Good Distribution Practice of Human and Veterinary Medicinal Products and Medical Devices

1. Good Distribution Practiceof Human and Veterinary Medicinal Products and Medical Devices

2. Overview • Introduction (page 1) • Scope (page 2) • Quality Management (page 3) • Personnel (page 14) • Premises and Equipment (page 19) • Documentation (page 28) • Operations • Complaints, Returns, suspected falsified Medicinal Products and Medicinal Product Recalls • Contract Operations • Self Inspection • Transportation • Brokers

3. Introduction Distributionis an important activity in the integrated supply-chain management of pharmaceutical product. Numerous people and entities are responsible for the handling, storage and distribution of such products. In some cases, a specific person or entity is responsible only for specific elements of the distribution process. The objective of this presentation is to assist in ensuring the quality and identity of Pharmaceutical product in the storage and distribution process is maintained.

4. Scope This training applies to the procuring, storage, sale and distribution of pharmaceutical and veterinary medicines and medical devices. The training covers controls to be applied in ensuring the product Quality, Safety and Efficacy is not compromised during the supply chain handling of product. Note: Distribution of starting materials is not covered in this training.

5. Organisation Structure Policy Procedure Process Resource Quality Management (1)Quality System • Quality System

6. Quality Management (2)Quality System • A Responsible Person (RP) must be appointed at each distribution site with direct contact with company Managing Director • The RP is suitably qualified with a number of years working knowledge of pharmaceutical storage, distribution and Quality.

7. Quality Management (3)Quality System • The RP should have a defined authority and responsibility in ensuring that a quality system is implemented and maintained • The Quality System must be adequately resourced with competent personnel, suitable premises, equipment and facilities • All quality activities to be well defined in procedures and their effectiveness monitored • A quality Manual or equivalent should be established • A change control system should be in place to manage critical process changes. This system should be part of the risk management programme.

8. Quality Management (4)Quality System • Ensure…. • Products are procured, stored and supplied or exported in accordance with the requirements of GDP • Clearly defined management responsibilities • Product delivered to correct recipient and within the agreed time period • Quality related activities are documented at the time they are performed.

9. Quality Management (4)Quality System • Deviations from procedures are documented and investigated within a defined time period • CAPA system is in place to correct deviations and prevent them in line with principles of Quality Risk Management .

10. Quality Management (5)Management of Outsourced Activities • To control and review the outsourced activity, the Quality Risk Management programme should be followed. This will include: • Assessing authorisation status, suitability and competence of contractor prior to outsourcing services • Defining in a Quality Agreement the responsibilities and communication process for quality related activities between involved parties • Monitoring and reviewing outsourced services and implementing any improvements required on an ongoing basis.

11. Quality Management (6)Management Review and Monitoring • Periodic senior management review of QMS to include assessment of: • Complaints • Deviations • Recalls • CAPA • Change Control • Self inspection and regulatory audits • External audits • Risk assessments

12. Quality Management (7)Management Review and Monitoring Continued…. • Regulation updates – likely to impact company QMS • Innovations to enhance company QMS • Changes in Company strategy Note: This list is not exhaustive • Senior management reviews should be performed at least annually. Must be effectively documented and communicated to all applicable parties.

13. Quality Management (8)Quality Risk Management (QRM) • A systematic process for: • Assessment • Control • Communication • And review of the risk to the quality of product • Can be applied both proactively or retrospectively • Evaluation is based on scientific knowledge and experience with the process and product • The greater the risk the greater the amount of information required for assessing the risk (documentation commensurate with level of risk) • Further information on the application of QRM can be found in ICH Q9.

14. Personnel The Responsible Person (RP) for GDP (1) • Every Distribution company must have a permanently available RP • They should meet the conditions provided for by the legislations of the member state concerned in relation to qualification and experience • Must be able to demonstrate that wholesale distributor is in compliance with GDP and public service obligations are met

15. Personnel The Responsible Person (RP) for GDP (2) • Responsibilities include and are not limited to: • QMS implemented and maintained • Focus on authorised activities and accuracy and quality of records • Approval of initial and continual training programme for all personnel involved in distribution activities • Coordinate and perform effectively the recall of product • Timely investigation and closure of complaints • Qualification and approval of suppliers and customers • Authorising the return to saleable stock on any returns • Approving GDP technical agreements in relation to storage and transportation • Self inspections effectively managed and documented with follow up on corrective actions • Involved in the decision on product disposition • Any product specific requirements imposed by national law are adhered to.

16. Personnel Other Personnel for GDP • Adequate number of personnel to ensure quality of product is maintained • Organisational structure detailed in an organogram to show all personnel responsibilities • Personnel roles and responsibilities detailed in a job description with any delegation of duties clearly documented.

17. Personnel Training • All personnel involved in wholesale distribution must receive formal documented initial and ongoing training that is job specific and on general GDP • This should include aspects of product identification and avoidance of falsified medicines entering the supply chain • Training should be based on written procedures and training programmes • The RP should maintain their continued professional development to fulfil their RP obligations • A record of all personnel training should be maintained and effectiveness of training should be periodically assessed and documented.

18. Hygiene • There should be procedures relating to health, hygiene and clothing. Initial and ongoing training on these procedures should be provided to all employees • Storage of food, drinks, smoking materials or medication for personal use must be prohibited in storage areas

19. Premises and Equipment Premises (1) • The Premises to be designed to ensure: • good storage conditions are maintained • Suitably secure • Structurally sound • Sufficient capacity to allow safe storage and handling of product • Adequate lighting to allow safe and accurate operations • Segregated areas for products; • to clearly define products for sale, return, reject, disposal and recalled products • Physical segregation to ensure defective products are not reintroduced into the supply chain.

20. Premises and Equipment Premises (2) • Storage areas are within defined temperature, and humidity conditions • Qualified system for monitoring storage temperature and humidity • Safety and security of any hazardous or potent products • Goods In and despatch bays should protect product from harsh weather conditions • Adequate separation between receipt, despatch and storage areas • Reception area where delivery is received and examined to be designated and suitably equipped.

21. Premises and Equipment Premises (3) • Authorised access only through appropriate access control. Site security to include, and not limited to, intruder alarm, CCTV, security patrol, perimeter ring fence and security controlled entry exit gates • Storage facilities are clean and free from litter and dust. Cleaning procedures and records should be in place and appropriate cleaning equipment should be sourced • Protection against the entry of insects, rodents or other animals. A preventative pest control programme should be in place • Rest, wash and refreshment rooms for personnel should be adequately separated from the storage areas • Agreement to be implemented with any contracted premises and ensure site has wholesale distribution authorisation prior to commencement of service.

22. Premises and Equipment Temperature and Environment Control • Suitable equipment and procedures should be in place to ensure adequate control of the storage area environment. The factors to be considered include, and are not limited to, temperature, humidity and cleanliness of the premises • Storage areas should be temperature mapped, taking into account any seasonal variations • Any initial mapping must be performed before use of the storage area • The mapping exercise should be whenever significant changes are made to the facility or temperature controlling/monitoring system. Risk assess any potential changes prior to making the change • Temperature monitoring equipment should be located according to the results of the mapping exercise.

23. Premises and Equipment Equipment (1) • All critical equipment, vital to the functionality of operations, should be on a planned preventative maintenance programme • Equipment used to control or monitor product environment should be calibrated at regular intervals • Calibrations should be traceable to a primary standard • Alarm levels should be appropriately set to alert when there is a deviation from pre-defined storage conditions. Alarms should be regularly checked to ensure they are functioning correctly.

24. Premises and Equipment Equipment (2) • Records of calibration, maintenance and repair should be maintained for the equipment listed below: • Refrigerators • Thermo hygrometers • Cold stores • Temperature and humidity recording devices • Air handling devices • And any equipment utilised in conjunction within the onward supply chain.

25. Premises and Equipment Computerised Systems (1) • Should achieve the desired results • Documentation on the computerised system: • Scope • Principles • Objectives • Security measures • Main features • How it is used and how it interacts with other systems

26. Premises and Equipment Computerised Systems (2) • Data entry and amendments by authorised personnel • Data should be secured by physical and electronic means. Stored data should be checked for: • Accessibility • Durability • Accuracy • Data should be backed up at regular intervals and stored for a period stated by national legislations • A back up procedure should be in place in the event of system failure.

27. Premises and Equipment Qualification and Validation • Q&V of key aspects of wholesale distribution activities • The scope and extent should be determined by a documented risk assessment • Validation should be planned and specify acceptance criteria • Systems should be validated and revalidated after any significant changes. E.g. expansion of cold storage • Validation report should be prepared and any deviations and CAPAs to be detailed in report. Report to be approved by appropriate personnel • Re-qualification of equipment, after repair/maintenance should be decided utilising a risk based approach.

28. Documentation (1) • Part of the QMS • Clearly written documents: • Policies • Procedures • Instructions • Records and Data (paper or electronic form) • Personnel should have access to the procedures and instructions applicable to their job role.

29. Documentation (2) • Documentation should be: • Clear and unambiguous and easily understood by personnel • Approved, signed and dated by authorised personnel and should not be hand written • Signed and dated for any alterations made and should permit the reading of the original text. Where possible the reason for alteration should also be stated • Readily available and retained for a minimum of five (5) years or for a period stated in national legislations.

30. Documentation (3) • Valid and approved and managed by authorised personnel to ensure document system is effectively managed and controlled • Reviewed regularly, version controlled with details of changes for each revision • Superseded versions archived and all copies replaced with current version

31. Documentation (4) • Records should be retained in hard copy or electronic format • Records should include, and not limited to: • Date • Name of product • Quantity received • Supplied or brokered • Name and address of supplier • Broker or consignee • Batch number where required • Records should be completed at time of operation being performed so that any significant activities or events are traceable.

32. Operations • Ensure the product identity is not lost and the product is handled in accordance with the marketing authorisation • The supplier of all products sourced should be known to minimise the risk of Falsified products entering the legal supply chain • If distributor intends to import a product, for which they do not hold the MA (marketing authorisation), they must first notify the MA holder and the competent authority in the member state of their intention to import into that market. This process of notification should be defined in a procedure.

33. Operations - Qualification of Suppliers (1) • They must hold a Wholesale Distribution Authorisation or a Manufacturing Authorisation • They must comply with this training • They must have written procedures for critical distribution activities. eg. complaints, recalls, returns, verification and other areas covered by this training • They must be audited using questionnaires and site visits prior to the service commencing • An audit report must be completed and will form part of the risk based approach of supply selection.

34. Operations - Qualification of Suppliers (2) • If product is obtained through a broker, check that the are appropriately authorised to supply product and comply with the requirements of this training.

35. Operations - Qualification of Customer (1) • They must have authorisation to supply product to the public in the member state concerned. The checks performed should be documented • These checks and periodic re-checks may include and are not limited to: • Requesting copies of customer’s authorisation • Verifying status on an authority website • Requesting evidence of qualification or entitlement according to national legislation • Monitor transactions and investigate any irregularities in sale patterns to avoid diversion of product and risks of misuse.

36. Operations - Marketing Authorisation (MA) • If a wholesale distributor is supplying, or intending to supply product to a member state other than the member state in which the MA was granted, they should make available copy(ies) of the MA to the national competent authority of the market in which they intend to supply • Where applicable the competent authority will inform the wholesale distributor of the obligations imposed for operating on their territory.

37. Operations - Receipt of Goods • If product is received into warehouse in Europe from a third country, for the purpose of placing product in the EU market, they must possess a Manufacturer’s Importation Authorisation (MIA) • Procedures in place to detail checks performed on Goods Receipt. • Checks performed to ensure Quality of Product received: • Received from approved supplier • Correct product and quantity • If temperature controlled product, temperature logger data downloaded to observe any temperature excursions during transit • Free from damage • If product suspected to be counterfeit, to be immediately segregated and reported to local competent authority and marketing authorisation holder.

38. Operations - Storage • Conditions for storage of medicinal products • Protected from the harmful effects of light, temperature and moisture • Outer packaging and pallets cleaned before storage in warehouse • Various categories of product appropriately sealed to prevent cross- contamination • Clear segregation of products in quarantine, released, rejected, returned or recalled products and those suspected to be counterfeit products • Stock rotation based on expiry date of product • Handled with care to prevent spillage, breakage or cross contamination. Minimise risk by not storing product directly on floor. • Through regular checks any products not suitable for sale to be immediately segregated from saleable stock (physically and electronically) • Stock inventories to be performed at defined periods using a risk based approach. Any discrepancies to be investigated and documented.

39. Operations – Segregation of Goods • There should be a system in place with written procedures to allow for the segregation from harmful products (rejects, returns, toxic. counterfeits). • These products should be clearly labeledwith access to only authorised personnel • If segregation only performed electronically then system to be risk assessed to ensure it will provide security and it is appropriately validated before electronic segregation is implemented. • Segregated areas to be clearly defined and referenced in the applicable procedures.

40. Operations - Destruction of Obsolete Goods • Products for destruction to be handled separately and stored separate for saleable stock • Written procedure should detail how these products should be handled • Destruction should be in accordance with national and international requirements for disposal • Records of all disposed products should be maintained and destruction witnessed for any controlled drug substances • A technical agreement should be in place between the distribution warehouse and the destruction company.

41. Operations - Picking and Packing • When picking: • Procedure should be in place to ensure the correct product is picked • Ensure minimum shelf life of product as agreed with customers and detailed in a procedure • Should follow the FEFO rotation of stock • When packing: • Ensure packaging materials used will protect product from any likely damage and maintain it’s storage conditions (e.g. temperature) during transit • Seal the container in which the product is packed to avoid contamination

42. Operations - Delivery • When Delivering: • Ensure the customer receiving the product is appropriately authorised/licensed to receive medicinal product • Following information to be provided on delivery note to customer: • Delivery date • Product name • Form • Batch number • Quantity • Any safety handling instructions • Transport and storage conditions • Name and address of supplier and consignee • Temperature data or temperature loggers for temperature sensitive products - to observe any adverse temperature conditions during transit

43. Operations - Export • An exporter of medicinal products must hold a wholesale dealer licence or a manufacturing authorisation • The export of medicines for wholesale distribution should follow these training guidelines with the following exceptions: • The product does not need to have a Marketing Authorisation (MA) in Europe or in the member states • The customer does not need to hold a distribution authorisation • Any products imported from a third country for export, where the imported product does not have a MA in the country of origin, the supplier does not need to hold a wholesale distribution authorisation, however they may be required to hold a specials licence subject to local regulatory requirements • If the product is exported to a person in a third country where they are entitled (licensed) to supply products to public then the requirements of this training would apply.

44. Complaints, Returns, Suspected Falsified Medicinal Products and Medicinal Product Recalls • All complaints potentially concerning medicinal product defects must be reviewed carefully in appropriate timescales to minimise any risk to patient safety • An assessment must be performed on all returns before deciding on product disposition • A good relationship must exist between partners within the supply chain to prevent entry of falsified medicines • A system must be in place for an effective recall of product and this system must be challenged periodically • Procedures must be in place to detail how complaints, returns, falsified medicines and recalls will be managed.

45. Complaints • There should be: • A written procedure on how to handle complaints on product Quality defects and those relating to distribution. The MA holder should be notified of any Quality/Safety related complaints promptly • A person/ department responsible for handling complaints • A system of documenting and investigating all complaints. The national competent authority should be notified promptly of any justified complaints • Where applicable, follow up action should be taken after investigation and evaluation of complaint.

46. Returned Medicinal Products (1) • There should be: • A written procedure on handling and acceptance of returned medicinal products • A segregated area for returns. Returns should be kept in this area until a decision is taken regarding the disposition of product • Stock should only be returned to saleable stock if all of the below requirements are met: • The MA holder does not accept returns • Secondary packaging is un-opened and not damaged, and in good condition • The customer returning product must return within five days of original dispatch if they do not hold a wholesale distribution authorisation

47. Returned Medicinal Products (2) • Sufficient documentation/data exists to show the product has been transported, stored and handled under specified conditions • The documentation/data has been reviewed and assessed by an appropriately trained, competent, authorised person. This person should certify that the conditions, in which the product was stored and handled, were in compliance with GDP • Distributor has supporting documentation, including original delivery note, to confirm the customer to whom the product was supplied, batch and expiry details, and to satisfy themselves that the product returned has not been falsified • For cold chain products, there must be supporting temperature data to show product stability has not been compromised when outside the control of the distributor.

48. Returned Medicinal Products (3) • The MA holder has assessed the packaging components to ensure they are the regulatory approved artwork • The return to saleable stock or for disposal should be approved by the Responsible Person and this should be documented • Any stock returned to saleable stock should be placed back into the FEFO system

49. Suspected Falsified Medicinal Products There should be: • Procedures in place on how to handle suspect or confirmed falsified medicinal products, and on informing the MA holder and the competent authority • Initial and ongoing GDP training for staff to raise the awareness of the risk of falsified medicinal products entering the supply chain • Physical and secure segregation of falsified medicines from legitimate stock and a stock inventory maintained.

50. Medicinal Product Recalls • Procedure required for Management of recalls; this should be periodically challenged and effectiveness reviewed • A system for actioning recall from market promptly • Distributor should follow instructions from MA holder and should ensure where applicable, that the competent authority has given approval for recall to commence • Records available for recall activities performed and should be made available to the competent authorities • All records relating to the distribution of product should be made available to the person(s) responsible for initiating the recall. This should also include details of all customers who were supplied the recalled product. Details of batch, expiry and Quantity • A segregated and secure location for recalled products while awaiting a decision on disposition • The progress of the recall should be documented and a final report issued. This should include a reconciliation between the delivered and recovered quantities of the recalled product.