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SOP On Process Simulation by Media Fill study 0

BY PHARMACEUTICAL GUIDANACE ON AUGUST 24, 2016 PRODUCTION, SOP

Objective:
To lay down a guideline for Designing, Planning, Executing, Reviewing of results,
investigating the failures and approving aseptic media fill study.
Scope:
This SOP applies to Sterile Powder Injectable section of pharmaceutical plant.
Responsibilities:
Microbiology Laboratory
Microbiology Department has overall responsibility of conducting, supervising the
aseptic media fill. FACEBOOK

Responsible for environmental and personnel monitoring during aseptic media fill.
Responsible for inspecting media filled units, in order to detect probable
contamination, and investigating to find the root cause of the contamination if any.
Quality Assurance
QA department shall schedule media fill according to validation planner in
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coordination with the other departments.
Shall prepare Protocol & BMR in line with this SOP.
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Shall review and prepare final report upon completion of the Aseptic Media Fill activity.
Investigates to find out root causes, in-case media fill results are beyond the
acceptance criteria.
Manufacturing:
Production department shall execute the aseptic media fill as per the schedule. Confocal
Identifying and executing the interventions.
Manufacturing shall schedule involvement of operating personnel and department
Microscope
personnel for each media fill, in order to assure that all personnel involved in aseptic Capturing cell images quickly,
area operations participates at least once a year in aseptic media fill. easily, and not in the
Warehouse darkroom!
The warehouse shall maintain the required inventory of primary packaging
components, and nutrient media required by the media fill program in coordination
with Production, QA and microbiology department.
Accountability:
Head Q.A, Head Microbiology and Head Production are accountable for planning,
implementation and compliance of aseptic media fill with this SOP. FIND US ON GOOGLE PLUS

Abbreviations and Definitions

SCD : Soyabean Casein Digest
NLT : Not Less than

Procedure:
To ensure the sterility of products purporting to be sterile, sterilization, aseptic filling
and closing operations must be adequately validated.
The goal of even the most effective sterilization processes can be defeated if the sterilized elements of a
product (the drug formulation, the container, and the closure) are brought together under conditions that
contaminate any of those elements. Hence aseptic media fill is required to simulate actual and worst
case conditions to ensure the products produced by aseptic processing remains sterile.
This process simulation, also known as aseptic media fill, normally includes exposing the
microbiological growth medium to product contact surfaces of equipment, container closure
systems, critical environments, and process manipulations to closely simulate the same exposure
that the product itself will undergo. In case of aseptic process simulations for sterile powders,
filling of liquid nutrient media into the vials along with powder is an additional activity. Pharmaceutical Guidance
An aseptic processing operation shall be validated using a microbiological growth medium in place
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of actual product.
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In case of sterile powder Injectables the powder filling operation shall be simulated using
microbiologically inert or growth promoting material (Ex: Sterile Mannitol/ sterile Lactose) and a liquid
nutrient media (Ex: 3% sterile Soyabean casein digest medium in water for injection) to support growth of
microorganisms. However a justification for the use of these media shall be addressed in the protocol.
In place of routinely used sterile Nitrogen or Carbon dioxide (for specific products) flushing sterile
filtered compressed air shall be used.
In order to achieve a confidence in the aseptic process designed, simulation of the total
process shall be carried out using all the equipment routinely used in the production
excepting the product.
The process simulation test should imitate as closely as possible the routine aseptic
manufacturing steps except where the activity may lead to any potential microbial
contamination.
The production process should be accurately simulated using media and conditions that
optimize detection of any microbiological contamination.
The sealed containers filled with the nutrient medium are then incubated to detect microbial
contamination.
Results are then interpreted to assess the potential for a unit of drug product to become
contaminated during actual operations (e.g., start-up, sterile ingredient additions, and aseptic
connections, filling, and closing).
Environmental monitoring data from the process simulation shall also be collected in order to get
useful information for the processing line evaluation and failure investigation if any.
Considerations for Planning and Execution Of Aseptic Media Fills
The following are some considerations for planning and execution of the media fill
All the calibrations and Validations carried out shall be reviewed for the completeness in
order to ensure that the equipment, systems and support systems are performing
satisfactorily.
The following material shall be made available before planning executing media fill studies.
Sterile Mannitol: Gamma irradiated (Sterilized) Mannitol shall be procured from
approved vendors. This material shall be packed in trilaminated pouches and shall be
fixed with gamma irradiation indicators. A sample pouch shall also accompany each
pack for sterility testing before use.
Required quantity of SCD media powder shall procured based on the vial size i.e. the
fill volume to be filled in each vial.
Required quantity of Glass vials which are used in routine production shall be selected.
Quantity shall be as per the batch size planned for aseptic media fill.
Rubber stoppers of both Non-RFS and RFS shall be simulated in the aseptic media fill,
as both the processes are different. Both 20mm and 32mm shall be used in the media
fill depending on the size of the neck of the bottle.
Aluminum seals of any color may be used. However both sterile and non-sterile seals
shall be simulated during the aseptic media fill.
Other considerations
Other material like disinfectants shall be the ones used in routine practice.
Required routine utilities and specific to media fill (Ex: compressed air connection)
shall be ensured before start up.
GPT shall be done to arrive appropriate concentration of Mannitol in 3% SCDM.
Area Preparation, Component preparation, Sterilizations, Transfer and Holding of the
sterilized material before use, Environmental monitoring, Personnel monitoring shall
 be in line with routine practices. Sterilized equipment parts and accessories may be
stored for longest holding period possible after sterilization.
Preparation of Liquid nutrient media: shall be done in the presence of microbiologist.
Filling machine set up; Sampling during filling shall be in-line with the designed BMR.
Filling activity and Interventions shall follow instruction of BMR
Collection and marking of vials shall approximately indicate the interventions
conducted at that time. Record in BMR and crate label in which vials are collected.
Filled vials shall be inspected, after gentle swirling of vials to dissolve the solid
material, by microbiologists. Do not shake the vials for dissolving the contents.
All the vials shall be accounted and reconciled.
Study Design
A media fill program should incorporate the contamination risk factors that occur on a
production line, in order to assess the state of process control.
Media fill studies should closely simulate aseptic manufacturing operations
incorporating, as appropriate, worst-case activities and conditions that provide a
challenge to aseptic operations.
Media fill program shall address the following issues:
Identify the factors associated with the longest permitted run on the processing line that can
pose contamination risk (e.g., operator fatigue)
Identify representative number, type, and complexity of normal interventions that occur with
each run, as well as non-routine interventions and events (e.g., maintenance, stoppages,
equipment adjustments)
Aseptic assembly of equipment (e.g., at start-up, during processing)
During processing adjustments of the equipment assembly like removal and replacement of filling wheel
pistons, adjustment of alignment of other components shall be considered.
To assess contamination risks during initial aseptic setup (before fill), valuable information can be
obtained by incubating all such units that may be normally removed. These units are typically incubated
separately, and would not necessarily be included in the acceptance criteria for the media fill.
Number of personnel and their activities.
Identify number of personnel involves in the routine aseptic operations and assume the possibility of
maximum number of persons at a time in the aseptic area for different activities/ reasons and simulate
this worst case condition in the media fill.
All personnel who are authorized to enter the aseptic processing room during manufacturing, including
technicians and maintenance personnel, should participate in a media fill at least once a year.
Participation should be consistent with the nature of each operators duties during routine production.
The personnel includes
Machine operators.
Helpers supporting the aseptic operations in the aseptic area.
Production supervisory staff.
IPQA personnel.
Maintenance personnel.
Any other senior personnel who are required to enter the areas less frequently. For example All
department Head, senior department staff who are required to enter aseptic areas when occasion
demands.
Activities and interventions representative of each shift, and shift changeover, should be
incorporated into the design of the semi-annual qualification program.
Example: Movement of personnel into and out of the aseptic processing and gowning change rooms
during a shift change. Change of the total set of operators at the end of shift shall be considered at least
in one day media fill runs. Men exit and entry during Breakfast/ lunch/ tea breaks shall be considered.
Gowning changes may be done deliberately.
Written procedures regarding aseptic interventions should be clear and specific (e.g., intervention
type; quantity of units removed), providing for consistent production practices and assessment of
these practices during media fills
If a production procedure requires removal of 10 units after an intervention at the stoppering
station infeed, batch records (i.e., for production and media fills) should clearly document
conformance with this procedure. In case of no units are removed during a media fill intervention
than would be cleared during a production run.
Identify representative number of aseptic additions like charging of closures as well as sterile material
and transfer materials.
Shift changes, breaks, and gowning changes. Type of aseptic equipment disconnections / connections.
Ex: Connection of canister to filling machine.
Aseptic sample collections.
Collection of vials, stoppers, and filled vials for in-process checks shall be considered at different
intervals.
Line speed and configuration.
The aseptic media fill for sterile powder filling activity needs simulation of powder filling along with some
liquid nutrient media to support growth of microorganisms. As the liquid filling assembly is not a
permanent set-up with the filling machine, the speed of this may be a constraint. Further the speed of
liquid filling needs to be controlled to avoid flying of powder, during liquid dispensing into vial on-line, and
escaping into the aseptic area to avoid contamination issues.
Weight checks: Collection of vials for in-process weight checks shall be at regular intervals similar
to routine production.
Container closure systems (e.g., sizes, type, compatibility with equipment).
The following vials used and expected to be used in routine commercial production, are considered for
simulation during Aseptic Media Fill, and may be matrixed as required to rotate all the vials in use at least
in one year.
Rubber stoppers in RFS bags and 20mm rubber stoppers in Non-RFS (which are washed and siliconised)
are considered for simulation.
Ruber with plastic PP disc (both gamma radiation sterilized and non-sterile) are considered for simulation
during aseptic media fill.
Designing of Batch Record.
The documentation of production conditions and simulated activities during the each aseptic
media fill run shall be recorded in the form of batch record.
Similar formats of Batch Manufacturing Record shall be used to record media fill runs in-line with
routine production runs.
The firms rationale for the conditions and activities simulated during the media fill should be
clearly defined.
It is very important to understand that the aseptic media fills should not be used to justify practices
that pose unnecessary contamination risks.
Specific provisions in written procedures relating to aseptic processing (e.g., conditions permitted
before line clearance etc.,)
Table showing vials under use or proposed for commercial production:

Vial Manufacturer Body Height Neck Neck Overflow Empty

description OD (mm) ID OD volume Vial
(mm) (mm) (mm) (ml) weight
(g)

10ml
moulded

10 ml
TUBULAR

15ml
moulded

15ml
TUBULAR

20ml
tubular

50ml
moulded

100ml
moulded

Frequency and Number of Runs

 For initial processing line qualification, individual media fills should be repeated enough
times to ensure that results are consistent and meaningful. US FDA recommends, at least
three consecutive separate successful runs be performed during initial line qualification.
During initial qualification study, each vial proposed to be used in routine production activity shall
be subjected to process simulation study for three consecutive days.
This approach is important because a single run can be inconclusive, while multiple runs
with divergent results signal a process that is not in control.
Semi-annual qualification (every six months) shall be conducted for each processing line to
assure the state of control of the aseptic process.
Semi-annual qualification shall be conducted at least for three consecutive days. If there are
more number of vial types, Matrixing approach may be used by verifying the equivalency of
the vials by size and neck/ mouth diameter. However all the vials under routine production
shall be rotated at least once a year.
Duration of Runs:
The duration of aseptic processing operations is a major consideration in media fill design.
The duration of the media fill run shall be determined by the time it takes to incorporate
manipulations and interventions, as well as appropriate consideration of the duration of the
actual aseptic processing operation.
Interventions that commonly occur should be routinely simulated, while those occurring
rarely can be simulated periodically.
The duration of the process simulation should generally be not less than the length of the
actual manufacturing process to best simulate contamination risks posed by operators.
However at least on one of the three days media fill activity 16hours operation shall be
carried out.
Size of Runs
The simulation run sizes should be adequate to mimic commercial production conditions
and accurately assess the potential for commercial batch contamination.
A generally acceptable run size is in the range of 5,000 to 10,000 units. As batches are
produced over extended shift to fill units over 100,000 vials. Based on these factors the
following batch sizes are proposed to adequately address conditions and any potential risks
associated with the production batches.
Each day fill size should be 20,000 vials in case of 10ml to 20ml and 10000 vials in case of 50ml to
100ml vials.
In case of introducing a new vial a full day run may be considered appropriate, using above
mentioned run sizes.
Line Speed
The aseptic media fill for sterile powder filling activity needs simulation of powder
filling along with some liquid nutrient media to support growth of microorganisms. As
the liquid filling assembly is not a permanent set-up with the filling machine, the speed
of this may be a constraint. Further the speed of liquid filling needs to be controlled to
avoid flying of powder, during liquid dispensing into vial on-line, and escaping into the
aseptic area to avoid contamination issues.
In this case of sterile powders use of slow line speed will be appropriate for evaluating
manufacturing processes with prolonged exposure of the containers and closures in
the aseptic area.
Collection of filled vials
All the media filled vials shall be collected on hourly basis to identify the interventions
conducted at that particular time interval.
Each crate of vials shall be identified with date and time of collection which is
approximately equal to the filling time.
Other details like B. Number or Run Number, Batch/ run size, Date of fill, time of fill,
Crate number shall be recorded on the status label.
Environmental Conditions
Media fills should be adequately representative of the conditions under which actual
manufacturing operations are conducted.
To the extent standard operating procedures permit stressful conditions (e.g.,
maximum number of personnel present and elevated activity level); it is important that
media fills include related challenges to support the validity of these studies.
 Stressful conditions do not include artificially created environmental extremes, such
as reconfiguration of HVAC systems to operate at worst-case limits.
Media
The criteria for the selection of growth medium include: low selectivity, clarity, medium
concentration and filterability. In general, a microbiological growth medium, such as
soybean casein digest medium, shall be used.
Low Selectivity: The medium selected should be capable of supporting a wide range of
microorganisms, which might reasonably be encountered and be based also on the in
house flora (e.g. isolates from monitoring etc.).
Media used in the evaluation must pass a growth promotion test. The control
organisms used should include those relevant strains of test micro-organisms
identified by relevant Pharmacopoeias (growth of gram-positive and gram-negative
bacteria, and yeast and mold Ex: USP indicator organisms) as being suitable for use in
the growth promotion test. The QC laboratory should determine if USP indicator
organisms sufficiently represent production-related isolates.
Growth promotion tests should demonstrate that the medium supports recovery and
growth of low numbers of microorganisms, i.e. 10-100 CFU/unit or less.
Growth promotion testing of the media used in simulation studies should be carried
out on completion of the incubation period to demonstrate the ability of the media to
sustain growth if contamination is present. Growth should be demonstrated within 5
days at the same incubation temperature as used during the simulation test
performance.
If the growth promotion testing fails, the origin of any contamination found during the
simulation should nonetheless be investigated and the media fill promptly repeated.
Clarity: The medium should be clear to allow for ease in observing turbidity.
Medium Concentration: Recommendations of the supplier should be followed unless
alternative concentrations are validated to deliver equal results.
Each unit should be filled with an appropriate quantity and type of microbial growth
medium to contact the inner container closure surfaces (when the unit is inverted or
thoroughly swirled) and permit visual detection of microbial growth. The following
shall be considered.
Sterile Mannitol powder to simulate powder filling process and Soyabean Casein Digest
Medium having 3% concentration shall be used to support growth of microorganisms.
Find out quantity liquid nutrient media required to be more than half of the volume of each
size of vial under up-right and inverted conditions.
Quantity of the solid media to be dispensed in each vial shall be based on the concentration
in the liquid derived from the above volume. This concentration shall be finalized by
Microbiology department after verifying growth promotion testing at each concentration to
find out ideal concentration of powder which does not affect the growth of the
microorganisms.
Note: The medium should be handled properly and is promptly followed by the cleaning, sanitizing, and,
where necessary, sterilization of equipment, so that subsequently processed products are not
compromised.
Incubation and Examination of Media-Filled Units
Incubation conditions and duration
Media units should be incubated under conditions adequate to detect microorganisms that might
otherwise be difficult to culture. Incubation conditions should be established in accord with the
following general guidelines:
Two Incubation temperatures (22.52.50C and 52.50C) are selected to have suitable for recovery
of bioburden and environmental isolates.
Two different rooms with the above said temperatures are identified for this incubation purpose
and the filled vials shall be incubated. After incubation at 22.52.50C media filled vials shall be
transferred to another room with 32.52.50C temperature condition.
Total incubation time should not be less than 14 days. As two temperatures are used for the
incubation of the media filled units, the units should be incubated for at least 7 days at each
temperature (starting with the lower temperature).
First seven days the vials shall be incubated in Up-right position and the next seven days the vials
shall be incubated in inverted position.
 Microbiological Support:
Following incubation and inspection the Microbiologist shall withdraw a specified number of sterile
filled units. The media in these units shall be tested for its ability to support growth of a small
inoculum (10-100 cf) of each of an array of challenge microorganisms (Growth Promotion Test
GPT).
The array of challenge microorganisms used for the GPT shall include all of those microorganisms
specified in the pharmacopoeias to be used for SCDM when used in the Test for Sterility plus
representative of locally isolated microorganisms.
Each challenge microorganism shall be tested for GPT against two uncontaminated filled
containers.
Following incubation and inspection the Microbiological Quality function shall withdraw a specified
number of sterile filled units and perform the Container Clouse Test by Microbiological Method.
Inspection of media filled vials
Each media-filled unit should be examined for contamination by microbiologists who have
appropriate training, and experience in inspecting media fill units for microbiological
contamination.
All suspect units identified during the examination should be brought to the immediate attention of
the Head-QC. If required visual detection of doubtful units may be done by using magnifying glass.
Ensure gentle swirling of all the vials immediately after filling, in order to dissolve the Mannitol in
SCDM.
Perform final product inspection of units immediately following the media fill run, all integral units
should proceed to incubation. Units found to have defects not related to integrity (e.g., cosmetic
defect) should be incubated; units that lack integrity should be rejected. Erroneously rejected units
if any should be returned promptly for incubation with the media fill lot.
During incubation period, any unit found to be damaged should be included in the data for the
media fill run. Any decision to exclude such incubated units (i.e., non-integral) from the final run
tally should be fully justified and the deviation explained in the media fill report.
If a correlation emerges between difficult to detect damage and microbial contamination, a
thorough investigation should be conducted to determine its cause.
Appropriate criteria should be established for yield and accountability (reconciliation of filled units).
Media fill record reconciliation documentation should include a full accounting and description of
units rejected from a batch.
Interpretation of Test Results
The process simulation run should be conducted under the supervision of the
Microbiologists.
Contaminated units should be reconcilable with the approximate time and the activity being simulated
during the media fill. (Total units incubated/total number of units filled)
Video recording of a media fill shall be used as a useful aid in identifying personnel practices that
could negatively affect the aseptic process.
Any contaminated unit should be considered objectionable and investigated. The microorganisms
should be identified to species level. The investigation should survey the possible causes of
contamination. In addition, any failure investigation should assess the impact on commercial drugs
produced on the line since the last media fill.
Whenever contamination exists in a media fill run, it should be considered indicative of a potential
sterility assurance problem, regardless of run size. The number of contaminated units should not
be expected to increase in a directly proportional manner with the number of vials in the media fill
run.
Test results should reliably and reproducibly show that the units produced by an aseptic
processing operation are sterile, should normally yield no media fill contamination.
Acceptance criteria:
The target for any media fill run should be zero contaminated units. However for the
following criteria for assessing state of aseptic line control shall be followed:
When filling fewer than 5000 units, no contaminated units should be detected.
One (1) contaminated unit is considered cause for revalidation, following an investigation.
When filling from 5,000 to 10,000 units:
One (1) contaminated unit should result in an investigation, including consideration of a repeat media fill.
Two (2) contaminated units are considered cause for revalidation, following investigation.
 When filling more than 10,000 units:
One (1) contaminated unit should result in an investigation.
Two (2) contaminated units are considered cause for revalidation, following investigation.
Reconciliation of Media Fill units
Reconciliation of the following shall be done as per the formats in the BMRs.
Liquid nutrient medium.
Sterile Mannitol powder.
Rubber stoppers
Glass vials
Aluminum seals
Abortion or Invalidation:
A simulation run may be aborted or abandoned if an event occurs as a result of which the trial
cannot continue, for example media spillage, serious mechanical breakdown of equipment etc
Permission to abort or invalidation a simulation trial shall be on the decision of the Head QA.
Product units filled in an aborted simulation trial shall not be incubated.
A simulation trial may be invalidated if, within 48 hours of completion of the trial, the Unit
Head or Unit Head of Production notifies the Unit Head of Quality that an event occurred
during the trial which would not be permitted in routine production.
Invalidation of a simulation trial shall be on the joint authority of the Unit Head and the Unit Head of
Quality.
Product units filled in an invalidated simulation trial shall be removed from incubation.
Reasons for contamination
The following are some of the identified causes for contamination, but not limited to:
Aseptic practices:
Operator reaches over open vials to remove fallen vial on line with gloved hands
Poor personnel flow.
Damage of the protective gowning observed during the activity
Poor gowning practice
Poor aseptic connections
Improper connection of butterfly valve to the powder container,
Improper connection to main hopper,
Poor Sanitization:
Procedures deficient
Poorly executed procedures
Contaminated disinfectants.
Disinfectants not-suitable for the purpose
HVAC related:
Variable velocities between filters.
Inadequate laminar flow resulted.
Low or undetectable velocity at work surface.
Leakages found in the HEPA filter grid,
Excursion of temperature and Relative Humidity.
Excursion in the differential pressures between different classes.
Mechanical failures:
Vacuum pump failure,
Compressed gas filter failure,
Leakage of the filling vessel and
Pinholes in the tubing used for liquid nutrient media
Power failure and resuming times.
Other reasons
Improperly dried hands and foot especially during rainy seasons.
Personnel hygiene.
Personnel with un-noticed communicable diseases.
Note: Any observations that may cause contamination shall be added to this list, whenever observed and
reported.
Action failure
When data from a media fill indicate the process may not be in control,
 An investigation should be conducted to determine the origin of the contamination and the scope
of the problem.
Once corrections are instituted, process simulation run(s) should be performed to confirm that
deficiencies have been corrected and the process has returned to a state of control.
When an investigation fails to reach well-supported, substantive conclusions as to the cause of the
media fill failure, three consecutive successful runs in tandem with increased scrutiny of the
production process may be warranted.
Actions that shall be taken in the event of a Media Fill failure are described below:
The investigations shall be performed by an investigation team comprising of experts from
Production, Maintenance, Quality Assurance and Microbiology.
Isolation and Identification of the micro-organism observed shall be done up to the genus level and
species level.
Possible source of the contaminating micro-organism into Media Fill process shall be investigated.
This shall include statistical tools for investigation, such as, Cause and Effect Analysis or other
tools to find out the root cause(s) or the most probable root cause(s).
Batch Records for Media Fill studies shall be closely examined by the investigation team for any
deviation or incident.
All Media Fill study records shall be reviewed. These shall include sterilization records,
depyrogenation records, disinfection records, and microbiological monitoring records, physical
monitoring records for temperature, RH and P of the aseptic processing and adjacent rooms and
Video recording, if done.
Any deviation from the relevant SOPs or aseptic practices shall be investigated.
The operating personnel who have participated in the Media Fill studies shall be interviewed to
check for any untoward incident or lack of proper aseptic practice.
Any deviation from the validation protocol shall be investigated.
If any deviation is found, it shall be reported.
Outcome of Investigation: The investigation report shall be discussed by the investigation team
members.
Detailed investigation report shall be made. Deficiencies shall be discussed.
The corrective actions and preventive actions shall be identified, justified and approved before
implementing.
The operating team members shall be identified and entrusted with the responsibility to undertake
the corrective actions and preventive actions.
Corrective actions may demand the process simulation to be either fully or partly re-qualified as
decided by the investigation team. This shall be decided based on the causes and stage of failure.
There shall be follow-up by the investigation team to determine whether the corrective actions and
preventive actions have been indeed implemented and were effective.
The Investigation and CAPA shall be closed only after full satisfaction of its implementation and
effectiveness is ascertained.
The Investigation report and CAPA implementation shall be signed by the investigation team
members and approved by the QA Head.
The QA Head shall communicate to the senior management about the Media Fill failure, cause of
failure, its implications on the productivity, facility, GMPs, Regulatory and Action Plan for CAPA and
re-qualification of the facility.
The senior management shall review the points of investigation and implications of media fill
failure and provide directions to the manufacturing facility.
The QA Head shall also communicate to the Quality Person (QP) or clients / customers who are
affected through Quality Agreement or Technical Agreement.
Decision on Disposition of products
The investigation team shall determine through discussion the fate of the products and the batches
that were:
Processed immediately after the last Media Fill run was completed,
Processed between the execution of last Media fill study and the execution of this Media fill study.
The decision may not necessarily result in Product Recall from the market as the cause
could be due to operator one-off error, operational deviation or an accidental effect or an
incident from a worst-case scenario or equipment breakdown; in either case it may not
reflect on true batch failure.
 However, if the cause is identified to be a systemic contamination failure due to Facility
failure, HVAC system failure, LAF failure, Tunnel or autoclave sterilization process failure,
inadequate competency of personnel, then it could result in a decision for Product Recall.
In such a case, the investigation team shall decide the products and number of batches to be
recalled. The QA Head shall finally approve of such a decision and initiate Product Recall as
per current SOP on Product Recall.
Re-qualifications:
Normally process simulation tests should be repeated twice a year. However 30
days deviation from the pre-scheduled activity may be allowed if required.
Each change to a product or line change should be evaluated using a written change
control system.
Any changes or events that have the potential to affect the ability of the aseptic
process to exclude contamination from the sterilized product should be assessed
through additional media fills.
For example, facility and equipment modifications, line configuration changes, significant changes in
personnel, anomalies in environmental testing results, container closure system changes, extended
shutdowns, or end product sterility testing showing contaminated products may be cause for revalidation
of the system.
After completion of de-activation these vials shall be destroyed by crushing, and liquid is drained
into ETP system.
After completion of incubation time and completion of relevant activities the media filled vials shall
be de-activated by sterilizing the media filled vials by moist heat at 1210C for 1 hour.
List of Annexure / Formats
None
Reference (If any):
US Guidance for Industry Sterile Drug Products Produced by Aseptic Processing 2004.
PICS Recommendation on the Validation of aseptic process (PI 007-6/ 1 January 2011)
WHO Technical Report Series, No. 961, 2011.
EU guideline (EUGMP) for Manufacture of sterile Medicinal Products Volume 4 Annexure1
Forms and Records (Annexures)
Proposed types of Interventions during Media Fill runs Annexure I

Distribution
Master copy Quality Assurance
Controlled copies Quality Assurance, Production, Quality Control, Stores,
Engineering.
History:

Date Revision Number Reason for Revision

00 NEW SOP

Annexure-I

Proposed types of Interventions during Media Fill runs

Worst case Normal Production Worst case scenario Justification for selection
factor condition

Normal Aseptic filling stoppages More aseptic filling More exposure time and
Aseptic very few stoppages to adjust for of contamination and
Routine extended run time; Sterility Assurance.
Interventions
In-process fill weight More number of In- Risk to contamination and
checks only; process fill weight & fill Sterility Assurance.
volume checks;

Normal powder Filling Vial Powder Filling, extra liquid Extra activity of SCDM
sampling & inspection; SCDM Filling, Vial filling hence more Risk to
sampling & inspection; contamination and Sterility
Assurance.
 Adjustment of hopper of
powder filling.
Non-Routine Filling equipment
Aseptic adjustments not done
Interventions routinely;
Bunging equipment
adjustments not done
routinely;
Breakdown maintenance
not done during aseptic
filling,
Entry of maintenance
technician normally not
enters during aseptic
filling process;
Line speed Vial Washing Equipment
adjustments Speed adjustments i.e.
staggered supply of vials
into tunnel sterilizer.
Aseptic filling Line speed
adjustments and
stoppages to adjust time
for normal production
time;
Extra More number of personnel
personnel inside the aseptic
processing area.
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AUGUST 18, 2016 0 JULY 31, 2016
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SCDM filling;
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Breakdown maintenance Risk to contamination and
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aseptic filling,
Entry of maintenance Risk to contamination and
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Vial feeding in to tunnel Extended exposure of the
little disturbed; vials to the environment.
Hence chances of
Vial feeding to aseptic
capturing any
filling line little disturbed
microorganisms in the
leading to over-exposure
environment will be more.
of empty vials;
Mannitol powder filling Risk to contamination and
into vials as well as Sterility Assurance.
subsequent liquid SCDM
filling will have intermittent
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More personnel can add to Risk to contamination and
contamination (viable & Sterility Assurance.
non-viable)
0 JULY 31, 2016 0
SOP on Control of Change Parts of
Machines/Equipments
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