Cleaning validation. Presented by Marc Fini 21 May, 2013

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1 Cleaning validation Presented by Marc Fini 21 May, 2013

2 What is cleaning validation? Cleaning validation is documented evidence that the cleaning process can effectively and reproducibility clean equipment to a predefined acceptable level. Slide 2 PharmOut 2013

3 What does CLEAN mean? Oxford Dictionary definition: To be free from dirt, marks, or unwanted matter Slide 3 PharmOut 2013

4 Types of cleaning Clean in Place (CIP) Skid WFI System Recirculation Clean out of place Equipment washer Loading patterns Manual Cleaning Brushes Procedural Operator Slide 4 PharmOut 2013

5 Cleaning agents Solvent: A substance, usually a liquid, capable of dissolving another substance Water (WFI, RO, Municipal Supply) Ethanol or other organic solvents Detergent solutions Acidic or Caustic Solutions Placebos Slide 5 PharmOut 2013

6 Cleaning agents Solute: A substance dissolved in another substance, usually the component of a solution present in the lesser amount. API Excipients Cleaning Agents Degradation Products Solvents Intermediates Slide 6 PharmOut 2013

7 Cleaning modes of action Physical High Pressure Spray High Velocity Flow Scrubbing Vacuuming Slide 7 PharmOut 2013

8 Cleaning modes of action Chemical Solubility Emulsification Wetting Chelation Dispersion Hydrolysis Oxidation Like dissolves Like Slide 8 PharmOut 2013

9 Examples of critical process parameters Temperature Pressure Flow Contact Time Cleaning Agent Concentration Dirty Hold Time Clean hold conditions Slide 9 PharmOut 2013

10 Examples of critical quality attributes Visual detection Cleaning Agent Residues Product Residues Microbiological residue limits Drainability/drying Conductivity/resistivity Slide 10 PharmOut 2013

11 Performing cleaning validation Create a Cleaning Validation Team Write a Cleaning Validation Master Plan Collect Information Group products Set limits Group equipment Determine Sampling Sites Slide 11 PharmOut 2013

12 Performing cleaning validation Select Analytical Method Perform Recovery Studies Perform an Engineering Study Perform the Cleaning Validation Study Write a Validation Summary Report Implement Cleaning Procedures 14. Monitoring Slide 12 PharmOut 2013

13 Create a team Cross-functional/departmental team: Quality Assurance Operations/Manufacturing Engineering & Maintenance Validation Research and Development (R&D) Medical Affairs Regulatory Affairs Slide 13 PharmOut 2013

14 Cleaning validation master plan Documents the rationale and important aspects of the cleaning validation program: Purpose and Scope Responsibility Validation Approach Risk Assessment Acceptance Criteria Assessment for the Removal and Toxicity of Drug Product Formulation Excipients Slide 14 PharmOut 2013

15 Cleaning validation master plan Validation for the removal of Cleaning agents Defining Equipment Train for Cleaning Validation Equipment Train Surface Area Calculation Product Grouping Equipment Bracketing Selection of Sampling Sites Validation of 'Dirty' Holding Periods Validation of 'Clean' Holding Periods Single use Components Dedicated Equipment Slide 15 PharmOut 2013

16 Cleaning validation master plan Analytical Methodology Development of Analytical Methods Product Specific versus Product Non-Product Specific Analytical Methods Sensitivity Requirements for Cleaning Validation Samples Recovery Studies Sampling Methodology for Cleaning Verification and Cleaning Validation Monitoring Program Slide 16 PharmOut 2013

17 Cleaning validation master plan Data Collection Deviations & Deficiencies Handling Change Control Reporting Protocol Execution Validation Summary Reports (VSR) Routine Monitoring Slide 17 PharmOut 2013

18 Collect information about the products Dosage, toxicity, concentrations Excipients, degradants and impurities Material compatibility/interactions Solubility in water and in the cleaning agent Stability of product Difficulty of cleaning Slide 18 PharmOut 2013

19 Collect information about the equipment Define the equipment train and sequence in which equipment is used Materials of Construction Surface Finish Geometry (hard to reach areas) Surface Area Disassembly and Assembly Requirements Condition and suitability of equipment Slide 19 PharmOut 2013

20 Collect information about the process attributes Product list including media, buffers and non-routine cleaning agents Batch sizes Cleaning procedures Cleaning agents Cleaning temperature requirements clean and dirty holding times Slide 20 PharmOut 2013

21 Collect information This is the most difficult and time consuming part of any cleaning validation program, but if the information is complete and accurate it will prove to be highly beneficial at later stages of the validation process. Slide 21 PharmOut 2013

22 Group products If possible, group products and select a worst-case or representative product by considering: Solubility in water and proposed cleaning agent(s) Therapeutic dose Toxicity (e.g. LD50) Affinity to certain materials of construction Interaction with product which will follow on? Equipment train Product characteristics Class of drug Slide 22 PharmOut 2013

selection is documented, scientifically justified

23 Group products Whilst this can significantly reduce the validation effort, ensure that each product selection is documented, scientifically justified and defendable in an audit situation. Slide 23 PharmOut 2013

24 Calculate limits Limits and acceptance criteria should be: Practical Verifiable Achievable Scientifically Sound Slide 24 PharmOut 2013

25 Calculate limits MAC =MDD x SF x MBS LDD MAC = Maximum Allowable Carryover MDD = the minimum daily dose of the active of cleaned product SF = Safety Factor, which is typically or 1/1000 MBS = the Minimum Batch Size of the next product LDD = the largest daily dose of the next drug product to be manufactured in the same equipment Slide 25 PharmOut 2013

26 Calculate limits. Largest Daily Dose 2 units 10 µg 10 µg 1/1000 Safety Factor 10 mg Minimum Daily Dose Minimum Batch Size 50,000 units Slide 26 PharmOut 2013

27 Calculate limits Example: MDD (Product A) = 10 mg Safety Factor = 1/1000 or MBS (Product B) = 50,000 units LDD (Product B) = 2 units Surface Area (Equipment Train) = 75,000 cm 2 MAC (µg/cm2 ) = 10 x x 50,000 2 x 75,000 = 3.3 µg/cm 2 Slide 27 PharmOut 2013

28 Calculate limits Other methods to calculate limits: Using LD50 and modifying factor (determined by toxicologist) Default limits such as 10 ppm LD 50 = 50% lethal dose of the target residue in an animal, typically in mg/kg of body weight 10 ppm = 10 mg of residue per litre of next batch Slide 28 PharmOut 2013

29 Calculate Limits: Visually clean Visually clean acceptance criteria may be considered appropriate for dedicated equipment however possible degradants and bioburden need to be considered. Equipment should always be inspected when dry Minimum visual limit should be established in terms of amount Slide 29 PharmOut 2013

30 Group equipment Same design but differs only in size It may be acceptable to only validate the largest and smallest of each item (e.g. vessels?). Dedicated and shared equipment Same material of construction Slide 30 PharmOut 2013

31 Group equipment As with the product grouping, ensure that each equipment grouping is scientifically justified and defendable in an audit situation. Slide 31 PharmOut 2013

32 Determine sampling sites A Riboflavin or Fluoroscein study to determine hard to clean area Representative surface with respect to different materials of construction Role in process likely to lead to build-up or difficult to clean areas Hot spots i.e. locations that are considered hard to clean or have complex geometries Critical sites i.e. locations that may disproportionately contribute residue to the next process (e.g. filling needles ) Slide 32 PharmOut 2013

33 Select analytical method New analytical methods should typically occur concurrently with the development of new products. Methods should be product specific Non-specific methods may be used if it is not possible or practical to use a specific method Method must be sensitive enough Method must be appropriately validated particularly in the expected residue limit working range Slide 33 PharmOut 2013

34 Select analytical method Specific Non specific HPLC GC/MS Total Organic Carbon (TOC) Conductivity UV/Vis ph Slide 34 PharmOut 2013

Recovery Studies The recovery studies should ordinarily be performed in conjunction with the development of the analytical methods Recovery studies are performed to establish the effectiveness of the

35 Recovery Studies The recovery studies should ordinarily be performed in conjunction with the development of the analytical methods Recovery studies are performed to establish the effectiveness of the sampling technique Should be done for all product contact surfaces, e.g. stainless steel, plastics, glass, gaskets and hoses Usually carried out in the laboratory using coupons to simulate the product contact surface Slide 35 PharmOut 2013

36 Recovery method Swab Recovery Generally 70% recovery required Less than 50% recovery needs a justification Typically 15-30% RSD between samples acceptable Slide 36 PharmOut 2013

37 Recovery studies Rinse Recovery Should be treated the same as swabs. Used for sampling areas that can t be reached by swabs. For example, transfer lines. Innovative ways may be required when applying or collecting rinsate. Slide 37 PharmOut 2013

Perform an engineering study It is very important that the cleaning process capability is well understood before any validation takes place.

38 Perform an engineering study It is very important that the cleaning process capability is well understood before any validation takes place. Develop a cleaning validation protocol and report to document findings. Validation should not be a learning exercise but a verification of what is already known about your process. Slide 38 PharmOut 2013

39 Perform the cleaning validation study Once the cleaning validation plans and protocols have been prepared and approved, it is time to execute it. Ensure the protocol and procedures to be validated are being followed correctly. Preparation and pre-determined acceptance criteria are crucial in achieving a successful cleaning validation outcome. Ensure that any deviations or exceptions/ observations are captured via an exception reporting system. Slide 39 PharmOut 2013

Validation summary report At the conclusion of the validation exercise, a validation summary report will bring together all the aspects of the validation

40 Validation summary report At the conclusion of the validation exercise, a validation summary report will bring together all the aspects of the validation and allow conclusions to be drawn regarding the suitability of the cleaning programme and overall compliance with the validation plan. Slide 40 PharmOut 2013

41 Implement the cleaning method Once all the cleaning validation is complete and approved then its time to implement the cleaning system into the production process. It is not acceptable to use a cleaning process that has not been adequately validated. Ensure implemented method is consistent with validation and has not been changed in the process. Slide 41 PharmOut 2013

42 Monitoring Once the cleaning process is validated revalidation is generally not required providing the process is appropriately managed by a change control system Review of the cleaning methods can be done during annual product reviews Routine monitoring of equipment can be done on a rotating basis Slide 42 PharmOut 2013

43 Common deficiencies Unsuitable equipment (Surface finish or poorly maintained e.g. diaphragm valves and surface of tanks) Scientifically unsound justifications for product and equipment groupings Cleaning methods does not consider critical process parameters (temperature or contact time) Cleaning methods are not followed or reflect actual validation Control and lifespan of gaskets and silicone hosing Removal of cleaning agents unvalidated Incorrect limits set Slide 43 PharmOut 2013

US FDA Process Validation Guidance. Presented by Marc Fini 21 May, 2013

US FDA Process Validation Guidance Presented by Marc Fini 21 May, 2013 Validation The risk based approach to validation must be used to determine: What to validate When to validate How to validate How