Goals
When you have completed this module, you should be able to:
* Perform an audit of warehousing and distribution
* Access and understand warehousing and distribution requirements, including licensing requirements
* Use a range of tools and information, including the contents of this module and the Internet, in support of auditing warehousing and distribution
* Understand and apply applicable GMP standards/regulations to an audit of warehousing and distribution
* Recognize compliance or non-compliance of regulations pertaining to warehousing and distribution requirements.
Definitions
FEFO: An inventory management system where the products expired first are the ones sold first. Known by the abbreviation “FEFO”, First Expire; First Out.
FIFO: An inventory management system where the products received first are the ones sold first or the oldest inventory is the first to be distributed. Known by the abbreviation “FIFO”, First In; First Out.
Finished Product: A product, which is packaged and labeled for supply to a wholesaler, hospital, pharmacy, doctor or patient. The use of this definition in this document includes medicinal products/prescription drugs.
Investigational Medicinal Product: A pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial, including already with a marketing authorization but use or assembled (formulated or packaged) in a way different from the authorized form, or when used for an unauthorized indication or when used to gain further information about the authorized form.
Manufacturer: A firm who is engaged in manufacturing, preparing, propagating, compounding, processing, packaging, repackaging, or labeling of a prescription drug.
In EU-regulation the definition is: A manufacturer is the holder of a Manufacturing Authorisation as described in Article 40 of Directive 2001/83/EC.
Medicinal product: (a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings; or (b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.
Mis-shipment: A shipment of a drug product that is sent to the wrong location.
Prescription drug: Any human drug required by Federal law or regulation to be dispensed only by a prescription, including finished dosage forms and active ingredients subject to section 503(b) of the Federal Food, Drug, and Cosmetic Act.
Quarantine: The status of starting or packaging materials, intermediate, bulk or finished products isolated physically or by other effective means whilst awaiting a decision on their release or refusal.
Sample: A unit of a prescription drug/medicinal product that is not intended for sale but is intended for physicians.
Stop shipment: A drug shipment that is placed on hold pending investigation.
Wholesale Distributor: Any person or firm engaged in wholesale distribution of prescription drugs, including, but not limited to, manufacturers; repackers; own-label distributors; private-label distributors; jobbers; brokers; warehouses, including manufacturers’ and distributors’ warehouses, chain drug warehouses, and wholesale drug warehouses; independent wholesale drug traders and retail pharmacies that conduct wholesale distributions.
In EU-regulation wholesale distribution includes: all activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the public. Such activities are carried out with manufacturers or their depositories, importers, other wholesale distributors or with pharmacists and persons authorized or entitled to supply medicinal products to the public in the Member State concerned.
Explanation of Topic
Warehousing and Distribution covers all activities consisting of procuring, holding, supplying or exporting medicinal products, apart from supplying medicinal products to the public. Since the drug product may not be under company control during warehousing and distribution the distributor is responsible for making sure that no drug gets to an illegal market or is compromised/adulterated and sold on the market. This training module will outline the steps to follow in performing a quality assurance (QA) audit of Warehousing and distribution.
The auditor should cover several GMP Systems and need to be familiar with Good Distribution Practice, GDP as described in the reference section. GDP includes requirements on:
Ø Quality System
Ø Personnel
Ø Documentation
Ø Premises
Ø Storage and delivery on Medicinal Products
Personnel
Wholesalers may not have a “Quality Unit/Quality Assurance function” in place as in most GMP operations. However a representative should be appointed in each warehouse and distribution point and this representative should have defined authority and responsibility for ensuring that a quality system is implemented and maintained. This may not be a full time job and he or she may have other tasks.
Documentation
The principles for documentation should be as follows. SOPs should be in place and cover areas such as
Ø Cleaning and maintenance of the premises,
Ø Pest control
Ø Receipt and checking of the deliveries
Ø Storage, including monitoring and where necessary control of the storage conditions
Ø Transportation conditions
Ø Management and control of road/air and sea transportation
Ø Stock security on site and in transit
Ø Cross contamination control
Ø Withdrawal of stock from saleable distribution
Ø Records, including records of orders & distribution
Ø Handling of returned and recalled products.
Ø Destruction of material
Ø Complaint handling
Ø Handling of suspected counterfeit products
Ø Management of personnel (including training)
Ø Self inspections
Records should be kept of dispatch and receipt transaction, showing
Ø When it was performed
Ø Name, strength, package size and quantity of the product including strength
Ø Batch number
Ø Name and address of customer/supplier
As an auditor you need to ensure that records are detailed enough to support the recall of any product.
Premises
The general requirement for premises is that they should be suitable and adequate to ensure proper storage and distribution of products and any special storage requirements should be met.
Thus it is very much the task of the auditor to tour the facilities and to review the activities to be able to come to a conclusion if the requirements are met. One requirement for example is that receiving and dispatch bays should protect goods from the weather. The solution to that requirement may differ very much in different parts of the world depending on the climate.
Unauthorized entry to the premises must also be prevented. Premises will also differ if the wholesaler applies physical separation of material of different status or uses a computerized system e.g. administrative quarantine. If physical quarantine is used areas must be clearly segregated and with restricted access. If administrative quarantine is used the computerized system must be validated.
Recalled and returned goods should be identified as such and stored in a physically segregated area at all times. Special precautions should be taken for the storage of hazardous, sensitive and dangerous materials. Narcotic drugs should be stored in compliance with National and International regulations on narcotics. Physician samples, registration samples and Investigational Medicinal Products should normally be stored apart from other goods and under the conditions specified by the manufacturer. Storage temperature should be monitored with calibrated devices and recorded at a defined frequency.
The records should be reviewed regularly. Temperature limits should be set based upon the requirements of the product being stored. Placement of measuring probes should be based on appropriate mapping studies. There should be a system to manage stock rotation thus ensuring that material with the earliest expiry date is used first. Regular and frequent checks to verify that the system is operating correctly should be performed.
Transportation and Distribution
Products should only be distributed to authorized wholesalers or to other units authorized
to receive/supply product. Products should be distributed in such a way that:
Ø Product identification is maintained.
Ø Products do not contaminate, and are not contaminated by, other products or materials.
Ø Adequate precautions are taken against spillage, breakage, theft or tampering.
Ø Products are secure and not exposed to unacceptable degrees of heat, cold, light, moisture or other adverse influences.
Ø Cold chain is maintained if required
Ø Temperature is monitored if required
Returns
Returns should be handled in a way that the following is ensured:
Ø Non-defective finished product, which has been returned, should be separated
from saleable stock to prevent redistribution until a decision has been reached regarding their disposal, or recovery.
Ø Finished product, which has left the care of the wholesaler, should only be returned to saleable stock if examination, testing or other investigations prove the drug meets appropriate standards and the site is in agreement
Ø Records of returns should be kept.
Controlled Drugs
If the wholesaler/distributor handles controlled drugs, special precautions need to be in place to ensure safe storage and transportation of these products. The auditor needs to consult and be familiar with the applicable legislation.
Key Parameters in Auditing Warehousing and Distribution
Prior to the audit
* Find out what prescription drug products/medicinal products are at the site.
* Determine if any products have special storage or handling requirements including controlled drugs.
* If available, review observations/actions from previous regulatory inspections
* Review observations/actions from previous audits.
* Review listed reference materials to assure that you are familiar with the regulatory requirements.
* Obtain a list of reported product quality complaints.
During the audit
Inspect the facility and equipment:
Ø Tour the facility.
Ø Look for cracks, peeling paint in the ceiling, walls, and floor.
Ø Look for dust and dirt on racking and equipment.
Ø Review housekeeping logs for frequency of cleaning.
Ø Look for a secured quarantine area – administrative quarantine through a computerized system may be applied.
Ø Inspect the area used to store returned, outdated and damaged drug products.
Ø Review pest control program, logs and receipts.
Ø Review preventive maintenance program and logs.
Ø Ensure products are stored in accordance with their labeling.
Ø Ensure prescription drugs/medicinal products are stored apart from other products
Ø Ensure controlled drugs, if any are stored as required by legislation
Ø Ensure Investigational Medicinal Products are stored separately
Ø Review temperature/humidity charts, logs.
Ø Ensure probes are positioned to give representative values and as found during mapping.
Ø Review calibration program.
Ø Review security system for facility; ensure facility is secure from
unauthorized entry.
Ø Review alarm system and investigations if alarms are activated.
Ø Determine if the facility stores and distributes penicillin or other sensitizing
agents and if there are adequate procedures in place to contain spills and decontaminate the area.
Ø Determine if the facility stores in-process materials, raw materials or excipients that are returned to the manufacturer for further processing.
Ø Determine if the firm has a control system for implementing changes to facilities and equipment, which includes reporting major modifications to the site.
Review the quality system.
Ø Verify that there is an established and approved Quality System/Quality
Policy that is endorsed by management.
Ø Determine if there is a representative with defined authority to implement and maintain the quality system
Ø Verify that the quality system includes individual(s) with the authority to
approve or reject procedures, specifications, and process changes that impact the quality of the finished products.
Ø If in the US review all in state and out of state authorized distributors/wholesale
distributor licenses for the states in which the wholesaler distributes.
Ø Verify that customers are authorized to receive prescription drug
products/medicinal products prior to shipment.
Ø Review disaster recovery plan and testing of plan.
Ø Verify there is a written approved SOP for handling complaints.
Ø Review complaints.
Ø Review the wholesalers role in recalls
Ø Determine if records are detailed enough to permit a recall
Ø Determine if the wholesaler has been involved in recalls and that they have been carried out appropriately and in a timely manner
Ø Verify that there is a system to handle deviations and that deviations are properly investigated
Ø Verify there is a written approved SOP for change control.
Ø Review documentation of changes that have occurred.
Ø Verify that product quality complaints received with returned goods are forwarded to the site.
Ø Verify that an appropriate system for self inspections have been implemented
Ensure that personnel have received adequate training.
Ø Verify that there is a documented training program.
Ø Review actual training documentation for specific employees.
Ø Verify that drug screens and criminal background checks were performed prior to hiring (US requirement).
Ø Verify that job-specific training is conducted and documented for employees.
Ø Verify that training is conducted with sufficient frequency to assure that employees remain familiar with applicable regulations.
Ø Verify that there are clearly written job descriptions for employees.
Ø Verify that the training program incorporates requirements for temporary employees and consultants.
Ø Review list or organization chart of officers, directors, managers and other persons in charge, including a description of their duties and a summary of their qualification.
Ø Verify annual GMP/GDP training is performed.
Ø Verify that a record with an employee’s name, signature, and initials written by the employee, exists.
Review the materials system and ensure that there is adequate documentation.
Ø Verify that the firm has written approved SOPs/procedures that include:
o Generation, change control, approval and issuance of SOPs.
o Receipt of prescription drugs/medicinal products.
o Distribution of prescription drugs/medicinal products, including stop shipments, mis-shipments, and FIFO.
o Conducting an inventory of prescription drugs/medicinal products, including correcting all errors and inaccuracies.
o Returned, outdated, damaged, deteriorated, misbranded or adulterated prescription drugs/medicinal products.
o Storage of prescription drugs/Medicinal Products.
o Recall and/or withdrawal of prescription drugs/medicinal products from the marketplace.
o Identifying, recording and reporting losses or thefts of prescription drugs/medicinal products.
o Documenting deviations and notifying the site.
o Managing temperature sensitive products.
o Managing penicillins or other sensitizing agent spills.
Ø Review actual inventories performed.
Ø Review actual receiving records.
Ø Verify that there are procedures in place to ensure retention of the records for every receipt, distribution or disposition of prescription drug product/medicinal product for the required retention time
Ø Review loss/thefts investigations and reports.
Ø Review the returned/damaged drug log and verify that inventory received matches inventory sent to a site approved reverse distributor.
Ø Ensure that computer systems used to maintain drug inventory and distribution records are validated and subject to change control.
Ø Ensure that computer systems are controlled to prevent diversion and theft of drug inventory.
Ø Review the management and control of road , air and sea transportation
Ø Ensure that products are transported in a secure manner Eg Box/hard sided vehicles for road transportation.
Ø Ensure that if the authorized distributor/wholesale distributor distributes controlled substances, they are following the legal requirements