GDP and Integrity of The Supply Chain

Transcription

1 GDP and Integrity of The Supply Chain Presented by: Karen S Ginsbury B.Pharm, MSc, MRPharmS For: IFF, October 2010

2 What are the Risks

3 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

4 Every Picture Tells a Story Distributors, Wholesalers, Importers, Exporters, Pharma companies

5 ONE CALL STARTS THE PROCESS CUSTOMER CALL PROCESS INITIATION CONTAINER RENTAL (DRY ICE & BATTERIES) PICKUP AT AIRLINE ENROUTE CONTAINER 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

6 To be discussed... Regulations: EU directive WHO Guideline EU concept paper for updating Scope of the regulations Quality Management System Quality Agreements with customers Personnel Requirements: training and qualification Premises and Equipment Documentation Repackaging / Re-labeling controls Quality Control

7 To be discussed... Warehousing and temperature control Qualification and Validation of GDP activities, with a very brief look at computerized systems Picking goods / preparing orders, FiFo vs FeFo Controls and documentation Managing a controlled temperature vehicle fleet Contractors: cars / trucks; printers for packaging materials; maintenance, calibration and qualification of equipment The role of the QP Deviations and Change Control Returned Goods, Complaints and Product Recall Auditing of your company by customers and of your subcontractors and vendors

8 Counterfeit Medicines

9 MHRA Press Release Date:05 Nov 2007 Time:15:00 Subject: Counterfeit medicines supplier sentenced A woman who supplied counterfeit prescription drugs to the UK was sentenced to two and a half years at Croydon Crown Court today. Shazia Amjad, 39, of Uxbridge, was arrested as part of a joint investigation between the Medicines and Healthcare products Regulatory Agency (MHRA) and City of London Police. Enforcement officers found counterfeit prescription drugs worth over 250,000, including more than 50,000 units of Ephedrine and a selection of slimming pills, erectile dysfunction pills, painkillers and anabolic steroids, when they searched Amjad s address in November In addition, officers found twelve passports hidden inside a suitcase. A total of 30 bank and visa cards were also recovered during the search. Officers discovered that the drugs originated in Pakistan and were mailed over to Amjad, who was paid in cash. The money was then credited to a bank account in the name of Reena Khan, a pseudonym used in one of the false passports

10 The size of the problem WHO estimates that 5-10% of global medicines are counterfeit, costing the industry up to 32 billion a year Annual growth of counterfeit medicines will outstrip that of legitimate medicines worldwide through 2010 In 2004, counterfeiting was a 25.9 billion business projected to grow 13 percent year-over-year through 2010 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

11 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

12 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

13 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

14 Pharma Supply Chain Manufacturer Wholesaler Raw Material Supply Production Warehouse Transport Distribution End use GMP GDP

15 Main activities of a Distributor Purchasing of medicinal Products Manufacturers Wholesalers Warehousing Acceptance Storage Quarantine Release Customer call service Picking Packaging Transport Delivery to authorized customers Handling of Returns Handling of Rejected products Relabeling activities

16 EU Regulations Directive 2004/93/EC laying down the principles and guidelines of good manufacturing practice of medicinal products for human use Directive 2001/83/EC, Title VII, on the wholesale distribution of medicinal products for human use. Directive 2005/28/EC on the requirements for authorisation of the manufacture or importation of clinical trial materials Guidelines on good distribution practice of medicinal products for human use (94/C 63/03)

17 The Legal Basis - EU

18 The Legal Basis - EU

19 The Legal Basis EU Concept paper to adopt WHO?

20 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

21 WHO

22 TOC

23 Counterfeit Medicine - Definition Medicine deliberately and fraudulently mislabelled with respect to identity and/or source Can apply to branded and generic products May include product with: correct ingredients wrong ingredients without active ingredients with the quantity of active ingredients outside the product specification with fake packaging (too much active ingredient less likely)

24 EU Legislation Under Consideration A legal basis for the Commission to render obligatory specific safetyfeatures on the packaging for prescription medicines. An extension of certain rules for wholesalers to other economic actors in the distribution chain who are involved in the transactions (for example, by auctioning products) without actually handling the products. Obligatory audits of distributors and harmonised rules for official inspections. Moreover, compliant wholesalers would be listed in a European database to enhance transparency of reliable traders. Strengthened requirements for importations of API if it is established that the regulatory framework in the respective third country does not ensure a comparable level of protection of human health for products exported to the EU Audits and notification of economic actors handling API in the EU

25 US Legislation Under Consideration FDA Globalization Act of 2008 Expands powers of FDA to impound and DESTROY adulterated products at ports of entry Requires mandatory registration of foreign facilities Requires inspections at same frequency as for domestic suppliers

26 What can I do? Training should include the topic of product security as well as aspects of product identification and measures taken to avoid introduction of counterfeit medicines into the supply chain Organizations in charge of pharmaceutical distribution must include in their existing security features, appropriate measure to prevent intruders entering their warehouses and to make known the presence of same, should they breach the existing security measures A record of all training should be kept WHO guide on GDP (under revision)

27 What can I do? The quality system should include provisions that the holder of the marketing authorization, labelled entity (if different from manufacturer) the appropriate national and/or international regulatory bodies, as well as other relevant competent authorities, should be informed immediately in case of confirmed or suspected counterfeit medical products Such products have to be stored in a secure segregated area and have to be clearly identified to prevent further distribution or sale WHO GDP

28 What Can I do? All parties involved in the distribution of pharmaceutical products should share responsibility for the quality and safety of products to ensure that they are fit for their intended use There should be a procedure in place that describes pedigree documentation as well as the visual and/or analytical identification of potential counterfeit products WHO GDP Guide

29 What Can I do? Defined procedures for e-commerce and systems in place to ensure traceability and confidence in product quality. The sale of medicines via the Internet should be limited to registered and authorized mail order pharmacies and other legal entities only 6.6 Authorized procurement and release procedures for all administrative and technical operations performed should be in place, to ensure that appropriate products are sourced from approved suppliers and distributed by approved entities. There should be a written procedure in place to ensure and document traceability of products received and distributed based on batch numbers. 6.7 All entities in the supply chain should be traceable with written procedures and records to ensure traceability of distributed products

30 What Can I do? 6.9 To avoid penetration of counterfeits into the supply chain pedigree procedures and records should be developed for tracking and tracing of material and product. Each supplier should maintain and provide pedigree records to the next recipient in the supply chain ending with the final recipient before purchase/use by end-user (usually the patient) 6.10 Seal control programs for transit shipment: seals issued in a tracked and sequential manner, seals are intact and numbers verified during transit and upon receipt Written procedures for the control of incoming materials including a plausibility check: might the products be counterfeit? 6.11 Establish measures to ensure that pharmaceutical products have. a form of documentation that can be used to permit traceability of the products throughout distribution channels from the manufacturer/importer to the retailer

31 Who is responsible for maintaining product quality in the supply chain? The marketing authorisation holder The manufacturer and the Qualified Person The distributor and the Responsible Person The delivery driver The pharmacy and hospital (where relevant) The patient Everybody involved in the chain!

32 Duties of the Responsible Person To ensure provisions of licence are met To ensure operations are carried out in accordance with GDP To ensure an adequate quality system is established and maintained To oversee audit of the quality system and to carry out independent audits To ensure that adequate records are maintained To ensure that all personnel are trained To ensure full and prompt co-operation with MA holders in the event of recalls

33 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

34 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

35 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

36 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

37 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

38 Quality Management

39 Quality Management - Principle To achieve the quality objective reliably there must be a comprehensively designed and correctly implemented system of Quality Assurance incorporating: Good Manufacturing Practice Quality Control and Quality Risk Management It should be fully documented and its effectiveness monitored All parts of the Quality Assurance system should be adequately resourced with competent personnel and suitable and sufficient premises, equipment and facilities MUST have a Quality Policy

40 Premises and Equipment Premises and equipment should be suitable and adequate to ensure proper conservation and distribution of medicinal products. Receiving Area Receiving bays should protect deliveries from bad weather during unloading. The reception area should be separate from the storage area. Monitoring devices should be calibrated Equipment should be validated

41 Typical Equipment Heating Ventilation Air Conditioning (HVAC) Refrigerators Temperature/Humidity monitoring system Alarm system Generator Computerized systems

42 Equipment Critical equipment should be validated Measuring devices should be calibrated according to a written procedure A procedure for Preventive maintenance should be followed Log books should be kept for or critical equipment recording, as appropriate, any validations, calibrations, maintenance, cleaning or repair operations, including the dates and identity of people who carried these operations out. Any change in critical equipment should be subjected to change control procedure

43 Storage Practice

44 Storage Medicinal products should normally be stored apart from other goods and under the conditions specified by the manufacturer. Storage areas should be clean and dry and maintained within acceptable temperature limits. Where special storage conditions are required on the label (e.g. temperature, relative humidity), these should be provided, checked, monitored and recorded.

45 Storage Storage areas should provide adequate lighting to enable all operations to be carried out accurately and safely. Products should be stored off the floor and suitably spaced to permit cleaning and inspection. Pallets should be kept in a good state of cleanliness and repair.

46 Storage Different products, and/or different batches of the same product should be stored on different pallets When upright orientation of storage is signed products should be stored in accordance

47 Storage A written cleaning program should be available indicating the frequency of cleaning and the methods to be used to clean the premises and storage areas. There should also be a written program for pest control. The pest-control agents used should be safe, and there should be no risk of contamination of the materials and pharmaceutical products. There should be appropriate procedures for the clean up of any spillage to ensure complete removal of any risk of contamination.

48 Storage Physical or Logistical (validated computerized system with barcode) segregation Quarantined Released Rejected Returned Recalled products

49 Storage Where quarantine status is ensured by storage in separate areas, these areas must be clearly marked and their access restricted to authorized personnel Any system replacing physical quarantine should provide equivalent security For example, computerized systems can be used, provided that they are validated

50 Storage Physical or other equivalent validated (e.g. electronic) segregation should be provided for the storage of rejected, expired, recalled or returned materials or products. The materials or products, and areas concerned should be appropriately identified.

51 Storage Narcotics as well as substances presenting special risks of abuse should be stored in a dedicated area that is subject to appropriate additional safety and security measures.

52 Storage Products should be handled and stored in such a manner as to prevent contamination, mix-ups and cross-contamination. Products should be stored in conditions which assure that their quality is maintained, and stock should be appropriately rotated. The first expired/first out (FEFO) principle should be followed.

53 Receipt of incoming pharmaceutical products Medicinal products subject to specific storage measures should be immediately identified and stored in accordance with written instructions and with relevant legislative provisions. On receipt, each incoming delivery should be checked against the relevant purchase order and each container physically verified, e.g. by the label description, batch number, type of material or pharmaceutical product and quantity. The consignment should be examined and if necessary, should be subdivided according to the supplier s batch number should the delivery comprise more than one batch.

54 Receipt of incoming pharmaceutical products Each box/pallet should be carefully inspected for possible contamination, tampering and damage. Medicinal products with broken seals, damaged packaging, or suspected of possible contamination should be withdrawn from saleable stock, and if not immediately destroyed, they should be kept in a clearly separated area so that they cannot be sold in error or contaminate other goods. When required, samples should be taken only by appropriately trained and qualified personnel and in strict accordance with written sampling instructions. Containers from which samples have been taken should be labelled accordingly.

55 Receipt of incoming pharmaceutical products Following sampling, the goods should be subject to quarantine. Batch segregation should be maintained during quarantine and all subsequent storage. Products should remain in quarantine until an authorized release or rejection is obtained. Measures should be taken to ensure that rejected products cannot be used. They should be stored separately from other products while awaiting destruction or return to the supplier.

56 Stock rotation and control Periodic stock reconciliation should be performed by comparing the actual and recorded stocks. All significant stock discrepancies should be investigated All stocks should be checked regularly for obsolete and out-dated products. All due precautions should be observed to prevent the issue of outdated products.

57 Picking Picking of medicinal products for delivery should be performed in accordance with approved procedures and records should be maintained. Records should allow tracability of products in case of recall

58 Deliveries to Customers Deliveries should be made only to other authorised wholesalers or authorised pharmacies For all supplies a document must be enclosed, making it possible to ascertain the date, the name and pharmaceutical form of the medicinal product, the quantity supplied, the name and address of the supplier and addressee..

59 Good Transportation Practice

60 Transport Medicinal products should be transported in such a way that : a) their identification is not lost; b) they do not contaminate, and are not contaminated by, other products or materials; c) adequate precautions are taken against spillage, breakage or theft; d) they are secure and not subjected to unacceptable degrees of heat, cold, light, moisture or other adverse influence, nor to attack by microorganisms or pests.

61 Transport Medicinal products requiring controlled temperature storage should be transported by appropriately specialised means. Special care should be exercised when using ice in cold chains. It must be ensured that the material or product does not come in into contact with ice, as this may adversely affect the product quality, e.g. by freezing. Where appropriate, the use of devices to monitor conditions such as temperature during transportation is recommended. Monitoring records should be available for review.

62 Returned Products Returned goods should be handled in accordance with approved procedures and records should be maintained. Non-defective medicinal products which have been returned should be kept apart from saleable stock to prevent redistribution until a decision has been reached regarding their disposal. Products which have left the care of the wholesaler, should only be returned to saleable stock if:

63 Returned Products a) the goods are in their original unopened containers and in good condition; b) it is known that the goods have been stored and handled under proper conditions; c) the remaining shelf life period is acceptable; d) they have been examined and assessed by a person authorised to do so. This assessment should take into account the nature of the product, any special storage conditions it requires, and the time elapsed since it was issued. Special attention should be given to products requiring special storage conditions. As necessary, advice should be sought from the holder of the marketing authorisation or the Qualified Person of the manufacturer of the product.

64 Returned Products Records of returns should be kept. The responsible person should formally release goods to be returned to stock. Products returned to saleable stock should be placed such that the "first expired first out system operates effectively.

65 Temperature mapping Initial validation Empty state Maximum loaded state Cold season Hot season Revalidation Warehouse -Following significant changes Refrigerators Every year (loading as is)

66 Temperature Monitoring Sensors of the monitoring system should be located at the worst case areas identified by the temperature mapping Temperature records should be reviewed and confirmed and signed by an authorised person on a daily basis. Records should be kept for at lease 6 years (One year beyond products expiry date)

67 Temperature Monitoring Deviations should be investigated and corrective actions should be implemented MA Holder may by notified in accordance to the quality agreement.

68 Cold Chain

69 Cold Storage Biological products must be protected from freezing; even a brief period at sub-zero temperatures may irreversibly denature the protein, leading to a loss of efficacy. There are also products such as emulsion systems and solutions of sparingly soluble components which may become physically unstable at sub-zero temperatures.

70 Cold Storage Before setting up a cold storage facility or transport system, or before taking on a new range of products, it may be useful for distributors to carry out a risk analysis to establish a list of high, medium and low risk products and to make appropriate arrangements for their handling.

71 Cold Storage Domestic refrigerators are generally not suitable for high risk products because they may not have the precise electronic control necessary to maintain the temperature within the range 5±3ºC. Refrigerators are available which are specially designed for the storage of medicinal products and their use is to be encouraged for all products requiring storage between 2 C and 8 C.

72 Cold Storage Care should be exercised when placing goods in domestic units. If they are placed next to, or allowed to come into contact with the chiller plate or coil, their temperature may fall below the minimum recommended by the manufacturer. Sufficient space should be maintained between the goods and the internal surfaces of the unit to permit adequate air circulation

73 Cold Storage The probe may be placed within the load (or within a suitable buffer) to record the load rather than the air temperature The device should be calibrated annually against a certificated thermometer. The unit should have an auto-defrost facility and the temperature within the unit should not be affected during the defrost cycle. The correct functioning of the alarm should be checked annually at the high and low set points.

74 Cold Storage Refrigerators should be sited in an environment where the ambient temperature does not affect the temperature control within the unit. For example, it should not be sited in an unheated loading bay, or in an area of potential heat gain. Most refrigerators will function efficiently in an external environment of between 10 C to 32 C.

75 Cold Storage Condensate from chiller units should not be collected inside the cold store in an open vessel. All units, should be cleaned and disinfected regularly to prevent mould growth, and (as for all storage facilities) goods should not be stored directly on the floor.

76 EC GDPs: storage temperatures Products requiring controlled temperature storage should be identified on receipt and stored in accordance with written instructions Temperatures should be monitored and recorded periodically. Records should be reviewed regularly Controlled temperature storage areas should be equipped with temperature recorders. Control should be adequate to maintain all parts of the area within the specified temperature range

77 EC GDPs: shipping temperatures Medicines should be transported in such a way that they are secure and are not subjected to unacceptable degrees of heat and cold. Medicinal products requiring controlled temperature storage should also be transported by appropriately specialised means.

78 Why is MHRA concerned about temperature control? 32% of all critical and major deficiencies recorded by MHRA s GDP inspectors during 2005/2006 related to the control and monitoring of storage and transportation temperatures

79 Documentation and Records Documents, such as procedures, instructions, protocols and reports should be approved, signed and dated by appropriate and authorised persons. Documents should be regularly reviewed and kept up-todate. When a document has been evised, systems should be operated to prevent inadvertent use of superseded documents. Documents should not be handwritten; although, where documents require the entry of data, these entries may be made in clear, legible, indelible handwriting. Sufficient space should be provided for such entries.

80 Documentation and Records Any alteration made to the entry on a document should be signed and dated; the alteration should permit the reading of the original information. Where appropriate, the reason for the alteration should be recorded. The records should be made or completed at the time each action is taken and in such a way that all significant activities are traceable. They should be retained for at least one year after the expiry date of the product.

81 Documentation and Records SOPs should cover activities such as Purchase Receipt Sampling Storage Release/Reject Picking Dispatch and transport Returns Destruction Re-labeling Security Computerized systems and electronic data Maintenance and Calibration Cleaning Pest Control Recall Complaints Self inspections

82 Re-labeling Re-labeling activities are subjected to GMP requirements

83 Printed Materials Master File Printed Materials Master File should include Approved samples of the printed materials Serial number and edition of the printed materials Instructions for re-labeling Specifications of the printed materials Re-labeling procedure should be in accordance with the instruction within the Master File

84 Re-labeling. Before re-labeling operations are begun, steps should be taken to ensure that the work area is clean and free from any products, materials or documents previously used, if these are not required for the current operation. The lineclearance should be performed according to an appropriate check-list. All products and packaging materials to be used should be checked on delivery to the re-labeling department for quantity, identity and conformity with the re-labeling instructions.

85 Re-labeling Before re-labeling activities are begun employees should be trained in accordance to the product specific re-labeling instructions and training should be recorded Samples of labels/inserts should be attached to the re-labeling batch record Defected labels/inserts discovered along the process should be rejected and signed as rejected The process should be controlled by sampling and testing of re-labeled packages in predefined intervals

86 Re-labeling At the end of the process the amount of the pre-labeled products, and printed packaging materials and the number of units produced should be reconciled. Any significant or unusual discrepancy observed during reconciliation should be investigated and satisfactorily accounted for before release.

87 Re-labeling Upon completion of a packaging operation, any rejected printed material (and leftovers) should be destroyed and the destruction recorded. A documented procedure should be followed if printed materials are returned to stock. Re-labeling batch record should be reviewed and approved by an authorised person. Re-labeling approval should be a perquisite for release of the product.

88 Printed Materials Management Printed Materials should be purchased from qualified printers only. Incoming printed materials should be placed in quarantine and to be sampled according to a predefined sampling procedure. Samples should be tested for accurate text in accordance with the Master file, and for meeting specifications limits.

89 Printed Materials Management Testing results should be documented and if satisfactory the printed material should be released and removed to relesed printed materials area. Printed Materials should be stored in a designated area with limited access to authorised personnel in suitable conditions for preservation of the materials. Use of printed materials should follow FIFO principles

90 Complaints There should be a written procedure in place for the handling of complaints. A distinction should be made between complaints about a product or its packaging and those relating to distribution. In the case of a complaint about the quality of a product or its packaging the original manufacturer and/or marketing authorization holder should be informed as soon as possible. Any complaint concerning a material defect should be recorded and thoroughly investigated to identify the origin or reason for the complaint (e.g. repackaging procedure, warehousing procedures, etc.).. Where necessary, appropriate follow-up of corrective actions should be taken

91 Emergency Plan and Recalls An emergency plan for urgent recalls and a non-urgent recall procedure should be described in writing. A person should be designated as responsible for execution and co-ordination of recalls. Any recall operation should be recorded at the time it is carried out and records should be made available to the competent authorities. In order to ensure the efficacy of the emergency plan, the system of recording of deliveries should enable all destinees of a medicinal product to be immediately identified and contacted. In case of recall, wholesalers may decide to inform all their customers of the recall or only those having received the batch to be recalled.

92 Emergency Plan and Recalls In case of batch recall, all customers to whom the batch was distributed should be informed with the appropriate degree of urgency.. The recall message approved by the holder of the marketing authorisation, and, when appropriate, by the competent authorities, should indicate whether the recall should be carried out also at retail level. The message should request that the recalled products be removed immediately from the saleablestock and stored separately in a secure area until they are sent back according to the instructions of the holder of the marketing authorisation.

93 The Role of the Responsible Pharmacist Responsible Pharmacist is required by the Israeli law The responsible pharmacist has the sole authority for release/reject products following batch release of MOH (in imported products) and as such should be independent of operations department The responsible pharmacist is the liaison person with MOH and with MA holders Responsible pharmacist normally plays an active role in the quality system in coordination with the quality assurance manager

94 Compliance issues: storage Temperature monitoring records Temperature mapping Alarm systems Response to out-of-specification (alarm) conditions Qualification/requalification Cleanliness Receipt of cold chain goods (time outside cold store)

95 Compliance issues: transportation Monitoring devices and their location Temperature monitoring records Shipping containers Controlled use of cooling elements Uncertain audit trail Temperature mapping (vehicles) Contract transport and audit

96 Other issues Training - warehouse personnel, drivers, etc. Written procedures Calibration of temperature monitoring devices Returns of cold chain goods Representatives samples Maintenance of the cold chain of imports Maintenance of the cold chain to patient level

97 Calibration Manual and electronic recording devices used in critical areas should be calibrated at least annually against a traceable reference device Records should include pre- and post-calibration readings and details of any adjustments made or corrections to be applied Alarms should be checked at least annually for correct functioning at the designated set points

98 Risk assessment: matters to consider Nature of the products (solids, semisolids, liquids) Labelled storage requirements and associated warnings Sensitivity of product to extremes of temperature Likely period of exposure to temperatures outside the labelled storage requirements Maximum and minimum temperatures that may be experienced by the product Exposure to fluctuating temperatures

99 Risk assessment: matters to consider Number and nature of the stages in the chain Number of drop-off points in delivery chain MA holder s advice (in writing) Scale of the operation Support available (service providers) Knowledge and experience of potential contract acceptors

100 High risk products Products at risk from freezing: vaccines, insulins, biotech products, blood products those physically unstable, e.g. some emulsion systems Products at risk from elevated temperatures those described above, and those chemically unstable at elevated temperatures, e.g. chloramphenicol eye drops some semi-solids, e.g. fatty-based suppositories

101 UK top 10 critical/major GDP deficiencies for 2005/2006 Description % General storage - temperature control & monitoring 16.7 Unauthorised activity 9.6 Lack of or inadequate written procedures 8.8 Supplier status 7.9 Cold storage - temperature control & monitoring 7.9 Premises 7.0 Cold chain transportation 7.0 Quality management and duties of the Responsible Person 5.3 Segregation of unsaleable stock 3.5 Returns 3.5

102 Inspection finding: temperate storage Temperatures are not monitored in the general storage areas. A thermometer taken from one of the offices indicated a temperature of 35 C on the mezzanine floor at the time of inspection. The warehouse has not been temperaturemapped under extremes of external temperature to determine the hot and cold spots and the general temperature distribution

103 Inspection finding: cold storage A external monitoring station recorded an out of temperature limit alarm in a wholesale distributor s 2-8 C cold room on a Saturday evening. The company s Responsible Person was advised of this shortly afterwards, but no corrective action was taken until the following Monday, by which time the temperature in the cold room had risen to 25 C.

104 Inspection finding: cold chain transportation In general, cold chain products are not transported to customers under conditions that ensured that the labelled storage requirements of 2-8ºC are maintained The company has no knowledge of the temperatures that goods in transit might experience during extremes of external temperature

105 What happens when things go wrong? Risk to patients Expensive recalls Loss of confidence in the company Regulatory action suspension of manufacturing/distribution authorisation compulsory variation of authorisation revocation of authorisation sanctions against the QP or RP

106 Challenges facing regulators Counterfeits non-legitimate supply chain legitimate supply chain Clones or copies Internet sale and advertising

107 What distributors should have in place A comprehensive quality management system A process for continual quality improvement A cold chain distribution strategy A temperate chain distribution strategy A risk assessment programme

108 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

109 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)

110 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

111 Measures of Improvement- Reports Complaints Product Quality Review Critical Systems Review Deviations (planned or not) Rejected Product Returns (Policy?) Goods Destruction Change Control Validation / Calibration Status SOP Review Audits Training

112 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

113 Program in place, Audit, Management Involvement

114 What does the future hold ICH Q10 on Pharmaceutical Quality Systems: Use quality risk management to develop a product control strategy including rapid analytical test methods Product Control Strategy: A planned set of controls, derived from current product and process understanding, that assures process performance and product quality includes test methods

115 In conclusion 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 EU GDP and USP requirements Need quality contracts in place (more of that later) and need to audit: Your distributor Their distributor Their print houses (or rely on their audits)

116 Risks to Pharmaceuticals during Mix up of products Mix up of batches Contamination High humidity High temperatures Excess of light Freezing Pests Filth Non secure storage & distribution Distribution of non released products Use of unsuitable vehicles Damage to products Loss of products Delay in supply Supply of wrong products Substitution with counterfeit product Distribution of expired / damaged products

117 Risks to Pharmaceuticals in transit Shipment of wrong product Shipment to wrong destination Shipment by wrong carrier Inappropriate handling/loading Damage in transit Loss in transit Delays in transit Temperature deviations Unauthorised access Use of unapproved or inappropriate equipment Mixing of batches Breakdown of pallets Co-loading with inappropriate cargo Late delivery Untrained drivers/administrators Poor record keeping Substitution by counterfeit products