Equipment Design Consideration for Cleaning & Cleaning Validation

Transcription

1 Equipment Design Consideration for Cleaning & Cleaning Validation Gamal Amer, Ph. D. Principal Premier Compliance Services, Inc. All rights reserved. Do not copy without permission. 1

2 Cleaning and Cleaning Validation The Overall Picture Life Cycle* Operating Information and Monitoring Data Design/Development Phase Cleanable Equipment and Facility Cleaning Procedure and Validation Protocol Implementation & Maintenance Phase Validated Procedure Execution & Qualification Phase * Based on FDA Guidance on Process Validation of January 2011 All rights reserved. Do not copy without permission. 2

3 Cleaning and Cleaning Validation Life Cycle The Development Phase Science, Technology and Risk Knowledge Information from execution & Implementation phases Equipment/Facility Design as cleanable & with cleaning in mind Define required level of cleanliness Develop/modify cleaning procedure To execution phase Develop cleaning validation protocol Test cleaning SOP capability Method Development Method Validation All rights reserved. Do not copy without permission. 3

4 Cleaning and Cleaning Validation Life Cycle Execution & Qualification Phase Repeat From Implementation or Development Phase Clean and validate the cleaning Pass No Investigate Cleaning validation Complete Yes Develop Validation report Need for Change To implementation phase Change management? Back to development All rights reserved. Do not copy without permission. 4

5 Cleaning and Cleaning Validation Life Cycle Implementation and Maintenance Phase Back to Execution or Development Phase Change Management Yes No Modification? From Execution Phase Clean using validated SOP Monitor effectiveness of cleaning Review Identify trends & possible issues Back to Development Phase Information for continuous process improvement All rights reserved. Do not copy without permission. 5

6 The Cleaning Continuum Dedicated Equipment..vs..Non-dedicated Single Product Use.. vs...multiple Products Use Single Product Facility.. vs...multiple Products Facility Existing/Established Product.. vs... New/unknown Product Low Risk/Potency Drug.. vs... High Risk/Potency Drug Sterile Operation/Product.. vs... Non-sterile Operation/Product PDA Points to Consider for Cleaning Validation, Tech Report 29, August 1998 All rights reserved. Do not copy without permission. 6

7 The Cleaning Continuum (Cont.) Solid Formulation.. vs... Liquid Formulation Manual Cleaning..vs..Automated Cleaning Product Contact Surface.. vs...non-products Contact Surface Bulk Ingredient.. vs...finished Pharmaceutical Early Processing Step.. vs... Final Purification Step Active Ingredient.. vs... Non-Active Ingredient PDA Points to Consider for Cleaning Validation, Tech Report 29, August 1998 All rights reserved. Do not copy without permission. 7

8 Implications You need to consider all these factors when designing a piece of equipment A piece of equipment must be tailored to specific cleaning challenges You must consider the entire operation & facility when designing equipment You must consider the material you will be cleaning during the design You must consider where within the process the equipment is used You must consider how you will clean All rights reserved. Do not copy without permission. 8

9 Categories/Types of Equipment 1. Off the shelf 2. Unique/made to order 3. Hybrid All rights reserved. Do not copy without permission. 9

10 Off the shelf Equipment available and meets user requirement Short lead time for delivery Established and known Lower cost Purchase from experienced quality suppliers Limited possibility to modify User must define any required minor or limited modifications early on and work with supplier on implementing All rights reserved. Do not copy without permission. 10

11 Unique or Specialized No vendor or off-the-shelf equipment available to meet requirements User develops the design Need an equipment fabricator Involvement of many groups Long lead time Increased cost All rights reserved. Do not copy without permission. 11

12 Hybrid Normally Off-the-shelf requiring considerable modification to meet user requirements Requires extensive collaboration with equipment manufacturer to define modifications Lead time is somewhere in between Cost somewhere in between All rights reserved. Do not copy without permission. 12

13 Issues to Consider Prior to Designing the Equipment Intended Use of Equipment (determines the need to clean, etc.) How toxic or potent is the material to be processed? (determines residue allowed in next product) How difficult it is to clean the material? (based on solubility in cleaning agent and intrinsic difficulty of cleaning) How do you plan to clean the equipment? Where will you clean the equipment? All rights reserved. Do not copy without permission. 13

14 Intended Use Will equipment be used for multiple products or single product (Cleaning requirement) Will equipment be dedicated? Processing volume (equipment size and location, can it be moved for cleaning vs. in place cleaning, etc.) Where within the process is the equipment used (early step, late step, step with further purification, Bulk, finished, etc.) Material to be processed and its risk level to the public wellbeing (Should it be cleaned? Should it be dedicated? Risk analysis) All rights reserved. Do not copy without permission. 14

15 Risk Analysis Risk associated with cleaning can be determined by defining three factors: Residue allowable R (1 large amount - 5 very small amount) Solubility in cleaning agent S (1 very soluble - 5 highly insoluble) Cleaning difficulty C (1 easy to clean - 5 difficult to clean) All rights reserved. Do not copy without permission. 15

16 Risk Analysis Cleaning Risk Priority Number CRPN = R x S x C Low Risk 1-20 Medium Risk High Risk All rights reserved. Do not copy without permission. 16

17 How toxic/potent is the material? Defines the level of cleanliness that must be reached Analytical methods that can detect material at low levels accurately Ability to sample the surface and the cleaning solutions and collect sufficient samples for analysis Multiple use design in cases where contaminants are not excessively toxic/potent Closed equipment to prevent compound migration Possibly dedicate equipment All rights reserved. Do not copy without permission. 17

18 How toxic/potent is the material? Multiple use equipment require a design that is easy to clean High potency or highly toxic compounds should warrant extra vigilance when applying the principles of equipment design outlined later in this presentation. Accessible, No difficult to reach, no areas where contaminants can accumulate, Smooth surfaces, eliminate appendage that are difficult to reach and clean, etc. All rights reserved. Do not copy without permission. 18

19 How difficult it is to clean the material Defined based on R&D work The nature of the material defines cleaning methodology (manual, automated, etc.) thus establishing needs for ports, connections, and manholes Establishes the cleaning agent and the conditions for cleaning thus possibly dictating the material of construction All rights reserved. Do not copy without permission. 19

20 How will the equipment be cleaned? Manual cleaning Automated cleaning Semi automated or combined manual and automated cleaning All rights reserved. Do not copy without permission. 20

21 Manual Cleaning Large opening to access interior (hand holes, manholes) Lighting for viewing capability Dismantle-able equipment for cleaning (clamps, fittings, gaskets, etc.) Movable would require easy disconnect & connect capability, wheels, etc. Movable equipment would affect facility design (wash room, storage room, size and finishes of corridors) All rights reserved. Do not copy without permission. 21

22 The Facility Air Flow People Flow Clean Storage Wash Soiled Storage Equipment Flow Dirty Clean Return Corridor Degown Buffer & Media Prep Fermentation Isolation Utilities Gown Clean Corridor Storage & Staging Packaging Finishing Rounded corners All rights reserved. Do not copy without permission. 22

23 Automated Cleaning Washers and dryers for cages, glassware, small equipment, tools and utensils, etc. must be sized appropriately for such Utilities for automated cleaning should be available at the locations where the cleaning would take place Equipment to be properly sized for the washer Layout of equipment to allow for access of personnel or equipment for washing. All rights reserved. Do not copy without permission. 23

24 Automated Cleaning Automated cleaning in place dictates the equipment be equipped with spray ball & nozzle connections, drainage capability, and their location. Defines some of the controllers and the logic Quick-connect ability from the exterior. Equipment to be capable of complete draining. Locating the equipment within the space close to drainage, near needed utility, etc. All rights reserved. Do not copy without permission. 24

25 Automated Cleaning Again, piping of the utilities to where the equipment is located and providing proper drainage in the facility. Floor drains to be piped to appropriate containment. Floor pitched towards drains Wall and floor finishes to withstand excessive liquid use and draining. Affects room size and equipment layout to allow CIP skid movement. All rights reserved. Do not copy without permission. 25

26 Semi-Automated Cleaning Some components are cleaned in a washer and other parts will be cleaned manually Require dismantling Require moving parts to washer Cleaning parts in place or moving to sink Requires reassembly with clamps, fittings, gaskets, etc. All rights reserved. Do not copy without permission. 26

27 In-Place Where will it be cleaned? For large equipment Many of the details outlined in automated cleaning would apply (spray balls, coverage, drainage, connections, etc.) Manholes and hand-holes as well as access to them (no exterior obstacles) to clean difficult to reach spots Short pipe runs without sharp bends to make it easy to access for cleaning All rights reserved. Do not copy without permission. 27

28 Where will it be cleaned? Remotely Equipment reasonable in size and weight to allow for moving Equipment with wheels if too heavy to carry or load on cart Ability to disassemble for washing Open design in case of remote washer use All rights reserved. Do not copy without permission. 28

29 Once all the factors associated with cleaning the equipment have been identified, the following general consideration for designing and specifying a piece of equipment should be addressed. All rights reserved. Do not copy without permission. 29

30 General Design Consideration Material of Construction and Surface Finish Material to withstand processing conditions or cleaning conditions which ever is harshest Material should be inert to content Should not deteriorate over time Surface finish quality and smoothness (prevent contaminant accumulation and microbial contamination) All rights reserved. Do not copy without permission. 30

31 General Design Consideration Material of Construction and Surface Finish (cont.) Cost of material and of finer surface finish should be balanced with the process and cleaning requirements Use a risk assessment approach Expected life of equipment may dictate material thickness to allow for future resurfacing Request supplier provide coupons for cleaning studies of the material when ordering the equipment All rights reserved. Do not copy without permission. 31

32 General Design Consideration Disassembly and reassembly Sanitary design implies ease of disassembly and assembly Use of clamps, threads, and/or pressure fittings for easy connecting and disconnecting Small equipment design to dismantle to basic components for washing in a washer or sink Large equipment dismantle hard to reach appendages, inlets, outlets, pipes, covers, and possibly agitators to wash separately All rights reserved. Do not copy without permission. 32

33 General Design Consideration Accessibility of all surfaces Through hand-holes, manholes, to spray balls and nozzles Ensure no unreachable surfaces where contamination accumulates Lighting to assist with manual cleaning (sight glass or hook to hang a light) Proper location of spray ball or nozzle usually established empirically All rights reserved. Do not copy without permission. 33

34 General Design Consideration Visual inspection consideration Cleaning and its validation necessitates ensuring equipment is visibly clean Design to provide ability to visually inspect Sight glass, lighting capability, opening to look-in and their location, ease of access to openings for inspection All rights reserved. Do not copy without permission. 34

35 General Design Consideration Sampling consideration for cleaning Ports to withdraw samples of rinse solutions, cleaning solutions, product, etc. Sizing of sampling ports and location are important design consideration Cleaning and sanitizing sampling ports considerations Sterilize-able ports for microbial sampling (ability to steam) All rights reserved. Do not copy without permission. 35

36 General Design Consideration Use of disposable liners Hoppers in tablet filling machine could be lined with disposable liner to reduce the burden of cleaning Design to consider equipping with appropriate fasteners for the liner Design for easy introduction and removal of the liner Design so that liner fits snuggly All rights reserved. Do not copy without permission. 36

37 General Design Consideration Avoiding or minimize sharp corners Where surfaces meet should be rounded Smoothed weld and other protruding elements and maintain level with general surface Requirement should be outlined in specification Confirm that it was achieved through inspection and certification All rights reserved. Do not copy without permission. 37

38 General Design Consideration Gaskets and connections All gaskets and connections must be flush with surface Must be accessible for cleaning Tight to prevent leaking and accumulation of materials within Gaskets should be easy to remove and clean or disposable (low cost) All rights reserved. Do not copy without permission. 38

39 General Design Consideration Pipes and valves Pipes within the piece of equipment should be of short runs to allow for cleaning and draining Should be slanted to allow for proper and complete draining Venting to allow for complete draining of pipe runs Avoid dead legs within the pipes, near valves, and near sampling ports All rights reserved. Do not copy without permission. 39

40 General Design Consideration Pipes and valves (cont.) Avoid sharp (90 ) bends which would be difficult to clean Proper valve selection such as diaphragm valves and not globe valves Use sanitary valves and pipe fittings All rights reserved. Do not copy without permission. 40

41 Diaphragm valve

42 General Design Consideration Surfaces Flat surfaces should be slanted towards drain to avoid pooling of liquids Appropriate smoothness/finish to prevent accumulation of contaminants & microbes Sufficient thickness to allow resurfacing depending on the expected life of equipment Testing ability for glass lined equipment to identify if cracks exist All rights reserved. Do not copy without permission. 42

43 Documentation to Support Cleaning Validation and Operation Documentation for equipment is required for GMP compliance and needed to prepare and execute cleaning validation protocols. Should be considered during the design stage. Many are produced prior and during the design/development phase.(user requirements, specification, drawings, Cleaning SOP) All rights reserved. Do not copy without permission. 43

44 Documentation to Support Cleaning Validation and Operation Documents needed to support cleaning Validation: User requirements Equipment specification Engineering and design drawings O&M Manual Cleaning procedure Certifications (material, finishes, welds, passivation) Equipment cleaning log MSDS for material being processed and cleaning agents All rights reserved. Do not copy without permission. 44

45 Documentation to Support Cleaning Validation and Operation Always order sufficient number of documents to address the needs of the operation as well as the validation requirements. Store one set in a controlled area. Ensure documents are in the appropriate language. Ensure they are correct from a syntax point of view if translated. All rights reserved. Do not copy without permission. 45

46 Pre-Installation Testing of Equipment Factory Acceptance tests (FAT) Spray ball coverage, operation and pressure Weld testing and scope visualization Confirmation of sanitary pipes, valves, gaskets, finishes, etc. Leak testing during SAT Many of the design aspects related to cleaning to be confirmed during IOQ testing All rights reserved. Do not copy without permission. 46

47 Analytical and Testing Consideration Validate analytical procedures and methods for analysis of residuals and cleaning agents Insure critical aspects of method such as LOD, precision, linearity, selectivity, recoveryspiking, consistency of recovery, are addressable. Coupons for swab recovery studies should be of same material and finish - order with equipment All rights reserved. Do not copy without permission. 47

48 Analytical and Testing Consideration Surface sampling techniques and recovery confirmation (e.g. Swab Recovery Studies) Rinse solution analysis and relation to residue on surface Surface examination procedures Sampling methodology and proper sampling ports. All rights reserved. Do not copy without permission. 48

49 Checklist for Equipment Cleaning Design Considerations Choose proper material of construction. Define appropriate surface finish requirement. Define appropriate welding requirements. Ensure awareness of pipe length limitations and avoid unnecessary log pipe runs All rights reserved. Do not copy without permission. 49

50 Checklist for Equipment Cleaning Design Considerations Minimize or eliminate dead legs. Ensure all surfaces and pipes are slanted to promote draining. Design equipment so that it could be dismantled if necessary. Equipment should have accessibility to the interior. All rights reserved. Do not copy without permission. 50

51 Checklist for Equipment Cleaning Design Considerations Equipment should have appropriately located sampling ports. Equipment should be designed to give the ability to inspect its interior. Ensure that the equipment is equipped with lighting for the interior. All rights reserved. Do not copy without permission. 51

52 Checklist for Equipment Cleaning Design Considerations Spray balls and/or nozzles should be located in such a way to provide full coverage of the surface to be cleaned. Can liners or throw-away bags be used to reduce the cleaning requirements? All rights reserved. Do not copy without permission. 52

53 Checklist for Equipment Cleaning Design Considerations If disposable single use implements are to be used how will they be used? Documentation requirements and number of copies. All rights reserved. Do not copy without permission. 53

54 In Summary Equipment design is the first step in the life cycle approach to cleaning Validation When designing a piece of equipment you must consider its use and how to clean it Design of the equipment may dictate some of the design aspects of the facility Ensure proper development of necessary documentation during equipment design Insure proper (equipment and material specific) analytical techniques are developed and validated. All rights reserved. Do not copy without permission. 54