Aseptic Process validation--Media Fill operation in the sterile dry powder filling

1.0             OBJECTIVE: To lay down a procedure for Media Fill operation in the sterile dry powder Filling facility..

2.0       RESPONSIBILTY

            Microbiologist, Operator concerned/Production officer/QA Officer

3.0       ACCOUNTABILITY

            Quality Control Manager/ Production Manager

4.0      PROCEDURE

           PRE-START UP:    

4.0                  Ensure that all the equipments, HVAC system, water system and other utility services of the facility are validated.

4.1                  Ensure that the Gamma irradiation certification report of the lactose + SCDM (Soyabean Casein Digest) mixture (3:1) from BARC and sterility test report (done in-house) is available.

4.2                  Ensure that solubility test report and growth promotion/inhibition test report of sterile  

            lactose+SCDM mixture is available.  [Solubility should be NLT 1gm/10 ml of WFI].

4.3                  Ensure that solubility test report and growth promotion/inhibition test report of sterile   lactose+SCDM mixture is available.  [Solubility should be NLT 1gm/10 ml of WFI].

4.4                  Ensure that freshly distilled WFI to be used for filling, is autoclaved and the sample given for sterility test.

4.5                  Ensure that all the contact parts of Dry Powder Filling machine are duly cleaned and sterilized or sanitized.

4.6                  Ensure that the last Environmental Control Reports of the area are conforming to the acceptance standard.

4.7      Ensure that the Liquid Filling machine is done inside the sterile filling area on the previous day after autoclaving /sanitization.

4.8   Ensure by manometer readings, that the pressure balancing of the sterile area is as per requirement.

4.9      Ensure that the cleaning, sanitization and fumigation of the area is done on the previous day.

START UP

4.9      Enter the sterile area as per SOP using gowns sterilized 4days back.

4.10    Check the cleanliness of the sterile area.

4.11    Check the cleanliness of the Liquid Filling machine.

4.12    Check and confirm the temperature and RH of liquid filling room is as per the requirement.

4.13          Assemble the Liquid Filling machine.Ensure that that filling of liquid and liquid can be done     

           simultaneously.

4.14    Measure the nonviable particulate count of filling cabinet and filling room.

OPERATION

4.15   Bring the autoclaved WFI container near the liquid filling assembly. 

4.16   Transfer sterile SCDM liquid from the container in to liquid hopper.

4.17  Transfer sterile dried rubber stoppers (sterilized 4 days back) in to the hopper of stoppering unit.  Send sample for sterility testing simultaneously.

4.18    Put the inlet suction tube of Liquid Filling Assembly into the WFI container.

4.19    Set the Liquid Filling machine for the respective dose.

4.20  Remove the Liquid Filling Assembly and all the contact parts.  Disinfect it, clean it and get it sterilized/sanitised.

4.21      Ensure that all the left over rubber stoppers are given outside the sterile area for destruction.

4.22      Shut down the vial liquid-filling machine as per SOP

CLEANING:

4.23   Ensure that all the tools and accessories containers etc. used during media fill are given for cleaning/sanitization/sterilization.

4.24     Follow the cleaning and sanitization SOP for cleaning of sterile area.

4.25   Do the extra cleaning and sanitization of the floor/walls/machine after media fillrun with 10% Bacillocide and Lysol solution

   ACCEPTANCE CRITERIA:

4.26      Initial validation:  During initial validation, it should qualify all three consecutive media fill run i.e. during each run there should not be growth in more than two vials.

4.27       Revalidation:  Only one media fill run in which there should not be any growth in more than two vials.

  ELIGIBILITY CRITERIA FOR PERSONNEL PERFORMING MEDIA FILL RUN :

4.28    Persons involved in media fill should be medically examined and declared fit within last one year.

4.29   Persons should be trained on general hygiene and current gowning procedure, and the present health condition should be O.K.

4.30    The personnel should be microbiologically monitored during run.

NOTES

In case of any positive growth in any vial during the incubation period.\

4.31     It should be isolated and identified to the genus level.

4.32     If the isolated organism is other than the house flora, thorough investigation shall be carried out by Quality Assurance and Production.

4.33     The source of the contamination must be established.

  In case of any failure in media fill run:

4.34     When there is no assignable cause, media fill shall be repeated three times and production should commence only after all the three runs meet the acceptance criteria.

4.35             When there is assignable cause, after rectification of the cause, repeat the media fill run             once.

4.36     Before and during media fill run no special cleaning shall be carried out.

4.37   Normal production can resume only after minimum one day of environmental monitoring compliance report.

4.38     Batches filled before the final result of the media fill run shall not be released to the market till the media fill run passes in case of initial validation.

4.39   The routine environmental monitoring plates shall be kept for 14 days (in case of any growth) to help in investigation of any positive growth in the media filled vials.      

4.40   If for any reason the media fill run is considered invalid vials shall not be incubated.

4.41   Media fill runs can be aborted for the same reason that a product lot would be aborted. All      media filled units filled before an incident that would cause an aborted fill must be incubated.

4.42   During media fill all the Operators, Officers& Maintenance staff who are authorized to do the sterile filling, supervision and maintenance must be involved in media fill trial.

4.43         The volume of liquid filled must be sufficient to wet all surfaces including the closure and to facilitate inspection.

4.44         The line must be run at a slower speed than normal production run to give greater exposure time.

4.45  Total duration of the routine media fill must be the same or more as the longest process conducted on that line.

4.45         The incubation temperature of the filled containers must be sufficient to promote microbial  growth at 30-35^oC. for 336hrs(stored upright) followed by 20-25^oC. for 336 hrs. (stored  upside down).

4.47             Personnel that conduct the inspection of incubated media fills must have training on basic microbiological concepts ,concepts of media fill and examples of contaminated container   showing various stages of growth.

POST MEDIA FILL RUN :

4.48             Filled incubated vials should be optically checked by microbiologist and certified.

4.49     Incubate the vial samples with no growth approximate 5 vials for 14 days with normal house flora and 5 vials with organisms used for the sterility test growth promotion for 14 days.

4.5       Temp. range for incubation 1^st  two  week at30 to 35^o C. (vials stored upright).

4.51     Next two week at 20 to 25^o C. (vials stored upside down).

4.52            These vials should show promotion of growth.

ANNEXURE - I

LIST OF PERMITTED INTERVENTIONS DURING FILLING

These are the activities which are performed during normal working in the sterile filling area:

1)         Adjustment of weight in the dosing wheel.

2)         Adjustment of Stopper holding spring.

3)         Transfer of liquid from container to hopper.

4)         Transfer of stoppers from bag to hopper.

5)         Picking unstoppered vials from the outfeed back to conveyor for stoppering.

6)         Adjustment of separator.

7)         Picking up of fallen vials from turn table.

8)         Cleaning of machine with vacuum cleaner.

9)         Adjustment of stoppering channel height.

10)      Adjustment of stoppering pressure rollers.

11)      Replacing of a piston from the wheel.

12)     Adjustment of turn table over load sensor.

13)      Lifting and closing of the LAF cabinet door.

14)      Checking the weight in balance.

15)      Adjustment of dosing air.

16)      Cleaning of vacuum pot.

17)      Pushing stopper in the channel by forceps.

18)      Power interruption (samples should be marked)

19)      Number of personnel in sterile filling area (8 persons).

20)     Multiple dosing of the liquid.

21)     Running  the machine at a slower speed than actual production run.

22)     Covering the working shift usually 12 hours and shift Change over

23)     Entry of maintenance person for repairing of M/C

ANNEXURE - III

ACCEPTANCE CRITERIA FOR MEDIA FILL SIMULATION

MAXIMUM NO.OF REJECTED VIALS ACCEPTABLE AT 95% CONFIDENCE LEVEL	PERCENTAGE OF FAILURE	BATCH   SIZES
		5000	10000	20000	50000	100000	INFINITY
0	0.1%	2469	2668	2808	2912	2951	2995
1	0.1%	3676	4047	4339	4575	4670	4747
0*	0%	4684	5207	5670	6044	6207	6294*
0	0.01%				24698	26686	29944
1	0.01%				46093	47047	47047
2	0.01%					62911	62911
* Normal media fill run size

PROCESS VALIDATION PROTOCOL Autoclave

1.         PRE-EXECUTION APPROVAL

Successful completion of this protocol will provide documented evidence that all key aspects of the Autoclave used in LARGE VOLUME PARENTRALS SECTION adheres to appropriate application criteria, comply with standard operating procedures, and meet current Good Manufacturing Practices (cGMP) requirements.

1.1       SIGNATORY LIST

The signature below indicates approval of this protocol and its attachments for execution.

	Name & Designation	Signature	Date
Prepared By
Checked and Reviewed By
Approved By

1.2              Validation Team

All individuals participating in the execution of this protocol must fill out a row in the table below.

Name & Designation	Responsibility	Signature & Initial	Date
	Prepare the protocol and coordinate the validation study. Generate amendments to the protocol as required
	Microbiological validation of the sterilization process. document the microbiological aspects of the study
	Protocol training of operators and provide the resources for validation study

2.0       GLOSSARY OF TERMS

2.1       List of Abbreviation

CGMP             Current Good Manufacturing Practices

FDA                 Food and Drug Administration

GAMP              Good Automated Manufacturing Practice

GMP                Good Manufacturing Practice

IQ                    Installation Qualification

OQ                  Operation Qualification

2.2       Definitions

Acceptance Criteria                Agreed standards or ranges, which must be achieved.

Critical component                  A component within a system where the operation, contact, data, control, alarm, or failure may have a direct impact on the quality of the product.

Critical Instrument                   Any instrument that directly affects product safety, purity, or efficacy.

Direct Impact System             An engineering system that may have a direct impact on product quality.

Factor Acceptance Test         Documenting the performance characteristics of equipment prior to shipment to site.

Impact Assessment                The process of evaluating the impact of the operating, controlling alarming and failure conditions of a system on the quality of a product.

Indirect Impact System           An engineering system considered not having a direct impact on product quality.

Installation Qualification          Documenting the process equipment and ancillary system are constructed and installed according to pre-determined specifications and functional requirements.

No Impact System                  This is a system that will not have any impact, either directly or indirectly, on product quality. These systems are designed and commissioned following Good engineering Practice only.

Non-critical Component          A component within a system where the operation, contact, alarm or failure may have an indirect impact or no impact on the quality of product.

Operating Limits                     The minimum and /or maximum values that will ensure that product and safety requirements are met.

Operational Qualification        Establishing confidence that process equipment and ancillary systems are capable of consistently operating within established limits and tolerances.

Performance Qualification      The documented verification that al aspects of a facility, utility or equipment that can affect product quality perform as intended meeting pre-determined acceptance criteria.

Performance Testing              The process by which the performance of interdependent system is demonstrated as within the required tolerances, the output of interdependent system is demonstrated as delivering the required duty or capacity, the interdependent functions of system are interdependent to be as specified and appropriate.

Piping and Instrumentation

Diagrams                                Primary source of design information for utility systems and process equipment. They are used to depict the process flow, equipment configuration, process parameters, instrumentation, and materials of construction. They also are used to perform overall material and energy balances and pressure balances.

3.0       INSTRUCTION

3.1.      General Instruction

All performers and reviewers must complete qualification forms using the following guidelines:

·                     Complete all items on a form in full, except the optional comment’s section.

·                     Document any deviation from defined protocols and expected results. Owner approval of protocol deviations must be documented before final approval signatures can be obtained.

·                     Write additional comments on an addendum sheet when there is not enough space on a form to accommodate all comments. Use these three steps when adding an addendum sheet.

1.         Number the page alphanumerically.

2.         Initial and date additions.

3.         Insert the addendum sheet behind the original page.

·                     Make all entries in permanent black or blue ball pen.

3.2       Correcting Entries

If you need to make corrections on a form, use the procedures described below:

3.2.1    Correcting Short Entries

To correct a short entry [such as a single word or test result] on a form:

1.         Draw a diagonal line, bottom left to upper right, through the miss entered or incorrect information.

2.         Write the correction to the upper right of the original entry.

3.         Give brief explanation of change

4.         Initial and date the change.

3.2.2    Correcting Long Entries

To correct a long entry or information block on a form:

1.         Draw a diagonal line, bottom left to upper right, through the miss entered or incorrect information.

2.         Write the correction on a separate addendum page.

3.         Give brief explanation of change.

4.         Initial and date the changes.

5.         Number the page alphanumerically

6.         Place the addendum page behind the original page.

3.3       Marking Elements That Are Not Applicable

Mark each element carefully according to the instruments below, so that it will be clear that the element is unnecessary and that you have not skipped or forgotten the element.

1.         Draw a diagonal line, bottom left to upper right corner, through the element that is not required.

2.         Write the letters NA [Not Applicable], your initials, and the date above the line. Include comments above the line or on the form to document the reason the element is not required.

3.         Where NA is indicated as an option, select this field.

The performer and reviewer must sign and date all forms, as usual, even when part or all of the form is marked “NA”.

Note:               All original entries must remain legible after any corrections have been made.

3.4    Caution

The following conditions require “re-qualification”;

·                     When a Instrument modification has been completed, it affects the installation qualification.

·                     When the software or firmware has been upgraded or changed

·                     When this Instrument is being removed from where it was originally installed.

3.5       Re-calibration / Re-certification Requirements

The following conditions require “re-calibration / re-certification;

·                     For a pre-determined period of time or use.

·                     After any minor service has been done or replacement of parts.

·                     When this Instrument is being removed from where it was originally installed.

4.         RESPONSIBILITIES

4.1       Validation Team

·                     Prepare and approve the validation protocol.

·                     Provide training to the personnel regarding protocol execution.

·                     Assure complete adherence to the protocol during the execution

·                     Generate amendment to the validation protocol, as required.

·                     Document any deviations that occur during protocol execution.

·                     Document Operator SOP Training.

·                     Provide the resources required in executing the validation protocol.

4.2       PRODUCTION MANAGER

·                     Review the validation protocol and the final reports

4.3       QUALITY CONTROL/ASSURANCE MANAGER

·                     Approve the validation protocol and the final reports

5.0     Objectives:

To verify and establish that the Autoclave is working as per recommendations of the manufacturer.

6.0       Scope:

This validation protocol is applicable to the Autoclave intended to be used for steam sterilization in LARGE VOLUME PARENTRALS SECTION.

The protocol will be implemented under the following conditions

§         The validation of sterilization process using saturated steam as the steriliant

§         Prior to the production of a new sterilizer.

§         A change In the load design or weight that would result in a load that is more difficult to sterilize.

7.0       Equipment Identification

Equipment Name	Autoclave	Verified
Model Number		Yes ¨  No ¨
Serial Number		Yes ¨  No ¨
Make		Yes ¨  No ¨
Asset No.		Yes ¨  No ¨
Location		Yes ¨  No ¨

It has the following sub-components

S. No.	Description	Check
1	Time controller	¨
2	Pressure controller	¨
2	Temperature  controller	¨
3	Pressure gauge	¨
4	Safety Valve	¨
5	Thermometer	¨

Completed By:__________________                          Date:_____________

Reviewed By:___________________                                    Date:_____________

8.0       EQUIPMENT DESCRIPTION

The Autoclave intended to be used for steam sterilizations process. It has following specifications:-

S. No.	Parameter	Range	Readability	Check
01	Timer	0—60 min	1 min	¨
02	Pressure	0—60 Lb/inch²	2.0 Lb/inch²	¨
03	Temperature	0 –150°C	0.5°C	¨

8.1        LOAD IDENTIFICATION

Nature of load	1000ml bottles
Quantity of load	2000 Bottles

8.2       STERILIZATATION CYCLE PARAMETERS

Sterilization set point	106°C
Temperature range	106°C +0.5°C
Expose time	45 minutes

8.3       Equipment Used for PROCESS VALIDATION

Equipment	Calibration		Certificate No.	Issue Date
	YES	NO
Recording potentiometer	¨	¨	___________	________
Thermocouples & lead wires	¨	¨	___________	________
Biological indicator i.e. B. stereothermophyllus	¨	¨	___________	________

Completed By:__________________                           Date:_____________

Reviewed By:___________________                                    Date:_____________

9.0    strerilizatation procedure:

§               Place six thermocouples in the load at the slow to heat points as determined

        Previously by(Heat Distribution and Heat Penetration studies)

§               Place thermocouples exterior and near to (Penetration TC)and expose to  chamber steam distribution TC)

§               Place BIs (Biological Indicators) at each of the slow to heat penetration location.

§               Load autoclave extend TC out of autoclave and attach to potentiometer

§               Position one TC by controller record sensor

§               Close autoclave door

§               Perform, function check of TC .replace if defective.

§               Replace autoclave sensor chart with a new one

§               Check to make sure that cycle parameters are set

§               Set potentiometer for a 3.0 Hours scan cycle.

§               Initiate sterilization cycle and potentiometer cycle at same time                 

§               Allow cycle to continue until it is completed. Collect all potentiometers, controls and computer control record and place with protocol.

§               Have computer graph results and calculate Fo value. After load has cooled, remove BIs and have tested

§               Incubate BIs in incubator at 55Cº for 48 hrs

10.0             ACCEPTANCE CRITERIA

1-       BDS Strip

All four colors segment of the processed indicator are black. If all other critical process parameters such as temperature, pressure and sterilization are in accordance with cycle reference.

2-       Bio-Indicator i.e. B. stereothermophyllus

No growth should be observed after incubation for 48 Hours.

10.1            Results

Temperature                  :           106°C

Pressure                       :           10 Lb/inch²

Sterilization Time           :           30 minutes

1-      Evaluation of the BDS strip.

S.#.	Position of Indicator strip	Stick BDS-test indicator strip on	Acceptance Criteria		Results
			All four color segment of indicators strip are black
			Yes	No
1			¨	¨
2			¨	¨

2-      Evaluation of the Bio-indicator i.e. B. stereothermophyllus

S.#.	Position of B. stereothermophyllus			Acceptance Criteria		Observation
				No growth is observed after incubation for 48 Hours
				Yes	No
1	Front/top left	Fornt/bttm center	Middle /centleft	¨	¨
2	Middle/ bttmleft	Rare/top center	Rare/bttm left	¨	¨
3	Front/top center	Front/bottm center	Middle/cent left	¨	¨
4	Middle/bttm right	Rare/top bottom	Rare/bottm center	¨	¨
5	Front/top right	Front/ bottmleft	Middle/ center	¨	¨
6	Middle/ Bttm/Cent	Rare/top right	Rare/bttm center	¨	¨

All acceptance criteria have been met.                             Verified By / Date

Yes ____________No _____________                             _____________

If No or N/A, explain in Comments.

 Comments:_____________________________________________________________

 Completed By:__________________                                            Date:_____________

 Reviewed By:________________                                               Date:_____________

11.0.   Incidents/Deviations

To document any discrepancy or variations noted during the execution of the Process Validation Protocol. Any action to be taken to resolve an outstanding issue is to be identified within the incident report.

INCIDENT #	DESCRIPTION OF INCIDENT	RECORDED BY	DATE

COMMENTS: ____________________________________________________________ ____________________________________________________________

12.0     Final Comments about PROCESS VALIDATION

________________________________________________________________

________________________________________________________________

________________________________________________________________

________________________________________________________________

13.0             SIGNATURE IDENTIFICATION SHEET

This sheet is a record of each individual who signs or initials any page included in this protocol or in the attached document. Each person shall be identified by typed or printed name.

Name                                Signature and Initials                                 Company

__________________       _________________________                _____________________

__________________       _________________________                _____________________

__________________       _________________________                _____________________

__________________       _________________________                _____________________

__________________       _________________________                _____________________

__________________        ________________________                 _____________________

__________________        ________________________                 _____________________

__________________        ________________________                 _____________________

__________________       _________________________                _____________________

FINAL APPROVAL OF QUALIFICATION

This document certifies that the process of Autoclavation has been validated as specified and complies with Standard Operating Procedures, and satisfies the requirements for cGMPs.

	Name & Designation	Signature	Date
Prepared By	Tahir Ibrahim Quality Assurance Executive
checked and Reviewed By	Abdul Hafeez Production manager
Approved By	Tajjamal A Qurashi Manager Quality Control

PROTOCOL TRAINING

Training Session Date         :        ____________________

Instructor                               :        ____________________

Protocol Reference             :        ____________________

Name	Title	Signature	Date