MediaFill WHO

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Media Fill Protocol

Luisa Stoppa

Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, the Peoples Republic of China 16-20 November 2009


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2 |Manufacture of sterile medicines Advanced workshop for SFDA GMP inspectors

Nanjing, the Peoples Republic of China, 16-20 November 2009

Objectives of the hands-on

To evaluate the aseptic process simulation (media fill orbroth 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


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aseptic process:

Objectives of the hands-on


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Principles of media fill

Why the validation of aseptic process is required by pharmaceuticalregulations?

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, monitoringprogramme)

Despite such measures, contamination is an ever-present dangerbecause aseptic processing is a process being operated in a

controlledbut not sterile- environment and sample numbers aretoo small; so that only gross contamination is likely to be detected


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Pharmaceutical regulations:- Regulations: FDA guidance for industry, sterile drug products

produced by aseptic processingcGMP-

- EU GMP Part I annex 1

- PIC/S PI 007-2 recommendations on the validation of aseptic

process

Although media fills must duplicate aseptic manufacturingconditions, it is not possible for them to be conducted in exactly thesame way as the manufacture of a production batch of apharmaceutical product

What medium? How many units? How long?


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In aseptic processing, the greatest risk comes from thepersonnel working in the clean room: the operators haveto participate in media fills

Which qualifications to the operators need and when can

operators be considered qualified?

Environmental monitoring activities are required duringaseptic filling operations

Are there additional monitoring activities necessary or not?


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It is usual to include the worst case conditions that canoccur in production runs

Which kind of interventions have to be considered ?


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washing machine

depirogenating tunnelfilling machine

stoppering machinecapping machine

Hands-on: aseptic liquid filling line


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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

Interventionsboth routine and non-routine-

Incubation method

Acceptance criteria


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Hands-on: Media Fill Protocol


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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 isrecommended (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


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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


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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. Generallyat 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


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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


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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


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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 thatsize.

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


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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 programClear containers should be used as a substitute for amber containers

to allow visual detection of microbial growth

Media fill Protocol


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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 visualdetection 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


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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 processescharacterized 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


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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 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 lengthof the longest approved campaign

Media fill Protocol


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Key element: operators shiftsEach 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 participateinto all three initial validation runs and at least one run in re-validation

(every six months)

Media fill Protocol


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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 respectthe routine procedure

Media fill Protocol


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Key element: interventionsboth 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 thefirst 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


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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 20-35C (+/- 2,5C): it is performed for 7 days at 20-25C and further 7

days at 30-35C; it is performed for 7 days at 30-35C and then move the

filled containers to 20-25C

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


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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 unitsregardless 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


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Key element: acceptance criteria

Media fill Protocol

Contaminated units permitted

(action level)

Filled units per

run

03000

14750

26300

37750

49150

510510

611840

713150

814430915710

1016960

The table indicates the

maximum permitted

number of contaminated

units per various Media Fillrun sizes to indicate a

0,10% contamination limit

with a 95% confidence

level

Health Canada


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Contamination

The root cause of a failure (contamination), or at least the mostprobable 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 beimplemented

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


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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 mediatank, 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


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Contamination

rate


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.


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Contamination

rate


Contamination

Contamination spike during filling

A spike (some contaminated

units in a short time interval

could be linked to a not correctly

performed critical interventionduring 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)


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Contamination

rate


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. changeof media tank, replacement of a

pump / needle)


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Contamination

rate


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, itcould 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)


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Contamination


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Contamination


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Conclusion

Even if all media fills are negative in a Company, it does notnecessarily 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, )


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36 |Workshop on WHO prequalification requirements for reproductive health medicines,

Jakarta, October 2009

[email protected]


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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 byaseptic processing cGMP

PIC/S Recommendations PI 007-5

USP media fill testing / growth promotion test

EP 2.6.1 sterility

Documents

MediaFill WHO