Media fill validation ppt (1)

media fill validation

1. Sardar Patel University, Department of Pharmaceutical science, VVN, Anand Topic: 1. Aseptic Filling: Media Fill validation 2. USFDA guideline on Process Validation- A lifecycle Approach 1

2. Content: Media Fill Validation: Introduction Why require in Pharmaceutical region Issues to carry out Media fill test When requalification is required Parameters which affects the sterility USFDA guideline on Process validation- lifecycle Approach: Introduction: Approach of Process Validation Why it is Lifecycle Approach? Is this really a new Approach? 2

3. 1. Media Fill Test (Process Simulation): 3

4. What is a media fill? A “media fill” is performance of an aseptic manufacturing procedure using a sterile microbiological growth medium in place of the drug solution whether the aseptic procedures are adequate to prevent contamination during actual drug production. Media fill validation is cGMP, FDA and ISO regulatory requirement for validation of aseptic processing. Conducted within manipulations normally performed in actual processing e.g. filling and closing operations, operational environment, processing operations, number of personnel involved etc are conducted under processing conditions that include worst case considerations. 4

5. What is the media fill designed to evaluate? Evaluate the Aseptic assembly and operation of the critical (sterile) equipment, Qualify the operators and assess their technique, and Demonstrate that environmental controls are adequate to meet the basic requirements necessary to produce a sterile drug by aseptic processing. But, Does not validate the ability of the filter to sterilize growth media. 5

6. What is the issue on media fill test? OR Elements of Aseptic process Validation (FDA Guidance-2004) 6

7. 1. Study Design: Objective: Accurately assesses the state of process control.   Approach: Incorporate contamination risk factors that occur on a production line. Closely Simulate aseptic manufacturing operations incorporating worst-case activities and conditions that provide a challenge to aseptic operations. 7

8. 2. Frequency of Media Fill: A. Initial performance qualification: Conducted for new facility, item of equipment, filling line and container design (Except for multiple sizes of the same container design) etc. For production batch sizes exceeding 3000 units, a minimum of three media fill runs should be conducted on separate days. For production batch sizes of less than 3000 units. Continue…. 8

9. 9 Production lot size Numbers of media fill runs Alert level and action required Action level and action required <500 A minimum of 10 media fill runs using the maximum lot size of the product One contaminated unit in any run. Investigate cause. Two Contaminated units in single run, or one each in two runs. Investigate cause and repeat initial qualification media fills. 500-2,999 A minimum of 3 media fill runs using the maximum lot size of the product One contaminated unit in any run. Investigate cause. Two Contaminated units in single run, or one each in two runs. Investigate cause and repeat initial qualification media fills. ≥3000 A minimum of 3 media fill runs using at least 3000 units When any of the media fill runs exceeds the alert level take action level When any of the media fill runs exceeds the action level and take action set in action level.

10. B. Periodic Performance Requalification: When filling lines have not seen used for over six months, conduct appropriate numbers of medial fill runs in the same ways as for the initial performance qualification prior to resumption of use of the filling lines. In cases of facility and equipment modification changes in personnel working in critical aseptic processing, abnormalities in environmental testing results or a product sterility test showing contaminated products, conduct appropriate numbers of media fill runs in the same way as for the initial performance qualification prior to the scheduled media fills. 10

11. 11 Production lot size Numbers of media fill runs Alert level and action required Action level and action required <500 A minimum of 3 media fill runs using the maximum lot size of the product       -- Contaminated units in single run. Investigate cause and repeat initial qualification media fill runs. 500-2,999 One media fill run using the maximum lot size of the product.       -- One Contaminated units in single run. Investigate cause and repeat initial qualification media fills. ≥3000 One media fill run using at least 3000 units When any of the media fill runs exceeds the alert level take action level When any of the media fill runs exceeds the action level and take action set in action level.

12. 3. Media Fill Procedure: Methods to validate aseptic processing of a. liquid b. powder and c. freeze-dried products are described. 12

13. Media fill procedure for liquid products: Media fill should include normal facility/equipment operations and clean-up routines. Containers, closures, parts of filling machine, trays etc. are washed and sterilized according to the standard operating procedures. Conducted under processing conditions that include “worst case” conditions e.g. correction of line stoppage, repair or replacement of filling needles/tubes, replacement of on-line filters, permitted interventions, duration and size of run, number of personnel involved etc. A predetermined volume of medium is filled into sterilized containers at a predetermined filling speed and the containers are sealed. The media are contracted contacted with all product contact surfaces in the containers by an appropriate method, and then incubated at the predetermined temperature. 13

14. Media fill procedure for Powder Drug Products: Powder selection and antimicrobial activity test: Actual products or placebo powder are used. In general, lactose monohydrate, D-mannitol, Polyethylene glycol 6000, carboxymethyl cellulose salts or media powder etc. are used as placebo powders. Prior to employing any of the powders, evaluate whether the powder has antimicrobial activity. Media powders are dissolved in water and other powders in liquid medium and the solutions are inoculated with 10 to 100 viable microorganisms of each kind for the growth promotion test. If obvious growth appears in medium incubated at the predetermined temperature for 5 days, the powder has no antimicrobial activity and is available for the media fill test. Continue… 14

15. Sterilization of powders: Dry powders are bagged in suitable containers and are subjected to radiation sterilizations. Sterility of filling powders: The powders must pass the Sterility test. However, if the sterilization is fully validated, sterility testing of the powders can be omitted. b.4. Media fill Procedures: Chose a suitable procedure from among the following procedures: Fill sterilized liquid media into containers by suitable methods, and then fill actual products or sterilized placebo powder with the powder filling machine. If sterilised powder media are used as a placebo powder, fill sterilized water instead of sterilized liquid media. Distribute liquid media into containers, and then sterilize them in an autoclave. Remove the containers to the filling area, and then fill actual products or sterilized placebo powder into the containers with the containers with the powder filling machine. 15

16. Media fill procedure for Lyophilized products: In the case of lyophilized products, it may be impossible to conduct a media fill run in the same way as used for actual processing of lyophilized products. The process of freezing and lyophilization of the solution may kill contaminant organisms and change the characteristics of the media too. The use of inert gas as a blanket gas may inhibit the growth of aerobic bacteria and fungi. Therefore, in general, the actual freezing and lyophilization process should be avoided and air used as the blanket gas. Continue… 16

17. After filling of the media into containers by the filling machine, cap the containers loosely and collect them in pre-sterilized trays. After placing the trays in the lyophilizer, close the chamber door, and conduct lyophilization according to the procedures for production operation. Hold them without freezing under weak vacuum for the predetermined time. After the vacuum process, break the vacuum, and seal the stoppers. Contact the media with all product contact surfaces in the containers by appropriate methods, and then cultivate them at the predetermined temperature. 17

18. 4. Incubation and Inspection of Media Fill Units: Leaking or damaged media fill evaluation units should be removed and recorded prior to incubation of media filled units. Incubate at 20°-25° C for 1 week, and then at 30°-35° for 1 week, or at 30°-35°C for 2 weeks. Observe the media fills units for growth of microorganism at least once between the third day and seventh day and on the last day of the test period, twice in total. 18

19. 5. Number and frequency of runs : In start-up simulation at least three consecutive separate successful runs should be performed (it is recommended they are performed in different days). For on-going simulation, a routine semi-annual qualification is recommended (one run) Extraordinary media fill should be performed after all changes to a product or line changes evaluated as a potential danger for the aseptic process. 19

20. 6. Medium Culture: The medium needs to support the growth of a wide variety of microorganisms, including aerobic bacteria, yeasts and moulds (non-selective medium). For aerobic conditions: Soybean Casein Digest Medium (SCD) also known as tryptone soya broth (TSB). For anaerobic conditions: usually in a nitrogen environment fluid thioglycolate medium (FTM). The media have to support the growth of microorganisms (growth promotion test). The organisms to be tested are stated by pharmacopoeia. Generally, at the end of incubation period, some vials (taken from the beginning, at half and at the end of the process) are inoculated with < 100 CFU and incubated for 3 days (bacteria) and 5 days (yeast and mould). 20

21. 7. Number of units filled: Number of units filled should reflect the real batch size. It is allowed to fill a lowest number of units provided that the number of units filled is sufficient to reflect the effect of potential operator fatigue adequately represents the maximum number of interventions. Some regulations suggest the number of units to be filled in consideration of batch production size.  21

22. 8. Fill Volume: The volume of media filled into the containers need not the routine fill volume. It should be sufficient to contact the container-closure seal surfaces (when the unit is inverted and swirled) and sufficient to allow visual detection of microbial growth post incubation. Smaller containers should not be over-filled as sufficient air must be available in the container headspace to support the growth of aerobic organisms (generally 25% of volume is not filled). 22

23. 9. Container size : The largest container (often filled at the lowest speed because of its large fill volume) often has the large opening, so the potential for microbial entry from the environment should be the greatest for that size. The smallest container (often filled at the highest speed for its lower fill volume) represents the greatest handling difficulty; the smaller containers are more fragile and less stable and be more subjected to breakage and jamming in the equipment. In the initial qualification two runs might be performed using the largest container and the third run using the smallest container. In routine evaluation of the line, any container should be included in the validation program Clear containers should be used as a substitute for amber containers to allow visual detection of microbial growth. 23

24. 10. Line (or filling) speed: The speed chosen for each batch during simulation should be justified. Use of high line speed is justified for manufacturing processes characterized by frequent interventions or a significant degree of manual manipulation. Use of low speed is justified for manufacturing processes characterized by prolonged exposure of sterile components in the aseptic area. 24

25. 11. Duration of fill : Long enough to include all of the required interventions and stoppage and should reflect the potential operator fatigue: a typical media fill might be at least 3-4 hours long. Ideally a media fill should use more units than are in the product being simulated (for all batches up to 5000 units). For very large batches or long campaigns, some blank units (either empty or water filled) are used to maintain operating conditions during the simulation: this technique can be used to validate processes that may run for several days in order to validate the full length of the longest approved campaign. 25

26. 12. Operators shifts: Each operator performing aseptic processes are participate in media fill. Set-up and line operators should be part of not less than one process simulation per year. Operators such as line mechanics and environmental samplers should be managed in a similar manner. A maximum number of personnel present in the aseptic processing room should be established. When a firm operates on multiple shifts, the second and third shift should be included in the media fill program. In case of manual operations (filling), each line operator should participate into all three initial validation runs and at least one run in re-validation (every six months). 26

27. 13. Environmental monitoring activities: There are regulatory and pharmacopoeia references that states the microbial conditions. Air sampling using either active and passive sampling methods should be performed during the execution of the process. Surface sampling is best performed at the end of aseptic process. Also, personnel should be monitored. Microbiological monitoring (air, surfaces, personnel) and particle monitoring should be performed during media fill employing the same procedure in force. Sometimes the number of sampling locations might be increased respect the routine procedure. 27

28. 14. Interventions : Interventions: An aseptic manipulation or activity that occurs at the critical area. 1. Routine interventions: Aseptic line set-up in which sterilized parts are removed from protective materials and installed is a potential danger; it is common to identify the first containers filled as they may be more indicative of potential problem with aseptic assembly. Other routine interventions: stoppers bowl feeding, remove fallen vials, remove jam stoppers, operators break, gloves change, environmental monitoring. 2. Non routine interventions (occur randomly): Glass breakage, change / reset of filling needles, interventions on weight adjustments, sensor failure, rail adjustments. 28

29. Grade A Intervention Rule: Make sure that machine is stopped first. Always sanitize hands thoroughly before going to grade A space. Keep as much as your body out of Cabinet. Never Lean over to top of an open vial, stopper/Cap bowl or the filling needle. Use sterile forceps to retrieve or remove unturned vials. Do not intervene to remove stoppers, vials, caps that are not interfering with processing-Clean up at the end. Sample gloves post intervention. Practice Good Aseptic technique EVERY TIME. 29

30. 15. Incubation methods : Any filled units should be inspected prior to incubation; any defects that compromise the container closure or non-integral units are rejected and documented. Divergence in industry practice: incubation is performed for 14 days at 20-35°C (+/- 2.5°C): it is performed for 7 days at 20-25°C and further 7 days at 30-35°C; it is performed for 7 days at 30-35°C and then move the filled containers to 20-25°C The lack of agreement suggest that the selection of incubation conditions employed. Units are incubated in an inverted position for the first half of the incubation period and then returned to an upright position for the remainder. 30

31. Some Important terms: Alert Level: An established microbial or airborne particle level giving early warning of potential drift from normal operating conditions and triggers appropriate scrutiny and follow-up to address the potential problem. Alert levels are always lower than action levels. Action Level: An established microbial or airborne particle level that, when exceeded, should trigger appropriate investigation and corrective action based on the investigation. 31

32. 16. Acceptance criteria : The target should be zero growth but a contamination rate less than 0.10% with 95% confidence level is acceptable (approx. 1 contaminated unit in 5000 filled units). FDA agree that the target should be zero contaminated units regardless of size of run. The alert level is more than 0.05% but less than 0.1% and the action level is more than 0.1% contamination rate at the upper 95% confidence level. 32

33.   Alert and action levels for large numbers of media fills units: Units*: It is necessary to relate the number of units with lot size of actual products. Number of units* Number of contaminated units Acceptance level Alert Level Action Level 3,000 Not applicable ≥1 4,750 1 ≥2 6,300 1-2 ≥3 7,760 1-3 ≥4 9,160 1-4 ≥5 10,520 1 2-5 ≥6 11,850 1 2-6 ≥7 13,150 1-2 3-7 ≥8 14,440 1-2 3-8 ≥9 15,710 1-3 4-9 ≥10 16,970 1-3 4-10 ≥11 33

34. Contamination Rate: By using 95% confidence limit(U), The contamination rate(P) of observed numbers of contaminated units(k) per filled units(n) can be calculated as For example, If 5000 units were filled and two contaminated units were observed So, n=5000 U=6.30 P= P= =0.0013 So, upper 95% confidence limit for the contamination rate should be 0.13%.     34 P=

35. When Requalification is required? When result of media fill run is less than the alert level, the media fill run meets the requirement of the MFT. When the result of the media fill run exceeds the alert level, an investigation regarding the cause is required, and one more media fill run is to be done. If the result is less than the alert level, the media fill run meets the requirement of the MFT. When result of medial fill run exceeds action level, a prompt review of all appropriate records relating to aseptic production between the current media fill and the last successful one, and an investigation regarding the cause must be conducted simultaneously. If necessary, appropriate action to sequester stored and/or distributed products should be taken. After investigation regarding the cause, repeat three serial media fill runs. If the results are less than the alert level, the media fill runs meet the requirement of the MFT. 35

36. Parameter which affect the Sterility : 36

37. 37

38. Data guidance for media fills: Each media fill runs should be fully documented and the following information recorded: Date and time of media fill Identification of filling room and filling line used Container/closure type and size Volume filled per container Filling speed Filter lot and catalogue number Type of media filled Number of units filled Continue…… 38

39. Number of units not incubated and reason Number of units incubated Number of units positive Incubation time and temperature Procedures used to simulate any step of a normal production fill Microbiological monitoring data obtained during the media fill set-up and run List of personnel who took part in the media fill Growth promotion results of the media Characterization of the microorganisms from any positive units Review 39

40. 2. USFDA guideline on Process Validation-Lifecycle Approach:   40

41. Introduction: Validation of manufacturing processes is a requirement of the Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals (21 CFR 211.100 and 211.110) and is considered as an enforceable element of Current Good Manufacturing Practice for active pharmaceutical ingredients (APIs) under the broader statutory CGMP provisions of section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act.   Process validation involves a series of activities taking place over the lifecycle of the product and process.”     41

42. Definition of Process Validation: Stated in the 2011 guidance is as follows: “Process validation is defined as the collection and evaluation of data, from the process design stage throughout production, which establishes scientific evidence that a process is capable of consistently delivering quality product” 1987 Definition : “Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality characteristics”   42

43. Approach to Process Validation: Stage 1: Process Design: The marketable manufacturing process is defined during this stage based on knowledge gained through development and scale-up activities. Stage 2: Process Qualification: Throughout this stage, the method design is estimated to determine if the process is capable of reproducible marketable business. Stage 3: Continued Process Verification: Constant assertion is gained during routine production that the process remains in a state of control. 43

44. Stage1: Process Design : - Constructing and Apprehending Process Knowledge and Understanding: The functionality and limits of commercial manufacturing equipment should be considered in the process design. Design of experiments (DOE) studies can help to develop process knowledge by revealing relationships, including multivariate interactions, between the variable inputs and the resulting outputs. 44

45. Stage 2: Process Qualification : - Element (1): Design of a facility and qualification of utilities and equipment Ensure qualification of facility, utilities and equipment is completed & documented prior to initiate process qualification. Element (2): Process Performance Qualification (PPQ) The PPQ combines the actual facility, utilities, equipment’s and the trained personnel with the commercial manufacturing controls. A company must successfully complete PPQ before commencing commercial distribution of the drug product. Continue……. 45

46. Strongly recommend firms employ objective measure (e.g. Statistical Metrics) wherever feasible and meaningful to achieve adequate assurance. The increased level of inspection, testing, and sampling should continue through the process verification stage as correct, to establish levels and occurrence of routine sampling and checking for the particular product and process. Considerations for the duration of the intensified sampling & checking period could include (not limited to): Volume of production Process Complexity Level of process understanding Experience with similar products and process. 46

47. PPQ Protocol: A written protocol that specifies the manufacturing conditions, controls, testing, and expected outcomes is essential for this stage of process validation. Protocol discuss the following elements: The manufacturing conditions, including operating parameters, processing limits, and component (raw material) inputs. The data to be collected and when and how it will be evaluated. Tests to be performed (in-process, release, characterization) and acceptance criteria for each significant processing step. 47

48. The sampling plan, including sampling points, number of samples, and the frequency of sampling for each unit operation and attribute. The number of samples should be adequate to provide sufficient statistical confidence of quality both within a batch and between batches. The confidence level selected can be based on risk analysis as it relates to the particular attribute under examination. Sampling during this stage should be more extensive than is typical during routine production. 48

49. Criteria and process performance indicators that allow for a science- and risk-based decision about the ability of the process to consistently produce quality products. The criteria should include: A description of the statistical methods to be used in analyzing all collected data (e.g., statistical metrics defining both intra-batch and inter-batch variability). 2. Provision for addressing deviations from expected conditions and handling of nonconforming data. Data should not be excluded from further consideration in terms of PPQ without a documented, science-based justification. 49

50. Design of facilities and the qualification of utilities and equipment, personnel training and qualification, and verification of material sources (components and container/closures), if not previously accomplished. Status of the validation of analytical methods used in measuring the process, in-process materials, and the product. Review and approval of the protocol by appropriate departments and the quality unit. 50

51. PPQ Report: To state a clear conclusion as to whether the data indicates the process meets the conditions established in the protocol. If not the report should state what should be accomplished before such a conclusion can be reached. This conclusion should be based on entire compilation of knowledge and information gained from the design stage through the PPQ stage. 51

52. Stage 3: Continued Process Verification: - To confirm that “the process remains in a state of control during commercial manufacture.” An ongoing process to collect and analyse product and process data that relate to product quality must be established. The results obtained should be statistically trended and reviewed by trained personnel. Recommend that a person with suitable training in statistical process control techniques develop the data collection plan and statistical methods. Good process design and development should anticipate significant sources of variability and establish appropriate detection, control and or qualification schemes, as well as suitable alert and action limits. 52

53. Study of intra-batch as well as inter-batch variation is part of a comprehensive continued process verification program. Deviation can be detected by the timely assessment of Defect complaints, OOS findings, Process deviation report, Process yield variations, Batch record & reports Manufacture line operatives and quality unit staff should be encouraged to provide feedback on process performance. 53

54. Quality unit meet periodically with production staff to evaluate data, discuss possible trends and coordinate any correction or follow-up actions by product. Data collected during this stage might recommend ways to improve and/or optimize the process by altering some aspect of the process or product, such as the operating conditions, process controls, etc. Well justified rationale for the change, implementation plan, quality unit approval before implementation.   54

55. Documentation: Documentation at each stage of the process validation lifecycle is essential for effective statement in difficult, lengthy, and multidisciplinary projects. Documents is important so that knowledge gained about a product and process is accessible and comprehensible to others involved in each stage of the lifecycle. The degree and type of records required by CGMP vary during the validation lifecycle. Records requirements are greatest during Stage 2, process requirement, and Stage 3, continued process confirmation. Studies during these stages must conform to CGMPs and must be approved by the quality unit in accordance with the regulations. 55

56. WHY THE LIFECYCLE APPROACH? For manufacturing processes to be truly validated, each of the stages must be addressed and integrated. This integration of development work, process conformance, and continuing verification provides assurance that the product or process will consistently remain in control throughout the entire product lifecycle. Process validation must not be considered a one-time event or a focused one-time task performed just prior to commercial launch that emphasizes only the manufacture of three conformance lots. Acceptable manufacture of three conformance batches must not be interpreted as completion of validation. 56

57. These lots cannot truly represent the future manufacturing process with unexpected and unpredictable changes. Conformance lots are often inadvertently biased (i.e., they may utilize well-characterized and controlled API and excipients, be manufactured under well controlled conditions, be monitored by expert individuals, and performed by most experienced or well-trained personnel—all “best-case” conditions). It is highly unrealistic to contend that the manufacture of three conformance lots under “best-case” conditions conclusively predicts successful manufacturing over the product lifetime. True process validation must be a process that is never completed and is always ongoing. 57

58. Positive Aspects Of Life Cycle Approach: New life cycle validation model is a science and risk based approach and consistent with the “Quality by Design” approach that is articulated in ICH guidelines Q-8, Q-9, Q-10 & Q11, positive aspects of the new approach are as follows: Robust process validation approach will lead to consistent and reliable quality of product. Reduction in cost of quality, time and energy. Ongoing statistical evaluation of data will detect the trending at early stage to avoid potential failures at later stages. 58

59. 4. Right first time solutions can be offered in avoiding reduction in rejections/recycles. 5. Continuous improvement overtime rather than incidental based such as failures/OOS. 6. Increased into the machine efficiency in enhancing the productivity outlet. 7. Implementation of real time release testing in lieu of end product testing based on statistical evaluation. 8. Relief in drug application approval process and reduction/fast approval in post approval changes. 59

60. Conclusion : By doing validation as per USFDA process validation guideline, product and process understanding will be improved and also reduction in waste, rejections, lead time and any other failures. This guideline also helps for continual improvement of validation process through the product life cycle. 60

61.  References: R. A. Nash and A. H. Wachter “Pharmaceutical Process validation”; Third edition Agallo James, Carleton J. Fredric “Validation of Pharmaceutical Processes”; Third edition USP <797> ‘media fill testing’ / <71> ‘growth promotion test’ FDA “guidance for industry, sterile drug products produced by aseptic processing – cGMP” 6. PIC/S PI 007-2 “recommendations on the validation of aseptic process on 28/02/2020 https://www.fda.gov/media/81974/download on dated 07/02/2020 FDA (CDER and CBER), Process Validation: General Principles and Practices, Current Good Manufacturing Practices (CGMP), Revision 1,January 2011. 61