Lสำน กงานตรวจเง นแผ นด นภ ม ภาคท 12 สงขลา

1 GMP Design of Pharmaceutical Facilities Process design Layouts and Flow Diagrams OSD Facilities Biopharma and Aseptic facilities

2 Speaker - Leonid Shnayder, Ph.D, P.E. Industry Professor in Pharma Manufacturing and Engineering (PME) Program at Stevens Institute of Technology Work experience: Pharmaceutical Process Development and Optimization Design of Pharma Plants (Process Engineer) Designed plants for Merck, Pfizer, Sanofi-Pasteur, Amgen etc. Teaching in the PME program at Stevens 2

3 Speaker - Leonid Shnayder, Ph.D, P.E. Courses taught: Intro to Pharma Manufacturing Validation in Pharma Manufacturing GMP in Pharma Facilities Design Manufacturing of Biopharmaceutical Products Manufacturing and Packaging of Oral Solid Dosage Products Statistical Methods in Pharma Manufacturing [email protected] 3

4 PME Program at Stevens Institute of Technology Master of Science in Pharma Manufacturing degree 10 courses (5 foundation plus 5 elective courses) All PME courses are offered in both on-campus and online delivery modes. It is possible to earn the degree entirely online Applicants must have Bachelor s degree in science, pharmacy or engineering Graduate Certificates Pharmaceutical Manufacturing Validation, Compliance and Quality 4 courses each 4

5 Current Good Manufacturing Practices (cgmp) cgmp is a set of regulations published by the US Food and Drug Administration (FDA) Most national and international agencies regulating pharma industry have similar regulations or guidelines cgmp regulations cover many aspects: organization and personnel, building and facilities, equipment, control of components, production controls, packaging and labeling controls, laboratory controls etc.) We ll discuss aspects related to building and facilities and equipment 5

6 GMP Requirements Highlights Building shall be of suitable size, location and construction, easily cleanable and maintainable Building shall be designed to prevent equipment and material mix-ups and contamination Separate areas shall be provided for different operations Provide adequate control of air pressure, microorganisms, dust, humidity and temperature as appropriate Written procedures required for cleaning and sanitation 6

7 Process design considerations Basic unit operations Process configuration Equipment requirements Process utility requirements Waste treatment Process control Facility requirements Facility layout and process flows Cleaning of equipment and piping 7

8 Process Design Tools Process description Block Flow Diagrams (BFD) Process Flow Diagrams (PFDs) Piping and Instrumentation Diagrams (P&IDs) Material and energy balances Process and utility equipment list Utility requirements table Instrument list Equipment specifications and/or Data Sheets Piping specs 8

9 Block Flow Diagram Tablet Manufacturing Active Ingredient 1 6 Raw Material Raw Material 2 7 Raw Material Raw Material 3 Weigh 8 Raw Material Excipient 4 9 Lubricant Raw Material Raw Material Purified Water/Solvent 11 Mill/Sift Gran Solution Prep Granulation Dry Mill Blend Blend Compress 11 Purified Water/Solvent Coat Coating Solution Prep 9

10 Block Flow Diagram and its Uses BFD identifies major process operations and their relationships to each other BFD can be useful for: Determining the needs for process rooms/areas Visualizing relationships between different rooms Creating a conceptual building layout or bubble diagram Identifying major process equipment needed BFD is used at very early project stages BFD can be considered as a precursor to a PFD Process Flow Diagram 10

11 Process Flow Diagrams (PFD s) PFD s are graphical representations of the manufacturing process based on manufacturing instructions PFD s are reference tools that support manufacturing and assist engineers and constructors with developing facilities and equipment design requirements. There are no universal standards for PFD s. Each company uses its own methodology and symbology. All PFD s contain at a minimum the following basic information Material balance and material streams based on formulation and batch size Graphical representation of the major steps in the manufacturing process Identification of the equipment used in the manufacturing process 11

12 Process Flow Diagram 12

13 Process Flow Diagrams PFDs may be used to describe only the main manufacturing steps or (better) include the support operations, such as liquid as solid waste treatment, exhaust gas treatment, generation and distribution of purified water and other utilities PFD is a document generated early in a project usually during conceptual design stage, and may be updated to reflect changes incorporated at later stages PFDs may be used for developing preliminary equipment list and sizing of the major equipment PFDs help architects to allocate appropriate spaces for all process operations and develop logical plant layout PFDs are also used as a basis for more detailed process drawings called P&IDs Piping and Instrumentation Diagrams 13

14 Personnel Flow & Gowning Diagram 14

15 Material Flow Diagram 15

16 Portable Equipment Flow Diagram 16

17 Process and Facility Design - Summary Facility design and layout must satisfy: Process requirements Personnel flows Material flows (raw materials and products) Equipment layout requirements Operational access requirements Maintenance access requirements Facility should be designed around process needs! 17

18 Building Materials

19 Clean Room Features Walls and floors designed for easy cleaning, resistant to wear and cleaning chemicals Coved floor and wall corners Minimize horizontal piping, ducts, equipment surfaces where dust can accumulate Lighting is supplied by sealed fixtures, often incorporated into ceiling HEPA filter modules. 19

20 Clean Room Features (cont d) Typical clean room finishes include: Epoxy terrazzo floors Epoxy painted walls Suspended drywall or plaster ceiling, painted for easy cleaning Clean rooms can be built at the site or purchased as modules from a vendor 20

21 Examples of Modular Clean Rooms Clean room may be purchased as a vendor supplied and installed module 21

22 Building Materials and Finishes - Summary Materials and Finishes are selected for suitability within every select environment in the facility. A very informed basis of understanding is required to properly select materials and finishes. Knowledge of the manufacturing process(s), SOP s, staff activities and maintenance needs for all areas within the facility are vital to a successful solution. 22

23 Manufacturing of Solid Dosage Products Guiding Principles for Facility Design

24 Guiding Principles for Regulatory Compliance Facility Criteria Facilitate operations Provide adequate space Provide the proper flow of materials Provide control of materials Prevent contamination of materials and products Processes Perform as required by the applications approved by the regulatory agency Are demonstrably under control Will not contaminate Have procedures for proper operation and record keeping 24

25 Guiding Principles for Regulatory Compliance Environmental Provide suitable conditions of temperature, humidity, and particulate control Prevent cross contamination Prevent microbial growth or infestation Facilities and Equipment Surfaces that will not contaminate Provide ease of cleaning and maintenance 25

26 Contamination and Level of Protection Criteria Potential Contamination Sources HVAC Systems Process equipment cleanliness Room construction issues Containerization and transport of materials Personnel Infiltration from other areas 26

27 Unit Operations in Solid Dosage Manufacturing

28 Unit Operations and Equipment Applications Dispensing and Weighing Sifting and Classifying Milling Granulation Drying Blending Compression Encapsulation Coating 28

29 Dispensing Small Volume Dispensing Down Flow Laminar Flow Hoods Dedicated Rooms with Environmental Controls Large Volume Dispensing Silos Super Sacks Pneumatic Conveyance and Weigh Systems Gravity Transfer and Weigh Systems 29

30 Technical Considerations for API Dispensing Systems APIs typically handled in small amounts Occupational Exposure Limits Handled in a Controlled or Contained Environment: Dust collection systems for benign materials Down flow booths for low toxicity materials Closed systems with split valve technology for high toxicity materials Glove Box Isolators for the most toxic materials Split Butterfly Valve Personal Protection Equipment Isolator 30

31 Other Design Considerations Storage and handling of materials in bulk containers (IBC), drums, bags, etc Partials inventory (Unused material in drums to be returned to inventory) Material Handling Equipment Staging and Put Down Areas Wash Areas and Equipment Storage Pallet washers IBC washers 31

32 Sifting and Classifying Purpose: De-lumping of powders Improve particle size distribution - removal of oversized and undersized particles Equipment: Vibratory screen sifters Manual sieves 32

33 Milling Used for: Particle size reduction Change particle shape De-lumping 33

34 Wet Granulation High Shear Granulation High dispersion Improved homogeneity Good for small quantities of actives 34

35 Wet Granulation cont d Fluid Bed Granulation Control of particle size Materials that can not withstand high shear Granules dried in same machine 35

36 Drying Reduce moisture content of granules to 2-5% Methods Fluid Bed Dryers Tray Dryers (ovens) 36

37 Blending Combine granulation with excipients and lubricants Excipient - typically lactose Lubricants - typically magnesium stearate added to improve flow properties Convection mixing Use of paddles or blades to achieve mixing Ribbon blenders, Orbital screw blenders, planetary mixers, etc. Diffusion Blenders Use of Tumbling Action V Blenders, Cone Blenders, Bin Blenders 37

38 Tablet Compression Blend (powder or granules) is filled into die cavities Material is compressed into tablets 38

39 Encapsulation Capsules Hard gelatin capsules filled with solids Final blend must be uniform Better for products with high API content Filling done by volume, so constant bulk density is important 39

40 Coating Coatings: Aqueous or Solvent Based Film coating Thin film ( 2 to 5 mils) Clear or with colorant Sugar coating Heavy - may reach 50% of tablet weight Enteric coatings Delay dissolution until the tablet reaches the intestinal tract Bead Coating Time and sustained release products 40

41 Coating Process entails application of protective coatings to tablets Coatings are applied in solution. May be water or solvent based Multiple cycles of solution application and drying may be needed. Multiple layers of coatings are applied to obtain the desired result Equipment Used in the Process Open Coating Pans (Conventional Pans) Perforated Coating Pans: Batch or Continuous Process Wurster Columns (Fluid Bed Processors) used for coating beads or granules 41

42 Facility Layout Facility layout must: Provide short and logical routes for material and personnel flow Avoid cross-flows whenever possible Provide means of separation for quarantined, released and rejected materials Provide sufficient space for each operation, including staging, washing and other ancillary areas Help prevent cross-contamination 42

43 Layout of Mixing and Granulating Areas Easy movement of materials into separate processing rooms Minimize crosscontamination potential Air pressure in the corridor is higher than in the process rooms for product containment 43

44 Design Considerations for OSD - Summary HVAC Air Filtration Negative room pressurization Dealing with dust generation: Cleaning Dust collection Closed processing Containers must be moved to wash area for cleaning Risk of spreading contaminants through the facility May provide wash or vacuum cleaning capability inside process room 44

45 BioPharmaceutical Manufacturing Facilities Biopharmaceutical Processes and Facilities Room classification

46 What is Biopharmaceutical Technology? Processes using microorganisms or animal cells for synthesis of products Isolation and purification technology for biologically derived compounds Modern biotechnology uses genetically engineered cells or microbes Products include drugs, vaccines and other high value compounds Many biotech drugs are proteins 46

47 Process Block Flow Diagram 47

48 Building Design Considerations Operational Efficiency Operational Safety Protection of Product from contamination Protection of Personnel Protection of Facility Maintainability 48

49 Program Design Considerations Equipment Arrangements Material Flow Personnel Flow Product Flow Waste Flow Adjacencies Segregation Flexibility Expandability 49

50 Single Product Facility with Minimal Segregation 50

51 Single Product Facility with Moderate Segregation 51

52 Multi-Product Facility with Moderate Segregation 52

53 Layout Considerations - Summary Adjacency of related spaces Logical and simple flow of personnel, portable equipment and materials Avoid where possible clean and dirty equipment and personnel passing through the same corridors, gowning areas etc. Air locks are used at major separation points where maintaining pressure differential is important Cleaner spaces usually are located in the middle of a facility, and surrounded by areas of lower classification 53

54 Classification of Clean Rooms Grade Particles/m µm ISO Class At rest In operation A 3,520 3,520 5 B 3, ,000 5 at rest 7 in operation C 352,000 3,520,000 7 at rest 8 in operation D 3,520,000 Not defined 8 at rest 54

55 HVAC Techniques Air filtration, including High Efficiency Particulate Air filters (HEPA filters) Directional flow or air Pressure relationships within and between adjacent spaces Humidification (used mostly in winter in cold climates), dehumidification (mostly in summer) Heating and cooling to maintain constant temperature 55

56 Air Filtration The low particulate counts in classified rooms are achieved by continuous recirculation of room air with HEPA filters in the recirculation loop The cleaner the room needs to be, the higher recirculation rate required The degree of recirculation is commonly expressed as number of room air changes per hour (air flow rate divided by the room volume) 56

57 Air Filtration Guidelines for required number of air changes: changes/hr for Class A rooms changes/hr for Class B rooms changes/hr for Class C rooms These numbers are not regulations, just guidelines. They vary in different sources. Actual number of particles observed depends on activity level people present, dust-generating operations etc. Easier to achieve low particulates in static (no activity) than in dynamic conditions 57

58 Air Pressurization In general, rooms of higher class (cleanest) have positive air pressure as compared to adjacent spaces Airlocks are used to separate clean process rooms from corridors and adjacent rooms Airlocks and gowning rooms are normally negatively pressurized compared to the process room and positively to corridor 58

59 Air Pressurization Exception can be made in case the product or its component is hazardous (i.e. live virus), in which case containment consideration may require clean room to be negatively pressurized In such case airlock may be made positive to both process room and to the corridor. This provides both product protection and containment. 59

60 Air Pressurization Recommended pressure differential between adjacent areas is Pa, as measured with doors closed When a door opens, pressure differential essentially goes to zero. That is why air locks are installed at critical connection points, and the two doors in an air lock are never opened simultaneously (often enforced by interlocking controls on electrically operated doors) Rooms need to be sealed as tight as possible to enable maintaining required pressure differential 60

61 Air Pressurization Diagram 61

62 Air Locks Types AL and PAL Bubble Sink 3 ' - 0 " 3 ' - 0 " MAL Cascade 62

63 Personnel Air Lock 63

64 Material Air Lock 64

65 Air Flow Diagram 65

66 Air Quality Monitoring Number of particles per unit of air volume is tested during facility qualification and routinely. Such testing is done both at rest (no activity) and during normal operations. Portable (shown in the picture) or permanently installed particle counters may be used. Source

67 HVAC - Summary Clean room classes A, B, C (and sometimes D) are commonly used in biopharma facilities To maintain air cleanliness we use: Air recirculation at high flow rates with HEPA filters in the recirculation loop Air pressure differentials between adjacent spaces Air locks for personnel and materials Personnel gowning and access control Air quality monitoring (periodic or continuous) 67

68 Single- and Multi-product Plants If we have a product with high sales volume, singleproduct plant is better If we have multiple products with similar technologies and smaller volumes, multi-product plant may be better In multi-product plants: Flexibility must be built into the floor plan Avoidance of cross-contamination is critical May operate by campaigns or by parallel processing 68

69 Equipment and Piping Design Concepts Most large plants have fixed stainless steel equipment and fixed process piping Flexibility can be achieved by using flexible piping (hoses) in addition to the fixed piping Many smaller plants use disposable equipment storage bags, fermentation bags,, filters etc. 69

70 Plant Design Concepts - Summary Three principle variables that are in competition with each other: Investments (capital cost) Operating costs Flexibility Different designs may be used for different situations: Multi product versus single product facilities Stainless steel versus disposable (single use) equipment 70

71 Aseptic Processing Facilities

72 Introduction Aseptic processing - all the individual components (product, vials & stoppers) are sterilized individually and assembled in a very high quality environment Only a small fraction of the final product is tested to confirm its sterility and therapeutic value Manufacturer has no direct data other than the design of their process to confirm that the product is safe for human use 72

73 Containers for Aseptic Products Examples: Vial (sealed using a rubber stopper and aluminum seal) Ampoule (a glass container sealed using heat directly after filling) Syringe (sealed with a rubber stopper and a needle cover) Plastic bottle (sealed with a plastic cap) Blow-Fill-Sealed Bottles (a plastic bottle that is made filled and sealed in one step) 73

74 Sterile Dosage Forms Ampoule Vial Prefilled syringe Blow-fillseal vials Bottles 74

75 1. Prep Bulk Product 2. Filter Sterilize Bulk Product 6. Wash Vials 7. Depyrogenate Vials 2. Prep & Sterilize Change Parts 5. Assemble Change Parts 3. Wash & Sterilize Stoppers 4. Prep Overseals 8. Fill Vials 8. Check Weigh Vials 8. Stopper Vials 9. Overseal Vials 10. Inspect Vials 11. Package Vials 12. The Background Environment ISO 5 ISO 8 75

76 The Vial Filling Process Filling product into vials Checking vial weight Manual (destructive) versus automated cost impact Inserting vial stoppers fully partially (half way; used for freeze dried products) Over-sealing to secure the stopper 76

77 Vial Filling and Stoppering Orienting stoppers Vial Filling 77

78 Inspect Vials Every vial must undergo inspection: manual or automatic may be done in line with the filling process - less scratches fewer rejected vials 78

79 The Vial Filling Process The aseptic processing steps (where the product and product contact parts are exposed) are performed in a Class A / ISO5 environment The other classes are used for areas with other activities depending on the potential impact of on the process 79

80 The Vial Filling Process All steps involving clean operators and materials must be separated from dirty operators and waste. This requires separate airlocks and corridors for the clean and dirty activities (unidirectional flows) Even with all of these precautions (room pressurization, airflow, airlocks, garbing and treatment of materials) the ISO5 environment is under constant assault by the most contaminated object in the building - the operator To minimize the impact of the operator on the process, manufacturers are turning to a new technology isolators or RABS 80

81 The Vial Filling Process The equipment may be located in: Clean Room Environment (Traditional) Clean Room Environment & RABS Aseptic Filling Isolator 81

82 Clean Room 82

83 The Vial Filling Process Isolators: box around the process access the process via gloves must be decontaminated using automated technology (VHP or H2O2) because the clean zone is very small 83

84 The Vial Filling Process Advantages of isolators: The operator is removed from the process, so less product risk Can be located in an ISO8 environment Reduced ISO5 area Reduced requirements for the sterile garb Fewer airlocks and material sanitization steps Material and people movement in the facility is simplified Cleaning and cleaning validation reduced Lower long term operation cost than traditional clean room facility 84

85 The Vial Filling Process: Isolators or RABS? RABS Concept - to combine the advantages of an isolator with the flexibility of a clean room In reality RABS has not solved any of the perceived disadvantages of an isolator. Isolators are the future of aseptic processing. 85

86 Factors affecting Aseptic Filling - Summary Success of an aseptic process depends on: Equipment design Process design and controls Facility and Room design HVAC design Clean Rooms/Isolators/RABS Operators: gowning, training, procedures Clean Utilities 86

87 References 1. cgmp Regulations: ocs/cfcfr/cfrsearch.cfm?cfrpart= ISPE Biopharmaceutical Manufacturing Facilities Baseline Guide 3. International Standard ISO Cleanrooms and associated controlled environments Part 1: Classification of air cleanliness

88 Questions? 88

89 Regulatory requirement for Pharmaceutical facilities โดย ภญ.พ ชร วรรณ ฝ งน ล กล มกำก บด แลหล งออกส ตลำด สำน กยำ สำน กงำนคณะกรรมกำรอำหำรและยำ 16 ก มภำพ นธ 2560 ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

90 ป จจ ยท ต องคำน งถ งในกำรออกแบบสถำนท ผล ตยำ กฎหมำยท เก ยวข อง Protection aspects น ยำมศ พท สำค ญ เทคน คหล กเล ยงกำรปนเป อนข ำม Shell-like containment control concept Classification of airlock Differential pressure ห วข อกำรบรรยำย (1) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

91 ห วข อกำรบรรยำย (2) Type of Clean area Cleanroom condition กำรแบ งประเภทห องสะอำด (EN/ISO ) ข ดจำก ดสำหร บกำรตรวจต ดตำมจ ล นทร ย ของบร เวณสะอำด ระหว ำงปฏ บ ต งำน กำรปฏ บ ต งำนในแต ละระด บควำมสะอำด ต วอย ำงแบบแปลนสถำนท ผล ตยำแต ละประเภท ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

92 ป จจ ยท ต องคำน งถ งในกำรออกแบบสถำนท ผล ตยำ กฎหมำย ระเบ ยบ หล กเกณฑ เง อนไข ท สำน กงำนคณะกรรมกำร อำหำรและยำกำหนด ประเภทของผล ตภ ณฑ ยำท ต องกำรผล ต (ค ณสมบ ต เฉพำะ ร ปแบบ) กระบวนกำรผล ต และเทคโนโลย ท ใช เคร องม อ/อ ปกรณ กำรผล ตสำค ญ ท ต องใช ในกระบวนกำรผล ต สภำวะแวดล อมกำรผล ต (อ ณหภ ม ควำมช น ควำมด นอำกำศ ระด บ ควำมสะอำดของห องและบร เวณผล ต) ระบบสน บสน นกำรผล ต (ระบบอำกำศ (เช น HVAC system, De-dusting system, Compressed air) ระบบน ำ ระบบกำจ ดของเส ย) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

93 กฎหมำยท เก ยวข อง (1) ประกำศกระทรวงสำธำรณส ข เร อง กำรกำหนดรำยละเอ ยด เก ยวก บหล กเกณฑ และว ธ กำรในกำรผล ตยำแผนป จจ บ นและ แก ไขเพ มเต มหล กเกณฑ และว ธ กำรในกำรผล ตยำแผนโบรำณ ตำมกฎหมำยว ำด วยยำ พ.ศ ร ฐมนตร ว าการกระทรวงสาธารณส ข ลงนาม 18 พฤษภาคม ประกาศในราชก จจาน เบกษา ว นท 14 ก นยายน 2559 ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

94 กฎหมำยท เก ยวข อง (2) ประกำศกระทรวงฯ GMP พ.ศ.2559 (ต อ) - ให ยกเล ก (1) ประกาศกระทรวงสาธารณส ข เร อง การกาหนดรายละเอ ยดเก ยวก บ หล กเกณฑ และว ธ การในการผล ตยาแผนป จจ บ นสาหร บยาช วว ตถ ตาม กฎหมายว าด วยยา พ.ศ (2) ประกาศกระทรวงสาธารณส ข เร อง การกาหนดรายละเอ ยดเก ยวก บ หล กเกณฑ และว ธ การในการผล ตยาแผนป จจ บ น ตามกฎหมายว าด วย ยา พ.ศ ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

95 กฎหมำยท เก ยวข อง (3) ประกำศกระทรวงฯ GMP พ.ศ.2559 (ต อ) - สอดคล องตาม PIC/S Guide to GMP for Medicinal Products PE Issued date 1 October เน อหาครอบคล มท งยาเคม ยาช วว ตถ และยาแผนโบราณ - เอกสารแนบท ายประกาศฯ ประกอบด วย (1) ส วนท 1 (Part I) : 9 หมวดหล ก (2) ส วนท 2 (Part II) : หล กเกณฑ และว ธ การในการผล ต สารออกฤทธ ทางเภส ชกรรม (3) ภาคผนวก 16 ภาคผนวก (Annexes) จ ดเร ยงตามร ปแบบของ PIC/S โดยหากม การแก ไขเน อหา สามารถแก ไขแต ละส วนได โดยไม กระทบเน อหาส วนอ น ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

96 กฎหมำยท เก ยวข อง (4) ประกำศกระทรวงฯ GMP พ.ศ.2559 (ต อ) - ต วอย างเน อหาในส วนท เก ยวข องก บการออกแบบสถานท ผล ตท เหมาะสม เช น (1) ส วนท 1 (Part I) - หมวด 3 : อาคารสถานท และเคร องม อ - หมวด 5 : การดาเน นการผล ต (2) ส วนท 2 (Part II) : หล กเกณฑ และว ธ การในการผล ต สารออกฤทธ ทางเภส ชกรรม (3) ภาคผนวก (Annexes) - ภาคผนวก 1 : การผล ตยาปราศจากเช อ - ภาคผนวก 2 : การผล ตผล ตภ ณฑ ยาช วว ตถ สาหร บใช ในมน ษย - ภาคผนวก 3 : การผล ตเภส ชภ ณฑ ร งส ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

97 Protection aspects ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

98 น ยำมศ พท สำค ญ (1) กำรปนเป อนข ำม (Cross-contamination) กำรปนเป อนของว ตถ ด บหร อผล ตภ ณฑ ด วยว ตถ ด บหร อ ผล ตภ ณฑ ชน ดอ น แอร ล อค (Air lock) บร เวณป ดสน ทท ม ประต 2 ทำงหร อมำกกว ำ ซ งก นกลำงอย ระหว ำงห องหร อบร เวณท ม ระด บควำมสะอำดแตกต ำงก น เพ อ ว ตถ ประสงค ในกำรควบค มกำรไหลของอำกำศระหว ำงห องหร อ บร เวณเหล ำน เม อม กำรเป ดประต แอร ล อคน จะออกแบบและใช สำหร บเป นทำงเข ำ-ออกของคนและส งของ ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

99 น ยำมศ พท สำค ญ (2) บร เวณสะอำด (Clean area) บร เวณท ม กำรควบค มกำรปนเป อนของอน ภำคและจ ล นทร ย ใน สภำวะแวดล อมให อย ในเกณฑ ท กำหนด กำรก อสร ำงและกำรใช งำนจะต องทำในล กษณะท ลดส งปนเป อนท จะนำเข ำไปท จะ เก ดข น หร อท ถ กก กอย ในบร เวณน น บร เวณก กเก บ (Contained area) บร เวณท สร ำงข นและต ดต งระบบอำกำศ และกำรกรองอำกำศท เหมำะสม และใช งำนในล กษณะเพ อให บรรล ว ตถ ประสงค ใน กำรป องก นสภำวะแวดล อมภำยนอกจำกกำรปนเป อนโดยสำร ช วว ตถ จำกภำยในบร เวณน น ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

100 เทคน คหล กเล ยงกำรปนเป อนข ำม (1) ประกำศกระทรวงฯ GMP พ.ศ.2559 (หมวด 5 ข อ 19) ดำเน นกำรผล ตในบร เวณแยกต ำงหำก ซ งเป นข อกำหนดสำหร บ ผล ตภ ณฑ พวกเพน ซ ลล น ว คซ นท ม ช ว ต ผล ตภ ณฑ แบคท เร ยท ม ช ว ต และผล ตภ ณฑ ช วว ตถ บำงชน ด หร อทำกำรผล ตโดยกำร แยกเวลำผล ต หล งจำกน นให ทำควำมสะอำดอย ำงเหมำะสม จ ดให ม แอร ล อค และกำรกำจ ดอำกำศตำมควำมเหมำะสม ให ม กำรกรองอำกำศท หม นเว ยนหร ออำกำศท นำกล บเข ำมำใหม เพ อลดควำมเส ยงของกำรปนเป อนจำกอำกำศ ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

101 เทคน คหล กเล ยงกำรปนเป อนข ำม (2) เก บเคร องแต งกำยสำหร บใช ปฏ บ ต งำนไว ภำยในบร เวณท ทำ กำรผล ตผล ตภ ณฑ ท ม ควำมเส ยงเป นพ เศษท ทำให เก ดกำร ปนเป อนข ำม ใช ว ธ กำรทำควำมสะอำดและกำรกำจ ดส งปนเป อนท ม ประส ทธ ผล เน องจำกกำรทำควำมสะอำดเคร องม อท ไม ม ประส ทธ ผลม กเป นแหล งเก ดกำรปนเป อนข ำม ใช ระบบป ด ในกำรดำเน นกำรผล ต ม กำรทดสอบสำรตกค ำงและใช ฉลำกแสดงสถำนะสะอำด ต ดท เคร องม อท ผ ำนกำรทำควำมสะอำดแล ว ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

102 Shell-like containment control concept ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

103 Classification of airlock (1) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

104 Classification of airlock (2) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

105 Differential pressure ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

106 Type of Clean area ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

107 1. Conventional (Non-unidirectional flow or turbulently ventilated) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

108 2. Unidirectional flow (Laminar flow) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

109 3. Mixed flow ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

110 4. Isolators ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

111 Perforated plate diffuser (recommended) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

112 Swirl diffuser (recommended) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

113 Induction diffuser (not recommended) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

114 Cleanroom condition (1) The as built state is the condition where the installation is complete with all services connected and functioning but with no production equipment, materials, or personnel presents. ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

115 Cleanroom condition (2) The at rest state is the condition where the installation is installed and operating, complete with production equipment but with no operating personnel present. ประกำศกระทรวงฯ GMP พ.ศ.2559 สถำนะ ไม ม กำรปฏ บ ต งำน เป นสภำวะท ม กำรต ดต งระบบและ เป ดใช งำน พร อมท งม กำรทำงำนของเคร องม อผล ต แต ไม ม ผ ปฏ บ ต งำนอย ในบร เวณน น ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

116 Cleanroom condition (3) The in operation state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working. ประกำศกระทรวงฯ GMP พ.ศ.2559 สถำนะ กำล งปฏ บ ต งำน เป นสภำวะท ม กำรเป ดใช งำนระบบท ต ดต งไว ตำมว ธ กำรใช ท กำหนด พร อมท งม ผ ปฏ บ ต งำนกำล ง ปฏ บ ต งำนตำมจำนวนท ระบ ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

117 Cleanroom condition (4) ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

118 กำรแบ งประเภทห องสะอำด (EN/ISO ) ระด บ จำนวนอน ภำคส งส ดท ยอมให ม ได ในปร มำตรอำกำศ 1 ล กบำศก เมตร ท ม ขนำดเท ำก บหร อใหญ กว ำท ระบ กำล งปฏ บ ต งำน ไม ม กำรปฏ บ ต งำน (at rest) (in operation) 0.5 ไมโครเมตร 5.0 ไมโครเมตร 0.5 ไมโครเมตร 5.0 ไมโครเมตร A 3, , B 3, ,000 2,900 C 352,000 2,900 3,520,000 29,000 D 3,520,000 29,000 ไม ระบ ไม ระบ ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

119 ระด บ ข ดจำก ดสำหร บกำรตรวจต ดตำมจ ล นทร ย ของ กำรส มต วอย ำง อำกำศ โคโลน /ล กบำศก เมตร บร เวณสะอำดระหว ำงปฏ บ ต งำน ข ดจำก ดสำหร บกำรปนเป อนของจ ล นทร ย (ก) กำรวำงจำนอำหำรเพำะเช อ (เส นผ ำนศ นย กลำง 90 ม ลล เมตร) โคโลน /4 ช วโมง (ข) จำนส มผ ส (เส นผ ำนศ นย กลำง 55 ม ลล เมตร) โคโลน /จำน พ มพ ถ งม อ จำนวน 5 น ว โคโลน /ถ งม อ A <1 <1 <1 <1 B C D หมำยเหต (ก) เป นค ำเฉล ย (ข) อำจวำงจำนอำหำรเพำะเช อแต ละจำนให ส มผ สอำกำศน อยกว ำ 4 ช วโมง ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration 3

120 กำรปฏ บ ต งำนในแต ละระด บควำมสะอำด ระด บ กำรปฏ บ ต งำนสำหร บผล ตภ ณฑ ท เตร ยมโดยกระบวนกำรปรำศจำกเช อ A C D เตร ยมและบรรจ โดยกระบวนกำรปรำศจำกเช อ เตร ยมสำรละลำยก อนทำกำรกรอง กำรดำเน นกำรก บส วนประกอบหล งกำรล ำง ระด บ กำรปฏ บ ต งำนสำหร บผล ตภ ณฑ ท ทำให ปรำศจำกเช อในข นตอนส ดท ำย A บรรจ ผล ตภ ณฑ เม อม ควำมเส ยงกว ำปกต C เตร ยมสำรละลำยเม อม ควำมเส ยงกว ำปกต และกำรบรรจ ผล ตภ ณฑ D เตร ยมส วนประกอบสำหร บกำรบรรจ ส ำน กงำนคณะกรรมกำรอำหำรและยำ The Inspectorate 3 Food and Drug Administration

121 ต วอย ำง แบบแปลนสถำนท ผล ตยำแต ละประเภท ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

122 ผล ตยำน ก ก / เก บ ยำสำเร จร ป Air Lock ำ/ข ผ ง/คร ม ส วนผล ตยำ/ผง/เม ด/แคปซ ล เก บอ ปกรณ ช ง /ส ม ล ำงอ ปกรณ Non-sterile solids and liquids บรรจ ห บห อ IPC Air Lock เก บยำค น/ยำหร อ ว สด ท ไม ได มำตรฐำน IPC ก ก / เก บว สด สำหร บกำรบรรจ ก ก / เก บว ตถ ด บ Air Lock ห องน ำหญ ง ห องน ำชำย Air Lock ช ช ญ ญ เปล ยนช ด เก บว ตถ ด บท ช งแล วรอผล ต เก บยำต วอย ำง/ ยำทดสอบควำมคงต ว ห อง เคร อง ม อ ช ง ส ม ห องตรวจ ว เครำะห ส ำน กงำนคณะกรรมกำรอำหำรและยำ ว ตถ ไวไฟ Food and Drug Administration

123 Penicillin non-sterile critical area 6.00 A/L +1 A/L %RH %RH Sub - Corridor A/L %RH %RH %RH -1 Corridor 0 Corridor A/S Corridor -1 / IPC -1-1 Dry syrup A/L 10+10%RH 10+10%RH Corridor +1 A/L Bench -1 Alu PVC (Blister pack) -1 Alu Alu (Strip pack) -1 / LIFT 10+10%RH 10+10%RH 10+10%RH 0 A/L +1 A/L 0 0 Corridor -1-1 MOB ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration 3

124 ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

125 ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

126 Thank you for your attention ส ำน กงำนคณะกรรมกำรอำหำรและยำ Food and Drug Administration

127 PLANNING OF PHARMACEUTICAL FACTORIES CONCEPT AND IMPLEMENTATION

128 A Quote: PEOPLE AND PLANNING You do not really understand something unless you can explain it to your grandmother." Albert Einstein

129 WORLD CLASS PHARMA FACILITY PRESENT SCENARIO : The Globalization & Open Market Policy has proved to be a boon for the industries, but has generated need for a globally acceptable manufacturing facility. There are many flourishing manufacturing facilities, but not all are in compliance with the various regulatory standards. NEED FOR A FACILITY : Rapid change in manufacturing technology & various regulatory compliances to upgrade for better solution in line with cgmp. With globalization, the need for a compliant facility has become a statutory necessity.

130

131 PARTICIPANTS TO THE PLANNING PROCESS Forecasts for x years Objectives Budget Company internal approvals Technology Logistics Building services Building technology Planning Execution Approvals (pharmaceutical) Approvals (non-pharmaceutical) Internal Planner Authorities

132 PLANNING TEAM(S)

133 SCHEDULE EXAMPLE

134 NORMS, REGULATIONS AND REQUIREMENTS General laws + regulations Pharmaceutical regulations, EU, FDA, PIC/S, WHO, requirements of pharmacy inspectors, product registration... Labour and environmental requirements... Norms ISO, ATEX, etc... Specific guidelines, (Biosafety, Fed Std, OSHA) for conception, planning, operation... Company standards, planning conditions (quantities, technologies, products, deadlines, budget...)

135 PLANNING STEPS Process / Equipment GMP and Hygiene Zoning Quantitative data Layout Feasibility Concept Basic Design Detail Design Execution Refining of elements Calculations Functional tendering Layouts 1:100 Complete detailing for all disciplines Layouts 1:20, 1:50 Tendering

136 PLANNING MODELS CONVENTIONAL MODEL Feasibility Concept Basic Design Detail Design Execution IMPROVED MODEL Conceptual design Basic Design Detail Design Execution Not to scale

137 FEASIBILITY VERSUS CONCEPTUAL STUDY Feasibility Conceptual Study Static Dominated by economical criteria No project alternatives: Yes / No only No influence on schedule of subsequent phases Includes the feasibility study Dynamic / prospective Dominated by technical criteria Project alternatives are generated User oriented Choices possible - Costs - Technology - Organisation Reduces time spent on subsequent phases, while increasing their precision

138 PLANNING MODELS Strong Conceptual design Basic Design Detail Design Execution It pays to invest into a strong conceptual design Low initial costs Early clarification of main issues Powerful decision tool Possibility to develop alternatives Freewheeling

139 PLANNING SEQUENCE AND ITERATION PROBLEMS Planning Task Start easy Task Definition Targets Requirements Analysis Conceptual Design with Alternatives difficult Basic Design Detail Design Execution

140 RELATIVE COSTS OF THE DIFFERENT PHASES 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% Factory size Factory organisation Technology GMP concept Conceptual Design Basic Design Detail Engineering Execution Cost saving potentials The cheapest and most promising Phase is the Conceptual Phase!

141 POSSIBILITIES OF COST MINIMISATION 100% 90% 80% 70% 60% 50% Costs saving potential Factory size Factory organization Technology GMP Conceptual Design Basic Design Small teams Brainstorming Alternatives New ideas 40% Detail Engineering 30% 20% Execution 10% The best and cheapest chance to minimise cost of investment and operation is in Phase 1!

142 DETERMINATION OF COSTS in relation to the planning stage Feasibility Conceptual design The better the concept, the higher the precision Cost estimation Basic design Cost calculation Detail design Tender documents Offers Execution Supervision Documentation PRICE PAID Final quotations

143 PRECISION OF COSTS in relation to the planning stage stage Feasibility Conceptual design ± 30% Cost estimation The better the concept, the higher the precision Basic Design ± 20% Cost calculation Detail Design Execution Supervision Documentation ± 10% ± 5% Tender documents Offers Final Quotations

144 DETERMINATION OF COSTS in relation to the planning system - + Feasibility Conceptual design Basic design Turnkey price: poor control Detail design General planner: good control Execution Supervision Documentation

145 TARGETS OF PHARMACEUTICAL FACTORY PLANNING - Planning of a production plant future oriented flexible economical in investments and operating costs GMP conform conform to local / international regulations - High motivation of staff by high quality of working place - Efficient planning - Adequate quality standard (value for money) - Architecture compatible with local surroundings

146 PURPOSE OF CONCEPTUAL DESIGN GMP Considerations and Factory Planning go Hand in Hand The Purpose of the Conceptual Design is to arrive to Layout General Factory Organisation Procedures Hygiene Concept Technology Concept Air Handling and Utilities Concepts which can be successfully presented to Authorities for a Pre-Approval Design Review and to get a high degree of safety about Investments Schedule

147 PRELIMINARY CONTACT WITH AUTHORITIES PRE-APPROVAL DESIGN REVIEW US FDA / Europe It is not an establishment inspection report There are no Inspectional Observations It is a candid dialogue regarding potential issues (Red Flags) The outcome represents the opinion of an inspector, not necessarily that of the FDA Agencies act as consultants, not as police ASIA No dialogue Inspector can block further work, by imposing his point of view No appeal possibility in the practice (respect of authority, fear of later potential problems)

148 EXAMPLES OF STATEMENTS BY INSPECTORS Corridor should not be less than 2,5 m wide Preparation of binder should be separated from granulation Room for rejected raw materials must be larger to 10 m 2 Rapid doors not acceptable Separate building required for hormones, not just complete separation in building, with dedicated HVAC, entrance, utilities, etc. Utilisation of barcode system to replace labels unacceptable Hygiene classes for degowning: B to D not accepted, should be B to C Airlock in front of capping room Etc.

149 EXAMPLES Although binder preparation dedicated to the line, and preparation of binder just-in-time, obligation to have separate room and corridor: loss of space, no apparent benefit

150 EXAMPLES New capping systems, with rail crimpers, emit practically no particles, so why additional airlock? Machines are in addition equipped with air extraction at capping point.

151 EXAMPLES Type of rapid door frequently utilised in Europe and in the USA in cleanrooms ISO 8, but often rejected in some Asian countries

152 HOW TO REACH A GOOD CONCEPTUAL DESIGN RESULT? Right team Good method Right team Discipline Good method Right team Good data Discipline Good method Right team Some fantasy Good data Discipline Good method Right team Some fantasy Good data Discipline Good method Some fantasy Good data Discipline Some fantasy Good data Some fantasy

153 PEOPLE AND PLANNING A Quote: You do not really understand something unless you can explain it to your grandmother." Albert Einstein The idea is to work intensively with a small group of people, possibly detached from their daily chores. These people must have the necessary know-how (or back-ups) and the power of decision

154 PEOPLE AND PLANNING CORE TEAM Quality Assurance Production Manager Process GMP Expert Integrated Factory Planning Experts AD HOC MEMBERS Utilities Specialist Controller Other Specialists Logistics Engineering

155 PEOPLE AND PLANNING Generalists Specialists Number of people PLANNING Conceptual Design Basic Design Detail Design Execution Number of people Generalists Specialists VALIDATION

156 Judgement Errors JUDGEMENT ERRORS 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% Concept Team Individuals Large Organisations Number of Participants Role of Participants : To plan AND to decide

157 PLANNING METHODS By Experimenting and Innovating By Adding Individual Functions There are many planning methods By Cloning Existing Units By Systematic Planning By Turnkey Contracting

158 OPTIMAL PLANNING METHOD Site, Site selection Masterplan General organisation factory Departments Functional groups Equipment, single units PLANNING FROM INSIDE TO OUTSIDE PLANNING FROM MACRO TO MICRO PLANNING FROM IDEAL TO REAL

159 NEED FOR FOCUSING Economy of scale Efficiency / Best practice Flexibility Performance Organisation Requirements Vision of client Analysis of Product range Process Technologies Organisation Conceptional design Make or buy Specialisation Capacity increase Technology Standardisation Regulatory aspects Results versus costs

160 PLANNING METHOD DEVELOPMENT OF IDEAL ORGANISATION Information Strategy Resulting Organisation Analysis process Identification key problems Analysis Material / Information flow Verification process flow, material flow Other requirements, constraints, etc. Combination material flows functional interdependencies Analysis of products and production volumes Analysis organisation Idenfication necessary infrastructure Analysis space situation Analysis machinery / equipment Plant strategy + Process architecture Evaluation + Selection Definition Modules Functional units Vertical Horizontal Adaptation Process, machinery + equipment Verification GMP concept Calculation necessary space Definition of constraints, etc. B/W- Orientation of factory Rough layout development Layout alternatives START END

161 PLANNING METHOD RATIONALISATION, INNOVATION AND OPTIMISATION Morphological Analysis + Search for Solutions Capacity and Rationalisation Analysis Existing Technology GMP-Concept Technological Alternatives Project- Technology GMP-Concept Degree of Automation Dimension. Machines (Type/ Quantity) Degree of Automation Investment / Budget Batch Sizes Foreseen Equipment Shifts? Plant strategy + Process architecture Forecasts, Quantities, Product Mix Batch Sizes Galenical Properties Product Seasonality Campaign Sizes Cleaning + Change-over Times

162 PLANNING PROCEDURE: CONCEPTUAL DESIGN Production forecasts / next 6-10 years Description of process flows from starting materials until finished product Design of the overall flow diagram indicating all GMP-classes Calculation of material flow quantities Definition of - Process technology - Machinery + equipment - Transport systems + containers Definition of personnel, shifts, etc. Design of the ideal layouts + modules for each step Ideal layouts peripheral areas Ideal layouts personnel areas Combination of individual layouts to functional units --> Granulation, tabletting, preparation of liquids, filling... Design of the ideal overall total layout Development of the masterplan for the design onthe green field Development of the integration of the layout into an existing building structure

163 PLANNING PROCEDURE: CONCEPTUAL DESIGN FORECASTS Product lists, quantities Sorting by galenical forms Sorting by types ( conventional, toxic, hormones, beta-lactames, etc.) Strategy for marginal or special products (quantities, types, galenical forms): Make or buy

164 ABC ANALYSIS Example Number of products 50 Total number of units Number of products Volume of products % % A B C Average weight unit (g) 0,5 Number of products Volume of products % % kg A B C

165 CAPACITY CALCULATIONS ABC ANALYSIS OPTIMISATION OCCUPANCY EQUIPMENT

166 SELECTION OF TECHNOLOGY AND EQUIPMENT EXAMPLES OF SELECTION FACTORS Vision of client Properties of products to be processed Output requirements Degree of automation, sophistication Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Previous experience, available equipment (standardization) GMP issues Safety of operator

167 SELECTION OF TECHNOLOGY AND EQUIPMENT Vision of client: size, degree of sophistication, automated guided vehicles, architecture, budget, future-oriented or not Properties of products to be processed Output requirements Degree of automation, sophistication Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Previous experience, available equipment (standardization) GMP issues Safety of operator

168 SELECTION OF TECHNOLOGY AND EQUIPMENT Safety of operator Vision of client Properties of products to be processed: eg granulation properties: is a direct compression possible or a dry granulation? Aseptic processing or terminal sterilization, ampoules or syringes Output requirements Degree of automation, sophistication Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Previous experience, available equipment (standardization) GMP issues

169 SELECTION OF TECHNOLOGY AND EQUIPMENT Vision of client Properties of products to be processed Output requirements High capacity / one shift, low capacity / 2 or 3 shifts Degree of automation, sophistication Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Previous experience, available equipment (standardization) GMP issues Safety of operator

170 SELECTION OF TECHNOLOGY AND EQUIPMENT Vision of client Properties of products to be processed Output requirements Degree of automation, sophistication fully automated preparation of solutions, with CIP/SIP, equipment for solids with CIP capability, cartoning, palettisation, etc. Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Previous experience, available equipment (standardization) GMP issues Safety of operator Q U A N T T I T E S NUMBER OF PRODUCTS AUTOMATION POSSIBILITIES

171 SELECTION OF TECHNOLOGY AND EQUIPMENT Vision of client Properties of products to be processed Output requirements Degree of automation, sophistication Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Previous experience, available equipment (standardization) GMP issues Safety of operator

172 SELECTION OF TECHNOLOGY AND EQUIPMENT Vision of client Properties of products to be processed Output requirements Degree of automation, sophistication Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Can influence the type or the supplier: eg difference in size between FBG and one-pot system Previous experience, available equipment (standardization) GMP issues Safety of operator

173 SELECTION OF TECHNOLOGY AND EQUIPMENT Vision of client Properties of products to be processed Output requirements Degree of automation, sophistication Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Previous experience, available equipment (standardization) GMP issues Safety of operator

174 SELECTION OF TECHNOLOGY AND EQUIPMENT Vision of client Properties of products to be processed Output requirements Degree of automation, sophistication Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Previous experience, available equipment (standardization) GMP issues Aseptic processing problems: automated loading of freezedryer, increased automation, increased sterility assurance level Safety of operator

175 SELECTION OF TECHNOLOGY AND EQUIPMENT Vision of client Properties of products to be processed Output requirements Degree of automation, sophistication Supplier: price, service and serviceability Cleanability and maintenance needs Space constraints Previous experience, available equipment (standardization) GMP issues Safety of operator: containment or PPE? In most cases, several factors will play a role simultaneously

176 SELECTION OF TECHNOLOGY AND EQUIPMENT MORPHOLOGICAL ANALYSIS P R O C E S S S T E P S AAA BBB CCC DDD EEE FFF GGG HHH ABA BAA CAA DAA EAA FAA GAA HAA ACA BAB CAB DAB EAB FAB GAB HAB ADA BAC DAC EAC FAC HAC BAD DAD FAD PROCESS ALTERNATIVES BAE FAE

177 SELECTION OF TECHNOLOGY AND EQUIPMENT PROCESS SELECTION WSG WSG WSG MC MC WSG MC MC Doubl e Granul ati on MC convent ional mixer A gravit y mixer B MC Classi cal granul at i on A. Diosna-method WSG MC MC MC WSG WSG WSG WSG WSG WSG MC MC Cl assical g ranul ati on WSG WSG B. Vacuumat -Method MC Convention al mixer Gravity mix er Convent i onal mixer Gravity mixer MC MC MC MC MC vibration sieve Single Granulation MC MC MC MC convent ional mix er A gr avity mixer B Conventional mixer Gravity mixer Convent ional mixer Gravity mixer MC MC MC WSG WSG WSG Technical ar ea TP P A: Feed ing level granules + l ubri cants ( + formulations for direct MC compresion) Personnel+ T ransp o rt C or rid o r T ech. T echnical Ar ea o r Visi to rs B: t rade powders ( + formulations for direct compresion) C or rid o r Personnel P P Personnel+ T ransp o rt C or rid o r Technical ar ea TP T ech. MC C or rid o r Personnel

178 PLANNING METHOD PROCESS AND ORGANIZATION FLOW CHARTS Whereas a process flow chart reflects the process only, an organization flow chart includes the process, its organization as well as additional elements such as quantities, personnel needs, hygiene zoning, equipment and inter-relationships within the production or between production and related functions. The process flowchart must be transformed into an organisational flow chart Organization flow charts exist at different levels, microand macro: Micro: within a department Macro: within a production unit / plant

179 PLANNING METHOD PROCESS FLOWCHART (EXAMPLE: SOLIDS) Granulation Binder preparation Drying Sieving Addition lubricants Blending Compression

180 PLANNING METHOD ORGANIZATION FLOWCHART (EXAMPLE: SOLIDS) Granulation Binder preparation Drying Staging m 2? Sieving Weighing Staging m 2? Container washing Blending Compression Addition lubricants Staging m 2? Staging m 2?

181 PLANNING METHOD FLOWS PERSONNEL AND MATERIALS Exterior Exterior Lockers G Lockers G Lockers D Lockers D G D G D Lockers C Lockers A/B Lockers C C Lockers A/B C A/B A/B Selection of alternative ESSENTIAL, later changes practically impossible

182 RELATIONSHIPS DETERMINATION BULK CLEAN UTILITIES WH BULK WH QA QC CENTRAL LOCKERS W S FORM FILL QUA R UTIL BLACK STRONG RELATION WEAK RELATION NO RELEVANCE PACKAGING

183 PERSONNEL LOCKERS EXAMPLE LAYOUT Depend on Hygiene zone Local regulations Company / cultural habits to be considered

184 IDEAL LAYOUT MATERIAL / PERSONNEL FLOW PLANNING

185 FACTORY ORGANISATION MATERIAL SUPPLY ROUTES LF PRIMÄRVERPACKUNG SEKUNDÄRVERPACKUNG PRIMÄRVERPACKUNG SEKUNDÄRVERPACKUNG LF PRIMÄR

186 EXAMPLE SUPPLY ROUTES MATERIALS 2nd Floor Grey Area Zone C Refilling Booth Zone C Weighing Booth Maintenance Floor Air Lock Black to Grey Air Lock Grey to C Air Lock Black to Grey Grey Area Zone C LF Booth Zone A / B 1st Floor Lock Grey to C Solution to be filled Ground Floor i - Point Black Area Sampling Changing to internal Labelling pallets Green Area Basement Black Area Locker Zone A / B Zone C Zone D Zone Grey Zone Black Zone Green

187 C100 TABLETTING: IDEAL MODULE LAYOUT Results User oriented working place Optimized user identification Coordinated equipment layout and access areas Tailor-made area, volume and environment Modularized interior works

188 EXAMPLES OF IDEAL MODULES Pac ktisc h LF Anbruch- u. Faßlager Chargenbereitstellung WB Pumpe Ansatz IPC Alu Technik Hebeeinrichtung Plattform Kilian TX Paletten-Umwandlung Entnahme Handlager für Komm iss. Fe rtigpackg. (verschlie ßba r) Entnahme Entnahme Entnahme Pa l. Verpa ckungs -und Füllm ate rial Plattform Kommiss. Pakete Pac ktisc he Rollenbahn Lackieren Pult Hebeeinrichtung Gabelstapler Kilian T300 Entstaubungskab. PERS. Schleuse LF Proben Prozesstechnik Granulation Plattform Pros pek tbeigabe Falts chacht el Waage Bünd elp acker Palettierer Tiefzieh folie K artonierer Prozesstechnik

189 FROM IDEAL MODULE TO FACTORY LAYOUT

190 From process to space organisation Step 1 Process Flow Chart is transformed into layout

191 From process to space organisation Step 2

192 OVERVIEW GLOBAL CONCEPT From process to space organisation Step 3

193 EXAMPLE OF CONCEPT FOR SOLIDS PRODUCTION

194 EXAMPLE OF CONCEPT FOR SOLIDS PRODUCTION

195 SITE LAYOUT

196 LOGISTICS Goods IN handling Cleaning Administration Sampling Palletisation Etc Goods OUT handling Picking Commissioning Administration Etc Production Storage activities Main storage Special storages Exterior Clients Logistic centre

197 Bulk store Preparation area for raw - and primary packaging material weighing Raw material Primary packaging material Secundary packaging material Finished products LOGISTICS Receiving area pal / h pal / h pal / h Sampling Booth Warehouse Pharma pal / h pal / h pal / h pal / h Production area pal / h pal / h Shipping Storage capacity: pal / h pal / h pal / h pallet Marshalling pal / h places pal / h Packaging pal / h lines Sampling Quarantine separation Change of pallets to/from production Procedures in material air locks

198 LOGISTICS

199 «GOOD GMP» Minimized risk of contamination / cross-contamination Clear material flows (uni-directional whenever possible) Clear personnel flows (uni-directional whenever possible) Unambiguous definition of GMP zones Separation clean dirty (washing areas) Overkill Cost issues Nice to have GMP is not an attribute, no black and white attitudes

200 SUMMARY A good pharmaceutical factory is a factory that is: Pharmaceutically approved (qualification / validation ) Economical to operate and maintain Flexible and adaptable quantity-wise and for new technologies To design such an excellent pharmaceutical plant, an integrated, multi-disciplinary and experienced team is required. The objectives, the vision, the method and the involvement of each member of the team will achieve this goal, and not the principle function follows adding up individual inputs

201 75