Best Practices For Cleaning Validation in the Aseptic Environment SUMMARY OF OUTLINE

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1 Best Practices For Cleaning Validation in the Aseptic Environment Vivienne Yankah, PhD, CQE sanofi pasteur Ltd. Toronto, Canada SUMMARY OF OUTLINE Review Regulatory Standards for CV Designing and Developing the Robust Cleaning Cycle Validating and Qualifying the cleaning process Effective Control and Maintenance of the Cleaning Program Interactive Exercise 2 1

2 Review Regulatory Standards for CV 3 Definition: Cleaning Validation The purpose of cleaning validation is to establish documented evidence with a high degree of assurance that the cleaning process will consistently yield results that meet predetermined specifications and quality characteristics The action of proving in accordance to principles of GMP that the cleaning procedure actually leads to expected results Validation helps to know the process capability and create an avenue for process improvement 4 2

3 Regulatory Guidance for GMP FDA Guide to cgmp for Finished Pharmaceuticals: 21 CFR 210 & 21 CFR 211 Health Canada : Cleaning Validation Guidelines EU Guide to GMP 5 FDA Guide to cgmp for Finished Pharmaceuticals 21 CFR Subpart D Equipment Cleaning i. Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent contamination that would alter the safety, identity. ii. Written procedures on cleaning schedules, protection of clean equipment from contamination prior to use.. iii. Equipment stored for longer time than during validation should be sampled to demonstrate that the cleaning procedure was effective. 6 3

4 Health Canada: Cleaning Validation Guidelines (Guide 2008) 6.0 Microbial Considerations.. Time-frames for the storage of unclean equipment, prior to commencement of cleaning, as well as time frames and conditions for the storage of cleaned equipment should be established. Equipment should be dried before storage,.no stagnant water in equipment after cleaning Documentation ti The interval between the end of production and the beginning of the cleaning procedure in CV protocols 7 European Commission Annex 15: EU guide to GMP Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Considerations should be given to noncontact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined. 8 4

5 EU Regulatory Considerations for Cleaning Validation EU Guide to GMP Sensitivity of analytical methods Worst-case approach Number of runs: three consecutive applications Use of surrogates-simulate the physicochemical properties Test until clean not acceptable The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. 9 Application of ICH Guidelines Provide a structured way to define product critical quality attributes, design space, the cleaning process and the control strategy Utilizes continuous cleaning process verification/monitoring Risk assessment highlights focus areas for demonstrating robustness 10 5

6 Application of Quality System Concepts ICH Q8 Pharmaceutical Development Quality by Design Design Space Real Time release (RTR) testing includes those in-process tests that directly impact the decision for batch release through evaluation of critical quality attributes Parametric Release Control Strategy- controls from product and process understanding that assures process performance and product quality 11 Application of Quality System Concepts ICH Q9 Quality Risk Management Systematic process for assessment, control, communication and review of risks to quality over product life cycle Risk is the combination of the probability of occurrence of harm and severity of that harm Risk to quality evaluation should be based on scientific knowledge and link to protection of patient Level of effort formality and documentation of quality risk management commensurate with level of risk 12 6

7 Application of Quality System Concepts ICH Q10 Pharmaceutical Quality Systems Facilitated robustness of processes Consistency in global pharmaceutical environment Transparency of systems, processes organizational management responsibility Reduce risk of product failure Increased compliance with GMPs Better process performance 13 Designing and Developing the Robust Cleaning cycle 14 7

8 Process Parameters for Robust Design Factors to be considered in designing an effective cleaning process include the biochemistry of the residue, the manufacturing process, equipment design and testing methods for the target analyte. Cleaning process Parameters: i. Time ii. Temperature iii. Cleaning agent & concentration iv. Flow rate 15 Equipment Design and Compatibility Generate required equipment specifications based on existing needs e.g. piping and flow designs Spray ball design and location Proper equipment design and cleanability affects cleaning time, chemical use, disassembly required 16 8

9 Equipment Design & Specifications 17 Selection of Cleaning Agent Selection should be based on suitability to remove the product residues and for low toxicity Should be acceptable to the process and for use with pharmaceutical products Acceptable limits for cleaning residues should be established using scientific rationale similar to limits for product residues Review vendor specification sheets and descriptions, ingredients and percentage of constituents 18 9

10 Cleaning Process Development - Design Space The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change Including additional information allows for demonstration of a high degree of understanding of the manufacturing process, which can lead to more flexible regulatory overview 19 Defining Operating Range Characterization space=characterized space Acceptable operating range = design space Operating range = operating space Risk analysis to determine the probability of falling outside the design space 20 10

11 Choosing the Cleaning Method CIP : Clean in Place Cleaning of permanently stationed items Performed by circulating cleaning solutions through the equipment. Automated, semi automated COP: Clean out of place Equipment is removed and cleaned remotely Semi automated, manual 21 Detergent Selection for Target Residues Two types of cleaning agents: alkaline or acid. Often formulated with surfactants, chelating agents and emulsifiers to enhance effectiveness. Acid cleaning agents e.g. phosphoric acid, nitric acid, Alkaline cleaning agents e.g. sodium hydroxide, sodium percarbonate, sodium hydrogen carbonate, sodium orthosilicate, sodium metasilicate, 22 11

12 Developing Cycle Times for Cleaning Procedure CIP- Cycle times determined by controlling the primary factors of cleaning efficacy e.g. detergency, contact time. On line monitors and sensors for temperature, conductivity, ph, detergent supply flow rate, pressure sensors 23 Establishing Cleaning Cycle Cycle developed must be validated for specified critical cleaning process parameters e.g. Temperature, Time, cleaning agent concentration, # of rinses, A test method is used to evaluate consistency in acceptability of cleaning Test until clean scenario to be avoided 24 12

13 Identifying Critical Areas of Equipment Critical cleaning locations are more difficult to clean and most probable sites for contaminant carryover Sucrose- Riboflavin test under UV light Swab sampling performed at critical locations Product contact surfaces must be identified Worst case sampling locations eg. Piping, i valves, tubing 25 Residue Removal Capability Residue removing capability can be enhanced by yprewash steps in the cleaning cycle Should be linked to a measurement system that shows how much residue present Acceptable residue levels after cleaning has direct impact on acceptance criteria and carry over calculations 26 13

14 Validating and Qualifying the Cleaning Process 27 The Validation Strategy Specify acceptable clean endpoint, what is measured for acceptance criteria Include holdtimes during manufacturing Specify sampling locations and rationale Specify the test methods Specify type of samples rinse, swab Approach for assessment of equipment groups/bracketing 28 14

15 Validation Versus Verification Validation: Documented evidence shows repetition in demonstrating consistency and meeting predefined quality attributes Verification: Similar to validation however data generated apply only to that specific cleaning event. 29 Challenges of Aseptic Manufacturing No terminal sterilization in final container, containers must be filled and sealed in an extremely high quality environment Parts of final product must be sterilized prior to aseptic assembly After sterilization any manual or mechanical manipulation of components during assembly poses the risk of contamination 30 15

16 Cleaning Validation Considerations for Control of contaminant carry over Prior to sterile filtration, in-process controls used to ensure cleaning agents, product and process related residues are at a minimum Use of dedicated equipment Bioburden and LAL controls for sanitized equipment Define number of uses for reusable chromatographic systems e.g. column resins and NWP for UF units Conduct simulation runs to estimate contaminant carry over from one batch to another 31 Demonstrating Process Qualification Sampling points must align with rationale for design of validation strategy Risk evaluation of any selected worse case conditions All test results from the three consecutive runs must conform to pre-defined acceptance criteria Any non-conformances must be resolved prior to process qualification and must have no impact on the three qualification runs Acceptance criteria for cleaning study must address the critical factors that affect the performance of the cleaning procedure 32 16

17 Sampling Recovery Studies Recovery studies performed to qualify the rinse and swab sampling procedure Acceptable recovery range from 100% 70 % Recoveries between 70% to 50 % must be included in the calculation of acceptance criteria At recoveries below 50% sampling method should be revaluated 33 What is Being Removed by Cleaning Procedure Active ingredient Decomposition products Excipients Particulates Cleaning/Sanitizing agents Bioburden Endotoxin 34 17

18 Assessment Criteria after Cleaning Acceptance criteria for selected test markers include the following: Bioburden -Microbial load cfu/ml LAL -Endotoxin (Eu/mL) Conductivity -Cleaning agent us/cm TOC -Total organic carbon (ppm) Test method for any analyte associated with process/product/ cleaning agent and critical for demonstrating effectiveness of cleaning procedure. 35 Test Methods For Cleaning Validation Testing cleaning validation samples requires a validated method. The extent of validation is dependent upon the type of method employed, the capabilities of the method, the scientific and regulatory needs of the resulting data and the anticipated outcome of the testing

19 Analytical Test Method Specificity Test Method Specific Non-Specific Detection specific to target analyte only Detection of any compound responding to the analytical method 37 Selecting Analytical Test Methods Product Specific Assay GC Capillary electrophoresis Protein methods e.g.. ELISA TLC HPLC 38 19

20 Selecting Analytical Test Methods Non Specific Assay TOC (non volatile residue) ph (cleaning agent residue) Conductivity (cleaning agent residue) Titrations UV Bioburden Limulus Amoebocyte Lysate (LAL) 39 Considerations for Executing the Cleaning Validation Process 40 20

21 Types of Sampling Two types of sampling acceptable are the rinse and swab sampling methods Swab most desirable direct method of surface sampling Rinse for inaccessible areas and sampling large surface areas A combination of the two methods is most desirable 41 Choosing the Sampling Locations Sample the worst case locations for contaminants Sampling information in protocol should specify i. Sample volumes required for specific tests ii. Sampling containers iii. Sampling for positive and negative controls where applicable iv. Storage conditions for collected samples 42 21

22 Critical Background Information Supporting Cleaning Study Surface recovery studies e.g. Stainless steel, glass etc. Hold time studies- Clean equipment hold times, Dirty equipment hold times, sample hold times Procedure for collecting rinse, swabs and performing visual inspection Analytical test method validation Matrices for test methods- Ensure sample matrix does not interfere with the test method Raw Data File for Protocol Execution 43 Information on Hold Times Dirty Equipment Hold Times Time when equipment dirty to equipment cleaned Clean Equipment Hold Times Time equipment cleaned to time equipment sterilized Sample Hold times Time test t samples collected to time test t samples tested 44 22

23 Why Specify DEHT & CEHT DEHT Nature of soil may change overtime with drying or microbial proliferation Changes make soil more difficult to remove by the cleaning process CEHT Possible Microbial proliferation (FDA cleaning validation guidance- 1993) Storage conditions of the cleaned equipment 45 Protocol Execution: Raw Data File Supporting details relevant to sections of the protocol is kept in a Raw Data File as reference documentation e.g.. information supporting derivation of acceptance criteria, information on analytical test methods, justification for sampling sites, surface area calculations etc

24 How to Maintain the Cleaning Process 47 Considerations for Process Capability, Reliability and Consistency Goal is to operate at process capability that ensures that predefined acceptance limits are consistently met in a reproducible manner Residue data is used to generate process limits Acceptance limits should be scientifically justifiable, achievable and risk-based

25 Investigating Non-conformances An investigation is initiated if the acceptance criteria is not met for any of the pre-determined specifications required to evaluate the cleaning procedure. Quality tools for root cause analysis example Ishikawa Fish bone diagram i. An assignable cause to the OOS ii. No assignable cause 49 Creating OOS Document Describe the OOS Investigation of OOS Impact and assessment of OOS on the validation study Resolution Conclusion Review & Approval Operator/Personnel conducting validation study Production Quality unit 50 25

26 Monitoring the Cleaning Validation Process Two main opportunities for monitoring cleaning data: During process development monitoring generates data for setting acceptance criteria for cleaning validation study After qualification of the cleaning process monitoring provides the data for setting process limits 51 Application of Continuous Process Improvements Monitoring data provides important information for defining the cleaning process capability. The trend is to depart from the use of general default limits, NOELs and toxicity limits to risk and statistically derived criteria that are based on process performance 52 26

27 Statistical Process Control Process Capability- Cp and Cpk USP = Upper specification Limit LSP = Lower Specification Limit Cp = Process Capability Cp = USL-LSL/ 6s Cpk = USL-x/3s Where s = process standard deviation 53 Control Chart for Data Monitoring (I-MR Chart) Individual Measurement of TOC (ppm) 8 6 UCL=7.11 TOC (ppm) 4 2 Avg= Sample LCL=-1.01 Specification Lower Spec Limit Upper Spec Limit Spec Target Value. 10. Portion Below LSL Above USL Total Outside % Actual

28 Normal Quantile Plot for TOC Data USL Normal Quantile Plot 55 Process Capability Graph -3s Mean +3s USL 56 28

29 Process Capability Indices Capability Index Lower CI CP... CPK CPM... CPL... CPU Upper CI Portion Percent PPM Sigma Quality Below LSL... Above USL Total Outside Z LSL. Z USL QUESTIONS / DISCUSSIONS 58 29