Media Fill Protocol
Objectives
●To evaluate the aptic 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
conquences they have
Principles of media fill
●Why the validation of aptic 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 minimi the risk of contamination (finishing, HVAC, pressure differentials, cleaning procedure, monitoring
programme)
Despite such measures, contamination is an ever-prent danger becau aptic 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
Principles of media fill
●Pharmaceutical regulations:
同学的作文- Regulations: FDA “guidance for industry, sterile drug products produced by aptic processing –cGMP” -
- EU GMP Part I annex 1 –
- PIC/S PI 007-2 “recommendations on the validation of aptic process”
●Although media fills must duplicate aptic 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
W hat medium? How many units? How long?
Principles of media fill
●In aptic 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
aptic filling operations
劳务派遣管理制度
Are there additional monitoring activities necessary or not?
Principles of media fill
●It is usual to include the “worst ca” conditions that can
occur in production runs
Which kind of interventions have to be considered ?
washing machine
depirogenating tunnel
filling machine
stoppering machine
capping machine
Hands-on: aptic liquid filling line
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
Hands-on: Media Fill Protocol
●Key element: number and frequency of runs
In start up simulation at least three concutive parate successful runs should be performed (it is recommended they are performed in different days).
For on-going simulation, a routine mi-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 aptic process .
Media fill Protocol
●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-lective medium).
Guidance notes the u of Soybean Cain 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 ud: fluid thioglycollate medium (FTM).
Media fill Protocol
●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 u 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
●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 u medium TSB derived from vegetable materials.
Media powder is generally subjected to mycoplasma contamination that are not removed by sterile filtration; in this ca previously sterilid powder (with gamma rays) can be ud.
Media fill Protocol
●Key element: number of units filled
增强食欲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 reprents the maximum number of interventions.
Some regulations suggest the number of units to be filled in consideration of batch production size.
Media fill Protocol
●Key element: container size (1/2)
The extremes of size containers should be considered.
The largest container (often filled at the lowest speed becau of its large fill volume) often has a large opening, so the potential for
microbial entry from the environment should be the greatest for that size.
金牛和水瓶
The smallest container (often filled at the highest speed for its lower fill volume) reprents the greatest handling difficulty; the smaller containers are more fragile and less stable and more likely to break or jam in the equipment.
Media fill Protocol
●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 ud as a substitute for amber containers to allow visual detection of microbial growth
Media fill Protocol
●Key element: fill volume
The volume of media filled into the containers does not need to coincide with the routine fill volume.
The fill volume should be sufficient to contact the container-closure al 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
●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.
题都城南庄U of high line speed is justified for manufacturing process
characterid by frequent interventions or a significant degree of manual manipulation.
U of low speed is justified for manufacturing process characterid by prolonged exposure of sterile components in the aptic 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
●Key element: duration of fill
Even if the most accurate model would simulate the actual production run, other models cab 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 u 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 ud to maintain operating conditions during the simulation: this technique can be ud to validate process that may run for veral days in order to validate the full length of the longest approved campaign.
Media fill Protocol
●Key element: operators shifts
Each operator performing aptic process is requested to participate in media fill. Set-up and line operators should be part of at least 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 prent in the aptic processing room should be established.
When a firm operates on multiple shifts, the cond and third shift should be included in the media fill programme.
In ca 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
●Key element: environmental monitoring activities
Air sampling using either active and passive sampling methods should be performed during the execution of the process. S urface sampling is best performed at the end of aptic process. Also personnel should be monitored.
Microbiological monitoring (air, surfaces, personnel) and particle monitoring should be performed during media fill employing the same procedure as during normal operations.
Sometimes the number of sampling locations might be incread in respect of the routine procedure.
Media fill Protocol
●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: aptic line t-up in which sterilid parts are removed from protective materials and asmbled is a potential danger; it is common to identify the first containers filled as they may be more indicative of potential problem with aptic asmbly.
Other routine interventions: removal of fallen vials, removal of jammed stoppers, operator breaks, glove changes, environmental monitoring.
Non routine interventions (occur randomly): glass breakage, change / ret of filling needles, interventions on weight adjustments, nsor failure, rail adjustments.
Media fill Protocol
●Key element: incubation methods
Filled units should be inspected prior to incubation; any defects that compromi 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 lection of incubation conditions employed vary.
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.测量工
Media fill Protocol
●Key element: acceptance criteria
The target should be zero growth but a contamination rate less than 0.1% with 95% confidence level is acceptable.
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
●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 0.1% contamination limit with a 95%
confidence .level
Contamination
●The root cau 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 relead (if any) must be evaluated. ●After the corrective actions have been implemented, a new media fill study is performed to confirm their efficacy.
C o n t a m i n a t i o n r a t e
Filling chronology (time or units)
Contamination
●Contamination rate increasing during filling
This result could indicate the contamination originated in the liquid media path (i.e. wrong aptic connection to the media tank, contamination in the recirculation loop).
C o n t a m i n a t i o n r a t e
金菌灵胶囊
Filling chronology (time or units)
Contamination
●Contamination rate decreasing during filling
This could be indicative of a contamination occurred during the line t-up (stopper bowl / guides, dosing pumps / needles), partially or totally “washed out” during filling.
C o n t a m i n a t i o n r a t e
Filling chronology (time or units)
Contamination
●Contamination spike during filling
A spike (some contaminated units in a short time interval
could be linked to an incorrectly 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)
C o n t a m i n a t i o n r a t e
乡镇公务员面试Filling chronology (time or units)
Contamination
●Contamination spike followed by an increa
Similar to the previous example, but in this ca the wrong
intervention could have affected the liquid path/loop (i.e. change of media tank, replacement of a pump or needle).
