Integrating the Global GDPs into the Quality Management System (QMS) Dave Ulrich

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3 Integrating the Global GDPs into the Quality Management System (QMS) Dave Ulrich Abbvie QA Director Global Supply Chain

4 Agenda: GDP, QMS and QRM 1. What do the regulations say What are the GDPs? Do we need them? Can t we just use the GMP 2. What is a QMS and integrating GDPs Supply Chain Temp Mgt ICH Q1A standard stab testing Establishing storage label claim Temperature cycles studies File the cycling studies Develop a stability budget Excursion management Supply Chain map What is it, where did it come from Are you sure? To have a good QRM program you must have 1. A well designed process (QMS) to demonstrate control 2. Great data (data integrity) 4

5 What are the GDPs? GDP Dashboard Countries General GDPs GIP TCM DCS Port Handling / Offloading Customs General Layout / Contruction Loading & Receiving Bays Building Cleanliness General Security Temperature Monitored Storage Areas Product Stability Profiles Temperature- Controlled Transport Humidity Control and Monitoring Shipping Containers & Packing General Packaging, Lableling Prcoessing Relabeling Qualified Personnel, Training Good Documentatio n Practices Stock Control Systems Exception Management & Product Compaint Procedures Product Return, Recall, Withdraw, Control and Disposal Serialization & epedigree GPS and Bulk Security, Counterfeits Traceability / GS1 Stock Identification Tracking LAA Region Argentina Regulating the Cold Chain of Medicines (Ley X X X Brazil Resolution - RDC No. 234 X X X X X X X X X Mexico Guidelines for Imported Biotechnological & x x x x x x x x Australia Code of Good Wholesaling Practice for X X X X X X X X X X X X X X Cold Chain Pharmaeutical Products X X X X X X X X India (OPPI) Guideline on Good Distribution Practices for X X X X X X X X X X X X X X X X Japan Biological Pharma Revision H X X X Malaysia Guidelines 3. on Good Distribution Audits Practice X(Internal X X and X External), X X X SQA: X X QTA, X QQ X Xand X QTA X X X X X X X X Singapore Guidance Notes on Good Distribution X X X X X X X X X X X X X X X X X South Africa Good Whilesaling Practice for Wholesales, X X X X X X X X X X X X X X X X X Phillipines Adoption and 4. Implementation Change of the World X Control X X / XChange X X Mgt X X X X X X X X X X X X X X Central European Region Austria Austrian GDP Regulations X X X X X X X Czech Guidelines 5. for Correct Distribution Exception of Human Mgmt., X X CAPA, X Complaints, X X X AE X / XPV X X X X X X X Republic Czech GDP Guidelines X X X X X X EMA European Medicines Agency: " QP X X Guidelines 6. on Good Distribution QRM Practice of X X X X X X X X X X X X X X X X Directive 2001/83/EC of the European X X X X X X X EU The IPEC Good Distribution Practices Guide X X X X X X X X X X X X X X X X X Europe - Good Distribution Practices Audit Rx-360 Summary of IPEC GDP x x x x x x x x x x x x x x x x x Ireland Guide to Control and Monitoring of Storage X X X X X X X X X X X X X X X Switzerland Distribution of Temperature Controlled X X X X X X X X X X X X X North American Region Canada Guidelines for Good Temperature Control of Drug Distribution XPractices X X (GDPs) X X X Good X X Import X X Practices (GIPs) FDA to Revise Component GMPs to Bolster United States Bar Code Technologies for Drugs and X X Standards for Securing Drug Supply Chain... X X X X X Middle-Eastern European Region Temperature Control Management Product Protection Distribution Control Systems Egypt Minster Decree for Wholesalers - Circular X X X X X X Pharmacist Regulations - Circular 6 X X X X X X X X X X X X Israel Status of Current (TCM) GDP Regulations in Israel X X X X X X X X X X (DCS) X X X X X X X X X X Romania NMA No. 30/ X X X X X X Saudi Arabia, GCC Guidelines for Stability, PP-SPC-9031, Saudi Food & TOPA GTS Drug Authority X X X X X X UAE Circular No X X X X X X International Health Organizations MHRA WHO GDP's Quality Systems Regulations Importation Storage Buildings / Warehousing Transport, Delivery, Storage Labeling Updated Policy on Returns of Non-Defective Guidance on Preventing Breaches in the Cold Chain Distribution GDP Risk GDP Risk Assessment Strategy Regulatory Provisions for Quality Controlled Model requirements for the storage and New Guidance for storage and transport of Just like there are core elements to other GxPs (e.g. cgmps): 1. PV, Cleaning Validation, E/U/F Validation 2. Test Method Development and TMT What is it? Where did it come from? Is it allowed to come into commerce? Can you prove it is what you say it is? Inventory Procedures X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X 5

6 From GMPs to GDPs GDPs cover the whole development process Migration of GMPs into the pharma supply chain GDPs are the new kid on the (cgxp) block Theses include clinicals (IND NDA) 6

7 GDPs are a Logical extension of the GMPs Countries General GDPs GIP TCM DCS Port Handling / Offloading Customs General Layout / Contruction Loading & Receiving Bays Building Cleanliness General Security Temperature Monitored Storage Areas Product Stability Profiles Temperature- Controlled Transport Humidity Control and Monitoring Shipping Containers & Packing General Packaging, Lableling Prcoessing Relabeling Qualified Personnel, Training Good Documentatio n Practices Stock Control Systems Exception Management & Product Compaint Procedures Product Return, Recall, Withdraw, Control and Disposal Serialization & epedigree GPS and Bulk Security, Counterfeits Traceability / GS1 Stock Identification Tracking LAA Region Argentina Regulating the Cold Chain of Medicines (Ley X X X Brazil Resolution - RDC No. 234 X X X X X X X X X Mexico Guidelines for Imported Biotechnological & x x x x x x x x Australia Code of Good Wholesaling Practice for X X X X X X X X X X X X X X Cold Chain Pharmaeutical Products X X X X X X X X India (OPPI) Guideline on Good Distribution Practices for X X X X X X X X X X X X X X X X Japan Biological Pharma Revision H X X X Malaysia Guidelines on Good Security Distribution Practice XAudits X X& Supply X X Chain X X Controls X X X X Export X X Controls X X X X X X X X Singapore Guidance Notes on Good Distribution X X X X X X X X X X X X X X X X X South Africa Good Whilesaling Practice for Wholesales, X X X X X X X X X X X X X X X X X Phillipines Adoption and Implementation Marketing of the World X Authorization X X X X and X XLicense X X X X Supply X X Chain Maps X X X X X X X Central European Region Austria Austrian GDP Regulations X X X X X X X Czech Guidelines for Correct Control GPP Distribution of Human X X X X X X X X X What X Xis it X where X did it come X X Republic Czech GDP Guidelines X X X X X X EMA European Medicines Agency: " QP X X Guidelines on Good Distribution Practice S. of Africa GWP X X X X X X Global X X X X from X X X X X X Directive 2001/83/EC of the European X X X X X X X EU The IPEC Good Distribution Practices Guide X X X X X X X X X X X X X X X X X Europe - Good Distribution Practices Audit x x x x x x x x x x x x x x x x x Rx-360 Summary of IPEC GDP Ireland Guide to Control and Monitoring of Storage X X X X X X Product X X X X X X X X X Switzerland Distribution of Controlled X X X X X X X X X X X X X Temperature Control Management Distribution Control Systems (DCS) North American Region Canada Guidelines for Temperature Control of Drug X X X X X X X X X X FDA to Revise Component GMPs to Bolster (TCM) Protection GS1, Track and Trace, Serial United States Bar Code Technologies for Drugs and X X Standards for Securing Drug Supply Chain... X X X X X Middle-Eastern European Region Cold End-2-End Supply Chain Number Mgmt., Trade Relations Egypt Minster Decree for Wholesalers - Circular X X X X X X Pharmacist Regulations - Circular 6 X X X X X X X X X X X X Israel Status of Current Management GDP Regulations in Israel X X X X X X X X X X X X X X X X X X X X Romania NMA No. 30/ X X X X X X Saudi Arabia, GCC Guidelines for Stability, PP-SPC-9031, Saudi Food & TOPA GTS Drug Authority X X X X X X UAE Circular No X X X X X X International Health Organizations MHRA WHO GDP's Quality Systems Regulations Importation Storage Buildings / Warehousing Transport, Delivery, Storage Labeling Good Distribution Practices (GDPs) Updated Policy on Returns of Non-Defective Guidance on Preventing Breaches in the Cold Chain Distribution GDP Risk GDP Risk Assessment Strategy Regulatory Provisions for Quality Controlled Model requirements for the storage and New Guidance for storage and transport of Good Import Practices (GIPs) Inventory Procedures X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

8 Supply Chain Maps Where do you ship your product from to? 2012 European Commission: Health and Consumers Directorates Central EU GDPs (Good Distribution Practices) Commission Guidelines on Good Distribution Practice of Medicinal Products for Human Use Approval Dec. 2012, effective June 2013 Sec. 5.4 The supply chain of medicinal products should be known and documented. Stresses GMP, supply chain security and temp mgt API importation into the EU listed and non-listed countries and SC maps Control of APIs (Active Pharmaceutical Ingredients) Importation Safety Features Barcodes and TEP (Tamper Evident Packaging) Falsified Medicine Directive Good Distribution Practices Issued March 2013 Re-issued Nov Internet Sales 8

9 Standard Supply Chain Maps Regulatory Starting Material through Distribution Example

10 1 0 Structure of EU GDP Guideline Chapters Introduction: 1. Quality Management 2. Personnel 3. Premises and Equipment 4. Documentation 5. Operations 6. Complaints, Returns, Falsified Medicinal Products and Recalls 7. Outsourced Activities 8. Self-Inspections 9. Transportation 10.Specific Provisions for Brokers

11 Wholesale and Broker Regulations (page 1 of 2)

12 Wholesale and Broker Regulations

13 IMB GDPs (Slide 1 of 3)

14 IMB s GDPs (Slide 2 of 3)

15 IMB s GDPs (Slide 3 of 3)

16 Temperature Management (Slide 1 of 2)

17 Temperature Management (Slide 2 of 2)

18 1 8 Steps to Show Control (QMS and QRM) 1. What do the regulations say Know your product Failure points high and low Demonstrate control (QMS) 2. ICH Q1A standard stab testing Establishing storage label claim Not good enough Temperature cycles studies To manage typical supply chain temp excursions File the cycling studies 3. Develop a stability budget (QRM) Excursion management Shipping outside of storage label claim

19 1 9 Know what use you are developing the data for! File the data!

20 Know Product Failure Points How the product reacts at highs (50C) and lows (-20C) That will help determine level of control needed during shipping

21 Control the Storage Label Condition

22 e.g. Controlled Room Temperature Stability Budget

23 So when the inevitable happens.. Options for CRT shipping 1. Active shippers 2. Passive shippers 3. Blankets 4. Controlled networks 5. Risk it

24 Cold Chain End-End Supply Chain Temp Mgt Cold Chain has expanded to be End to End Supply Chain Temp Mgt Includes mfg ing lanes to the Rx/POS (point of Sale) Includes all temperature ranges Including CRT controlled room temperature

25 EU GMP Annex 15: Qualification and Validation

26 Verification of Transportation in the EU GMP

27 2 7 Bulk Drug Shipment Temperature Monitoring Stability Budget Pack out at Mfg ing site Mean ambient temperature at Airport on 6/19/2014: C Mean ambient temperature at O Hare on 6/22/2014: C Held by Port (CBP, MoH, etc)) Transport to packaging site Belly of plane Arrival at packaging site

28 Passive Shippers: one origin, multiple destinations Internal & External Monitoring Know your product and know your data Tarmac handling Loading final unloading Example of multiple shipments same origin and destination Need to know your supply chain temps and How your product reacts

29 Summary / Conclusion GDPs need to be part of (integrated into) the QMS GMP and GDPs need to be integrated (not siloed) QRM needs to incorporate / use: Supply Chain Maps Product knowledge vs. temperature control needed Appropriate levels of risk management GMP Crxx 2-8 Granulator Room temp Fluid Bed Dryer 60C Tablet press Room temp GDP BDS (API) Singapore 2-8 Tableting (BDP) Ireland Room Temp Packaging (BDP) Germany Room Temp Finishing (market Specific) Netherlands

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32 Global GDP s - A Risk Based Approach to Management of Distribution Dave Ulrich, Ph.D. Abbvie QA Director Global Supply Chain

33 Patient Safety Patient health and safety is of the utmost importance to the pharmaceutical industry. Goal Maintain product quality, safety and efficacy by preventing security and temperature incidents* in our end-to-end supply chain (* e.g. counterfeiting, tampering, theft, illegal diversion, and temperature excursions)

34 GDP Regulations Risk Management SUPPLY CHAIN RISK MANAGEMENT

35 EU Falsified Medicines Directive (FMD) June 2011 Importation of Active Substances Active Pharmaceutical Ingredients Import Control Issued 23 January GDP for Active Substance Effective 25 May 2015 EU Good Distribution Practices (GDP) Issued March 2013 Re-issued Nov EU Safety Features 2D-Matrix barcode + Anti-Tampering Devices Effective 9 th Feb 2016 Internet Sales Common logo 24 June 2014

36 EU Falsified Medicines Directive (FMD) June 2011 Good Distribution Practices (GDP) GDP is that part of quality assurance which ensures that the quality of medicinal products is maintained throughout all stages of the supply chain from the site of manufacturer to the pharmacy or person authorized or entitled to supply medicinal products to the public Purpose Maintain quality and integrity of medicinal products across complex global supply chains safeguard product quality and integrity (patient impact) prevent unnecessary product loss, scrap (availability to patients)

37 Risk Management as per the EU GDP 1. Quality Management Wholesale distributors must maintain a quality system setting out responsibilities, processes and risk management principles in relation to their activities 1.5 Quality Risk Management Refers to ICH Q9 (2005) The level of effort, formality and documentation of the process should be commensurate with the level of risk. 3. Premises and Equipment qualification activities should be determined using a documented risk assessment approach 6.3 Returns Returned products must be handled according to a written, risk based process 9. Transportation A risk based approach should be utilized when planning transportation Risk assessment of delivery routes should be used to determine where temperature controls are required Also reference: PDA Technical Report 58 Risk Management for Temperature Controlled Distribution

38 GDP s Around the World Countries General GDPs GIP TCM DCS Port Handling / Offloading Customs General Layout / Contruction Loading & Receiving Bays Building Cleanliness General Security Temperature Monitored Storage Areas Product Stability Profiles Temperature- Controlled Transport Humidity Control and Monitoring Shipping Containers & Packing General Packaging, Lableling Prcoessing Relabeling Qualified Personnel, Training Good Documentatio n Practices Stock Control Systems Exception Management & Product Compaint Procedures Product Return, Recall, Withdraw, Control and Disposal Serialization & epedigree GPS and Bulk Security, Counterfeits Traceability / GS1 Stock Identification Tracking LAA Region Argentina Regulating the Cold Chain of Medicines (Ley X X X Brazil Resolution - RDC No. 234 X X X X X X X X X Mexico Guidelines for Imported Biotechnological & x x x x x x x x Australia Code of Good Wholesaling Practice for X X X X X X X X X X X X X X Cold Chain Pharmaeutical Products X X X X X X X X India (OPPI) Guideline on Good Distribution Practices for X X X X X X X X X X X X X X X X Japan Biological Pharma Revision H X X X Malaysia Guidelines on Good Distribution Practice X X X X X X X X X X X X X X X X X X X X X Singapore Guidance Notes on Good Distribution X X X X X X X X X X X X X X X X X South Africa Good Whilesaling Practice for Wholesales, X X X X X X X X X X X X X X X X X Phillipines Adoption and Implementation of the World X X X X X X X X X X X X X X X X X X X X Central European Region Austria Austrian GDP Regulations X X X X X X X Czech Guidelines for Correct Distribution of Human X X X X X X X X X X X X X Republic Czech GDP Guidelines There are core elements X X to X all Xworld-wide X X GDPs, just like there X X EMA European Medicines Agency: " QP X X Guidelines on Good Distribution Practice of X X X X X X X X X X X X X X X X Directive 2001/83/EC of the European are core elements X to other XGxPs (e.g. X XGMP) X X X EU The IPEC Good Distribution Practices Guide X X X X X X X X X X X X X X X X X Europe - Good Distribution Practices Audit Rx-360 Summary of IPEC GDP x x x x x x x x x x x x x x x x x Ireland Guide to Control and Monitoring of Storage X X X X X X X X X X X X X X X Switzerland Distribution of Temperature Controlled X X X X X X X X X X X X X North American Region The EU GDP is the basis of our Quality Management Canada Guidelines for Temperature Control of Drug X X X X X X X X X X FDA to Revise Component GMPs to Bolster United States Bar Code Technologies for Drugs and System (QMS) on Supply Chain Controls. X X Standards for Securing Drug Supply Chain... X X X X X Middle-Eastern European Region Egypt Minster Decree for Wholesalers - Circular X X X X X X Israel Pharmacist Regulations - Circular 6 X X X X X X X X X X X X Status of Current GDP Regulations in Israel X X X X X X X X X X X X X X X X X X X X Romania NMA No. 30/ X X X X X X Saudi Arabia, GCC Guidelines for Stability, PP-SPC-9031, Saudi Food & TOPA GTS Drug Authority X X X X X X UAE Circular No X X X X X X International Health Organizations MHRA WHO GDP's Quality Systems Regulations Importation Storage Buildings / Warehousing Transport, Delivery, Storage Labeling Updated Policy on Returns of Non-Defective Guidance on Preventing Breaches in the Cold Chain Distribution GDP Risk GDP Risk Assessment Strategy Regulatory Provisions for Quality Controlled Model requirements for the storage and New Guidance for storage and transport of Inventory Procedures X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X X

39 Temperature Controlled Management (TCM) Temperature Controlled Product Management Process 1. Define Product Temperature Requirements 2. Define Temperature Controls (Storage) (Transport) 3. Monitor Temperatures (Storage) (Transport) 4. Manage Exceptions Stability Budget, Temp. Cycle Studies, Product Stability Testing

40 Know Your Product (Failure Points, High and Low) Identify your product failure points will help determine level of control required during shipping

41 Know what use you are developing the data for!

42 Supply Chain Security, Risk Control 8. Lab Test Product Authenticity

43 Supply Chain Risk Assessment - Process

44 Supply Chain Risk Assessment - Process The entire supply chain of the active substance and medicinal product up to the stage of certification is documented and available for the QP This should include the manufacturing sites of the starting materials and packaging materials for the medicinal product and any other materials deemed critical through a risk assessment of the manufacturing process Same philosophy for Distribution The supply chain of medicinal products should be known and documented Routes Carriers / contractors Conditions End-To-End approach = knowledge!

45 GDP Risk Assessment Process SUPPLY CHAIN RISK MANAGEMENT

46 GDP Risk Assessment - Process A cross-functional team approach must be utilized to perform the task. Utilize the knowledge and experience of relevant staff A structured group discussion exercise can be an effective forum Risk assessment does not need to be a complicated process and should be appropriate to your company/processes Communication of assessment outcome and follow up actions SUPPLY CHAIN RISK MANAGEMENT

47 GDP Risk Assessment - Objectives The objective is to identify, understand and prioritize current risks, evaluate the robustness of current controls and develop remediation plans when required to further strengthen the integrity of the product supply chain. This risk assessment utilized quantitative evaluation tools which detailed the risk involved in the supply chain. The risk control strategy highlights the quantitative evaluation results.

48 GDP Risk Assessment - Rating Risk Severity Rating Scale (Process Impact) # Description Criteria Severity Rating Scale (Patient Impact) # Description Criteria 5 Severe Stock out: DC shutdown; Regulatory impact-- warning letter; Restock/return 5 Death or Life- Threatening Death or Life-Threatening 4 Significant Supply chain excursion; failed batch/mdo (Investigation) 4 High Harm (injury) with residual (nonreversible) pathology 3 Moderate Supply chain velocity slowdown (product or paperwork) 3 Moderate Harm (injury) with reversible pathology 2 2 Minor Minimal effect or injury 1 Minor No impact 1 Minimal/Nonsafety Related Regardless of the scale numbers (e.g. the above scale), you need to define corresponding criteria Non-safety Related

49 GDP Risk Assessment - Scope During transportation the product attributes that need to be assessed for potential impact to product quality are: 1. Transportation Security Typically involves the supplier status of the transportation carrier (approved, audited, etc.), the certification status of the transportation carrier and the physical security methods employed by the transportation carrier. 2. Temperature Control Management Is the temperature adequately maintained throughout the entire supply chain under evaluation. This incorporates qualitative testing as applicable, stability data, the stage of production and anticipated time in transit.

50 Manufacturing Supply Chain Risk Assessment & Risk Control Strategy 2016 SUPPLY CHAIN RISK MANAGEMENT

51 Manufacturing Supply Chain Risk Assessment (1) Supply Chain Security and (2) Temperature Control Management main focus during Transportation Risk Assessment because of potential direct product quality impact. The following information is showing an example of performing a manufacturing supply chain risk assessment using a basic risk ranking tool Various security attributes were assessed and assigned numerical risk values. By multiplying those risk values an overall risk associated was generated. Based on that overall value action is or is not then required to be taken per the criteria identified

52 Transportation Security Criteria (3x)

53 Transportation Security Risk Ranking By multiplying the determined rankings A, B & C an overall supply chain security risk is determined. Per the result: < 2: Security is adequate 2: Security is adequate however the ASL requires updating > 2: Security may be adequate however the carrier needs to be assessed, certified and added to the ASL

54 Transportation Security Criteria (3x)

55 Temperature Control Risk Ranking By multiplying the determined rankings A, B, C & D an overall temperature control risk is determined. Per the result: >47: Transportation temperature control, temperature monitoring and lane qualification are required 17-47: Transportation temperature control required, no temperature monitoring required however lane qualification recommended 5-16: No temperature monitoring, temperature controls or lane qualification required. For risk control ranking verification, periodic monitoring may be implemented 4: No temperature control or monitoring requirements, no further action required

56 Internal & External Monitoring Know your product and analyze your data Example of multiple shipments same origin and destination, using a passive shipper Need to know your supply chain temperature profiles and how your product reacts

57 Risk Control Strategy & Risk Assessment Summary - example - This risk control strategy concludes that the supply chain does maintain adequate product security and temperature. As the security and temperature risk is minimal, qualification of the lanes at this time is not required. Temperature monitoring will be performed for each shipping lane in the manufacturing supply chain. Verification of the transportation security and temperature requirements performed each time product is received at the manufacturing site.

58 Conclusion Supply Chain Risk Assessments are important to prevent drug shortages Supply Chain Mapping is a key element in the supply chain risk management process Supplier Management program must be in place to ensure supplier controls (e.g. audit program) Cross-functional team approach Warehouse operator training, driver awareness training to include security aspects Do not underestimate the risk of data flows

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60 Quality Management as a Foundation for Good Distribution Practices Compliance Glaucia Karime Braga, Ph.D. USP Packaging and Distribution Expert Committee Member USP <1079> Sub-Committee Co-Chair PPP Auditor, Quality Assurance, FURP - Sao Paulo State Government (BR)

61 Agenda Quality Management System QMS Understand the concept of a Quality System Know the key elements of a QMS for the storage and distribution processes Key point: Having a Quality System that is build based on risks and their mitigation strategies

62 Pharmaceutical Supply Chain - Overview

63 Risks and Mitigation Strategies HAZARD EFFECT MITIGATION STRATEGY Environmental storage or shipping conditions out of specification (Temperature out of specification) Product quality, integrity and patient safety (e.g. freezing of vaccine or biologic) Product loss (e.g. money) Warehouse, Vehicle and Packaging Qualification Operations SOP (storage, transportation) MITIGATION CATEGORY Qualification / Validation Documentation

64 Risks and Mitigation Strategies HAZARD EFFECT MITIGATION STRATEGY Personnel mistakes due to excessive duties and or lack of training Mishandling anywhere along the supply chain Appropriate number of personnel in order to avoid excessive duties being placed to one individual MITIGATION CATEGORY Organizational Training Evaluate the efficacy of training

65 GDP: Key Point Quality Management System Documentation Training Qualification/Validation Instructions, Schedules and Records INFORMATION Competence Development and Instructions Understanding COMPREHENSION Mitigation Strategies Ensure suitability of the purpose Warehouse/Packaging System/Transportation and ERP ASSURANCE Process Knowledge & Risk Identification The central idea is having a Quality System that is build based on risk. Generally, mitigation strategies are related to instructions (SOPs), training (ensure instructions understanding) and Qualification/Validation (warehouse temp map, packaging system, ERP software, process validation (in case of distribution, is the transport mode/route validation). And all of this are GDP requirements!

66 Quality Management Systems A Quality Management System (QMS) is defined as a set of interrelated or interacting elements, such as policies, objectives, procedures, processes, resources which individually or collectively, established to guide an organization QMS Risk-based approach QMS framework for all supply chain partners Can be integrated into other management systems: Quality (ISO 9001 and GMP) Environmental (ISO 14001) Occupational Health and Safety (OHSAS 18000)

67 Key Elements Management Responsibility Regulatory Affairs Documentation Validation/ Change Control QMS Resources Management Monitoring Improvement Complaints Returns Recalls Operations

68 Documentation

69 Documentation Quality Manual Brief information on the organization Types of material, products, services handled Activities as licensed by the competence authorities Scope and Overview of QMS Quality Police and Objectives Identification of the processes and their sequences, linkages, and interdependences Organizational Chart Matrix of key personnel responsibilities Reference to supporting procedures and documents, such as Validation Master Plan and a list of SOPs

70 Operations Core Operations for Distribution: Procurement Receiving Sampling Storage Sales Picking Packing Shipping Transportation Outsourcing and service agreements For each one a SOP should be written!

71 Operations Procurement and Sales A list of all qualified suppliers and customers should be in place Receiving and Shipping A checklist should be utilized as a reminder of what to inspect and what to record when receiving goods Deliveries should be verified at receipt in order to check that containers were not damaged and the consignment corresponds to the order

72 Operations Storage The organization should have: A written procedure should be established for storage and inventory control Each product and material should have a storage specification regarding Temperature, Relative Humidity, and other Special Requirements Storage areas should be qualified and a temperature mapping and monitoring program should be in place Storage: holding at production area is storage! Tablets or capsules waiting for packaging Picking & Packaging A written procedure should be established ensuring that the correct product was selected, property packaged and dispatched Package should be appropriated and its qualification tests should be performed according to approved protocols

73 Operations: Transportation Transportation A written procedure should be established, including at least: Responsibilities Approvals for subcontracting Methods for defining transportation routes Capacities and limitations of transportation systems Loading patterns (First-out, Last-in) Transportation modes: Choice criteria is related to: scale of transportation (national or international), nature of product, level of service Generally is used intermodal transportation 73

74 Resources Management Organization should have Organizational chart: responsibilities Job descriptions: tasks, competences, authorities Training: initial and ongoing, training needs, schedule, records and effectiveness assessment Training SOP, should describe: Who can be a trainer (competences of a trainer) How training needs are identified and linked to job description Types of training needs

75 Resources Management Premises should be designed taking into account Security and safety Product characteristics Ease of cleaning and maintenance Logical flow of personnel and material Means of preventing mix-ups and cross contamination Ergonomic measures

76 Validation and Change Control Commissioning: Factory Acceptance Test (FAT) Site Acceptance Test (SAT) Qualification: The documented verification that the facilities, systems, and equipment, as installed: Installation Qualification (IQ): comply with the approved design and recommendations of the manufacturer Operation Qualification (OQ): operate within the ranges established by the manufacturer Performance Qualification (PQ): operate for a long time with robusteness and reproducibility within the specification established by the organization Validation Includes: Analytical Method Process Cleaning Computerized System Should have a Validation Master Plan (VMP), containing the strategy and the rationale for the validation efforts

77 Validation and Change Control Core for packaging, storing and transportation is ensuring the control of environmental conditions Two approaches: By controlling the environmental conditions in equipment, storage rooms and transportation vehicles (e.g. heating, ventilation and air-conditioning HVAC, refrigerator, (de)humidifier) By using packaging materials that allow the control of environmental conditions (e.g. thermal blankets, temperature stabilizers, desiccants, light resistant material)

78 Validation and Change Control Environmental controlled facilities, equipment and vehicles: Should have a validated SOP for storage and in-transit storage considering: Product category (prescription pharmaceuticals, narcotic, medical devices) Storage layout (floor-standing pallet, pallet racking, boxes inside the refrigerator) Volume of Storage (including peaks of storage) Environmental conditions and air circulation Contingency Plan for outages and breakdowns Should have a validated SOP for shipping package, considering: Environmental conditions during shipping Package system selection Product-package configuration for shipping Monitoring device necessity Temper evident closure system Forms and Records (during shipping and temporary storage) Documentation necessary for shipping (including labeling, courier documents) 78

79 Validation and Change Control Should be carried out to evaluate if the equipment, warehouse facility, shipping container and temperaturecontrolled vehicles perform as required. Can be any of the following: Prospective (lab simulation): When documented evidence for PQ is generated before the start-up of the operation or system Concurrent (cargo monitoring): When documented evidence for PQ is generated during the actual operation of the system Retrospective (historical data): When documented evidence for PQ is generated using historical data for systems

80 Validation and Change Control Performance Qualification Protocols: Should be approved prior to execution and should have: Responsibilities including third parties Material or product storage requirements as established by means of stability studies (T and RH ranges allowed during storage and transportation) Description of the storage room or payload compartment, including dimensions, layout, active environmental controls (coolers, heaters, etc.), power systems Location and volume of the material or product inside the storage room or shipping container Packaging material Environmental conditions during storage and transportation Transportation mode, route, and duration Monitoring devices and alarms (warning systems) in place Temperature mapping to show whether temperatures are evenly distributed or if there are hot or cold spots in storage areas and dedicated vehicles Acceptance criteria and approvals Audible or visible alarms or both should be in place if temperature or relative humidity or both are out of specification: These alarms should be qualified and also periodically changed

81 Validation and Change Control Computerized Systems Extent of validation depends on the risk to/impact of the software on product quality An inventory of computerized systems should be done periodically, including at least: Software identification (name, version, supplier) Processes where software is used Process owner Risk assessment Status (validated, not validated, in progress, not applicable) A multidisciplinary team should be in charge of protocols and report approvals Software validation tests should cover: Security (e.g., access levels, profiles, responsibilities inclusion, exclusion, changing profiles) Data validity (e.g., challenge the software with entries above and below specification and with entry value errors) Documentation (e.g., software design in accordance with user requirements and other documents) Functionality (e.g., calculations, operations) Note: Most of these tests for embedded software are covered during equipment qualification (installation, operation, and performance qualifications) Data integrity (e.g.; changes, traceability, backup, recovery, protection) Records should be kept

82 Validation and Change Control Validation and Change Control The organization should have a written procedure describing the steps for change control, including at least: Responsibilities Impact assessment of the change based on risk Necessary validation Documentation review Regulatory impact Necessity to have planned activities for the change. Customers and regulatory bodies should be notified of any changes in packaging, handling, storage, transportation, or documentation

83 Complaints, Deviations, Returns, Recalls Complaints Deviations Recalls Returns RECALLS: Quality/safety/efficacy issue (GMP) recall is necessary to avoid the product from being used. Challenge: Send back what was shipped. However, product will be destroyed RETURNS: There is NO quality/safety/efficacy issue. It s a logistic issue (GDP) Challenge: the core question is deciding if the returned product is acceptable for restocking and resale or whether it should be destroyed. The product could be restocked for new selling (Risk)

84 Complaints, Deviations, Returns, Recalls Returns CRITICAL!!!! backward flow. A written procedure for handling returns should be in place A risk-based evaluation should be performed to determine if the product will be accepted for restocking and resale or if it will be destroyed During the evaluation, returned products should be kept in a segregated area. Restocking should be accepted only once The organization should inform customers if there is a returned product included in their order, prior to shipment The evaluation should take into account at least the following: Reasons for return Appearance and integrity of the original packaging Evidence of conditions in which the cargo was transported and stored throughout the entire time Duration of time between the original shipment and its return Authenticity of product Representative sampling for quality control analysis Expiry date and batch number Information from any track-and-trace system in place

85 Complaints, Deviations, Returns, Recalls Corrective Action and Preventive Action (CAPA) and Continuous Improvement CAPA is a system established to perform actions to eliminate the cause of a detected nonconformity or other untoward situation in order to prevent reoccurrence (corrective action) and actions to eliminate the cause of a potential nonconformity or other untoward potential situation to prevent occurrence (preventive action)

86 Complaints, Deviations, Returns, Recalls Monitoring and Improvement: Audit Product or Service Quality Reviews ~Annual Product Review: Management Reviews Corrective action and Preventive Action (CAPA) Continuous Improvement Management Reviews: QMS should be reviewed periodically Review by senior management of the suitability and effectiveness of the QMS at defined intervals and with sufficient frequency according to established procedures to ensure that the system satisfies the requirements of the FDA and the manufactures established quality policy and objectives

87 Complaints, Deviations, Returns, Recalls Some inputs for management reviews: Previous management reviews reports Audit and regulatory inspection reports and actions in place Complaints, deviations, returns and recalls Detected or potential counterfeiting Status and effectiveness of the CAPA system New or updated regulatory requirements Quality policy Quality objectives metrics as Key Performance Indicators Quality Manual and Change control reports Some outputs of the management reviews: Recommendations for improvement of the system, processes, products or services Demand for resources

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91 The Importance of Temperature Control and Best Practices for Products Moving Through the Supply Chain: Risks and Migration Strategies Chris J. Anderson USP Packaging and Distribution Expert Committee Member USP <1079> Sub-Committee Co-Chair Director, Quality Systems, Cardinal Health

92 Temperature Control Risks and Mitigation Strategies Storage, Packaging, and Transportation Maintaining manufacturer s labeled temperatures for storage and transportation is important to maintaining product integrity to include efficacy and expiry Contingency storage and temperature excursion response plans are (risk evaluation and mitigation) an important part of operational management Responding to exceptions/excursions is important to preventing product loss Documentation of temperatures and time is important to obtaining dispositions from manufacturers

93 Temperature Control Risks and Mitigation Strategies Storage, Packaging, and Transportation Storage Conditions Freezer: typically thermostatically between -25º and -10ºC (-13º and 14ºF) Refrigerator (Controlled Cold): between 2º and 8ºC (36º and 46ºF) Cold: Not exceeding 8ºC (46ºF) Cool: Between 8º and 15ºC (46º and 59ºF) Room Temperature: the temperature prevailing in a work area Controlled Room Temperature (CRT) product: Thermostatically maintained between 20º and 25ºC (68º and 77ºF). Warm: Any temperature between 30º and 40ºC (86º and 104ºF) Excessive Heat: any temperature above 40ºC (104ºF) Dry Place: does not exceed 40% average relative humidity at 20ºC (69ºF) Protect From Freezing Protect From Light Today we are going to focus on Controlled Cold and Controlled Room Temperature Product

94 Temperature Control Risks and Mitigation Strategies Storage, Packaging, and Transportation Refrigerated (Controlled Cold) Product: 2-8ºC (36º and 46ºF) Typically the most costly products Biologics, biosimilars, vaccines For packaging, colder is not better Dangers of freezing Shipping options: Active shippers Active temperature controlled vehicles Passive/qualified shippers

95 Temperature Control Risks and Mitigation Strategies Storage, Packaging, and Transportation Controlled Room Temperature (CRT) Product: 20-25ºC Excursions between 15º and 30ºC (59º and 86ºF) that are experienced in pharmacies, hospitals, and warehouses, and during shipment are allowed Maintain Mean Kinetic Temperature (MKT) 25ºC Provided the mean kinetic temperature does not exceed 25ºC, transient spikes up to 40ºC (104ºF) are permitted as long as the do not exceed 24 hours. Biologics (think fever or hypothermia), injectables and oral liquids and liquid suspension particulates The most challenging temperature range to maintain

96 Risk and Mitigation HAZARD EFFECT MITIGATION STRATEGY Storage Area Temperature Stability Temperature Monitoring Device Failure Out-of-range cold or hot areas; product storage temperature excursion; product loss; financial loss; patient product availability Out-of-range cold or hot areas; product storage temperature excursion; product loss Qualification and temperature evaluation; storage temperature monitoring program; homogenous airflow; monitoring, alarms; and response plan See Excursions under Hazard Back-up monitoring devices with independent power source See Excursions under Hazard MITIGATION CATEGORY Training for exceptions ; Documentation ; Validation; Planning Training for exceptions ; Documentation; Maintenance

97 Risk and Mitigation HAZARD EFFECT MITIGATION STRATEGY Storage /Temperature System Failure loss of electrical power failure of temperature control and air circulation systems unusual weather event Out-of-range cold or hot areas; product storage temperature excursion; product loss Temperature and power alarms, backup power and coolant systems (redundant) and/or contingency storage; See Excursions under Hazard MITIGATION CATEGORY Training for exceptions ; Documentation; Maintenance; Business Continuity Plans Product Stored in the Wrong Environment Product storage temperature excursion; product loss System storage coding; product storage notification; understanding storage labels Training; Documentation; Communication

98 Risk and Mitigation HAZARD EFFECT MITIGATION STRATEGY Fear of Reporting Nonconformance/Excepti on conditions Transportation Delivery Delays Product integrity and patient safety, serious conditions not communicated Out-of-range cold or hot areas; product storage temperature excursion; product loss Independent quality reporting structure; education on product integrity and the impact to patients and the supply chain if discovered Fuel contingencies, in-route; alternative/emergen cy storage; contingency vehicles; MITIGATION CATEGORY Organizational; Training; Policy Training for exceptions ; Business Continuity Plans See Excursions under Hazard

99 Risk and Mitigation HAZARD EFFECT MITIGATION STRATEGY Protective Packaging delivery delays beyond package qualification Out-of-range cold or hot areas; product storage temperature excursion; product loss Qualify to account for delays; alternative/emergency storage; conduct extended testing (you can t do anything without data); reconditioning contingency; temperature monitors MITIGATION CATEGORY Training for exceptions; Weather monitoring (don t assume that all is well just because a carrier / transportation company picked up your delivery); Contingency communication and decision making plan Excursions temperature or time excursion exception response: mitigation of out-of-range temperature and/or time excursions (effect of all Hazards listed above) Out-of-range cold or hot areas; product storage temperature excursion; product loss Response plan; data gathering plan (template); Product quarantine process; customer, trading partner and service vendor communication Training for exceptions; Documentation; Communication

100 Risk Mitigation Decision Map: Transportation Delay of Controlled Cold Product

101 Risk Mitigation Decision Map: CRT Product Storage Area Excursion

102 Risk Mitigation Decision Map: Product Temperature Excursion Management Process

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105 Good Distribution Practices (GDPs): Other Topics and Considerations Matin L. Jeiven, MS, BPharm, RPh USP Clinical Trials Expert Panel Member President, Jeiven Pharmaceutical Consulting

106 Agenda How much is distribution (commercial and clinical) considered by a company? How often is distribution an issue for clinical trials? What do the GMPs say regarding proper distribution?

107 Commercial and Investigational Drug Products Both must comply with GMPs (Good Manufacturing Practices) for manufacture, testing and packaging and labeling. Both most comply with the same warehousing (storage) and distribution practices.

108 The Phases of Clinical Trials Phase I Follow animal testing to help ensure the safety of the first human doses Typically at one or two sites, limited number of subjects Short duration Safety and perhaps some efficacy as the goal IDP (investigational drug product) limited in quantity Closely monitored Unusual to have robust stability profile Limited expiration date Phase II (a and b) Multi-site, larger subject population Larger quantities of IDP Longer trial duration Domestic and international (?) sites Goals: establish efficacy, determine dosing regimen and identify potential adverse events Usually include comparators

109 The Phases of Clinical Trials Phase III Increasing larger trials Additional international sites Almost always include comparators Similar goals as for Phase II Will include pivotal trial(s) Phase IV After-market trials Study additional indications and patient populations May or may not require large quantities of IDP Companies may have to commit to regulatory authorities that trials will have to be conducted as a condition for product approval

110 Controlled Temperatures Storage and Distribution Temperatures (USP): Liquid Nitrogen (submerged): -196 C Liquid Nitrogen (vapor phase): -150 C Dry Ice: -80 C Frozen: -25 C to -10 C Cold/Refrigerated: 2-8 C Cool: 8-15 C Controlled Room Temperature (CRT): C

111 Global Temperature Challenges

112 External Temperature Influences 24 Hour Shipping Profile Example

113 Good Distribution Practices Global initiatives to apply Quality principles to the distribution process: Guideline 2013/C 68/01: EU 2013 Good Distribution Practice of Medicinal Products for Human Use GUI-0069: Health Canada 2011 Guidelines for Temperature Control of Drug Products during Storage and Transportation <1079>: USP Good Storage and Distribution and Practices for Drug Products Many others, including WHO, multiple individual countries, IATA (International Air Transport Association), IPEC (International Pharmaceutical Excipients Council), etc.

114 Quality Systems for Distribution Implement Basic Quality Systems: Oversight and responsibility Management review Deviation investigation and CAPA Complaint handling; recall process EU: designate Responsible (Qualified) Person Expectations for Control of Storage Areas in line with GMPs Calibration and qualification Mapping Monitoring Recordkeeping Control of environmental conditions during transportation EU: transport conditions = labeled conditions US: MKT (mean kinetic temperature) concept allows for excursions

115 What is Mean Kinetic Temperature? Mean Kinetic Temperature (MKT) is a simplified way of expressing the overall effect of temperature fluctuations during storage or shipment of perishable goods. Consider the following example: EXAMPLE: A dozen eggs sat: In a 20 C room for 2 hours In a 2 C refrigerator for 4 hours And on a 25 C loading dock for 1 hour Using MKT we can calculate that the temperature profile of the eggs was thermally equivalent to storing them at C for 7 hours.

116 How Mean Kinetic Temperature is Calculated MKT is an expression of cumulative thermal stress experienced by a product at varying temperatures during storage and distribution. MKT is a calculated, single temperature that is analogous to the effects of temperature variations over a period of time. MKT is not a simple weighted average. The calculation of MKT gives the higher temperatures a greater weight when computing the average than would a simple numerical average or an arithmetic mean. This weighting is determined by a geometric transformation the natural logarithm of the absolute temperature.

117 Packaging Solutions Active Systems: Internal energy source Engine, battery, etc. Actively heat or cool the shipper contents Examples: Envirotainer/Unicooler Temperature-controlled Trucks

118 Packaging Solutions Thermo Chill Insulated Carton with Foam Shipper, Small, 6" Length x 5" Width x 6-1/2" Depth

119 Packaging Solutions Non Reversible Temperature Labels 29 C to 290 C / 84 F F Time Temperature Indicators -18 C to 37 C / 0 F to 98 F Relative Humidity Sensing Humidity Range 0%-100% RH

120 Packaging Solutions Single Use Strip Chart Temperature Recorder Sample of strip chart recording Low Cost Recording of Temperature for HACCP and Quality Control documentation. Introducing the TempCheck3, a reliable and cost-effective strip chart temperature recorder. The TempCheck3 is driven by a high-torque quartz motor and displays the time and temperature on strip chart paper in both Celsius and Fahrenheit.

121 Packaging Solutions Multi-Use Temperature Data Loggers Electronic data loggers have been designed to offer different models for varying applications. They range from the most exacting requirements such as laboratories who require NIST certification and calibration, to everyday use such as a temperature monitoring for refrigeration of perishable products. All data loggers use an internal thermistor for measuring temperature and share the same basic palm-sized or smaller design. RF Wireless Recorders Ethernet & WiFi Recorders Collect, monitor and manage temperature data via wireless communication in real time. -40 C to +72 C or - 80 C to +30 C. Our WiFi products let you leverage your existing WiFi network with the built-in WiFi b/g/n connectivity and avoid expensive installation costs for managing temperature data. Temperature range options of - 40 C to +72 C (-40 F to +160 F) or -80 C to +30 C (-112 F to +86 F).

122 Cold Chain Packout for IMP Temperature Control Packout Example Insulation Clinical Supplies PCMs

123 Packaging Solutions Passive Systems Rely on Phase Change Materials Insulated Shipper

124 Phase Change Materials Many companies have developed suitable PCMs of different (proprietary) composition Composition of PCM and construction of shipper allow temperature-controlled shipments at different temperature points and of varying durations

125 GDP for Controlled Room Temperature Evolution of established controls from refrigerated products to controlled room temperature products Storage conditions specified on label Conditions must be met during shipping and distribution

126 Qualification vs. Validation What is the difference when considering Distribution? Qualification: Quality of the equipment (i.e., container) Tested under standard highly controlled conditions ( Pre-Qualified Shippers) Validation: Quality of the process (i.e., combination container and environment) Tested by simulating/mimicking actual payloads and actual transport temperature profiles ( Validated Shippers)

127 Examples of Pre-Qualified Shippers Cryopak Credo Cold Chain Technologies

128 Temperature Monitoring Single use/multiple use Level of information Full curve Yes/no indicator Electronic/Paper Temperature range Readable at destination vs. Return to sender Most important: evaluate excursions to assess suitability of product