Uploaded byGuruprernaSehgal
PPT, PDF451 views

4. WHO Guidelines- Media Fill Validation.ppt

The document outlines the media fill protocol for aseptic process validation in the manufacture of sterile medicines, including key objectives such as evaluating aseptic process simulation and understanding regulatory expectations. It emphasizes critical elements like media culture, container size, and operator participation in media fill runs, highlighting the importance of stringent monitoring and evaluation protocols to minimize contamination risks. The document also discusses acceptance criteria for contamination rates and corrective actions to be taken in case of failures during the media fill process.

Embed presentation

Download to read offline
Media Fill Protocol Luisa Stoppa Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China – 16-20 November 2009
2 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Objectives of the hands-on  To evaluate the aseptic process simulation (media fill or broth fill)  To know the key points in designing a media fill protocol to meet regulatory expectations  To learn how failures have to be evaluated and which consequences they have  To discuss in a team
3 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 aseptic process: Objectives of the hands-on
4 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Principles of media fill  Why the validation of aseptic process is required by pharmaceutical regulations? A “sterile product” is defined as “free of viable organisms” As it is not practical examine every unit for confirmation of sterility, all efforts are made to minimise the risk of contamination (finishing, HVAC, pressure differentials, cleaning procedure, monitoring programme) Despite such measures, contamination is an ever-present danger because aseptic processing is a process being operated in a controlled –but not sterile- environment and sample numbers are too small; so that only gross contamination is likely to be detected
5 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Principles of media fill  Pharmaceutical regulations: - Regulations: FDA “guidance for industry, sterile drug products produced by aseptic processing – cGMP” - - EU GMP Part I annex 1 – - PIC/S PI 007-2 “recommendations on the validation of aseptic process”  Although media fills must duplicate aseptic manufacturing conditions, it is not possible for them to be conducted in exactly the same way as the manufacture of a production batch of a pharmaceutical product What medium? How many units? How long?
6 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Principles of media fill  In aseptic processing, the greatest risk comes from the personnel working in the clean room: the operators have to participate in media fills Which qualifications to the operators need and when can operators be considered qualified?  Environmental monitoring activities are required during aseptic filling operations Are there additional monitoring activities necessary or not?
7 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Principles of media fill  It is usual to include the “worst case” conditions that can occur in production runs Which kind of interventions have to be considered ?
8 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 washing machine depirogenating tunnel filling machine stoppering machine capping machine Hands-on: aseptic liquid filling line
9 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Hands-on: Media Fill Protocol  Key elements to be taken into account include: • Number and frequency of runs • Medium culture (to replace the product) • Number of units filled • Container (vial) size • Fill volume • Line speed (or filling speed) • Duration of fill • Operators shifts • Monitoring activities • Interventions –both routine and non-routine- • Incubation method • Acceptance criteria
10 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Hands-on: Media Fill Protocol
11 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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. Media fill Protocol
12 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: medium culture (1/3) The medium needs to support the growth of a wide variety of microorganisms, including aerobic bacteria, yeasts and moulds (non- selective medium). Guidance notes the use of Soybean Casein Digest Medium (SCD) also known as tryptone soya broth (TSB). If the product is being filled in anaerobic conditions, usually in a nitrogen environment, an anaerobic medium is used: fluid thioglycollate medium (FTM). Media fill Protocol
13 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: medium culture (2/3) The media have to support the growth of microorganisms (growth promotion test). The organisms to be tested are stated by pharmacopoeia (USA, EU, Japan). Moreover the use of one or two of the most common environmental isolates is recommended. 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). Media fill Protocol
14 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: medium culture (3/3) About prion contamination from component of animal origin found within media, it is important that medium supplier can provide the certification for confirming materials are sourced from “BSE-free” countries. An alternative approach would be to use medium TSB derived from vegetable materials. SDC powder is generally subjected to mycoplasmi contamination that are not removed by sterile filtration; in this case previous sterilised powder (with gamma rays) can be used. Media fill Protocol
15 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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 and adequately represents the maximum number of interventions. Some regulations suggest the number of units to be filled in consideration of batch production size. Media fill Protocol
16 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: container size (1/2) The extremes of size containers should be considered. 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 container are more fragile and less stable and be more subjected to breakage and jamming in the equipment. Media fill Protocol
17 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: container size (2/2) 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 Media fill Protocol
18 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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). Media fill Protocol
19 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: line (or filling) speed The media fill should address the range of line speeds employed during production. Sometimes more than one line speed should be evaluated. 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. In the initial validation of a filling line, one run might be performed at the lowest speed and two at the highest speed. In routine evaluation of the line, the speeds would be alternated Media fill Protocol
20 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: duration of fill Even if the most accurate model would simulate the actual production run, other models can be justified. In general media fills should be 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 Media fill Protocol
21 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: operators shifts Each operator performing aseptic processes are requested to 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 programme. 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) Media fill Protocol
22 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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 Media fill Protocol
23 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: interventions –both routine and non-routine- The interventions should simulate what occurs in a production run; media fill records should document all interventions performed and the number of units removed. Routine interventions: aseptic line set-up in which sterilised 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 breaks, gloves change, environmental monitoring. Non routine interventions (occur randomly): glass breakage, change / reset of filling needles, interventions on weight adjustments, sensor failure, rail adjustments. Media fill Protocol
24 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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. Media fill Protocol
25 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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 and PDA agree that the target should be zero contaminated units regardless of size of run It is important to note that “invalidation” of a media fill run should be a rare occurrence Each failure should be investigated Media fill Protocol
26 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: acceptance criteria Media fill Protocol Contaminated units permitted (action level) Filled units per run 0 3000 1 4750 2 6300 3 7750 4 9150 5 10510 6 11840 7 13150 8 14430 9 15710 10 16960 The table indicates the maximum permitted number of contaminated units per various Media Fill “run sizes” to indicate a 0,10% contamination limit with a 95% confidence level Health Canada
27 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination  The root cause of a failure (contamination), or at least the most probable one, must be identified  It is important to be able to isolate and identify (to species level) the microorganisms  An appropriate corrective action / preventive action plan must be implemented  The impact of the failure on product lots already released (if any) must be evaluated  After the corrective actions have been implemented, a new media fill study is performed to confirm their efficacy
28 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Contamination rate increasing during filling This could indicate a contamination originated in the liquid media path (i.e. wrong aseptic connection to the media tank, contamination in the recirculation loop). It is important to keep under aseptic conditions the media bulk tank at the end of filling, while waiting the media fill results, for verifying this hypothesis
29 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Contamination rate decreasing during filling This could be indicative of a contamination occurred during the line set-up (stopper bowl / guides, dosing pumps / needles), partially or totally “washed out” during filling.
30 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Contamination spike during filling A spike (some contaminated units in a short time interval could be linked to a not correctly performed critical intervention during filling. For this reason it is crucial to have an accurate time traceability of the filled units and the interventions performed (videotaping the filling operations can be helpful)
31 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Contamination spike followed by an increase Similar to the previous example, but in this case the wrong intervention could have affected the liquid path/loop (i.e. change of media tank, replacement of a pump / needle)
32 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Isolated events (few contaminated units per run) Unfortunately, this occurrence is the most common and also the most difficult to be investigated. If repeated on multiple runs, it could indicate that this profile is representative of the “background noise” of the process, so requiring radical actions (i.e. change of garments/dressing code, disinfectants, air flow patterns)
33 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination
34 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination
35 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Conclusion  Even if all media fills are negative in a Company, it does not necessarily indicate that no products were ever possibly contaminated because the frequency requirement of media fill testing is so minimal that it is not statistically significant  A robust media fill programme is a necessary step to validate process  Media fill testing is just one part of a necessary overall quality assurance program (HVAC qualification, cleaning procedure, sanitization, personnel training, …)
36 | Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 l.stoppa@aifa.gov.it
37 | Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Reference documents  WHO GMP guidelines – Technical Report series n. 937  EU GMP guidelines, Part I annex 1 & 15  ICH Q7A or EU GMP Part II chapter 13  FDA Guidance for Industry: sterile drug products produced by aseptic processing cGMP  PIC/S Recommendations PI 007-5  USP <797> ‘media fill testing’ / <71> ‘growth promotion test’  EP 2.6.1 ‘sterility’

More Related Content

PPTX
Media fill validation ppt (1)
byShraddhaParmar15
 
PPTX
Visual Inspection of Parentetal Drug Products in Pharmaceutical Quality testing
byKarishmaRK
 
PPTX
Tab. Auto. ppt.pptx
byDhruvi50
 
PDF
Cleaning Validation in Pharma Industry.pdf
byKiran Kota
 
PPTX
Manufacturing Documentation
bySagar K Savale
 
PPTX
Qualification Of Autoclave
by8669290285
 
PPTX
Process Validation
byANKUSH JADHAV
 
PPTX
validation of blister packaging machine
byNilesh Utpure
 
Media fill validation ppt (1)
byShraddhaParmar15
 
Visual Inspection of Parentetal Drug Products in Pharmaceutical Quality testing
byKarishmaRK
 
Tab. Auto. ppt.pptx
byDhruvi50
 
Cleaning Validation in Pharma Industry.pdf
byKiran Kota
 
Manufacturing Documentation
bySagar K Savale
 
Qualification Of Autoclave
by8669290285
 
Process Validation
byANKUSH JADHAV
 
validation of blister packaging machine
byNilesh Utpure
 

What's hot

PPTX
REGULATORY REQUIREMENTS IN ROW.pptx
byJeelJoshi8
 
PPT
Cleaning validation
bySagar K Savale
 
PPTX
Who Guidance on Process Validation for Non Serile Pharmaceuticals
byGMP EDUCATION : Not for Profit Organization
 
PPT
Cleaning validation
byShoab Malek (Certified Quality Auditor)
 
PPT
Media fill process and validation
bypaideeksha
 
PPTX
Non sterile manufacturing process technology
byPRANJAY PATIL
 
PPTX
Fda initiative on process analytical technology
byVaishaliMundhe1
 
PPT
Aseptic processing
bydeepakiitbhu
 
PPTX
Manufacturing facility of parentarals as per schedule m
byMalla Reddy College of Pharmacy
 
PPTX
Pat process analytical technique
bySalmanLatif14
 
PPTX
Ipqc tests of various dosage form
byParexel international, chandigarh, India
 
PPTX
Cleaning validation a complete know how
bySambhujyoti Das
 
PPT
STERILE PROCESS OF VALIDATION
bySagar K Savale
 
PPT
Asepting procesing
bySunil Boreddy Rx
 
PPTX
aseptic process technology
byPRANJAY PATIL
 
PPTX
Product registration procedure in USA
byGuru Balaji .S
 
PPTX
Advanced sterile product manufacturing technology
byroshankhetade2
 
PPTX
Qualification of FBD.pptx
byDhruvi50
 
PPTX
Process validation of capsules
bypritam kumbhar
 
PPTX
Qualification of Autoclave.pptx
byDhruvi50
 
REGULATORY REQUIREMENTS IN ROW.pptx
byJeelJoshi8
 
Cleaning validation
bySagar K Savale
 
Who Guidance on Process Validation for Non Serile Pharmaceuticals
byGMP EDUCATION : Not for Profit Organization
 
Cleaning validation
byShoab Malek (Certified Quality Auditor)
 
Media fill process and validation
bypaideeksha
 
Non sterile manufacturing process technology
byPRANJAY PATIL
 
Fda initiative on process analytical technology
byVaishaliMundhe1
 
Aseptic processing
bydeepakiitbhu
 
Manufacturing facility of parentarals as per schedule m
byMalla Reddy College of Pharmacy
 
Pat process analytical technique
bySalmanLatif14
 
Ipqc tests of various dosage form
byParexel international, chandigarh, India
 
Cleaning validation a complete know how
bySambhujyoti Das
 
STERILE PROCESS OF VALIDATION
bySagar K Savale
 
Asepting procesing
bySunil Boreddy Rx
 
aseptic process technology
byPRANJAY PATIL
 
Product registration procedure in USA
byGuru Balaji .S
 
Advanced sterile product manufacturing technology
byroshankhetade2
 
Qualification of FBD.pptx
byDhruvi50
 
Process validation of capsules
bypritam kumbhar
 
Qualification of Autoclave.pptx
byDhruvi50
 

Similar to 4. WHO Guidelines- Media Fill Validation.ppt

PPTX
Aseptic filling
byBUCHIRAJUVENKATASRAV
 
PPTX
Media fill validation ppt (1)
byShraddhaParmar15
 
PPTX
Aseptic Media Fill or Process simulation.
byMohan Bhaltadak
 
PPT
Media Fill Protocollllllllllllllllll.ppt
bymmonirsa
 
PPTX
Aseptic Media Fill Validation.pptx
byMansi792999
 
PPT
Aseptic processing
byShivaram
 
PDF
Best Practices on Media Fill
byTom Aspinall
 
PPT
Aseptic processing operation
bySai Datri Arige
 
PPTX
QUALITY ASSURANCE OF PHARMACEUTICAL RELATED TO PLANT DESIGN
bysiddy-07
 
PPTX
ISPE Good manufacturing practice
byCông ty Cổ phần Tư vấn Thiết kế GMP EU
 
PDF
Aseptic processing
byNarendra Edara
 
PPTX
cGMP of sterile area by faheem sb.pptx
byzohaibmaqsoodneutrop
 
PDF
mediafillvalidation-ppt1-211027092602.pdf
bylinh838802
 
PPTX
GOOD MANUFACTURING PROCESES IN FACTORY AND HOSPITAL HYGIENE
bySlientNight
 
PPT
2-1_2-2_AsepticProcessing.ppt
bybinhamid2
 
PPT
SterilisationValidationQualification_WHO.ppt
byltsang2715
 
PPTX
Aseptic Technique for sterile area .pptx
byNaeemSarwar37
 
PPTX
1. Manufacture of sterile products.pptx presentations
byHerbertNsoke
 
PDF
Ipt 17 2005_p90_92x
byEka Selvina
 
DOCX
3.L References.docx
bySamehMostafa33
 
Aseptic filling
byBUCHIRAJUVENKATASRAV
 
Media fill validation ppt (1)
byShraddhaParmar15
 
Aseptic Media Fill or Process simulation.
byMohan Bhaltadak
 
Media Fill Protocollllllllllllllllll.ppt
bymmonirsa
 
Aseptic Media Fill Validation.pptx
byMansi792999
 
Aseptic processing
byShivaram
 
Best Practices on Media Fill
byTom Aspinall
 
Aseptic processing operation
bySai Datri Arige
 
QUALITY ASSURANCE OF PHARMACEUTICAL RELATED TO PLANT DESIGN
bysiddy-07
 
ISPE Good manufacturing practice
byCông ty Cổ phần Tư vấn Thiết kế GMP EU
 
Aseptic processing
byNarendra Edara
 
cGMP of sterile area by faheem sb.pptx
byzohaibmaqsoodneutrop
 
mediafillvalidation-ppt1-211027092602.pdf
bylinh838802
 
GOOD MANUFACTURING PROCESES IN FACTORY AND HOSPITAL HYGIENE
bySlientNight
 
2-1_2-2_AsepticProcessing.ppt
bybinhamid2
 
SterilisationValidationQualification_WHO.ppt
byltsang2715
 
Aseptic Technique for sterile area .pptx
byNaeemSarwar37
 
1. Manufacture of sterile products.pptx presentations
byHerbertNsoke
 
Ipt 17 2005_p90_92x
byEka Selvina
 
3.L References.docx
bySamehMostafa33
 

Recently uploaded

PPTX
Multiple Linear Regression - Least Square Method X₁ on X₂ and X₃
bySundar B N
 
PDF
Cultivating Greatness Pune's Best Preschools and Schools.pdf
byWellington College
 
PDF
Micro Economics for class 12 and class 11
bysurajbajaj4116
 
PPTX
How to Configure Push & Pull Rule in Odoo 18 Inventory
byCeline George
 
PDF
Risk management in Moroccan public hospitals_ a literature review
byMan_Ebook
 
PPTX
Pig- piggy bank in Big Data Analytics.ppt.pptx
byVarshini M
 
PDF
The voice of the rain poem class 11th.pdf
byReeta Baral
 
PPTX
How to Manage Package Reservation in Odoo 18 Inventory
byCeline George
 
PPTX
The Cell & Cell Cycle-detailed structure and function of organelles.pptx
byAshish Umale
 
PDF
Biology Practical Class 12th 2025 PDF(2)-2-52.pdf
bySCPRPWomenCollegeChi
 
PPTX
Details of Epithelial and Connective Tissue.pptx
byAshish Umale
 
PPTX
PURPOSIVE SAMPLING IN EDUCATIONAL RESEARCH RACHITHRA RK.pptx
byssuser047b711
 
PPTX
How to Track a Link Using Odoo 18 SMS Marketing
byCeline George
 
PDF
IMANI Africa files RTI request seeking full disclosure on 2026 SIM registrati...
bynservice241
 
PDF
Using Charts and Tables in Presenting Data
byThelma Villaflores
 
PPTX
Introduction-to-Anatomy-and-Physiology.pptx
byAshish Umale
 
PPTX
3 G8_Q3_L3_ (Cartoon as Representation in Opinion Editorial Article).pptx
byNorafeSahagun
 
PPTX
Steve Hale - Developing Elite Young Goalkeepers 2024.pptx
bypjmfd
 
PPTX
Semester 6 Unit 2 Club foot (talipes).pptx
bysachin7989
 
PPTX
Growth & Development MILESTONES (ADOLESCENTS ).pptx
byAneetaSharma15
 
Multiple Linear Regression - Least Square Method X₁ on X₂ and X₃
bySundar B N
 
Cultivating Greatness Pune's Best Preschools and Schools.pdf
byWellington College
 
Micro Economics for class 12 and class 11
bysurajbajaj4116
 
How to Configure Push & Pull Rule in Odoo 18 Inventory
byCeline George
 
Risk management in Moroccan public hospitals_ a literature review
byMan_Ebook
 
Pig- piggy bank in Big Data Analytics.ppt.pptx
byVarshini M
 
The voice of the rain poem class 11th.pdf
byReeta Baral
 
How to Manage Package Reservation in Odoo 18 Inventory
byCeline George
 
The Cell & Cell Cycle-detailed structure and function of organelles.pptx
byAshish Umale
 
Biology Practical Class 12th 2025 PDF(2)-2-52.pdf
bySCPRPWomenCollegeChi
 
Details of Epithelial and Connective Tissue.pptx
byAshish Umale
 
PURPOSIVE SAMPLING IN EDUCATIONAL RESEARCH RACHITHRA RK.pptx
byssuser047b711
 
How to Track a Link Using Odoo 18 SMS Marketing
byCeline George
 
IMANI Africa files RTI request seeking full disclosure on 2026 SIM registrati...
bynservice241
 
Using Charts and Tables in Presenting Data
byThelma Villaflores
 
Introduction-to-Anatomy-and-Physiology.pptx
byAshish Umale
 
3 G8_Q3_L3_ (Cartoon as Representation in Opinion Editorial Article).pptx
byNorafeSahagun
 
Steve Hale - Developing Elite Young Goalkeepers 2024.pptx
bypjmfd
 
Semester 6 Unit 2 Club foot (talipes).pptx
bysachin7989
 
Growth & Development MILESTONES (ADOLESCENTS ).pptx
byAneetaSharma15
 

4. WHO Guidelines- Media Fill Validation.ppt

  • 1.
    Media Fill Protocol LuisaStoppa Manufacture of sterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China – 16-20 November 2009
  • 2.
    2 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Objectives of the hands-on  To evaluate the aseptic process simulation (media fill or broth fill)  To know the key points in designing a media fill protocol to meet regulatory expectations  To learn how failures have to be evaluated and which consequences they have  To discuss in a team
  • 3.
    3 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 aseptic process: Objectives of the hands-on
  • 4.
    4 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Principles of media fill  Why the validation of aseptic process is required by pharmaceutical regulations? A “sterile product” is defined as “free of viable organisms” As it is not practical examine every unit for confirmation of sterility, all efforts are made to minimise the risk of contamination (finishing, HVAC, pressure differentials, cleaning procedure, monitoring programme) Despite such measures, contamination is an ever-present danger because aseptic processing is a process being operated in a controlled –but not sterile- environment and sample numbers are too small; so that only gross contamination is likely to be detected
  • 5.
    5 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Principles of media fill  Pharmaceutical regulations: - Regulations: FDA “guidance for industry, sterile drug products produced by aseptic processing – cGMP” - - EU GMP Part I annex 1 – - PIC/S PI 007-2 “recommendations on the validation of aseptic process”  Although media fills must duplicate aseptic manufacturing conditions, it is not possible for them to be conducted in exactly the same way as the manufacture of a production batch of a pharmaceutical product What medium? How many units? How long?
  • 6.
    6 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Principles of media fill  In aseptic processing, the greatest risk comes from the personnel working in the clean room: the operators have to participate in media fills Which qualifications to the operators need and when can operators be considered qualified?  Environmental monitoring activities are required during aseptic filling operations Are there additional monitoring activities necessary or not?
  • 7.
    7 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Principles of media fill  It is usual to include the “worst case” conditions that can occur in production runs Which kind of interventions have to be considered ?
  • 8.
    8 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 washing machine depirogenating tunnel filling machine stoppering machine capping machine Hands-on: aseptic liquid filling line
  • 9.
    9 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Hands-on: Media Fill Protocol  Key elements to be taken into account include: • Number and frequency of runs • Medium culture (to replace the product) • Number of units filled • Container (vial) size • Fill volume • Line speed (or filling speed) • Duration of fill • Operators shifts • Monitoring activities • Interventions –both routine and non-routine- • Incubation method • Acceptance criteria
  • 10.
    10 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Hands-on: Media Fill Protocol
  • 11.
    11 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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. Media fill Protocol
  • 12.
    12 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: medium culture (1/3) The medium needs to support the growth of a wide variety of microorganisms, including aerobic bacteria, yeasts and moulds (non- selective medium). Guidance notes the use of Soybean Casein Digest Medium (SCD) also known as tryptone soya broth (TSB). If the product is being filled in anaerobic conditions, usually in a nitrogen environment, an anaerobic medium is used: fluid thioglycollate medium (FTM). Media fill Protocol
  • 13.
    13 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: medium culture (2/3) The media have to support the growth of microorganisms (growth promotion test). The organisms to be tested are stated by pharmacopoeia (USA, EU, Japan). Moreover the use of one or two of the most common environmental isolates is recommended. 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). Media fill Protocol
  • 14.
    14 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: medium culture (3/3) About prion contamination from component of animal origin found within media, it is important that medium supplier can provide the certification for confirming materials are sourced from “BSE-free” countries. An alternative approach would be to use medium TSB derived from vegetable materials. SDC powder is generally subjected to mycoplasmi contamination that are not removed by sterile filtration; in this case previous sterilised powder (with gamma rays) can be used. Media fill Protocol
  • 15.
    15 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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 and adequately represents the maximum number of interventions. Some regulations suggest the number of units to be filled in consideration of batch production size. Media fill Protocol
  • 16.
    16 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: container size (1/2) The extremes of size containers should be considered. 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 container are more fragile and less stable and be more subjected to breakage and jamming in the equipment. Media fill Protocol
  • 17.
    17 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: container size (2/2) 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 Media fill Protocol
  • 18.
    18 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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). Media fill Protocol
  • 19.
    19 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: line (or filling) speed The media fill should address the range of line speeds employed during production. Sometimes more than one line speed should be evaluated. 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. In the initial validation of a filling line, one run might be performed at the lowest speed and two at the highest speed. In routine evaluation of the line, the speeds would be alternated Media fill Protocol
  • 20.
    20 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: duration of fill Even if the most accurate model would simulate the actual production run, other models can be justified. In general media fills should be 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 Media fill Protocol
  • 21.
    21 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: operators shifts Each operator performing aseptic processes are requested to 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 programme. 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) Media fill Protocol
  • 22.
    22 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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 Media fill Protocol
  • 23.
    23 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: interventions –both routine and non-routine- The interventions should simulate what occurs in a production run; media fill records should document all interventions performed and the number of units removed. Routine interventions: aseptic line set-up in which sterilised 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 breaks, gloves change, environmental monitoring. Non routine interventions (occur randomly): glass breakage, change / reset of filling needles, interventions on weight adjustments, sensor failure, rail adjustments. Media fill Protocol
  • 24.
    24 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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. Media fill Protocol
  • 25.
    25 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: 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 and PDA agree that the target should be zero contaminated units regardless of size of run It is important to note that “invalidation” of a media fill run should be a rare occurrence Each failure should be investigated Media fill Protocol
  • 26.
    26 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009  Key element: acceptance criteria Media fill Protocol Contaminated units permitted (action level) Filled units per run 0 3000 1 4750 2 6300 3 7750 4 9150 5 10510 6 11840 7 13150 8 14430 9 15710 10 16960 The table indicates the maximum permitted number of contaminated units per various Media Fill “run sizes” to indicate a 0,10% contamination limit with a 95% confidence level Health Canada
  • 27.
    27 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination  The root cause of a failure (contamination), or at least the most probable one, must be identified  It is important to be able to isolate and identify (to species level) the microorganisms  An appropriate corrective action / preventive action plan must be implemented  The impact of the failure on product lots already released (if any) must be evaluated  After the corrective actions have been implemented, a new media fill study is performed to confirm their efficacy
  • 28.
    28 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Contamination rate increasing during filling This could indicate a contamination originated in the liquid media path (i.e. wrong aseptic connection to the media tank, contamination in the recirculation loop). It is important to keep under aseptic conditions the media bulk tank at the end of filling, while waiting the media fill results, for verifying this hypothesis
  • 29.
    29 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Contamination rate decreasing during filling This could be indicative of a contamination occurred during the line set-up (stopper bowl / guides, dosing pumps / needles), partially or totally “washed out” during filling.
  • 30.
    30 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Contamination spike during filling A spike (some contaminated units in a short time interval could be linked to a not correctly performed critical intervention during filling. For this reason it is crucial to have an accurate time traceability of the filled units and the interventions performed (videotaping the filling operations can be helpful)
  • 31.
    31 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Contamination spike followed by an increase Similar to the previous example, but in this case the wrong intervention could have affected the liquid path/loop (i.e. change of media tank, replacement of a pump / needle)
  • 32.
    32 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination rate Filling chronology (time or units) Contamination  Isolated events (few contaminated units per run) Unfortunately, this occurrence is the most common and also the most difficult to be investigated. If repeated on multiple runs, it could indicate that this profile is representative of the “background noise” of the process, so requiring radical actions (i.e. change of garments/dressing code, disinfectants, air flow patterns)
  • 33.
    33 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination
  • 34.
    34 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Contamination
  • 35.
    35 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Conclusion  Even if all media fills are negative in a Company, it does not necessarily indicate that no products were ever possibly contaminated because the frequency requirement of media fill testing is so minimal that it is not statistically significant  A robust media fill programme is a necessary step to validate process  Media fill testing is just one part of a necessary overall quality assurance program (HVAC qualification, cleaning procedure, sanitization, personnel training, …)
  • 36.
    36 | Workshop onWHO prequalification requirements for reproductive health medicines, Jakarta, October 2009 l.stoppa@aifa.gov.it
  • 37.
    37 | Manufacture ofsterile medicines – Advanced workshop for SFDA GMP inspectors Nanjing, the People’s Republic of China, 16-20 November 2009 Reference documents  WHO GMP guidelines – Technical Report series n. 937  EU GMP guidelines, Part I annex 1 & 15  ICH Q7A or EU GMP Part II chapter 13  FDA Guidance for Industry: sterile drug products produced by aseptic processing cGMP  PIC/S Recommendations PI 007-5  USP <797> ‘media fill testing’ / <71> ‘growth promotion test’  EP 2.6.1 ‘sterility’