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

SOP ON INPROCESS CONTROLS

PURPOSE: To lay down a procedure for in process control in dispensing area, oral preparation (Tablets, Capsules & Dry Syrup) and in Dry powder Injection.

SCOPE: This SOP is applicable for the Tablet Capsule dry syrup orals dosage Forms and Dry powder Injections for different products manufactured

RESPONSIBILITY:

Preparation of SOP: Officer/ Sr. Officer

Checking and Review of the SOP: Executive /Sr. Executive

 Approval of SOP: Assistance Manager or his designee

 Authorization of SOP:  Head QA/ Designee

ACCOUNTABILITY: Head QA/ designee shall be accountable for implementation and compliance of the SOP.

PROCEDURE: QA/Production person shall inspect various in process parameters at different processing stages.

INPROCESS CONTROL IN DISPENSING AREA:

Cleanliness of working area, equipment’s and involved personnel’s, proper housekeeping shall be checked.

The areas, equipment, containers shall be checked with proper status Labels. Line clearance and proper segregation of materials, equipment’s and process shall be verified.

Temperature and relative humidity of the area shall be verified.

Verify whether persons handling materials is using hand gloves, uniform and nose mask or not.

The dispensing operations shall be checked for its compliance with respective BMR. Following points shall be checked.

Verification of weight balance and its calibration status.

Raw materials: its quantity, identification, physical status/ dispensing labels.

Machine being used is identified on properly set using proper accessories etc.     

Documentation is being done simultaneously. 

Ensure the cleaning & availability of dispensing accessories i.e. barrel pump, Scoops, etc.

TABLET: INPROCESS CHECKS DURING PROCESSING:

Dry Mixing: Visually Check the Active ingredients & Excipients, it should be uniform mixed. Then send the sample to QC for blend uniformity analysis.

Granulation: Granulation process simply involves wet massing of the powder blend with a granulating liquid to produce granules with different physical properties. Check the mixing time and speed during granulation process. 

Milling: wet granulation might need to be milled to break up and enhance drying of the granulation. Check the mill speed, Screen size and its integrity as per BMR.

Drying: The optimal moisture content of the dried granulation needs to be determined. High moisture content can result in tablet picking or sticking to tablet punch surfaces and poor chemical stability as a result of hydrolysis. An over dried granulation could result in poor hardness and friability. So check the drying time during drying process and moisture content after drying process.

Lubrication: To reduce the friction during tablet ejection between the wallsof the tablet and die cavity. Check in process control Bulk Density, Particle Size distribution, Moisture content after lubrication. Moisture content should be within specified limit give in the respective Batch Manufacturing Record and record the observation in the Batch Manufacturing Record.

Compression: Check the physical appearance of tablet as per specification given in respective Batch Manufacturing Record and ensure that correct punches (lower and upper punch) are used and also for any defects like sticking, Chipping, Cracking or any collar projections due to punch damage.

Thickness, diameter, length and width (capsule shaped) – check thickness and diameter of five tablets from both sides in every two hours (limit as Specifications of the tablets) by using vernier caliper and record observation in the Batch Manufacturing Record.

Hardness- checks hardness of five tablets from both sides in every two hours (limit as per specifications of the tablets) by using calibrated Hardness tester and record observation in the Batch Manufacturing Record.

Friability – check friability of 20 tablets or 6.5 gm. of tablets, whichever is less from composite samples from both the sides in every two hour. (IP limit is NMT 1%).For tablets with unit weight equal to or less than 650 mg take a sample of 20 tablets. For tablet with unit weight of more than 650 mg take a sample of 10 tablets. Check the initial weight of 20 tablets, weight of 20 tablets after friability and record observation in the Batch Manufacturing Record.

Disintegration – check disintegration time of 6 tablets with or without disk from composite sample from both the sides in every two hours. Record observation in the Batch Manufacturing Record.

Uncoated Tablet	NMT 15 min, in water with Disc 370C ± 20C
Coated Tablet	NMT 30 min, In water with Disc for Film Coated Tab, and NMT 60 min Other than Film coated tablet
Enteric Coated Tab	Intact for 1 hr. in 0.1 N HCl & disintegrate within 2 hr. in Mixed 6.8 Phosphate buffer.
Dispersible/Soluble	Within 3 min in water at 15 – 250C (IP)
Effervescent Tab	5 min in 200 ml water at 15-250C (IP)

Average Weight of 20 tablets – check weight of 20 tablets from both the sides in every 30 minutes (±1% of the standard weight of 20 tablets).

Individual weight variation of tablets – check individual weight of 20 tablets from both the sides in every 2 hours equal to the number of punches rounded off the nearest value e.g. for 27 station machines, number of tablets to be Checked is 30, in every 2 hours (limit- depends on the average weight).

IP	USP	Limit
80 mg or less	130 mg or less	10%
More than 80 mg or less than 250 mg	130 mg to 324 mg	7.5%
250 mg or more	More than 324 mg	5%

If any abnormality found, stop the operation and inform to the concerned Production chemist to rectify.

Coating: Check the % Weight gain of tablet at the end of coating process and colour uniformity after coating process.

Check Average weight of 20 tablets (Limit ± 1%), Individual weight Variation, Thickness, Hardness, Disintegration time (except sugarcoated) Record observation in the Batch Manufacturing Record.

Packing: QA officer shall inspect the Status Labeling of Area and Equipment. QA/Packing officer shall inspect Various in process parameters during packing.

Cutting edges of Physical appearance of the forming should be proper –During packing after every 1 hr.

Embossing should be visible and readable – During packing after every 1 hr.

Check the printed and unprinted packing material as per packing order and verify the quantity (Refer BPR).

Check the coding details w.r.t. batch no. , Mfg date, exp, Date, (ref. BPR) Check the coding details on strip, blister, Label, unit carton,

Scratch marks and spots on strips. – During packing after every 1 hr.

Chipped/capped/broken tablets- During packing after every 1 hr.

Leak Test- During packing after every 2 hr.

Correct Batch number and Mfg. and expiry embossed on the aluminum foil-once in the beginning.

CAPSULE: INPROCESS CHECKS DURING PROCESSING:

Blending: Check and ensure that machine/equipment/accessories bears the machine/Equipment/ bin container status label of current batch as per Batch Manufacturing Record.Verified that all entries are completed in BMR up to the previous stage of that activity. Verified the RH, Temperature of Blending room which should be within specified limit and record the observation in the Batch Manufacturing Record. Check the integrity of sieve visually used for sifting randomly in sifter.

Filling: Ensure that blend powder is analyzed and released before starting up the filling   activity. Check that the container to be used for filling bears the product status label and is fixed on the machine at gravity feed receptor in such a way there is no spillage of powder. Verified the RH, Temperature of filling room which should be within specified limit and record the observation in the Batch Manufacturing Record. Various in process parameter is to be checked during filling stage.

Appearance, size and colour of the capsule as per specified in BMR- once in the beginning and checks at regular interval of 2 Hours.

Weight of empty capsules – check weight of 20 empty capsules-once in Beginning.

Locking length – check locking length of 10 filled capsules in every 2 hours.( limit – ± 0.5 mm of the standard value)

Individual weight variation of capsules – check individual weight variation of 20 filled capsules in every 2 hours.

Acc. to I.P/B.P.	Limit
Less than 300 mg	10%
300 mg or More	7.5%

Weight of 20 filled capsules – check weight of 20 filled capsules in every 30 minutes (limit ± 1% of the standard value)             

Disintegration – check disintegration time of 6 capsules with or without disk in every two hours.

If any abnormality found, stop the operation and inform to the concerned Production supervisor to rectify. Recheck and ensure that the parameters are within the limits record the observation in the Batch Manufacturing Record.

DRY SYRUP: INPROCESS CHECKS DURING PROCESSING: During granulation equipment used cleanliness to be checked.

During sugars drying and sifting in process check

Drying record to be filled in starting of process.

Check the mesh size, integrity of mesh before and after sifting.

Check the blender with speed as mentioned in BMR.

Bulk sample analysis to be done as per BMR.

Check the weight of the granules as per BMR.

Input material verification to be done.

Air pressure must be check at initial and every two hours

Filling and Sealing machine speed with environment condition initial every.

One hour and end process.

Check in process control of induction sealing frequency every two hours and initial and end of the process.

Check in process fill weight of bottles frequency every 30 minutes.

Check visual inspection for filled and sealed bottle.

Check sensor challenge test of labeling and carton coding initial end and every two hours.

DRY POWDER INJECTION: INPROCESS CHECKS DURING PROCESSING: Size, colour of the Vials as per specified in the BMR – Once in the beginning.

Vials decartoning and equipment cleaning in process check at starting.

Check the in-process clarity check of washed vials randomly at start and in every 2-hour interval.

Vial washing parameter in process check at every 2 hours (PW WFI compressed air pressure)

In process check during sterilization and depyrogenation every 1 hour.

Environment monitoring (RH and temperature and DP to be done every 2Hour. 

In process check in weight variation at starting of filling and frequency check every alternate hour.

Temperature and RH in process every alternate hour.

Vacuum leak test: Vials from all sealing heads (8 vials from each head) should be tested for the leak test initially then every two hours.

REFERENCES

SOP for SOP

USP 40

IP2018.

SOP ON GAP ASSESSMENT

PURPOSE:  The purpose of this Standard Operating Procedure is to lay down the procedures for periodic review of respective standard operating procedures, Validation Procedure and other activities to find out the possibilities of improvement.

SCOPE: This SOP is applicable for review and updating of standard operating procedure, Validation Procedure and other activities to find out the possibilities of improvement in all departments at manufacturing facility.

RESPONSIBILITY:

Preparation of SOPs: Officer/Sr. officer of Quality Assurance Departments

Checking and Review of the SOPs: Sr. 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

ACCOUNTABILITY:

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

PROCEDURE: User department and Quality assurance shall review and perform the gap assessment against the regulatory guidelines like data integrity, risk assessment, good manufacturing practices, good laboratory practices, good documentation practices, etc. to eliminate the possible non-compliances.

Gap assessment shall be carried out for specific inspection like FDA, MHRA, WHO-GMP, TGA, EU-GMP, etc. on the basis of respective regulatory guidelines.

The identified gaps shall be notified by QA department or Concern department user through a format along with change control.

Gap assessment shall be done step by step starting from purchase to finish product dispatch. Gap assessment shall be done in all departments in following steps:

Identification of Areas

Preparation of Checklist

Gap Analysis

Identification of Gaps

Corrective Action

Review of Implementation

Identification of gap closed according to the severity of the gap as seven days for high risk, 15 days for medium risk and 30 days for low risk.

QA Head shall decide if any identified gap requires risk assessment and subsequent risk mitigation plan.

In case a new regulatory requirement is introduced by the regulatory agency, a new SOP shall be prepared by respective user department or based on the feasibility and relevance, the same can be included in existing procedures.

The non – compliances issued by the regulatory agency to other organizations shall also be covered during the gap assessment and in case any gap is observed, QA Head shall decide the further course of action.

QA personnel shall allocate a twelve-digit number to the gap assessment and sign with date.

The number shall be in GA/DD/YY -001 format, where

GA:  Denotes gap assessment.

DD: Denotes the Department for Example for QA: Quality Assurance

YY : Denotes the last two digit of the current Year.

The last three numerical characters are serial number starting from 001 for the year and continuing serially in increments of one unit.

The Following code numbers shall be used to identify various departments for allotting Gap Assessment Number,

Quality Assurance shall maintain the logbook of gap assessment during the Year.

SOP FOR REPORTING OF INVESTIGATION

PURPOSE: To lay down a procedure for reporting of investigation.

SCOPE: This SOP is applicable to for the quality related failures of product, which do not meet the acceptance criteria.

RESPONSIBILITY: 

Personnel of concern department are responsible for the Quality Related failures of product.

Concern-HOD or designee shall investigate and conclude the investigation to find root cause

Head QA or designee shall evaluate root cause and ensure the compliance and implementation of agreed corrective and preventive actions.

ACCOUNTABILITY: User department Head and Head-Q. A Shall are Accountable for implementation and compliance of SOP.

PROCEDURE

Product failures shall be reported in the “Failure Investigation Report” form.

The “Failure Investigation Report” form shall be issued by QA on request. A “Corrective and Preventive action” form shall be issued along with “Failure Investigation Report” form.

Before issue the failure investigation report shall be numbered serially in the calendar year with an identification code of department.

A typical Failure investigation shall be numbered as:  FI/XX/ZZ-YYY

Where, FI: Failure investigation

XX: Department code

ZZ: Last digit of the calendar year

YYY: Serial number commencing at 001 in the calendar year.

The “Failure Investigation Report” number and details of failure shall be recorded in the failure investigation log.

“Failure Investigation Report” form shall be filled by concerned department.

The initiator shall fill the details like Department, Name of product, Batch No. and Date on the form, along with the description of the failure and source information.

The initiator shall sign and forward the form to the concerned department.

Concerned department shall fill the investigation of failure column with details of document review and probable reason and proposed corrective and preventive actions. If required additional sheets can be attached. The department head shall sign and forward the form to Head QA.

The investigation shall be conducted by concerned department Head in consultation with Head QA. Investigation team shall be cross functional team comprising of members from following functions like Initiating department, Quality Assurance, Quality Control, Manufacturing, Engineering, Formulation & Development and Warehouse etc.

Depending on the nature of the failure, the investigation team shall list down all the documents which need to be reviewed as part of the investigation like Batch Manufacturing Records / Batch Packaging Records of the specific batch for critical parameters. 

Control Samples: 

Analytical data of RM, PM 

In process & Finished products 

Stability data  

Cleaning records

Instrument / Equipment calibration /qualification status

Personnel training record

Interview of involved personnel

Trend data

Note: The personnel of Production, QC and QA shall carry out the review of the documents

Head QA shall review the investigation of the failure column with details of document review and the probable reason for failure by using investigation tools like

Brain storming

Affinity Diagram or chart

Root cause and Effect Analysis:

Fish bone diagram/ Ishikawa diagram (Cause and effect diagram)

5 why

Impact assessment

Conclusion

Brain storming:

Brainstorming is a situation where a group of people meet to generate new ideas and solutions to find a conclusion for a specific problem. In this session people are able to think more freely and they suggest as many spontaneous new ideas as possible. It is to be performed immediately upon receipt of complaint/ deviation. Following question to asked but not limited to:

What happened? Describe actual problem. Provide Details of the defect. What has happened to the product?

When did it happen? When was the defect discovered?

Where did it happen? What were the situation/ location?

What is the impact? What is the impact over the product? What could be impact over the batch/ other batches in market?

What could be the probable causes that have lead to this defect/deviation?

Whether similar nature of defect reported in past?

Was any breakdown observed in the equipment or instrument during the manufacturing?

Has any in-process check failed during manufacturing?

Was any deviation reported during manufacturing?

Note: Based upon the brain storming session, Fish bone diagram is to be derived. 

Affinity Diagram or chart:

The affinity diagram organizes a large number of ideas into their natural relationships. It is the organized output from a Brainstorming session. It can be used to generate, organize, and consolidate information related to a product, process, complex issue, or problem. After generating ideas, group them according to their affinity, or similarity. The affinity diagram organizes ideas with following steps:

Record each idea on cards or notes.

Look for ideas that seem to be related.

Sort cards into groups until all cards have been used.

Once the cards have been sorted into groups the team may sort large clusters into subgroups for easier management and analysis

Root cause and Effect Analysis : 

Fish Bone Diagram or Ishikawa diagram (Cause and effect diagram)

Ishikawa diagrams also known as fish bone diagram in which the defect is shown as the fish’s head, facing to the right, with the causes extending to the left as fish bones the ribs branch off the backbone for major causes, with sub-branches for root-causes, to as many levels as required.

Analysis of Fish Bone diagram:

Man:

Educational Qualification

Experience

Association with Company

Workload

Machine:

Qualification

Preventive Maintenance

Breakdown

Calibrations

Measurement:

Inprocess checks

Release testing

Control sample testing

Stability testing

Material:

Raw material (API& Excipients)

Packing materials

Semi-finished Goods

Method:

Dispensing

Sifting

Granulation ( Dry & Wet Granulation)

Blending

Capsule Filling

Compression

Coating

Visual Inspection

Packing (Blistering, Bottle packing & Dry Syrup Filling etc.)

Mother nature (Environment)

Details of Temperature, RH and DP during the process & storage 

5 WHY:

Based upon the probable root cause, conduct a 5 Why? Analysis to reach to root cause. For example but not limited to

WHY   → High DT

↓

WHY → Over lubrication → WHY

↓

More mixing in force feeder

↓

WHY   ← Slow machine speed with high feeder RPM      ← WHY

↓

Parameters not defined in BMR

Review of complaint history:

Include details of any similar defect/ deviation reported in past.

What was the root cause of that defect?

What were the CAPA derived?

What is the status of those CAPA? What is the difference between current scenario and the past scenario?

Impact assessment:

Include the impact of this defect over other batches.

Were the batches manufactured in campaign?

Whether the defective RM/ PM used in this batch was used in other batches?

What is the recommendation for those batches?

Include the details of the impacted batches’- batch no. mfg. expiry, customer etc.

Whether any action is required to be initiated for the impacted batches.

Conclusion:

Include the actual root causes.

Include the review of complaint history.

Include details of impact assessment

All the Investigation tools mentioned above shall be used in case of any Market complaint, Product complaint and in case of any deviation to find out the root cause but not limited to. Other tools also can be used to find out the root cause for any problem. Based upon the root cause Appropriate CAPA shall be taken. 

QA head shall be Performed a detailed investigation to identify the root cause for the reported non-compliance or failure in order to take an appropriate corrective action to avoid recurrence. 

Based on the investigations concerned department Head shall document the findings and shall propose Corrective and Preventive actions to correct the failure and to avoid recurrence. The proposed Corrective and preventive actions shall be reviewed by Head QA. 

Head QA shall evaluate all the relevant documents and the impact of failure on associated batches and on existing facility, system, equipment, documentation and suggest the necessary recommendations to correct the failure and to avoid the recurrence. Head QA shall sign on the form and a copy shall be forwarded to concerned department.

In case, where experiments are required to be conducted at Production / QC, necessary samples shall be withdrawn. Data shall be reviewed by QA.

Concerned department shall carry out the implementation of the Corrective and Preventive action by updating required documents and/or system.

Concerned department shall summarize the implementation of Corrective and Preventive actions and send the form to Head QA for comments.

Head QA shall review the corrective and preventive actions implemented and shall send the filled form to Head QA.

Head QA shall review and update the related documents, wherever applicable and verify the implementation of corrective and preventive action taken.

Failure investigation shall be closed by Head QA after verification of the implementation of CAPA.

REFERENCES 

SOP FOR SOP

Handling of out of specification

Handling of CAPA SOP

SOP ON BATCH CONVERSION

PURPOSE:  To lay down the procedure for Batch Conversion.        

 SCOPE: This SOP is applicable for Batch Conversion Procedure.

RESPONSIBILITY:

Preparation of SOP: Officer/ Sr. Officer

Checking and Review of the SOP: Executive/Sr. Executive

Approval of SOP: Head of Department/ Assistant Manger

Authorization of SOP: Head QA/Designee

Head Production shall be responsible for initiating conversion request.

Head Warehouse shall be responsible to ensure transferring of stock as per conversion note.

Head QC shall be responsible to ensure sampling & testing of material. (lf required).

IPQA Persons shall be responsible for compliance the procedure.

ACCOUNTABILITY: Head QA shall be accountable for this SOP.

PROCEDURE:

Product manufactured on generic/branded name shall be packed on different brand name or pharmacopeial status.

If manufacturing master formula is same then batch manufactured on any specific brand name/generic name, shall be packed for different brand name.

lf the product is manufactured and tested as per specific specification, same shall be converted into required specification, if all the raw materials and the finished product shall comply as per required specification.

As per the marketing requirement Production department shall initiate the finished product conversion request & takes the approval from manufacturing, packing and QA.

Based on the conversion request, lPQA shall withdraw the sample (if required) and send it to QC for analysis. After release by QC, batch shall be further packed as per approved request or QC person review the specification and carried out the additional test if required.

Production department shall fill batch record issuance request.

Attached copy of request to the BPR

REFERENCE:

SOP FOR SOP

SOP ON BATCH RELEASE SYSTEM OF FINISHED PRODUCT

PURPOSE: To lay down a procedure for release of finished products for distribution.

 SCOPE: This SOP is applicable for release of finished product manufactured.

RESPONSIBILITY: Preparation of SOP: Officer/ Sr. Officer.

Checking and Review of the SOP: Executive/Sr. Executive

Approval of SOP: Head of Department/ Assistant Manger

Authorization of SOP: Head QA/Designee

Production Head/Designee: For completeness, correctness of BMR, BPR.

QC Head/Designee: Analytical testing and Preparation of COA.

IPQA Personnel/Designee: To review batch manufacturing, Packaging and analytical records for batch release.

Head QA/Designee: Batch release.

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

PROCEDURE:

Definitions:

Finished Product: A Product in the marketable pack is classified as finished product. Practically a transportable pack, i.e. a shipper containing the salable pack (in retail) is considered the finished product.

Quality Review: Before a finished product is released for sale or distribution, the complete production and control records must be reviewed and assured satisfaction about the entire stage in the control process before the product moves out of the manufacturing premises.

Batch release document: All relevant paperwork for a particular batch, including samples of printed cartons, leaflet, shipper labels, Line Openings, Line Clearances records, etc. and collecting them together.

Finished products are packed into the final shippers as per the standard packing instruction present in Batch Packing Record.

Production officer and packing supervisor is responsible for packing of finished product as per the standard packing instructions.

In-Process Quality Assurance Personnel monitor and perform the different packing control tests and to ensure the fill value/standard coding details.

Production personnel prepare finished goods transfer Note (in Triplicate) after the completion of whole batch packing/part batch packing as per Format the FGTN no. Shall be given as G/XX-YYY.

Where G denotes General, XX denotes the last two digits of current year, next character is “-” and last three digits YYY are continuous serial number.

Production officer to compile all the attachments of the Batch Packing Records (BPRs) Viz., packing material dispensing tags, specimen sample of blister/carton/product label/shipper label as applicable along with compiled Batch Manufacturing Record (BMR) and its attachments and and submit to In-process Quality Assurance Personnel.

IPQA Personnel to attach the In Process Quality Assurance Report to BMR/BPR and verify the reconciliation rejected material destruction, recovery details, yield reconciliation, completion of Signature/ date and other investigation, if any incase of deviation.

The certification of finished product batch performed by a qualified person signifying that the batch is in compliance with GMP and the requirements of its marketing authorization. This represents the quality release of the batch.

IPQA personnel to check the packed shippers against the parameters mentioned in checklist.

All shippers should be checked for appearance, label details and in random should be opened to see the details/ fill value of the inner most container.

Sample for identification, if required shall be drawn from the packed finished product.

If satisfactory submit the duly signed Finished Product/ Goods Transfer Note, BMR/BPR along with all attachments to Executive-Quality Assurance for review.

Quality Assurance reviews the Batch Manufacturing Record (BMR) and Batch Packing Record (BPR) and ensures all deficiencies (If any) corrected.

Verify all check point as per the “QA Release Check List.

Hand over the two copies of “Finished Good Transfer Note” to Production and Warehouse Personnel.

Production Personnel transfer the finished goods to stores along with approved copy of finished goods transfer note.

Finally qualified person ensures the completion of Batch document, Analytical reports, IPQA reports, and QA release check list completion and to approve the Finished Product Transfer Note indicating the approval for transfer of batch to stores.

QA issue the “Batch Release Certificate”

Attach a copy of finished goods transfer note and original Batch Release Certificate and finished product release report along with BMR/BPR review check list, BMR/BPR deviations/ deficiencies form and filled QA release check list to the Batch document and archive in Quality Assurance.

Qualified Person (QP): 

Qualification/Experience: The QP must have relevant qualification and experience in the manufacture and quality control of finished pharmaceuticals formulations as required.

Education: He / She should have at least four years of theoretical and practical study In pharmacy or graduate / postgraduate in medicine, veterinary medicine, chemistry, pharmaceutical chemistry and technology or biology.

Experience: He / She should have minimum 5 years of practical experience in pharmaceutical manufacturing / Quality Assurance / Quality Control.

He/ She should have in-depth knowledge of manufacturing process, controls and QC.

He/ She should have the knowledge on current Regulatory Guidelines, PIC/S, WHO

GMP, EU and Schedule M.

Certification process: The QP shall be trained and evaluated as per SOP. 

Certification of QP as per SOP and List of QP shall be recorded. 

Re-certification: Periodic re-evaluation shall be done once in 2 years. After the

Satisfactory evaluation, Quality Assurance Head / Head of department / Designee shall issue the certificate for Qualified Person for batch release as per Format.

REFERENCE: Standard Operating Procedure for Standard Operating Procedure

Eudralex-The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 16: Certification by a Qualified Person and Batch Release.

SELF INSPECTION CHECKLIST FOR WAREHOUSE

RAW MATERIAL STORAGE AREA:

• General cleanliness
• Temperature and relative humidity measurement records
• Raw material receipt procedure
• Quantity verification of Raw material against purchase order
• Physical inspection of incoming goods for physical aspects
• Storage of materials as per the approved list of storage condition
• Weather freezer available for material stored at 2-8 ˚C
• Weather freezer available in RM receiving area, Approved RM area
• Calibration status of Balances
• QC sampling area and sampling procedure
• Labeling status of sampled containers
• Storage location of Under test material
• Storage location of QC approved materials
• Labeling status of QC approved materials
• Storage location of rejected materials
• Labeling status of rejected materials
• Procedure for handling of rejected materials / damaged containers
•  Raw material issuance Procedure
• Documentation system of R.M issuance as per product and batch no
• Inventory control and record
• Procedure for Re-testing of raw materials
• Routine housekeeping Procedure