QS, GDP (+GMP?) Maintaining the Integrity of The Supply Chain

Transcription

1 QS, GDP (+GMP?) Maintaining the Integrity of The Supply Chain Presented by: Karen Ginsbury For IFF 01 March, 2017

2 Pharma Supply Chain Manufacturer Wholesaler Raw Material Supply Production Transport Warehouse Distribution End user GMP GDP Standards of Good Distribution Practice (GDP) are applied to ensure that the high level of product quality achieved by observing Good Manufacturing Practice is maintained throughout the supply chain. 2

3 Who / What are you / your company? Importer? Wholesaler? Agent? Broker? MAH? Responsible and accountable

4 We are looking at the Quality System for Pharmaceutical distributors Wholesalers Importers Exporters Pharma companies [Pharmacies, hospitals, health care providers]

5 What happened When and why did GDP become such a major headache? Supply chain Temperature control of shipments Wooden pallets Track and trace

6 GDP development Timelines based on PDA TRs

7

8 Functional Requirements Document critical product paramaters: Transportation: duration, mode(s) route(s) Product stability (established temp range) Packaging Min / Max expected shipping volumes Min / max thermal mass Expected ambient profiles Materials requirements Marketing requirements / restrictions User requirements And so on.can purchase it for US$100

9 GDP but from the end of the line perspective E.g. can RT materials be shipped cold?

10 Map out the process for distribution PCI Pharmaceutical Consulting Israel Ltd 10

11 What could go wrong Write down three risks and three mitigations

12 Quality Agreements With whom A tool? Risk reduction? What is their role in the QS?

13 Has a 20 page checklist of audit questions for a pharmaceutical distribution warehouse / service provider

14 Every Picture Tells a Story

15 ONE CALL STARTS THE PROCESS CUSTOMER CALL PROCESS INITIATION CONTAINER RENTAL (DRY ICE & BATTERIES) PICKUP AT AIRLINE ENROUTE ENVIROTAINER LOADED, TEMPERATURE SET, CONTAINER SEALED AND IMMEDIATELY TAKEN TO AIRPORT NON-STOP FLIGHT CUSTOMS CLEARANCE IN EUROPE, CLEAR THE CARGO WHILE STILL IN- FLIGHT ENROUTE TO CONSIGNEE ARRIVAL AT CONSIGNEE LOCATION

16 Quality is Meeting all the requirements all the time We have to define the requirements

17 What is a Quality System A process The sum total of the organized arrangements made with the intention to ensure that the processes support / maintain a product meeting all its defined requirements all the time

18 GDP (and GMP) Regulations LEGISLATION REGULATION GOOD MANUFACTURING PRACTICE GOOD DISTRIBUTION PRACTICE CURRENT

19 Good Manufacturing Practice 1. Pharmaceutical Quality System 2. Personnel 3. Premises and Equipment 4. Documentation 5. Production 6. Quality Control 7. Outsourced Operations 8. Complaints, Quality Defects and Product Recalls 9. Self-Inspection

20 Size and Complexity of PQS 1.3 The size and complexity of the company s activities should be taken into consideration when developing a new Pharmaceutical Quality System or modifying an existing one While some aspects of the system can be company-wide and others site-specific, the effectiveness of the system is normally demonstrated at the site level.

21 Organizational Structure Communication especially of RISKs Start with AWARENESS that each link in the chain must be secured Management Responsibility (back to Cap 1)

22 Specifics Personnel responsibilities Oversight of outsourced operations Purchasing controls / supply chain Computerized systems annex 11

23 Specifics Documentation Reporting requirements Process and product monitoring CAPA

24 Specifics Change control Deviations and non-conformances, investigations Quality control Complaints, product quality defects and recalls Self- inspection / internal audits

25 Counterfeit Medicines

26 To Protect the Public

27 How can Counterfeits enter the legitimate supply chain

28 Too close for comfort?

29 The size of the problem WHO estimates >12% of global medicines are counterfeit, costing the industry up to US$ billions a year Annual growth of counterfeit medicines outstrips that of legitimate medicines worldwide The untrained eye wouldn t distinguish the difference. Some of them contain active ingredients; some contain no ingredients; some lighter ingredients; and some toxic ingredients

30 GDP Definition Good Distribution Practice (GDP) is that part of quality assurance which ensures that products are consistently stored, transported and handled under suitable condition as required by the marketing authorisation (MA) or product specification

31 Consider EU: Directive and regulations WHO The role of the pharmacist (responsible person) PCI Pharmaceutical Consulting Israel Ltd 31

32 What Has Changed Maintenance of a quality system setting out responsibilities, processes and risk management principles in relation to wholesale activities Suitable documentation which prevents errors from spoken communication; Sufficient competent personnel to carry out all the tasks for which the wholesale distributor is responsible Adequate premises, installations and equipment to ensure proper storage and distribution of products 32/40

33 What Has Changed Appropriate management of complaints, returns, suspected falsified medicinal products and recalls; Outsourced activities correctly defined to avoid misunderstandings; Rules for transport in particular to protect products against breakage, adulteration and theft, and to ensure that temperature conditions are maintained within acceptable limits during transport Specific rules for brokers (person involved in activities in relation to the sale or purchase of medicinal products) 33/40

34 GDP The Aim Integrity meaning two things: Lack of tampering / prevent counterfeiting opportunities Reconciliation of quantities Tamper evident seals on individual units and on boxes Visual inspection Relabeling activities Safety and Efficacy (continuation of GMP) Storage and distribution temperatures and times Relabeling activities 34/40

35 GDP The Aim To get the product, manufactured under GMP to the pharmacists and thereby to the end user in a manner that ensures the integrity of the product Parties to GDP: The manufacturer The transporters The wholesale distributor (and their transporters) The pharmacies

36 GDP The Aim Integrity meaning two things: Lack of tampering / prevent counterfeiting opportunities Reconciliation of quantities Tamper evident seals on individual units and on boxes Visual inspection Relabeling activities Safety and Efficacy (continuation of GMP) Storage and distribution temperatures and times Relabeling activities

37 Topics Covered by GDP Regulations Quality Systems Personnel Documentation Premises and Equipment Deliveries to Customers Returns Self Inspections

38 The Legal Basis - EU

39 EU GDP Regulations: Principle Quality Management 39/40

40 Quality System The system for managing quality should encompass the organisational structure, procedures, processes and resources, as well as activities necessary to ensure confidence that the product delivered maintains its quality and integrity and remains within the legal supply chain during storage and/or transportation 40/40

41 EU Directive November 2013 Wholesale distribution of medicinal products is 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

42 The legal basis - USA No specific GDP regulations Is apparently covered by state and interstate laws rather than FDA regulated USP has chapter <1079> Good Storage and Shipping Practices in the general information chapters BUT do have the Drug Quality and Security Act of 2013 and DSCSA

43 DSCSA FDA USA

44 DSCSA are you ready? s/drugsafety/drugintegrit yandsupplychainsecurit y/drugsupplychainsecur ityact/ucm htm

45 EU GDP Regulations: Principle The Community pharmaceutical industry operates at a high level of quality assurance, achieving its pharmaceutical quality objectives by observing Good Manufacturing Practice to manufacture medicinal products which must then be authorised for marketing This policy ensures that products released for distribution are of the appropriate quality

46 EU GDP Regulations: Principle This level of quality should be maintained throughout the distribution network so that authorised medicinal products are distributed to retail pharmacists and other persons entitled to sell medicinal products to the general public without any alteration of their properties

47 EU GDP Regulations: Principle The concept of Quality Management in the pharmaceutical industry is described in Chapter I of the Community Guide to Good Manufacturing Practice for medicinal products and should be considered when relevant for the distribution of medicinal products The general concepts of quality management and quality systems are described in the CEN standards (series ) = ISO 9000

48 EU GDP Regulations: Principle The quality system operated by distributors (wholesalers) of medicinal products should ensure that: medicinal products are authorised in accordance with Community legislation storage conditions are observed at all times, including during transportation contamination from or of other products is avoided an adequate turnover of the stored medicinal products takes place products are stored in appropriately safe and secure areas

49 EU GDP Regulations: Principle The quality system should ensure that the right products are delivered to the right addressee within a satisfactory time period A tracing system should enable any faulty product to be found There should be an effective recall procedure

50 WHO GDP 30 page guidance from 2010 Was basis for EU

51 What are the Risks in GDP? For a formal assessment need to use one of the tools in ICH Q9 / Annex 20: HACCP FMEA Ishikawa (Fishbone) diagram + one of the other methods Will take you to a lot of the points already mentioned

52 Relabelling Controls

53 Temperature Control Risks and mitigation?

54 Goods Picking track and trace FeFo / FiFo? documentation

55 Shipping / Vehicles / Fleet Qualification Dataloggers how MANY??? Contractors

56 Returns and Customer service Recalls, Complaints

57 Audit By you Of you

58 CHAPTER 2 PERSONNEL PRINCIPLE The correct distribution of medicinal products relies upon people. There must be sufficient competent personnel to carry out all the tasks for which the wholesale distributor is responsible. Individual responsibilities should be clearly understood by the staff and be recorded. Responsible Person: Quality Manager? Fulfill duties personally and be continuously contactable PCI Pharmaceutical Consulting Israel Ltd 58

59 Hygiene Appropriate procedures relating to personnel hygiene, relevant to the activities being carried out, should be established and observed. Such procedures should cover health, hygiene and clothing. PCI Pharmaceutical Consulting Israel Ltd 59

60 PCI Pharmaceutical Consulting Israel Ltd 60

61 Chapter 3 Premises and Equipment Principle Wholesale distributors must have suitable and adequate premises, installations and equipment to ensure proper storage and distribution of medicinal products In particular, the premises should be clean, dry and maintained within acceptable temperature limits PCI Pharmaceutical Consulting Israel Ltd 61

62 Premises Premises should be designed or adapted to ensure that the required storage conditions are maintained. They should be suitably secure, structurally sound and of sufficient capacity to allow safe storage and handling of the medicinal products. Storage areas should be provided with adequate lighting to enable all operations to be carried out accurately and safely. Where premises are not directly operated by the wholesale distributor, a contract should be in place. The contracted premises should be covered by a separate wholesale distribution authorisation. PCI Pharmaceutical Consulting Israel Ltd 62

63 Premises Medicinal products should be stored in segregated areas which are clearly marked and have access restricted to authorised personnel. Any system replacing physical segregation, such as electronic segregation based on a computerised system, should provide equivalent security and should be validated. PCI Pharmaceutical Consulting Israel Ltd 63

64 Premises Reception areas where deliveries are examined following receipt should be designated PCI Pharmaceutical Consulting Israel Ltd 64

65 Premises Premises should be designed and equipped so as to afford protection against the entry of insects, rodents or other animals. A preventive pest control programme should be in place. Rest, wash and refreshment rooms for employees should be adequately separated from the storage areas. PCI Pharmaceutical Consulting Israel Ltd 65

66 Temperature and environment control Suitable equipment and procedures should be in place to check the environment where medicinal products are stored. Environmental factors to be considered include temperature, light, humidity and cleanliness of the premises PCI Pharmaceutical Consulting Israel Ltd 66

67 Temperature mapping An initial temperature mapping exercise should be carried out on the storage area before use, under representative conditions. Temperature monitoring equipment should be located according to the results of the mapping exercise, ensuring that monitoring devices are positioned in the areas that experience the extremes of fluctuations. PCI Pharmaceutical Consulting Israel Ltd 67

68 PCI Pharmaceutical Consulting Israel Ltd :52:42 17:22:42 17:52:42 18:22:42 18:52:42 19:22:42 19:52:42 20:22:42 20:52:42 21:22:42 21:52:42 22:22:42 22:52:42 23:22:42 23:52:42 00:22:42 00:52:42 01:22:42 01:52:42 02:22:42 02:52:42 03:22:42 03:52:42 04:22:42 04:52:42 05:22:42 05:52:42 06:22:42 06:52:42 07:22:42 07:52:42 08:22:42 08:52:42 09:22:42 09:52:42 10:22:42 10:52:42 11:22:42 11:52:42 12:22:42 12:52:42 13:22:42 13:52:42 14:22:42 14:52:42 15:22:42 15:52:42 16:22:42 16:52:42 17:22:42 17:52:42 18:22:42

69 15:06:38 15:46:38 16:26:38 17:06:38 17:46:38 18:26:38 19:06:38 19:46:38 20:26:38 21:06:38 21:46:38 22:26:38 23:06:38 23:46:38 00:26:38 01:06:38 01:46:38 02:26:38 03:06:38 03:46:38 04:26:38 05:06:38 05:46:38 06:26:38 07:06:38 07:46:38 08:26:38 09:06:38 09:46:38 10:26:38 11:06:38 11:46:38 12:26:38 T = [C] time PCI Pharmaceutical Consulting Israel Ltd 69

70 :54:36 19:29:36 20:04:36 20:39:36 21:14:36 21:49:36 22:24:36 22:59:36 23:34:36 00:09:36 00:44:36 01:19:36 01:54:36 02:29:36 03:04:36 03:39:36 04:14:36 04:49:36 05:24:36 05:59:36 06:34:36 07:09:36 07:44:36 08:19:36 08:54:36 09:29:36 10:04:36 10:39:36 11:14:36 11:49:36 12:24:36 12:59:36 13:34:36 14:09:36 14:44:36 15:19:36 15:54:36 16:29:36 17:04:36 17:39:36 18:14:36 18:49:36 19:24:36 19:59:36 T [C] time PCI Pharmaceutical Consulting Israel Ltd 70

71 :53:47 22:28:47 23:03:47 23:38:47 00:13:47 00:48:47 01:23:47 01:58:47 02:33:47 03:08:47 03:43:47 04:18:47 04:53:47 05:28:47 06:03:47 06:38:47 07:13:47 07:48:47 08:23:47 08:58:47 09:33:47 10:08:47 10:43:47 11:18:47 11:53:47 12:28:47 13:03:47 13:38:47 14:13:47 14:48:47 15:23:47 15:58:47 16:33:47 17:08:47 17:43:47 18:18:47 18:53:47 19:28:47 20:03:47 20:38:47 21:13:47 21:48:47 22:23:47 T [C] time PCI Pharmaceutical Consulting Israel Ltd 71

72 EQUIPMENT Adequate records of repair, maintenance and calibration activities for key equipment should be made and the results should be retained. Key equipment would include for example cold stores, monitored intruder alarm and access control systems, refrigerators, temperature and humidity recording devices, air handling units and any equipment used in conjunction with the onward supply chain. PCI Pharmaceutical Consulting Israel Ltd 72

73 Chapter 4- Documentation Principle Good documentation constitutes an essential part of the quality system. Written documentation should prevent errors from spoken communication and permits the tracking of relevant operations during the distribution of medicinal products. PCI Pharmaceutical Consulting Israel Ltd 73

74 Documentation Documentation should be sufficiently comprehensive with respect to the scope of the wholesale distributor s activities and in a language understood by personnel. It should be written in clear, unambiguous language and be free from errors. PCI Pharmaceutical Consulting Israel Ltd 74

75 Documentation Version control should be applied to procedures. After revision of a document a system should exist to prevent inadvertent use of the superseded version. Superseded or obsolete procedures should be removed from workstations and archived. PCI Pharmaceutical Consulting Israel Ltd 75

76 Chapter 5 Operations Principle Actions taken by distributors should ensure that the identity of the medicinal product is not lost and that the distribution is performed according to the information on the outer packaging The distributor should use all means available to minimise the risk of falsified medicinal products entering the legal supply chain. All medicinal products distributed in the EU by a wholesale distributor must be covered by a marketing authorisation granted by the EU or by a Member State PCI Pharmaceutical Consulting Israel Ltd 76

77 Chapter 5 Operations Principle Any distributor, other than the marketing authorisation holder, who imports a medicinal product from another Member State must notify the marketing authorisation holder and the competent authority in the Member State to which the medicinal product will be imported of their intention to import that product All key operations described below should be fully described in the quality system in appropriate documentation PCI Pharmaceutical Consulting Israel Ltd 77

78 Receipt of Medicinal Products The purpose of the receiving function is to ensure that the arriving consignment is correct, that the medicinal products originate from approved suppliers and that they have not been visibly damaged during transport. PCI Pharmaceutical Consulting Israel Ltd 78

79 Damage during transport Can have pallets dropped or other accident (water damage) that is not visible on receipt Signs of opening PCI Pharmaceutical Consulting Israel Ltd 79

80 Qualification of Suppliers Only purchase products through an approved, documented supply chain with appropriate authorisations PCI Pharmaceutical Consulting Israel Ltd 80

81 Qualification of customers Wholesale distributors must ensure they supply medicinal products only to persons who are themselves in possession of a wholesale distribution authorisation or who are authorised or entitled to supply medicinal products to the public. PCI Pharmaceutical Consulting Israel Ltd 81

82 Destruction of obsolete goods PCI Pharmaceutical Consulting Israel Ltd 82

83 Picking PCI Pharmaceutical Consulting Israel Ltd 83

84 Cap 6 Complaints, Returns, Suspect Falsified and Recalls Principle All complaints, returns, suspected falsified medicinal products and recalls must be recorded and handled carefully according to written procedures Records should be made available to the competent authorities An assessment of returned medicinal products should be performed before any approval for resale A consistent approach by all partners in the supply chain is required in order to be successful in the fight against falsified products PCI Pharmaceutical Consulting Israel Ltd 84

85 Complaints Refer to Revisions to Chapter 8 in GMPs just revised and address QUALITY DEFECTS PCI Pharmaceutical Consulting Israel Ltd 85

86 Returns Case Studies Time limitations Conditions Separation Return to stock? PCI Pharmaceutical Consulting Israel Ltd 86

87 Chapter 7 Outsourced Activities Principle Any activity covered by the GDP Guide that is outsourced should be correctly defined, agreed and controlled in order to avoid misunderstandings which could affect the integrity of the product There must be a written Contract between the Contract Giver and the Contract Acceptor which clearly establishes the duties of each party. PCI Pharmaceutical Consulting Israel Ltd 87

88 Quality Agreement Shippers, forwarders, airlines Storage and distribution (distributors) Brokers and agents Importers Manufacturers if you import Other calibration, maintenance, pest control PCI Pharmaceutical Consulting Israel Ltd 88

89 Chapter 8 Self Inspections Principle Self-inspections should be conducted in order to monitor implementation and compliance with GDP principles and to propose necessary corrective measures PCI Pharmaceutical Consulting Israel Ltd 89

90 Chapter 9 Transportation Principle It is the responsibility of the supplying wholesale distributor to protect medicinal products against breakage, adulteration and theft, and to ensure that temperature conditions are maintained within acceptable limits during transport Regardless of the mode of transport, it should be possible to demonstrate that the medicines have not been exposed to conditions that may compromise their quality and integrity. A riskbased approach should be utilised when planning transportation PCI Pharmaceutical Consulting Israel Ltd 90

91 Transportation Packaging for transportation Type of boxes Sealing and other anti-counterfeit measures Method of loading within containers Insulating measures validation PCI Pharmaceutical Consulting Israel Ltd 91

92 Transportation Definition for temperature range during transport C (for Room Temperature) C (for Cold chain products) APPROPRIATE CONDITIONS AS PROVED BY STABILITY STUDIES COOLER IS NOT NECESSARILY BETTER PCI Pharmaceutical Consulting Israel Ltd 92

93 Transportation Temperature data loggers Type Number Location Calibration PCI Pharmaceutical Consulting Israel Ltd 93

94 Transportation Type of shipping container: Environtainer Insulated boxes/pallets Uncontrolled container For cold chain products in insulated boxes Note : insulated boxes with cooling packs may not be stored under refrigerated conditions PCI Pharmaceutical Consulting Israel Ltd 94

95 Transportation Transportation route Location of starting point Land shipper (train, trucks) In transit hubs Air/Sea shipper Customs Land shipping to warehouse PCI Pharmaceutical Consulting Israel Ltd 95

96 Transportation Transportation route Is the route fixed? Duration? Unexpected events? Forwarders Do they have the knowledge and expertise in handling of pharmaceuticals? How many are involved? How do they communicate? What is the exact point of delivery of charge? Where is it defined PCI Pharmaceutical Consulting Israel Ltd 96

97 Transportation Forwarders: Does the forwarder have a quality system in place? How many subcontractors are involved? How are subcontractors qualified? Does the forwarder have to inform where deviations during transport occur? Does the forwarder notify on major changes prior to implementation? How long are records kept? PCI Pharmaceutical Consulting Israel Ltd 97

98 Vehicles - Fleet Yours or theirs

99 PCI Pharmaceutical Consulting Israel Ltd 99

100 PCI Pharmaceutical Consulting Israel Ltd 100

101 Chapter 10 Brokers Principle A broker is a person involved in activities related to sale or purchase of products, except for wholesale distribution, that do not include physical handling and that consist of negotiating independently and on behalf of another legal or natural person PCI Pharmaceutical Consulting Israel Ltd 101

102 Chapter 10 Brokers Principle Brokers are subject to a registration requirement. They must have a permanent address and contact details in the Member State where they are registered. They must notify the competent authority of any changes to those details without unnecessary delay. Requirements for premises, installations and equipment do not apply However, all other rules in Directive 2001/83/EC that apply to wholesale distributors also apply to brokers PCI Pharmaceutical Consulting Israel Ltd 102

103 Quality Reviews CAPA system is an integral part of any functional quality system (Corrective and Preventive Actions) Periodic quality reviews at the management level (means General Manager or President) engages their attention and allows for resources to be diverted as needed

104 Quality Reviews Formal reviews should be performed Don t focus on positive!! Highlight UNRESOLVED problems so that management can provide the solutions We need 4 new refrigerated vans The warehouse cannot maintain the required temperature profile in summer and summer is approaching We need additional quarantine storage space (provide figures)

105 Measures of Improvement Complaints (logistics AND quality): Reduction in number Reduction in severity Decreased response time Deviations (as above) Self-inspection / vendor audits Reduction in severity of findings Improved quality of responses Improved response time

106 CAPA Program 1. ID existing problems CA ID quality data sources analyze data 2. ID potential problems PA as above (but trends, SPC) 3. Challenge Data complete, accurate, timely 4. Identify extent of problems 5. Failure investigation Follow SOP; depth relative to risk, root cause if possible, stop distribution 6. Appropriate Action Taken 7. Actions: appropriate; verified / validated, do not adversely affect product 8. Actions: implemented documented 9. Information Transfer to those responsible for assuring product quality preventing quality problems

107 Program in place, Audit, Management Involvement

108 In conclusion GMP / GDP regulations: EU and WHO, USP FDA appear to be lagging behind but ISO is certainly a good place to start Quality System MUST be in place Would expect a Quality Manager who is familiar with GDP requirements Need quality contracts in place and need to audit: Manufacturing sites Your distributor Their distributor Their print houses (or rely on their audits)