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ASCEPTIC PROCESS VALIDATION

(BY MEDIA FILL TRIAL)

ISSUED TO:
NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

MICROBIOLOGIST

PREPARED BY:

MICROBIOLOGIST

REVIEWED BY:

QUALITY CONTROL MANAGER

AUTHORISED BY:

C.E.O

AMENDMENT HISTORY

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

Rev. Initiated Page


#
Date
By # Nature Of Amendment Done By

Introduction:

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

To ensure the sterility of products purposing to be sterile, sterilization, aseptic filling and
closing operation 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.

As aseptic processing operation should be validated using a microbiological growth


medium in place of the product. This process simulation, also also known a a media fill,
normally includes exposing the microbiological growth medium to product contact
surfaces of equipment,container closure system, critical environments and process
manipulation to closely simulate the same exposure that the product itself will undergo.
The sealed containers filled with the 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, aseptic connections, filling, closing etc.) environmental monitoring
data from the process simulation can also provide useful information for the processing
line evaluation.

A written batch record, documenting production conditions and simulated activities


should be prepared for each media filled run. The same vigilance should be observed in
both media fill and routine production runs. The firm’s rationale for the conditions and
activities simulated during the media fill should be clearly defined. Media fills shouldn’t
be used to justify practices that pose unnecessary contamination risks.

(Abstract from: FDA dated September 2004 recommendation on guideline for industry,
sterile drug produced by Aseptic processing, Current Good Manufacturing Practices)

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

Objective:

The objective of this validation study is to:

Qualify and validate the aseptic filling process/facility in the area( liquid ampule
injection).

Assess the effect of variables/Interventions (within already set operating limits on


product quality and behavior.

Identify and solve the problem(s) if any, encountered during process.

Justify or reduce the frequency of in-process checks during manufacturing.

Establish confidence on established/existing procedures.

Find ways and means to increase productivity and improve quality.

Assure that complete process is under control.

As area have undergone recent construction( pre fabrication) ,for area qualification,
three successful media fill trials runs are recommended for three consecutive days.

Scope:
1. This validation protocol describes the work requires for the validation of the
aseptic Filling Process by media fill trial for recently renovated facility of liquid
injection(General Ampoule).
2. The validation protocol also describes the frequency of trial filling and the
acceptance criteria along with the filling procedure and pre start checking criteria.
3. This protocol also describes the laboratory (microbiology) testing
process/procedures, incubation and the methods to evaluate the test results.
4. This protocol will also highlight the acceptance criteria, revalidation and batch
size for trial fill.

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

5. This protocol also defines the facilities, responsibilities and equipment,


apparatus, glassware, material and documents that are involved in the validation
studies.
6. The media fill trial report will be generated as a result of activity performed that
shall contain observation, deviation and impact of deviation, corrective action to
be taken in response of any deviation and finally conclusion.
7. Filling of Sterile Tryptic Soy Broth (TSB) for media growth evaluation.
8. To describe the phases of validation dealing with the simulation, interventions,
sampling and testing at various stages of critical processes of area monitoring,
material handling, personnel involvement and manufacturing are according to the
pre-set requirement to ensure that the final product provides predetermined
specifications.

CHANGE CONTROL:
Any change in the Aseptic filling process or in utilities which directly or indirectly affects
the performance of the overall process shall be controlled in accordance with the
change Control procedure( Standard operating procedure for change control) and it will
be required to re-evaluate the process.
In order to ensure that changes in process and or the process environment introduced
either intentionally or unintentionally, have no adverse effect on process characteristics
and product quality, revalidation will be carried out .
Following are the changes which if take place in accordance with the change control
procedure,revalidation after the approval of the changes will be required.
I. Change in type of major equipment.
II. Change in site of manufacture.
III. Change in critical process parameters.
IV. Change/renovation in facility/building.
Minor changes or the changes have no direct impact of the in-process or final product
quality shall be handled through the system of the preventive maintenance program.
In addition, the data obtained during Annual Product Review will be used to assess the
process.

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

Responsibility:
Production Manager
Production officer
Representative quality assurance
Microbiologist
Representative of maintenance staff.

Frequency and number of Runs:

I. Initial three successful run for three consecutive days (all container size
employed for filling on the machine) before starting production for
Qualification of area/facility.
II. Than after every six months of single run, any suitable volume for re-qualification
of area or equipment.
III. If any change or modification of critical equipment or area then a single run
media fill trial with any suitable volume will be conducted before starting
production.
IV. If critical equipment or area is not in use for about one month than a single run
media fill trial with any suitable volume will be conducted before starting
production.
V. When data from a media fill run indicate the process is not under control, an
investigation will be conducted to determine the origin of the contamination and
the scope of the problem. Once correction is instituted a single processsimulation
run will 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

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

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 will be conducted.

Size of run:

The number of media filled units for this study is 10,000 ampoules per batch.

8.0 Revalidation:

I. Following initial aseptic process validation, media-fills are repeated to an extent


and at a frequency which will depend on an occurrence of events or changes
which may bear upon the potential microbial hazard to the process and product.
Significant modifications to equipment or facilities, changes in personnel,
undesirable trends in environmental monitoring results and sterility test failures
all indicate an immediate need to repeat a full process validation protocol
(minimum 3 consecutive successful media-fill runs). During this time the machine
in question is taken out of service until any problems have been resolved and the
results of the three media-fills have been evaluated and found acceptable.
II. In the absence of any significant changes or of any other events giving cause for
the concern then a minimum retest frequency shall be twice per year per
machine or where the machines are operated on a continuous 24-houroperation
basis, once per shift per year that is 3 times per year.

Adverse Conditions/Interventions:

Following adverse conditions are to be applied according to the requirement of filing


process. It should be noted that no FORCED change/adverse condition is to be applied,

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

purpose shall be to simulate the normal problem not to fail the Media fill study.

i. Filling machine is set OFF for 02 minutes, making filling impossible while Leminar
Flow Hood is ON.
ii. Laminar Flow Hood is switched off for 5 minutes but filling continued.
iii. Ir handling unit of area is switched off for 5 minutes but filling continued.
iv. Total power Off for 2 minutes,approximately 5,000 units are to be filled
afterwards.
v. Minimum speed of filling machine is achieved during process simulation,
approximately 15, 00 units to be filled with this speed.
vi. Highest speed of filling machine is achieved during process simulation,
approximately 25,00 units to be filled with this speed.
vii. Sending the maintenance (Supervisor) in area for simulation in maintenance task
during filling process.

10.0 Reports:

Following documents shall be part of the Aseptic Process Validation (Media Fill Trial)
report.

i. Temperature/Humidity monitoring.
ii. Sterilizer validation.
iii. Disinfectants efficacy.
iv. Particle counting of the area.
v. Environmental Condition (temperature and relative humidity) of area.
vi. No. of air changes in filling room and air velocity of laminar flow hood
vii. All copies of correspondence
viii. Check list
ix. Sterility report of TSB
x. Sterility reports for media fill trial
xi. Growth promotion test report of media

11.0 Procedure for conducting Media Fill Trial:

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

a) Arrangement for Media Fill Trial:


Following are the pre-start steps for conducting Media Fill Trial.
Intimation for trial:
Validation department will intimate production and Quality control department one
month before through Interoffice Memo for the arrangement of Media fill trial and
for the availability of the area, machine and relevant personnel.
Confirmation:
The production department affirms in writing program of Media Fill Trial and
ensures the availability of area ,machine and staff as per request.
Personnel:
Trained staff is required for trial filling.
Material required for Trial filling
Tryptic Soy Broth (TSB)
Glass ampoule of suitable size.
All components in sufficient quantity to fill three batches of 10,000 ampoules
each during media fill trial.
Material required for Environmental monitoring:
Different material is required for
i. Swab test
ii. Uniform and gloves check
iii. Non-viable particle count test
iv. Viable particle monitoring
v. Air Bioburden check
vi. Purified water check of sterile aea for ampoules ,ampoules washing etc.
vii. Incubator for the incubation of three batches of 10,000 ampoules each.
viii. Water for injection (WFI) for ampoule washing.

Pre-requests for Media trial filling:

The production manager/assistant production manager confirms about the following


before the start of trial.

i. The area has been disinfectant one day earlier as per relevant SOP.
ii. All required material has been properly sterilized and shifted according to

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

relevant SOP and shifted into the preparation room/filling room.


iii. All participants are ready to go inside for Media Fill Trial.
iv. Daily environmental monitoring report for last three consecutive days is
satisfactory.

12.0 Pre-start check list


Serial No Check Points detail
1 Check the general cleanliness of the filling room
2 Positive/differential pressure monitoring sheet to be attached
3 Temperature and relative humidity sheet to be attached.
4 Sterilization of the material
5 Sufficient numbers of sterilized jump suits/ garments are available
6 Heat distribution/heat penetration study of Dry heat sterilizer and autoclave is
satisfactory.
7 Validation of dry heat sterilizer and autoclaves by biological indicators is performed
and report attached.
8 Disinfactant efficacy report is available.
9 Any power breakdown before trial.
10 Operators ready for trial.
11 All materials and equipments are inside the filling room
12 Check the particle count report of the sterile area
13 Number
14 Air velocity of Laminar Flow hood(NLT 80 FPM)
15 Is the maintenance person ( supervisor) available for necessary corrective
measures and adjustment of filling machine?
16 All the material Required for Environmental Monitoring has been shifted in the
filling room.
17 The media selected shall be demonstrated to promote growth of gram-positive and
gram-negative bacteria and yeast and mold (e.g., USP indicator organisms).
18 Production operators, microbiologist and maintenance personnel have been
trained and ready for the activity?
19 Microbiologist has been trained for the inspection of Media Fill Trial ampoules?

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

20 Video recording of a media fill may serve as a useful audience in identifying


personnel practices that could negatively affect the aseptic process.
21 Ampoule type selected
22 Strength selected
23 Volume of TSB to be filled
24 No.of employees trained to go inside the filling room?

13.0 Filling Room Operation


Serial No Check point/Detail
1 Check environmental (Air Sampling) monitoring completion time _______
2 Make sure the availability of sterilized ampoules to fill 10,000 units per
batch.
3 Sterility test of Nitrogen gas:
Microbiologist will sample the nitrogen gas in media bottle from point of use
for sterility of gas.
4 Sterility of sterilized ampoules:
Microbiologist will take 50 sterilized ampoules from dry heat sterilizer from
5 boxes( 10 from each box) so that one box selected from each of four
corner and one box from center.
5 Adjust the sterilized machine parts if required.
6 Swab test of adjusted machine parts:
Microbiologist will swab the adjusted machine parts for microbiological
tests.
7 Run the machine idle and adjust the filling operation at slow speed to take
about 7-8 hours to fill 10,000 ampoules.
8 Dilute the TSB in Water for Injection (WFI) in pressure tank in
manufacturing room of area.
9 Pass the liquid from 0.22 micron cartridge filter to send to the filling room.
10 Note the media fill start time
11 Perform viable and non-viable particle monitoring during media fill trial

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

12 Send the maintenance person (Supervisor) inside the filling room for some
manipulation (if required).
13 Sample-01:
Run the liquid filling machine and pass 100 ampoules without TSB solution
but sealed, for negative control.

14 Start the liquid (TSB) filling machine /pump and adjust the dose of TSB as
2ml(2.1ml to 2.15ml) per ampoule
15 06 sample (each of at least 50ml) of liquid (TSB) from the pressure tank
should be taken in sterilized bottles after60+20 minutes for investigation
purpose.
16 Sample 02:
Collect first 100 TSB filled and sealed ampoules for growth promotion test.
17 Apply the following interventions and collect the corresponding samples and
label the boxes according to interventions applied.
18 Sample-03:
Filling machine is set OFF for one (1) minute while laminar flow hood is ON.
After starting 100 ampoules are collected and labeled.
19 Sample_04:
Continue filling with laminar flow hood is OFF for one(1) minute.
20 Sample-05:
Continue filling while air handling unit (AHU) of area is OFF for one (1)
minute.
After starting 100 ampoules are collected and labeled. Boxes from thisstage
are also labeled as sample-05.
21 Sample-06:
Total power off for 2 minutes. At least 6500 units to be filed after this

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

intervention.
After starting 100 ampoules are collected and labeled. Boxes from this
stage are also labeled as sample-06.
22 Sample-07:
Run filling machine at minimum possible speed during process simulation to
fill approximately 1000 units.
After starting 100 ampoules are collected and labeled. Boxes from this
stage are also labeled as sample-07.
23 Sample-08:
Highest speed of machine is achievd during process simulation to fill
approximately 3000 units to be filled with this speed.
After starting 100 ampoules are collected and labeled.boxes from this stage
are also labeled as sample-08.
24 Maintain the filling speed so that 1000ampoules take 8 hours to fill.
25 The uniform and gloves of all operators including maintenance person
inside the filling room are checked by the microbiologist during media fill
trial.
26 Note the temperature and humidity during Media Fill Trial.
27 Note the media fill completion time.
28 Observe any deviation during media fill trial.
29 Collect all 1000 filled ampoules in labeled box/trays and send for incubation
in microbiological lab.
30 After completion of the process disassemble the machine parts,clean the
machine and area thotoughly.
31 Intimate quality assurance for area clearance for next activity.

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

Microbiological Consideration:

Incubation and Storage of Filling Units:

All environmental tests including swab test,air bio burden check through gravimetric method and
through air sampler, machine/area surface check, uniform and gloves check of operators,
nitrogen and disinfectant check are incubated at 30-35©C for 14 days.

All these tests are read after 7 days and are retained in incubator with media fill trial ampoules
for 14 days.

All negative control ampoules and media fill trial ampoules must be kept in incubators at
following two different temperature for 14 days.

 Incubate at 2-25 C for first 7(1-7) days.


 After 7 days all these ampoules are incubated at30-35 Cat upside down position for next
7(8-14) days.
 Maintain temperature log sheet of incubators.

14.2 Lab (Microbiological) Testing:

Process all environmental tests.

50 empty and sealed ampoules are kept as negative control.

Rest of the TSB medium filled ampoules are incubated according to procedure.

Test Control:

Media used in the evaluation must pass a growth promotion test where a challenge with
between 10-100 organism per container is suitable to show the growth characteristics of the

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

organisms.

Observations:

Check and note

 The status of incubated ampoules in Media Fill Validation Report.


 Sterility for Nitrogen Purging System. ( Filter integrity forward flow or bubble point
test.
 Microbiological tests performed on Media Fill Trial.
 Growth promotion test.
 Observation after 7 days for incubated ampoules.
 Observation after 14 days for incubated ampoules.
 Results.

14.3 Acceptance Criteria:


One (1) contaminatedunit results in an investigation,including consideration of a repeat
media fill.
Two(2) contaminated units are considered cause for revalidation following investigation.
Ref: FDA Guidance for industry,Sterilr Drug Produced by Aseptiv Processing
cGMP,9/2004.

Evaluation of test results:


 Examine all filled untis visually after gentle shaking in the light. Evidence of
microbial growth such as turbidity,granular matter,filamentous matter and pellicle
or button formation is confirmed by sub-culturing for identification(bacterial or
fungal).
 Contaminated containers shall be examinedfor evidence of container/closure
damage which might compromise the integrity of the packaging
system.damaged containers shal not be included as failures (positives) when
evaluating results.
If the media fill trial fails then the reasons are investigated for the failure
including all tests parameters.All investigations must be documented.
Than QA must review critically prior to release al products filled by the discovery

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

of media fill trial failure.

14.6 Evaluation of test results:

After 14 days of incubation the media shall be destructed according to the SOP(________)

15.0 responsible Personnel/Equipment/Material Documentation

15.1 Facilities:

The validation of Aseptic Filling Process by Media Fill Trial will be performed for Injectable
Department (General Ampoule) and testing will be performed in Microbioogical Laboratory of
Quality Control Department at Nortech Pharmaceuticals.

Identification of Responsible Personnel:

Name Job title Signature


Quality control
manager/validation manager
Deputy QCM/Deputy
validation manager
Deputy manager QA
Production manager
Microbiologist

Identification of documents:

Document SOP/Qf number


Master validation plan
Aseptic process validation (Media fill Trial)SOP
SOP for growth promotion test
SOP for disposal of Media Fill Trial
SOP for inspection of Media Fill Trial ampoule
Volume variation in-process sheet

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

Sealing/leakage test in-process

Identification of Machine Equipment:

Machine Name Model/Make M/C ID SOP No Process stages


Ampoule washing machine Washing
Manufacturing Vessel TSB Dilution
Ampoule filling machine Filling
Dry Heat Sterilizer Depyrogenation
Steam sterilizer(Autoclave) Sterilization

Identification of Material:

Material Exce Units Quantity


ss
Tryptic Soy Broth (TSB) sterilized 3% Lit 25.75

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NORTECH PHARMACEUTICALS (PVT) LIMITED

QUALITY CONTROL DEPARTMETNT


Document # NOR /QC/MIC
STANDARED OPERATING PROCEDURE Revision #02
Date of effectiveness:10-07-18
Date of next review: 10-06-20
ASCEPTIC PROCESS VALIDATION
(BY MEDIA FILL TRIAL)

Clear Glass ampoule 5 ml USP Type-I 2% No 5100

Temperature and time

Media Storage:

Prepared Plates of Culture Media:

Sterile Reagents:

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