SOP FOR PREPARATION, APPROVAL, REVISION, CONTROL OF LISTS

PURPOSE: To lay down a procedure for Preparation approval revision and control of lists.

SCOPE: This procedure is applicable to all type of lists prepared.

RESPONSIBILITY:

Preparation of SOP: Officer Quality Assurance

Checking and Review of the SOP: Officer QA

Approval of the SOP: Executive QA/ Designee

Authorization of SOP: Head QA/ Designee

Preparation of List: User Department

ACCOUNTABILITY: The accountability of implementation and compliance of the SOP is Head Quality Assurance.

PROCEDURE: Various lists shall be prepared as required by respective departments but not limited to, for Example:

• List of SOP
• List of Equipment’s
• List of Authorized persons
• List of Product
• List of Process Validation
• List of Specification
• List of Standard Test Procedure

All lists that are not governed under any SOP shall be prepared.

List shall be approved by Head QA (Note: In case of multiple pages list the approval shall be on last page.)

The numbering system of list shall be follows DC/LNNN

Second

The First and Second letters of the alphabet denoting the Department Code” for which list is being prepared for the code of department is given as Per SOP for SOP.

Third letters denote “/” (which denotes slash) 

Fourth letter denotes “L” (which denotes List) 

5^th 6^th and 7^th letter denotes “serial number of List” three-digit number starting serially from 001).

Every department shall prepare a “List of Lists” for all the list prepares by the department.

After receiving the soft copy of List from the concern department. QA Documentation cell person shall review the documents for its accuracy and adequacy such as but not limited to: 

• Format & Format No.
• Page Numbering

• Typographical errors

• Compliances with Change control

• Other affected documents

QA Documentation cell person shall take the printout and this hard copy shall be forwarded to concern department for signature.

After approval of list, put the effective date.

QA Document control personnel shall stamp in each page of the list in green ink with a stamp, which has the words “MASTER COPY” so as not to obscure text present on the upper top right side of the page.

QA Document control department stores all Master Lists.

Make controlled copies by photocopying each master Lists and stamp in blue ink with the word “CONTROLLED COPY” on the bottom right corner of each page. Issue the Controlled copy as per SOP.

If specifically required by any Regulatory Authority or Auditor, a copy of document shall be provided which shall be stamped as “UNCONTROLLED COPY” in blue ink at bottom middle.

Master List will be revised as per requirements and shall be updated in list of lists.

REFERENCE:

SOP for SOP

Document Control System

SOP FOR ANNUAL PRODUCT QUALITY REVIEW

PURPOSE: To lay down the procedure for preparation, review and approval of annual product quality review (APQR).

SCOPE: This SOP is applicable is applicable to APQRs for products manufactured.

RESPONSIBILITY:

Preparation of SOPs: Officer QA Department

Checking and Review of the SOPs: Officer QA Department

Approval of the SOPs: Executive QA department

Authorization of SOP: Head QA/ His or her Designee.

ACCOUNTABILITY: Head-QA or Designee shall be accountable for the proper implementation & compliance of the SOP.

PROCEDURE:

Definitions:

Annual Product Quality Review: An evaluation, conducted at last annually, to assess the quality standard of each drug product with the objective of verifying the consisting process and appropriateness of current speeds, and highlight any trend, in order to determine the need for changes in drug product specification or of manufacture or general procedure.

Process capability (Cp): Process capability is a technique to find out the measurable property of a process to a specification. Generally, that final solution of the process capability is specified either in the form of calculation or histograms. Cp is used to evaluate the variation of the process.

Process capability index (Cpk): Process capability index is the measure of process capability It is shows how closely a process is able to produce the output to its overall specifications. Cpk is used to evaluate the centering of the process.

After release of the product, the trend shall be prepared in excel sheet and reviewed for out of trend, If any finally the trend shall be compiled on annual basis.

APQR shall be carried out for each commercialized & exhibit batch of product that area manufactured in the calendar year i.e. January to December. Summary report shall be available within 90 days after the end of calendar year.

APQR shall be prepared by quality assurance department as per SOP.

APQR shall be reviewed by, Quality assurance, production, and quality control departments.

APQR shall be done for product of which minimum 3 Batch executed, and previous year Annual Product Quality Review report shall be clubbed for the product of below 3 batches executed.

If there are less than three (03) batches of product manufactured in calendar year or no previous APQR of respective product are prepared, then these batches shall be covered in next year APQR.

APQR shall be grouped/ clubbed for similar product (i.e. formulation and primary packing is same, however brand name or market is different).

The Annual Product Quality Review of the products related to Loan License or third party can be made as per recommendations of the customers (if required).

Numbering system for APQR: APQR shall be logged in logbook during signing of APQR as per Format No. SOP.

Annual product review shall essentially include the Following information but not limited:

Product Details: Review and record product details like – Product name, Generic name, Label claim, Product description, Pack description, Standard batch size, Shelf life, Review Period (it is based on last period of APQR / Schedule or based on client requirement or annual period), year of review and Number of batches manufactured in the year/period.

Review of Batch Manufactured: Review and record the Batch details like Batch number, Batch size, Manufacturing Date and Expiry Date of all batches manufactured, packed, distributed during the review period. Also mention the details for numbers of batches released, numbers of batches rejected & numbers of validation batches during review period.

Formulation Details: Review and record formulation details like – Material code, Ingredients, use of material and Quantity.

Review of Starting Material (Raw Material): This section shall include Review of raw material used for manufacturing, A.R. No., assay, water content, raw material quantity used, vendor details.

Review of Packaging Material: This section shall include Review of the packaging material used for the packaging and it shall be complied the respective specification.

Review of in Process Test Result: This section shall include Review of process parameter, in process test results of pH, BET, particulate matter and non-viable particles (such as aseptic assembly, connections of equipments, filling, loading, unloading and sealing.)

Review of Finished Product Test Result: This section shall include review as finished product test result parameters such as, Assay, pH, Water Content / LOD, Sub Visible Particulate Matter, sterility, impurity, final yield and trending for the same shall be done. In case of impurity if any result obtained ND (None detected) & BDL (Below disregard limit) graphical trending shall not be done.

Review of Microbiological Environmental Monitoring: Review of results and methods used for microbiological environmental monitoring of dispensing, manufacturing, filling and packing area.

Review of Control Sample: This section shall include review of control sample details, which has been conducted annually for control samples of each packaging configurations.

Review of Stability Data: This section shall include review of stability results at various conditions / various pack configurations.

Review of Media Fill: Review the media fill report which has been conducted in previous year.

Review of Deviation, CAPA and Process Non-Confirmative: This section shall include Review of all batch related deviation & process related deviation, CAPA and Non-Confirmative that particular period Whenever, CAPAs are recommended, appropriate CAPA Shall be initiated and shall be completed in a timely and effective manner. Recommended CAPA shall be escalated to senior Management through routine Quality review meeting.

Review of Out of Specification: This section shall include review OOS related to the product that have been initiated, reviewed and approved during the year.

Review of Out of trend: This section shall include review OOT related to the product that have been initiated, reviewed and approved during the year.

Review of Market Complaint: This section shall include review of complaints received from the market for the particular product and the field alerts.

Review of Batch Rejections: This section shall include review of number of batches rejected for this product during the review period.

Review of Change Control: This section shall include review of changes carried out related to particular product like, process, analytical methods, specifications, validation and qualification of instruments/ equipments etc.

Review of Recalls: This section shall include review of recall history if any of particular product.

Review of Returned Goods: This section shall include Review of number of batches returned reason of return and other relevant detail.

Validation / Qualification Review: This section shall include review of validation / Qualification status of critical relevant equipments and utilities such as HVAC, Nitrogen etc.

Review of Technical Agreement: Review the Technical Agreement for any outsourced GMP activity with clients, outsourcing testing laboratories and API manufacturer & ensures that it is in compliance with current regulatory requirement.

Review of Recommendation and / or Unresolved Issues from Previous APQR: This section shall include the review of open issues from previous APQR corrective action and preventive actions recommended during previous APQR. shall be verified and ensure the adequacy and compliance. Detail observation shall be included.

Conclusion: Review and compare the observations & results of product data mentioned in protocol with their acceptance criteria. Derive the conclusion and recommendations based on the results & trends of the product data. If any results found out of trend, necessary investigation shall be done to find out the probable cause and corrective preventive action shall be decided for future batches.

Recommendation: Write recommendation based on the results and conclusions. Based on above recommendations as well as changes shall be implemented through change control.

Note: Each parameter of APQR shall be reviewed individually with its review comments.

Statistical data: 

Statistical analysis technique “process capability” and ‘process performance” shall be used to review the data collected as part of the APQR.

Process capability and process performance study are statistical method which shall be used to establish if specification limit are set appropriately by calculating of Cp (process capability), Cpk (process capability index).

For non-numerical data, no statistical analysis is necessary like: appearance, solubility etc.

Minimum ten lot or stability data shall consider for process capability study. If data are less than ten in the year than data shall be consider in next annual product quality review.

CpK value shall be calculated for critical process parameter and finish product results.

The purpose of a process capability study is to compare specification to the process output and determine statistically if the process can meet the specification.

In case Lower Control limit and upper control limit exceed the Lower specification limit and upper specification limit than Lower specification limit and upper specification limit consider as 3s limit.

In case lower specification limit is not available then the lower specification limit shall consider as zero (0).

In case upper specification limit is not available therefore Cpk value shall found in negative value and the negative Cpk value shall not consider for process capability so that the CPL value considered as Cpk value.

CpK Value:

CpK Value	Action taken
Below 1.0	Shall be recommended for improvement.
Between 1.0 to 1.33	Shall be recommended for further trending during APQR of next year.
Higher than 1.33	Has been meant that the process parameter is rugged and manufacturing process is capable for producing product.

 

Note: If any parameter found out of above acceptance criteria the same shall be reviewed and investigated. The QA shall suggest the further course of action based on the outcome of the investigation.

CpK value shall be calculated for critical process parameters and critical quality attributes.

Note: Other department head shall be responsible to provide the required data to Quality Assurance department for preparation of APQR.

REFERENCE:

SOP FOR SOP

WHO-TRS 961 Annexure-3

Guideline Notes on Product Quality review January 2013 Guide-MQA-024-004.

SOP FOR PROCEDURE FOR ASEPTIC PROCESS SIMULATION (MEDIA FILL)

PURPOSE: To define the procedure to be followed for validation of aseptic processes by process simulation   study through a media fill. Process simulation study provides a way-

• To demonstrate the capability of the aseptic process in producing the sterile drug product.
• To qualify the personnel involved in aseptic processing.
• To evaluate impact of any changes made to aseptic processing line.

SCOPE: This SOP is applicable for carrying out aseptic media fill run on vial filling line in production area.

RESPONSIBILITY

Preparation of SOPs: Officer of Quality Assurance Departments

Checking and Review of the SOPs: Officer of Quality Assurance Department

Approval of the SOPs: Executive/His Designee of Quality Assurance Department

Authorization of SOP: Head QA/ His or her Designee

Head / Designee (Production) Department: Review of media fills Protocol and BMR, Review of executed media fills BMR & report, ensuring media fill participation of personnel involved in aseptic operation.

Microbiology Personnel: Sampling, testing of sterilized liquid media and PPM, Environmental and personnel monitoring in aseptic area & Visual inspection of media fill vial for microbial growth.

Head / Designee QC (Microbiology) Department: Review of media fills BMR, Protocol, Report & Ensuring media fill participation of personnel involved in aseptic operation & Environmental monitoring.

Engineering Personnel: Ensuring that utility support shall be provided during media fill & Simulation of maintenance activity during media fill run.

Head / Designee Engineering Department: Review of media fills BMR, Protocol, report & ensuring media fill participation of the engineering personnel involved in maintenance activity in aseptic area.

Quality Assurance Personnel: Monitoring of over all media fill activity, carrying out in process testing during media fill, Review of executed media fills BMR / report & Ensuring media fill participation of QA personal involved in IPQA.

Head QA / Designee: Head QA shall be responsible for final approval of media fill Protocol,media fill report & for final certification.

ACCOUNTABILITY: Head-QA or Designee shall be accountable for compliance of SOP.

PROCEDURE:

PRECAUTIONS: All the personnel involved in the Aseptic Process Simulation (Media Fill) shall be appropriately trained both in their job-related activities and on the Aseptic Process Simulation Study (Media Fill) Protocol.

All Major Equipment’s used for Process, Facility and Utility shall be verified for their Performance Qualification and Calibration.

Throughout the media fill run Good Manufacturing Practices and aseptic techniques shall be followed

No special precautions / care shall be taken while execution of the media fill exercise (All the steps / stages are to be performed as followed during normal Production Batches).

Precaution must be taken with respect to handling of media.

Entire product exposing area like filling & sealing shall be cleaned as per respected SOP.

At any stage none of the filled unit shall be removed unless verified and authorized by QA.

The destruction of the left-over media (Bulk) and of the filled units after inspection shall be done as per the respective SOP.

The media fill shall emulate the regular product fill situation in terms of equipment, processes, personnel involved, and time taken for filling as well as for holding.

Where filling takes place over extended periods, i.e. longer than 24 hours (Worst Case Study), the Aseptic process simulation test shall be extended over the whole of the standard filling period.

For Aseptic process simulations sterile filtered air shall be used instead of inert gases, Nitrogen Flushing / Purging shall not be done at any stage (irrespective of the normal product requirement) as the Inert Gas will prevent the growth of aerobic microorganisms also for breaking a vacuum.

Where anaerobes are detected in the Environmental Monitoring or Sterility Testing, the use of an Inert Gas shall be considered for a Process Simulation, as Inert Gas is supporting the growth of Anaerobes.

All Aseptic pressure vessels shall be covered by a Process Simulation Test on a regular basis unless a Validated, Pressure Hold or Vacuum Hold Test is routinely performed.

Media fill Batch Document Numbering: The BPR number shall be assigned as –

BPR/MFC/CI-NNN – Where,

BPR – Batch Processing Record.

MFC – Stand for media fill Cephalosporin.

CI – Stand for Cephalosporin Injection.

NNN – Stand for Sequence No.

Example: BPR/MFC/CI-001

Batch Numbering: Media fill batch numbering shall be assigned as per following procedure: MXXX.          Where, M- Media Fill, XXX -Serial Number of the media fill

Example: CDM001 Represents the first media fill batch in cephalosporin dry powder injection area.

Operation:

3% w/v SCDM shall be used for media fill simulation following by dosing of sterile mannitol equivalent to product filling.

Growth Promotion Test (GPT) to 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 to 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.

Manufacturing of media shall be done as per the batch manufacturing record.

For new aseptic processing line initially as startup qualification, three consecutive separate successful aseptic media fill run shall be carried out for each size of vial with respect to all configuration of vial and stopper system. Three runs also shall be taken on container closure integrity change. Subsequently periodically Media fill run shall be planed semiannually with one media fill run and each vial size with respect to all configuration of vial and stopper system shall be covered annually in media fill.

Perform manufacturing, sample collection, filling; visual inspection operation and reconciliation of the media as per procedure given in media fill BPR.

Carry out steam sterilization of garments, manufacturing and filling machine parts, manufacturing, filling and filtration accessories as per respective SOP.

Fill volume of media shall be sufficient enough to wet all inner surface of the container on inverting or as per the batch size to be simulated.

The fill volume of the containers should be sufficient to enable contact of all the container-closure seal surfaces when the container is inverted and also sufficient to allow the detection of microbial growth.

In process checks during filling shall be carried out as per respective SOP.

Filling line shall be simulated over Minimum, Optimum and Maximum Filling machine speed.

Duration of runs shall be equal to or more than longest run taken in actual production or expected to take in production and shall be specified in the protocol.

Where filling takes place over extended periods, i.e. longer than 24 hours, the process simulation test shall extend over the whole of the standard filling period.

Media fill batch shall mimic the actual batch size of commercial production if batch size is lower than 5000 units.

Batch Size of the media fill shall be taken equivalent to the size of individual API Container.

All the steps and events shall be recorded in batch processing record.

The process simulation test shall represent a “worst case” situation and shall include all manipulations and interventions likely to be represented during a shift.

After completion of media fill activity reconciliation shall be done.

Personnel:

All personnel shall follow the entry and exit procedure as per respective SOP of area and only authorized personnel shall enter the aseptic area.

All personnel shall follow SOP (SOP/C/DI002) in aseptic area.

All personnel working in aseptic area shall participate in aseptic media fill at least once a year.

It is mandatory to participate in aseptic media fill for new personnel working in aseptic area & QA issue a certificate for working in aseptic area.

Number of maximum allowable persons in filling area shall be established after media filling operation.

Interventions during Media Fill:

During the aseptic media fill activity, planned interventions shall be performed that mimic the actual process interferences that can be encountered during the routine product manufacturing.

All interventions shall be recorded in BPR & vial shall be incubated separately to represent the each intervention. Two types of interventions are as follows:

Routine Interventions: Routine intervention is also called inherent interventions as these interventions are the inherent part of the media fill run. Routine intervention is as given below:

Inherent intervention (Routine intervention):

1. Aseptic Assembly of machine parts
2. Recharge Mannitol into powder filling hopper
3. Fill weight adjustment (Mannitol)
4. Fill volume adjustment of SCDM during validation
5. Assembling of Stoppering Unit
6. Transfer of stoppers to vibrator
7. Adjustment fitting and filling of syringe/nozzles
8. Microbial Environment monitoring
9. Picking of filled vials for in-process checks
10. Breakfast / Lunch / Dinner break line stoppage
11. Vial stuck in the in feed
12. Microbiological sample collection
13. Cleaning of infeed and outfeed conveyor by stopping the filling machine
14. Unavailability of vials on the feed turn table (line stoppage)
15. Filling at Minimum And maximum filling speed
16. Shift Change over
17. Pushing the seal cap in the seal rail and seal bowl by sterile forceps
18. Loading of seals into hopper
19. Height adjustment of seal chute, seal head and seal hopper

Routine Interventions/ Rare interventions (non-routine intervention):

1. Removals of tilted/fallen, filled/unfilled vials from the infeed turntable.
2. Removals of tilted/fallen, filled/unfilled vials from the outfeed turntable.
3. Movement of swing conveyor during the rubber stopper loading.
4. Removal of empty vials broken form the conveyor online
5. O-RABS glove replacement
6. Handling of spillage in filling line
7. Operator Fatigue due to extended working hours
8. Simulation of maintenance in Vial filling infeed tum table
9. Entry of maximum number of persons (07 persons)
10. Filling machine stoppage due non availability of compressed air

Environment Monitoring:

Environmental monitoring during media fill shall be equivalent to normal product filling.

Environment monitoring include Settle plate, Air sampling, surface monitoring (Swab/Contact plate), non-viable particle, Temperature, Relative Humidity and pressure differential monitoring shall be planned as per respective SOP.

Utility monitoring compressed air monitoring / water sampling shall be planed as per respective SOP.

Temperature, RH & Differential Pressure.

Personal Monitoring by RODAC Plate & Finger Dab of all persons involved in Media Fill at each exit.

Incubation of media fills units:

Inspected good units including cosmetic defects units (e.g. Particulate problem, Volume Variation etc.) shall be transferred for incubation.

Damaged (Cracked) units or broken or missing seal shall be rejected (not to incubate) and documented in aseptic simulation record. After visual inspection is completed, 100 % reconciliation of all filled units shall be done, and any deviation shall be justified.

The units filled during initial start-up for priming the machine as well as volume adjustments shall be incubated separately.

Production personnel shall handover the Media fill vials to Quality Control department for incubation as per SOP.

Before incubation at each stage all containers shall be inverted in such way that internal surfaces of closure of unit shall come in contact with the medium.

Incubation Temperature for I^st 7 days at inverted position (NLT 168 Hours) suitable for Yeast & Mold growth: 22.5 ⁰C ± 2.5 ⁰C.

Incubation Temperature for Next 7 days at upright position (NLT 168 Hours) suitable for Bacterial Growth: 32.5 ⁰C ± 2.5 ⁰C. 

The temperature shall be recorded continuously through the circular charts. At the end of the incubation period, these shall be attached to the BMR.

Incase temperature recording device is not functioning then temperature shall be monitored manually at frequency of twice a day.

Any excursion of temperature in incubation rooms shall be investigated and its impact on the incubation of the media filled units shall be evaluated.

Examination:

Visual inspection of each incubated unit shall be carried out after 7 days and 14 days for microbiological contamination using inspection hood with white background.

The examination of the filled units shall be performed by Trained and Qualified Microbiologist with + Ve & – Ve control.

If any unit (s) shows microbiological growth integrity of the unit(s) shall be checked and removed from incubation with appropriate labeling.

The cosmetic defects shall be considered for process evaluation along with good vials.

The passed leak test vials shall be counted for process evaluation.

The contamination (s) shall be identified up to the species level.

Sampling Plan:

Perform sampling as per Sampling Plan attached with respective protocol.

Interpretation and Acceptance Criteria:

If no contaminated unit found, then the aseptic media fill run is valid.

Following steps/actions shall be taken for assigning the state of control in the aseptic manufacturing process.

If contamination unit is found, an investigation shall be carried out Respective SOP which includes an investigation of processing conditions, environmental data, and identification of the contaminating organism up to the species level, to identify the source of the contamination detected.

Batch size (Units)	No. of contaminated units	Interpretation
≤ 5,000	1	Cause for revalidation, following an investigation.
5,000 to 10,000	1	Investigations, including consideration for repeat media fill.
	2	Cause for revalidation, following an investigation.
≥ 10,000	1	Investigation
	2	Cause for revalidation, following an investigation.

Investigation shall also be considered during following conditions:

If pre and post GPT test (after 14days incubation) of SCDM is not comply.

Media negative control shows any Microbial growth.

Destruction of media filled vials:

Destruction of the media fill vials after the incubation period shall be done as per respective SOP.

Cleaning after media fill:

The cleaning after aseptic media fill shall be carried out as per respective SOP.

Cleaning and disinfection of instrument and equipment shall be done as per the respective SOP of equipment and instrument.

In addition to verify the cleaning process of the equipments shall evaluate by TOC, pH, conductivity & visually cleaning check. The acceptance criteria of limits shall be given as:

Test	Limit
pH	5.0-7.0
Conductivity	NMT 1.3µs/Cm2
TOC	500 ppm

Media Fill failure investigation: If any growth observed than investigation shall be carried out as per Respective SOP.

A contaminated container shall be carefully examined for any breach in the integrity of the container system.

Damaged containers shall not be considered an evaluation (acceptance) of an aseptic processing capability of the process. However, a vial that is broken during incubation should be addressed.

All positives from integral containers shall be identified to at least genus and species whenever possible.

Identify the contaminant and compare the result to the database of the organisms most recently identified.

Processing records should be reviewed. Critical systems shall be reviewed and documented for changes.

Calibration records shall be checked.

All HEPA Filters in the Filling Area shall be inspected and decertified if warranted.

Personnel involved in the fill shall be assessed to assure the proper training was provided.

Validation and change control records shall be reviewed for any procedure or process changes.

A full risk analysis should be performed.

A media failure signals an underlying weakness of the system or the process.

The final investigation report should contain the following:

A summary of the occurrence

All systems investigated, not just the systems tied to the failure

A conclusion as to the cause and supporting documentation

Potential effect on previous batches since last media fill

Corrective action

Outcome of additional process simulation tests if they were performed

This investigation needs to be completed in a timely fashion. It may be necessary to issue   an interim report.

Three consecutive successful process simulations are required to qualify a new or significantly revised change aseptic line or area. If there has been a failure on any process simulation without an assignable cause, one process simulation is required for re-qualification of an aseptic processing line

Frequency of Aseptic media fill run:

Aseptic media fill run shall be carried out once in six months (once in six months ±01month).

After modification / shutdown in aseptic area.

Introduction of new container closure System,

If no assignable cause for sterility failure during routine manufacturing.

REFERENCE:

SOP for SOP

PIC/S recommendation on the “Validation of Aseptic Process”, January 2011.

Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice September 2004 Pharmaceutical CGMPs.

PDA Technical Report No. 22 (Revised 2011), Process Simulation for Aseptically Filled Products.

SOP FOR INVESTIGATION OF MEDIA FILL FAILURE

PURPOSE: To lay down a procedure for Media fill failure Investigation.

 SCOPE:  This Standard Operating Procedure is applicable for Media fill failure Investigation.

RESPONSIBILITY:

Preparation of SOP: Officer QA Department

Checking and Review of the SOP: Executive QA Department

Approval of SOP: Executive QA Department

Authorization of SOP: Head QA/Designee

Concern person from the department where contamination observed is responsible for intimation of media fills failure to QA.

Head – QA/ Designee shall inform to all departments about media fill failure and subsequently organize a team for investigation.

Concern department head/ designee is responsible to provide all necessary support to investigation team during investigation.

Head QA/ Designee is responsible to make final conclusion and to ensure the implementation of necessary Corrective and preventive action.

Head QA is responsible for overall compliance of this SOP.

ACCOUNTABILITY: The accountability of implementation and compliance of the SOP is Head Quality Assurance.

PROCEDURE: Concern person from the department where contamination is observed shall inform the media Fills failure to QA.

Head QA/Designee shall immediately organize a team to precede the media fill failure investigation and team names shall be mentioned in SOP.

Investigation team shall give the request to documentation cell-QA for issuance of investigation form; media fill failure report and other format as required.

Documentation cell QA shall issue the investigation checklist & media fill failure report to investigation team with reference number, allotted.

QA department shall allocate reference number to the Media fill failure, as per instruction given below.

Number shall be given as MFF XXYY, Where

MFF stands for Media Fill Failure.

XX stands for the year

YY stands for the media fill failure number which starts from 01.

e.g. First media fill failure in year 2025 shall be numbered as MFF2501.

Investigation team shall mention the media fill failure description and immediate action on failure.

Investigation team shall initiate the investigation as per checklist.

After completion of investigation as per investigation checklist, report shall be prepared by investigation team as per SOP.

If no root cause is found, then investigation team shall denote extended investigation is required and subsequently further investigation shall be started as per SOP.

All-encompassing brainstorming session on the Ishikawa fish bone diagram can be used during investigation as shown in SOP, but this is not limited for investigation.

Extended investigation shall be carried out as per following sequence:

Phase 1- Laboratory Investigation:  

During this investigation phase at quality control end, through review shall be carried out by investigation team including but not limited to media preparation, Sampling and microbiology related activities, training and expertise of analysts, trends of environmental monitoring of related areas, environmental isolates, personal qualification data, any other reason to all concerned person’s involved in sampling and    Environment monitoring etc.

Co-relation of identified isolate from the contaminated vials to any other Contamination observed on surfaces, environment, personnel etc.

Detailed conclusion report shall be prepared for investigation and if root cause found which is laboratory related then necessary CAPA shall be initiated.

If no laboratory related cause was found which lead to failure of media fill then further Phase 2 investigation shall be carried out.

Phase 2- manufacturing Investigation: 

Complete manufacturing: filtration and filling process and equipment’s /instruments involved shall be reviewed thoroughly for their qualifications, validations and calibrations.

All entry- exit procedures, cleaning procedures shall be reviewed.

The persons involved in related activities like aseptic connections, cleaning, sterilization shall be evaluated for all prospective.

All related record of disinfectant preparation, cleaning, sterilization, differential pressure etc. shall be reviewed.

Trends of environment monitoring of all the areas shall be reviewed.

Water and utilities used and their analysis results for all user points related to process shall be reviewed.

Detailed conclusion report shall be prepared for investigation.

After completion of extended investigation, media fill failure investigation report shall be prepared. report shall include but not limited to below details,

• Batch details.
• Date of incubation.
• Failure observed on.
• of contaminated vials.
• Details of primary packaging material used.
• Immediate action taken after reporting of failure.

Detailed Phase 1 investigation i.e. laboratory investigation at quality control end and Conclusion.

If required further Phase 2 investigation – Process related deformities and conclusion.

Suggested CAPA for implementation.

The effectiveness of corrective measures shall be verified separately prior to conducting additional run of media fill.

Conclusion shall be written in investigation report indicating root cause of failure.

Necessary CAPA, if required shall be suggested by investigation team with co-ordination to Head-QA and same shall be marked in investigation report.

Implemented and effectiveness of CAPA shall be accessed by concern department with co-ordination to QA department prior to conducting next media fill run.

After necessary CAPA implementation the investigation shall be closed and contaminated vials shall be destructed after authorization from Head QA/Designee.  

REFERENCE:                    

Standard Operating Procedure for Standard Operating Procedure.

PIC/S recommendation on the “Validation of Aseptic Process”, January 2011.

PDA Technical Report No. 22 (Revised 2011), Process Simulation for Aseptically Filled Products