While every effort has been made by the publishers, editor, and authors to ensure the accuracy of the information contained in this book, this organization accepts no responsibility for errors or omissions. The views expressed in this book are those of the editor and authors and may not represent those of either Davis Healthcare International or the PDA, its officers, or directors. PDA Davis Healthcare International Publishing, LLC Bethesda Metro Center 2636 West Street Suite 1500 River Grove Baltimore, MD IL United States United States

3 22 Overview Distribution Practices The storage, transport and handling of finished pharmaceutical products have gained a great deal of attention since the beginning of the 2000s. The rise in biotech products, the increased use and visibility of vaccines, more complicated distribution systems, an awareness of vulnerabilities, and a greater number of counterfeiters and illicit distribution channels have all contributed to the need to have appropriate, safe, secure, and monitored distribution systems and practices. Another expansion has been in the products of interest. Today, there is concern not just on products that must be kept under cold chain conditions (typically below freezing or at 2 to 8 degrees centigrade) but on those that are considered time and temperature sensitive. WHO has defined these as a pharmaceutical good or product which, when not stored or transported within pre-defined environmental conditions and/or within pre-defined time limits, is degraded to the extent that it no longer performs as originally intended. Some national authorities have issued formalized good distribution practices (GDP) and good storage practices (GSP) as guidelines and/or requirements while others (e.g., US FDA) view these practices as part of good manufacturing practice. WHO has developed additional requirements for time and temperature sensitive pharmaceutical products to emphasize special practices and controls needed for this class of pharmaceuticals. 383

4 384 GMP in Practice Assuring the proper environmental, storage, transport, and handling conditions of a pharmaceutical product extends beyond the pharmaceutical manufacturer: it involves all those who handle the product, from land and air cargo services to warehouses to distributors to those involved in the final mile of getting the product to the end user or patient, such as pharmacists and public health care workers. Proper distribution practices apply not only to approved or licensed pharma and biopharma products, but also those being transported to clinical testing sites; physician samples must also be stored and handled properly. Additionally, products that are returned, either for potential re-distribution or for destruction (e.g., damaged products or those subject to a recall) need to be properly handled to ensure their identity and to prevent mix-ups. Inevitably, something will go wrong: an active cooling system looses its primary and secondary power supplies, strikes interfere with the timely movement of a product through customs, or a volcano spewing ash closes down most all air traffic over a continent. Being prepared for such events is essential; having a thorough understanding of the product and data available allows the technical specialists and the quality unit to make decisions on the impact of the event on the product and what it might mean to patients. Relevant Risk Questions Some examples of relevant risk questions related to the concepts that apply to distribution practices include: What are the risks to temperature abuse that a product might experience in a given transport or shipping lane? What are the risks to a vaccine if water ice packs are used? What are the risks to the patient if a product has been exposed to sub-zero degree centigrade conditions for less than one hour? What are the risks to samples of a drug product that are stored in a representative s car during the day?

5 Distribution Practices 385 GMP Expectations 1. The environmental, storage, transport, and handling requirements for each pharmaceutical product are specified and based on relevant, valid evidence. A complete stability profile of the drug product needs to be prepared as the drug and its formulation and presentation (e.g., tablet, capsule, lyophilized) are developed. This would include understanding the impact of temperature, moisture/ humidity, light, and handling on critical quality attributes of the product. Consideration must be given to how the product will be transported, distributed, and used along with the climatic conditions in the markets where the produced will be registered or authorized. GMP Reference Examples US To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability testing described in [ (a)]. Expiration dates shall be related to any storage conditions stated on the labeling, as determined by stability studies described in [ (b)]. There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates [ (a)]. CA The purpose of the written stability program is to ascertain the normal shelf life of the products that is to determine how long the products can be expected to remain within specifications under recommended

6 386 GMP in Practice storage conditions. The requirements for the stability studies (primary and commitment batches) are outlined in the various Health Canada, ICH, and Veterinary International Conference on Harmonisation (VICH) Guidelines. Each packaged dosage form must be covered by a sufficient amount of data to support its shelf life in its trade package [C Rationale]. The stability of the drug is determined prior to marketing and prior to adoption of significant changes in formulation, fabrication procedures, or packaging materials that may affect the shelf life of the drug. This determination is made in accordance with Health Canada and ICH guidelines, which include conditions for storage of stability samples [C #1]. Drug products must be transported in a manner that ensures the products will be maintained within an acceptable temperature range as defined in the approved labelling and supported by stability data. Temperature excursions outside of their respective labelled storage conditions, for brief periods, may be acceptable provided stability data and scientific/technical justification exist demonstrating that product quality is not affected [CA GDP, 3.2.1]. EU The system of Quality Assurance appropriate for the manufacture of medicinal products should ensure that: satisfactory arrangements exist to ensure, as far as possible, that the medicinal products are stored, distributed and subsequently handled so that quality is maintained throughout their shelf life [EU 1.1(viii)]. Specifications for finished products should include or provide reference to: The storage conditions and any special handling precautions, where applicable [EU 4.16(f)]. WHO Quality control should establish expiry dates and shelf-life specifications on the basis of stability tests related to storage conditions [WHO Annex 3 GMP, 17.24]. Stability should be determined prior to marketing and following any significant changes in processes, equipment, packaging materials, etc. [WHO Annex 3 GMP, 17.26].

7 Distribution Practices 387 Transport TTSPPs in such a manner that transport temperatures meet local regulatory requirements at the sending and receiving sites and/or so that temperature excursions above or below the manufacturer s labelled storage temperature range do not adversely affect product quality. Product stability data must demonstrate the acceptable temperature excursion time during transport [WHO Annex 9 TTSPP, 6.2]. (NOTE: There are other relevant guidelines from the WHO, including: Stability testing of active pharmaceutical ingredients and finished pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization, 2009, Annex 2 (WHO Technical Report Series, No. 953), available at areas/quality_safety/quality_assurance/ regulatory_standards/en/ index.html.) ICH A CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs are generally associated with the drug substance, excipients, intermediates (in-process materials) and drug product. CQAs of solid oral dosage forms are typically those aspects affecting product purity, strength, drug release and stability [Q8 (R2), 2.2]. (NOTE: There are other relevant ICH guidelines, e.g., ICH Q1A-Q1F that discuss stability and are outside the scope of this book, available at 2. Vulnerabilities of the product and the storage, transport, and handling requirements are identified and considered when identifying systems, practices, and controls; these are considered when developing risk treatment plans. A vulnerability can arise from an inherent weakness in the design, implementation, or from any other various factor that can be randomly or intentionally exploited resulting in an unwanted

8 388 GMP in Practice event. For example, the protein structure of insulin makes that product vulnerable to freezing. Or, the abuse potential of particular opioid drugs make them vulnerable to theft. A risk assessment must consider the vulnerabilities and how they could contribute to the risk; risk management is used to proactively identify alternatives and prepare for unwanted events. Risk treatment includes control, mitigation, and preparation; they should be considered when reducing potential risks. GMP Reference Examples US (There are no references in 21 CFR 210 or 211 for this specific expectation.) CA GMP basic requirements are as follows: Control of storage, handling, and transportation of the drugs minimizes any risk to their quality [CA Quality Elements, ]. The use of recycled or reprocessed primary packaging components is permitted only after a full evaluation of the risks involved, including any possible deleterious effects on product integrity. Specific provision is made for such a situation in the specifications [C #1]. Storage conditions should be defined and described on the label of the product. All drugs should be stored according to the conditions described on the label. When specified on the label, controls for humidity, light, etc., should be in place. Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean, dry, have adequate circulation and maintained within acceptable temperature limits. To reduce human error, general storage areas are well lit [CA GDP, 3.1.1]. Drug products must be transported in a manner that ensures the products will be maintained within an acceptable temperature range as defined in the approved labelling and supported by stability data [CA GDP, 3.2.1]. The transport process and containers should be designed to prevent damage and maintain the integrity and quality of the drug products. For example, transport conditions for ampoules should limit

9 Distribution Practices 389 their exposure to physical stress to avoid the development of hairline cracks [CA GDP, 3.2.2]. Written procedures for the shipping of drug products should be established. Such procedures should take into account the nature of the drug products, local conditions, modes of transport and any seasonal variations experienced, as well as describe any special handling precautions. These procedures should be qualified to ensure that appropriate conditions are maintained under probable extremes of ambient temperature and should also account for possible unforeseen delays which may occur in shipping/transportation (for example, delays at the border) [CA GDP, 3.2.3]. EU Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that: the distribution (wholesaling) of the products minimises any risk to their quality [EU 1.2(viii)]. The quality risk management system should ensure that: - the evaluation of the risk to quality is based on scientific knowledge, experience with the process and ultimately links to the protection of the patient [and] - the level of effort, formality and documentation of the quality risk management process is commensurate with the level of risk [EU 1.6]. Highly active materials or products should be stored in safe and secure areas [EU 3.24]. Medicinal products should be transported in such a way that: (c) adequate precautions are taken against spillage, breakage or theft; (d) they are secure and not subjected to unacceptable degrees of heat, cold, light, moisture or other adverse influence, nor to attack by microorganisms or pests [EU GDP #20]. WHO The manufacturer must assume responsibility for the quality of the pharmaceutical products to ensure that they are fit for their intended use, comply with the requirements of the marketing authorization and do not place patients at risk due to inadequate safety, quality or efficacy [WHO Annex 3 GMP, 1.3].

10 390 GMP in Practice Highly active and radioactive materials, narcotics, other dangerous drugs, and substances presenting special risks of abuse, fire or explosion should be stored in safe and secure areas [WHO Annex 3 GMP, 12.20]. All entities involved in the distribution process should apply due diligence with adherence to the principles of GDP, for example, in procedures relating to traceability and in recognition of security risks [WHO GDP, 4.5]. Distributors should from time to time conduct risk assessments to assess potential risks to the quality and integrity of pharmaceutical products. The quality system should be developed and implemented to address any potential risks identified. The quality system should be reviewed and revised periodically to address new risks identified during a risk assessment [WHO GDP, 8.8]. Delivery schedules should be established and routes planned, taking local needs and conditions into account. Such schedules and plans should be realistic and systematic. Security risks should also be taken into account when planning the schedules and routes of the delivery [WHO GDP, 12.9]. Products containing narcotics and other dependence-producing substances should be transported in safe and secure containers and vehicles and be stored in safe and secure areas. In addition, applicable international agreements and national legislation should be complied with [WHO GDP, 13.9]. Ensure that buildings used to store TTSPPs have sufficient security to prevent unauthorized access and to prevent misappropriation of goods [WHO Annex 9 TTSPP, 3.6.1]. 3. The environmental, storage, transport, and handling conditions that a product is exposed to are within the defined specifications and consistent with what is required by procedure; monitoring results and records are available to reconstruct the environmental conditions the product was exposed to. With an understanding of the product and its vulnerabilities and environmental and handling requirements, specifications can be set.

11 Distribution Practices 391 Procedures need to be written and approved that describe how the equipment and practices for storage, transport, and handling will, together, contribute to the meeting of the specifications. There must evidence to show that the procedures have been executed and followed. Monitoring data can be collected through a variety of different types of devices to show the conditions that the product was exposed to throughout the storage, transport, and handling process. All data are reviewed to ensure the requirements have been met. Data and records need to be maintained and available. GMP Reference Examples US Written procedures describing the warehousing of drug products shall be established and followed. They shall include: (a) Quarantine of drug products before release by the quality control unit. (b) Storage of drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity of the drug products are not affected [ (a) and (b)]. Written procedures shall be established, and followed, describing the distribution of drug products. They shall include: (a) A procedure whereby the oldest approved stock of a drug product is distributed first. Deviation from this requirement is permitted if such deviation is temporary and appropriate. (b) A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary [ (a) and (b)]. Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or holding of a drug product [ ]. CA All handling of raw materials, products, and packaging materials such as receipt, quarantine, sampling, storage, tracking, labelling, dispensing, processing, packaging and distribution is done in accordance with pre-approved written procedures or instructions and recorded [C #1].

12 392 GMP in Practice The label should specify any special storage conditions required for the product. Adherence to these conditions should be checked, monitored and recorded. Temperatures should be controlled and monitored using calibrated monitoring devices and records of temperature and alarms, where applicable, should be maintained. Monitoring of storage facilities is conducted at points representing the worst case scenarios of the temperature range based on temperature mapping [CA GDP, 3.1.2]. Transportation practices by carriers, including any storage and/or transportation activities performed by sub-contractors, should be verified by reviewing documentation. A record of the review should be kept and any discrepancies should have a follow up [CA GDP, 3.2.8]. Distributors, importers and wholesalers should maintain transportation records of inbound and outbound shipments, including monitoring records where applicable, for a period of one year after expiry date of the product [CA GDP, 3.5.2]. Records of investigations and actions taken in the event of excursions outside predetermined temperature conditions, as per labelled storage conditions are kept for a minimum of one year after the expiration date of the product [CA GDP, 3.5.3]. Recorded temperature monitoring data and alarm records should be available for review. The maintenance and calibration records of the equipment used for monitoring should be maintained [CA GDP, 3.5.4]. EU Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g., temperature, humidity) these should be provided, checked and monitored [EU 3.19]. Written procedures should describe the different operations which may affect the quality of the products or of the distribution activity: receipt and checking of deliveries, storage, cleaning and maintenance of the premises (including pest control), recording of the storage conditions, security of stocks on site and of consignments in transit, withdrawal from saleable stock, records, including records of clients orders, returned products, recall plans, etc. These procedures should be approved, signed and dated by the person responsible for the quality system [EU GDP, 6].

13 Distribution Practices 393 Records should be made at the time each operation is taken and in such a way that all significant activities or events are traceable [EU 4.8]. WHO Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean, dry, sufficiently lit and maintained within acceptable temperature limits. Where special storage conditions are required (e.g., temperature, humidity) these should be provided, controlled, monitored and recorded where appropriate [WHO Annex 3 GMP, 12.16]. Storage areas should be designed or adapted to ensure appropriate and good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Pharmaceutical products should be stored off the floor and suitably spaced to permit cleaning and inspection. Pallets should be kept in a good state of cleanliness and repair [WHO GDP, 9.4]. Facilities should be available for the storage of all pharmaceutical products under appropriate conditions (e.g., environmentally controlled when necessary). Records should be maintained of these conditions if they are critical for the maintenance of the characteristics of the pharmaceutical product stored [WHO GDP, 9.18]. Records of temperature monitoring data should be available for review. There should be defined intervals for checking temperature. The equipment used for monitoring should be checked at suitable predetermined intervals and the results of such checks should be recorded and retained. All monitoring records should be kept for at least the shelf-life of the stored pharmaceutical product plus one year, or as required by national legislation [WHO GDP, 9.19]. Procedures should be in place to ensure that the integrity of the products is not compromised during transportation [WHO GDP, 10.16]. The required storage conditions for pharmaceutical products should be maintained within acceptable limits during transportation. If a deviation has been noticed during transportation by the person or entity responsible for transportation, this should be reported to the distributor and recipient. In cases where the recipient notices the deviation, it should be reported to the distributor. Where necessary, the manufacturer of the pharmaceutical product should be contacted for information about appropriate steps to be taken [WHO GDP, 13.5].

14 394 GMP in Practice Ensure that TTSPPs are stored in temperature-controlled rooms, cold rooms, freezer rooms, refrigerators and freezers which comply with the following requirements. capable of maintaining the temperature range defined by the system set points over the full annual ambient temperature range experienced at the store location; preferably equipped with an auto-defrost circuit which has a minimal effect on temperature within the unit during the defrost cycle and maintains temperature within specification for this period; equipped with a low temperature protection circuit in cold climates where there is a risk of breaching the low temperature set point for TTSPPs that are damaged by exposure to low temperatures; connected to a UPS as described in clause 3.9.1; equipped with a calibrated continuous temperature monitoring system with sensors located at points representing greatest temperature variability and temperature extremes; preferably equipped with continuous humidity monitoring devices with sensors located at points representing humidity extremes; equipped with alarms to indicate temperature excursions and/ or refrigeration failure; fitted with lockable doors, or an access control system, as necessary; locks must have a safety device so that doors can be freely opened from the inside; and qualified as defined in clause 4.7 [WHO Annex 9 TTSPP, 4.3]. Provide thermostatic temperature control systems for all temperature controlled rooms, cold rooms, freezer rooms, refrigerators and freezers, used to store TTSPPs. Comply with the following minimum requirements: system able continuously to maintain air temperatures within the set point limits throughout the validated storage volume; control sensors accurate to ± 0.5 C or better; control sensors calibrated as described in clause ; control sensors located in areas where greatest variability in temperature is expected to occur in order to maximize available safe storage volume;

15 Distribution Practices 395 control sensors positioned at the hot and cold spots determined by temperature mapping, even if affected by door opening, unless recommendations are being made not to store products in such areas; and control sensors independent of the temperature monitoring system [WHO Annex 9 TTSPP, 4.5.1]. Provide temperature alarm systems for temperature-controlled rooms, cold rooms, freezer rooms, refrigerators and freezers, used to store TTSPPs [WHO Annex 9 TTSPP, 4.6.1]. ICH (There are no references in Q8(R2), Q9 or Q10 for this specific expectation.) 4. The facilities, equipment, vehicles, packaging, and methods used for storage, transport, and handling are shown to be capable of meeting the pre-determined requirements; actions such as maintenance and calibration are taken to ensure proper functions are maintained. Consistent with other GMP expectations, facilities, equipment, and vehicles must be qualified to show they can perform as intended. In some cases, qualification activities are relatively simple temperature mapping of a chillroom, for example; other times the task is complex, such qualifying a passive cooling system that is being transshipped from a manufacturing facility to a distribution center in a different country. Risk-based thinking is essential to identify potential failures and take steps to control, mitigate, and then validate what has been put in place to reduce the risk. A risk-based approach can also be used to determine the level of effort to use in the qualification/validation activities. Maintaining a state of control that has been demonstrated involves maintenance and calibration. Risk-based thinking can also be used here to determine the frequency of the maintenance and calibrations.

16 396 GMP in Practice GMP Reference Examples US Written procedures shall be established and followed for cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing, or holding of a drug product [ (b)]. Automatic, mechanical, or electronic equipment or other types of equipment, including computers, or related systems that will perform a function satisfactorily, may be used in the manufacture, processing, packing, and holding of a drug product. If such equipment is so used, it shall be routinely calibrated, inspected, or checked according to a written program designed to assure proper performance. Written records of those calibration checks and inspections shall be maintained [ (a)]. Written procedures describing the warehousing of drug products shall be established and followed. They shall include: (b) Storage of drug products under appropriate conditions of temperature, humidity, and light so that the identity, strength, quality, and purity of the drug products are not affected [ (b)]. CA The label should specify any special storage conditions required for the product. Adherence to these conditions should be checked, monitored and recorded. Temperatures should be controlled and monitored using calibrated monitoring devices and records of temperature and alarms, where applicable, should be maintained. Monitoring of storage facilities is conducted at points representing the worst case scenarios of the temperature range based on temperature mapping [CA GDP, 3.1.2]. Refrigerators and freezers used to store drugs should: be qualified (please refer to "Validation Guidelines for Pharmaceutical Dosage Forms - GUI-0029)" ( dhp-mps/compli-conform/gmp-bpf/validation/gui_29-eng. php); be well maintained; be equipped with alarms;

17 Distribution Practices 397 be free from excessive frost buildup; when combined, be a two door unit with separate freezer compartment and door; allow for adequate air distribution and orderly storage within the chamber. Storage practices and loading configurations should not lead to the obstruction of air distribution; have sensors for continuous monitoring and alarms located at the points representing the temperature worst case scenarios; be calibrated as required by the calibration program; be equipped with a backup power source or have alternate storage available in the event of a power failure for critical refrigeration equipment, including both walk-in and stand alone refrigerators/freezers or warehouses; be of commercial grade and not be of household type, unless they incorporate the above controls. The use of household type refrigerators and freezers is discouraged [CA GDP, 3.1.2]. Written procedures for the shipping of drug products should be established. Such procedures should take into account the nature of the drug products, local conditions, modes of transport and any seasonal variations experienced, as well as describe any special handling precautions. These procedures should be qualified to ensure that appropriate conditions are maintained under probable extremes of ambient temperature and should also account for possible unforeseen delays which may occur in shipping/transportation (for example, delays at the border) [CA GDP, 3.2.3]. Refrigerated vehicles/transportation containers should be mapped and monitored, if they provide the primary means for environmental control. However, this may not be necessary if a qualified insulated container/package, or an appropriate temperature monitoring device on the package or selected packages, or gel packs or similar approved means, or lane profile data are used as the primary means of environmental control [CA GDP, 3.2.6]. Recorded temperature monitoring data and alarm records should be available for review. The maintenance and calibration records of the equipment used for monitoring should be maintained [CA GDP, 3.5.4].

18 398 GMP in Practice EU Storage areas should be designed or adapted to ensure good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required (e.g., temperature, humidity) these should be provided, checked and monitored [EU 3.19]. Premises and equipment should be suitable and adequate to ensure proper conservation and distribution of medicinal products. Monitoring devices should be calibrated [EU GDP, 9]. The first element of the validation of new facilities, systems or equipment could be design qualification (DQ) [EU Annex 15, 9]. Installation qualification (IQ) should be performed on new or modified facilities, systems and equipment [EU Annex 15, 11]. The completion of a successful Operational qualification should allow the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal "release" of the facilities, systems and equipment [EU Annex 15, 15]. Performance qualification (PQ) should follow successful completion of Installation qualification and Operational qualification [EU Annex 15, 16]. Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented [EU Annex 15, 19]. Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation [EU Annex 15, 45]. WHO Storage areas should be designed or adapted to ensure appropriate and good storage conditions. In particular, they should be clean and dry and maintained within acceptable temperature limits [WHO GDP, 9.4].

19 Distribution Practices 399 Physical or other equivalent validated (e.g., electronic) segregation should be provided for the storage of rejected, expired, recalled or returned products and suspected counterfeits [WHO GDP, 9.9]. Pharmaceutical products should be stored and transported in accordance with procedures such that: Appropriate environmental conditions are maintained, e.g., using cold chain for thermolabile products [WHO GDP, 13.4]. Qualify new temperature-controlled storage areas and new refrigeration equipment before it becomes operational. The qualification procedure should: demonstrate the air temperature profile throughout the storage area or equipment cabinet, when empty and in a normal loaded condition; define zones which should not be used for storage of TTSPPs (for example areas in close proximity to cooling coils, cold air streams or heat sources); and demonstrate the time taken for temperatures to exceed the designated limits in the event of power failure. Fully document the initial qualification. Carry out additional qualification exercises whenever modifications are made to the storage area that may increase loading or affect air circulation, or when changes are made to the refrigeration equipment, such as a change in the set point. Consider the need for requalification whenever temperature and/or humidity monitoring shows unexplained variability that is greater than normal. Qualification may not be required for equipment which requires little or no site assembly or commissioning, such as vaccine refrigerators and freezers that have been independently tested and found suitable for the storage of TTSPPs. Independent testing must be carried out between the chosen set points and under the ambient temperature conditions to which the equipment will be exposed during operation. Prequalified equipment of this type must be correctly installed in each location in accordance with written guidance [WHO Annex 9 TTSPP, 4.7]. Where temperature-controlled vehicles are directly owned and/or operated, qualify each vehicle before it becomes operational, wherever possible. The qualification procedure should:

20 400 GMP in Practice demonstrate that the air temperature distribution is maintained within the limits specified throughout the temperature-controlled compartment for both air and product temperatures for commonly used load layouts and at the ambient temperature extremes anticipated during normal operation over known routes; demonstrate the humidity distribution throughout the temperature controlled compartment for commonly used load layouts, where products are being transported that require a humiditycontrolled environment; define zones within the vehicle s payload area which should not be packed with TTSPPs (for example areas in close proximity to cooling coils or cold air streams); demonstrate the time taken for temperatures to exceed the designated maximum in the event that the temperature-controlling unit fails; and document the qualification exercise. An alternative approach is to perform an initial full qualification on each trailer/refrigeration unit type combined with an installation qualification (IQ) for each example when a new vehicle becomes operational. Carry out additional qualification exercises whenever significant modifications are made to the vehicle. Consider the need for requalification whenever temperature and/or humidity monitoring shows unexplained variability that is greater than normal [WHO Annex 9 TTSPP, 6.6]. Calibrate devices against a certified, traceable reference standard at least once a year, unless otherwise justified. Calibration should demonstrate the accuracy of the unit across the entire temperature range over which the device is designed to be used. Single-use devices that are supplied with a manufacturer s calibration certificate do not need to be re-calibrated [WHO Annex 9 TTSPP, 4.7]. ICH (There are no references in Q8(R2), Q9 or Q10 for this specific expectation.)

21 Distribution Practices Excursions and deviations are evaluated and decisions concerning the product are based on relevant, valid data. The environmental monitoring data and other records that are collected throughout the storage, transportation, and handling need to be reviewed in a timely way to ensure that there were no deviations, incidents, or excursions. Should a limit excursion, incident, deviation, or other unwanted event occur, it must be evaluated considering the scope of the problem and the impact of the event, excursion, etc. to the product and the patient/customer. Situations that are outside of the approval or marketing authorization must also be examined. The fact that there has been an excursion or deviation does not mean that the product has been adversely impacted. A critical evaluation by experts examining development and stability data can determine what, if any, potential impact there may be on the product and what that deviation would mean to the customer/patient. It is in these situations where product and process understanding, reliable monitoring and data collection systems, redundancies, and risk-based thinking can have a significant positive impact. Investigations need to be clearly documented with rationales that support the decisions made. These investigations need to be approved by the quality unit and, as required, by the responsible or Qualified Person. GMP Reference Examples US There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated. The quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company [ (a)].

22 402 GMP in Practice All drug product production and control records, including those for packaging and labeling, shall be reviewed and approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed. Any unexplained discrepancy (including a percentage of theoretical yield exceeding the maximum or minimum percentages established in master production and control records) or the failure of a batch or any of its components to meet any of its specifications shall be thoroughly investigated, whether or not the batch has already been distributed. The investigation shall extend to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy. A written record of the investigation shall be made and shall include the conclusions and followup [ ]. CA Temperature monitoring devices or temperature indicators should be used when appropriate. If temperature excursions outside predetermined temperature conditions, as per the labeled storage conditions occur, these excursions must be assessed and documented to determine product disposition. Corrective action should be implemented where necessary and documented. Clear directions should be provided to the recipient for the evaluation of monitoring devices/ indicators and disposition of the products [CA GDP, 3.3.6]. Written procedures should be available describing the actions to be taken in the event of temperature excursions outside the labelled storage conditions. All excursions outside the labelled storage conditions must be appropriately investigated and the disposition of the stock in question must be evidence-based (for example, stability data and technical justification) [CA GDP, 3.1.4]. Records of investigations and actions taken in the event of excursions outside predetermined temperature conditions, as per labelled storage conditions are kept for a minimum of one year after the expiration date of the product [CA GDP, 3.5.3]. Environmental controls play a key role in maintaining drug safety, quality and efficacy. Temperature is one of the most important parameters to control. Drugs must be stored, and transported according to predetermined conditions (for example, temperature,

23 Distribution Practices 403 etc.) as supported by stability data. Temperature excursions outside of their respective labelled storage conditions, for brief periods, may be acceptable provided stability data and scientific/technical justification exist demonstrating that product quality is not affected [CA GDP, 1]. EU Good Manufacturing Practice is concerned with both production and quality control. The basic requirements of GMP are that: records are made, manually and/or by recording instruments, during manufacture which demonstrate that all the steps required by the defined procedures and instructions were in fact taken and that the quantity and quality of the product was as expected. Any significant deviations are fully recorded and investigated [EU 1.2(vi)]. WHO The required storage conditions for pharmaceutical products should be maintained within acceptable limits during transportation. If a deviation has been noticed during transportation by the person or entity responsible for transportation, this should be reported to the distributor and recipient. In cases where the recipient notices the deviation, it should be reported to the distributor. Where necessary, the manufacturer of the pharmaceutical product should be contacted for information about appropriate steps to be taken [WHO GDP, 13.5]. Written procedures should be in place for investigating and dealing with any failure to comply with storage requirements, e.g., temperature deviations [WHO GDP, 13.7]. Damage to containers and any other event or problem that occurs during transit must be recorded and reported to the relevant department, entity or authority, and investigated [WHO GDP, 13.15]. The nature, content and retention of documentation relating to the distribution of pharmaceutical products and any investigations conducted and action taken, should comply with national legislative requirements. Where such requirements are not in place, the documents should be retained for at least one year after the expiry date of the product concerned [WHO GDP, 14.7].

24 404 GMP in Practice Quarantine defective or potentially defective products, products with incomplete or missing paperwork, products that experienced unacceptable temperature excursions during transport, or products suspected to be counterfeit. Do not release until checks have been completed satisfactorily. All unacceptable temperature excursions should be evaluated to determine their effect on the product [WHO Annex 9 TTSPP, 8.2.2]. ICH (There are no references in Q8(R2), Q9 or Q10 for this specific expectation.) 6. Product distribution records are kept to facilitate the withdrawal or recall of products from the market. Withdrawals and recalls of products are unwanted events, but, when they have to be done, detailed, reliable records make the process much easier and faster. GMP Reference Examples US Written procedures shall be established, and followed, describing the distribution of drug products. They shall include: A system by which the distribution of each lot of drug product can be readily determined to facilitate its recall if necessary [ (b)]. Distribution records shall contain the name and strength of the product and description of the dosage form, name and address of the consignee, date and quantity shipped, and lot or control number of the drug product. For compressed medical gas products, distribution records are not required to contain lot or control numbers [ ]. CA The following documents are maintained by the fabricator, packager/labeller, distributor, wholesaler, and importer of a drug as they relate to all operations in Canada: Distribution records of all sales of

25 Distribution Practices 405 drugs, including those of professional samples. Records of all sales are retained or are kept readily accessible in a manner that will permit a complete and rapid recall of any lot or batch of a drug. This requirement need not necessarily involve tracking by lot number. Records to indicate that all customers who have received a recalled drug have been notified [C #3, 3.1, 3.1.1, and 3.1.2]. EU In order to ensure the efficacy of the emergency plan, the system of recording of deliveries should enable all destinees of a medicinal product to be immediately identified and contacted. In case of recall, wholesalers may decide to inform all their customers of the recall or only those having received the batch to be recalled [EU GDP, 27]. Records should be maintained for the distribution of each batch of a product in order to facilitate recall of any batch, if necessary [EU 4.28]. WHO There should be established written procedures, which are regularly reviewed and updated, for the organization of any recall activity. Recall operations should be capable of being initiated promptly down to the required level in the distribution chain [WHO Annex 3 GMP, 6.3]. All competent authorities of all countries to which a given product has been distributed should be promptly informed of any intention to recall the product because it is, or is suspected of being, defective [WHO Annex 3 GMP, 6.5]. The distribution records should be readily available to the authorized person, and they should contain sufficient information on wholesalers and directly supplied customers (including, for exported products, those who have received samples for clinical tests and medical samples) to permit an effective recall [WHO Annex 3 GMP, 6.6]. All records should be readily available to the designated person(s) responsible for recalls. These records should contain sufficient information on pharmaceutical products supplied to customers (including exported products) [WHO GDP, 17.7].

26 406 GMP in Practice ICH (There are no references in Q8(R2), Q9 or Q10 for this specific expectation.) 7. Products returned are isolated and critically evaluated to determine the appropriate action that should be taken. Pharmaceutical products may be returned to the manufacturer, distribution center, or wholesaler for a variety reasons, e.g., overstock returns, damaged, expired, or recalled. Any arriving product must be placed in an isolated or quarantine area so to minimize the chance of its being inadvertently mixed up with releasable stock. In some limited situations, when there is clear, strong evidence that the product is acceptable and has been stored, transported, and handled in an appropriate way, it may be possible to make it available for use. GMP Reference Examples US Returned drug products shall be identified as such and held. If the conditions under which returned drug products have been held, stored, or shipped before or during their return, or if the condition of the drug product, its container, carton, or labeling, as a result of storage or shipping, casts doubt on the safety, identity, strength, quality or purity of the drug product, the returned drug product shall be destroyed unless examination, testing, or other investigations prove the drug product meets appropriate standards of safety, identity, strength, quality, or purity. A drug product may be reprocessed provided the subsequent drug product meets appropriate standards, specifications, and characteristics. Records of returned drug products shall be maintained and shall include the name and label potency of the drug product dosage form, lot number (or control number or batch number), reason for the return, quantity returned, date of disposition, and ultimate disposition of the returned drug product. If the reason for a drug product being returned implicates associated batches, an appropriate investigation shall be conducted in accordance with the

27 Distribution Practices 407 requirements of Procedures for the holding, testing, and reprocessing of returned drug products shall be in writing and shall be followed [ ]. Drug products that have been subjected to improper storage conditions including extremes in temperature, humidity, smoke, fumes, pressure, age, or radiation due to natural disasters, fires, accidents, or equipment failures shall not be salvaged and returned to the marketplace. Whenever there is a question whether drug products have been subjected to such conditions, salvaging operations may be conducted only if there is (a) evidence from laboratory tests and assays (including animal feeding studies where applicable) that the drug products meet all applicable standards of identity, strength, quality, and purity and (b) evidence from inspection of the premises that the drug products and their associated packaging were not subjected to improper storage conditions as a result of the disaster or accident. Organoleptic examinations shall be acceptable only as supplemental evidence that the drug products meet appropriate standards of identity, strength, quality, and purity. Records including name, lot number, and disposition shall be maintained for drug products subject to this section [ ]. CA Finished products returned from the market are destroyed unless it has been ascertained that their quality is satisfactory. Returned goods may be considered for resale only after they have been assessed in accordance with a written procedure. The reason for the return, the nature of the product, the storage and transportation conditions, the product s condition and history, and the time elapsed since it was originally sold are to be taken into consideration in this assessment. Records of any action taken are maintained [C #4]. Documentation is available to support the rationale to place returned goods into inventory for further resale. Wholesalers should obtain guidance from importers/distributors to make an informed decision pertaining to the restock of the product [C #4.1]. EU Any return, rejection, and recall operation and receipt of counterfeit products should be recorded at the time it is carried out and records