Quality Control

SOP on Retesting of Primary Packing material

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SOP on Retesting of Primary Packing material

Objective: To lay down the procedure for retesting of primary packing material for material lying in warehouse for longer period.

Scope: This SOP is applicable for retesting of primary packing material for material lying in warehouse for longer period.

Responsibility: Chemist or above of QC Department & Officer or above of Warehouse Department.

Accountability: Head – Quality Control.

Procedure: On receipt of material, warehouse shall send the GRN to QC as per SOP and QC shall perform sampling of packing material as per SOP and release the material as per SOP.

At the time of release of primary packaging material, QC person shall assign in-house retest date of material as per below mentioned table-1

Table-1.

Sr. No. Name of Primary Packing Material Retest Period
1 All type of Foils 2 years
2 Rubber Stopper 6 Months
3 HDPE Containers (Bottle) 2 years
4 White Closure with induction wad 2 years
5 LDPE Bag 2 years
6 Activated carbon 1 gram pouch 6 months
7 1 gram 2-in-1 desiccant  pillow pouch 6 Months
8 Triple Laminated bag 2 years
9 Glass Vials 2 years
10 1 gram Silica Gel Pouch (Roll Form) 6 Months

Retesting can also be carried out as per any directive from Quality assurance department on need basis or risk analysis.

In case, if expiry date assigned by vendor is coming before the in-house retest date, then re-test date shall not be applicable and material shall be considered expired as per label from vendor.

If retest or re-evaluation date assigned by vendor is coming before the in-house retest date, then retest date shall be in line with that of vendor. Thereafter the material shall be reassessed immediate before use to establish its suitability. The validity of this reassessment shall be as per given tablet -1 from the date of release. This shall be followed till the material continues to meet with the specification.

After receiving re-test request from ware-house, QC personnel shall enter the material details in re-test packing material control register.

QC personnel shall allot the A. R. No. by adding suffix ‘/ Rn’ where ‘/’ is for separation, R is for retesting and n is the number of times of re-testing after the initial analysis for the release of the material. For example, if request for re-testing of packing material is received first time and the initial A. R. No. is PM/25/0001 then A. R. No. of re-test material shall be PM/25/0001/R1 and packing Material sampling shall be done as per SOP.

‘TEST FOR RETESTING’ mentioned in the respective packing material specification, shall be performed during retesting of packing material.

Analysis and approval of re-test packing material shall be done as per SOP.

During COA preparation for retested packing material, the analytical data for the test performed during retesting shall be included and other test shall be taken from initial analysis and COA shall be prepared as per SOP.

Expired or rejected packing material shall be destroyed by ware-house as per SOP.

List of Annexure

  • Retest packing material Control Register
  • Test to be performed During Re-testing of primary packaging material

 

Quality Control

SOP on Backup / restore and archive of analytical data in electronic form

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SOP on Backup / restore and archive of analytical data in electronic form

Objective: To describe the procedure for backup / restore and archive of analytical data in electronic form.

Scope: This SOP is applicable for backup / restore and archive of analytical data in electronic form in quality control laboratory.

Responsibility: QC Executive or Nominee & QA Officer and Above

Accountability: Head-QC & Head-QA

Procedure: QC Executive / Nominee shall prepare list of instruments along with software for which backup of analytical data shall be taken as per Annexure.

Backup of Fortnightly Data:

QC Executive / Nominee shall take backup of Fortnightly data from primary drive to pre – defined secondary drive and to external hard disc. Primary Drive and Secondary Drive (to which fortnightly data shall be stored) shall be mentioned in Annexure.

Assign Id. No. to external hard disc as QCHRD-XX, where XX is the sequential number i.e. 01, 02.

Back up path for external hard disc shall be; External hard disc → Year →Month → Individual instrument Id. No. → Analytical data.

QC Executive / Nominee shall create ‘year’ folder, named as ‘YYYY’, where YYYY is for year.

‘Month’ sub folder shall be created on monthly basis and named as ‘XXX’, where XXX denotes first three letters of the month.

‘Instrument Id. No.’ sub folder shall be named as actual instrument Id. No. of the instrument.

Primary drive to external hard disc data backup process shall be maintained.

External hard disc shall be kept under the custody of QC Head.

Primary drive to secondary drive data backup process shall be maintained.

Monthly Archival of Data:

Data from secondary drive shall be archived on DVD on monthly basis and activity shall be recorded.

Note: Month shall be considered from first day to last day of the calendar month.

DVD shall be labeled as per following pattern; e.g. SM/XXXXX-ZZ/MM/YY

Where; SM denotes Storage media , XXXXX – Instrument Id., ZZ -Number……01, 02…… ,MM – Month ,YY- Year….07, 08, 09…

Monthly archival shall be completed within 15 days of next month.

The Data Storage media carrying the archived data shall be handed over to QA department.

QC Executive / Nominee shall ensure that primary drive and secondary drive of each system shall not contain data older than two months prior to current month at the time of monthly archival.

The Data Storage media shall be labeled for identification with following details:

Instrument Name & Id. No., Computer Id. No., Archived Data Period.

Verification of Archived data:

QC Executive / nominee shall verify the integrity of the archived data from primary drive to secondary drive or in DVD and in hard disk w.r.t the data lying in primary drive and record shall be kept.

QC Executive / nominee shall restore archived analytical data from DVD & hard disk and select randomly any set of analysis, open and compare it with the original hard copy of the same to check the data integrity and record shall be kept as per the respective format for verification of data integrity.

Incase where the analytical data is directly accessible from DVD / hard disk, through application software, there is no need to restore data in primary drive. Verification shall be done on DVD or hard disk directly.

QC Executive / nominee shall check the data integrity of the archived data of the January and June month of every year, after every 6 months for 5 years and record shall be kept as per the respective format for verification of data integrity.

A Person shall maintain logbook for received data media.

Data Retrieval and Restoration Procedure:

If it becomes necessary to restore the previous data, prior approval of Head – QA shall be taken.

Only QC Executive / Nominee shall be allowed to restore the data.

Log for restoration of data shall be maintained.

Data storage media shall be returned to the QA department.

Backup/ Restore Failure:

If any error or failure is reported in backup or restoration procedure, QC Executive / Nominee shall contact local InfoTech for problem solving.

Vendor support may be sought in cases where problem of backup / restoration failure could not be solved. Further usage of system shall be temporarily stopped till problem is resolved.

All backup and restore failures shall be recorded in remarks column of respective records.

Preservation of Records: All monthly archived data along with records shall be preserved for a period of 5Years.

Precautions for Record Keeping:

All storage media shall be kept in a proper cover to avoid scratches.

Storage media shall be kept within a flame proof cabinet.

Storage media shall be kept within controlled environmental conditions.

Storage media shall be kept in vertical position.

List of Annexures : 

  • List of Instruments for which Back up to be taken
  • Record Log for Data Backup Process (Fortnightly) (For Primary drive to secondary drive)
  • Label of Data Storage Media
  • Verification record for archived data from one drive to another drives
  • Record for Received Data Storage Media
  • Data Retrieval and Restoration request
  • Records of Retrievals of Backup Data
  • Record Log for Data Backup Process (Fortnightly) (For primary drive to external hard disc)
  • Verification of data Integrity for HPLC / GC
  • Verification of data Integrity for UV-visible Spectrophotometer
  • Verification of data Integrity for Polarimeter
  • Verification of data Integrity for FTIR
  • Verification of data Integrity for TOC analyzer
Quality Control

SOP on Retesting of Raw Material

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SOP on retesting of raw material

Objective: To lay down the procedure for retesting of raw material for material lying in warehouse for longer period.

Scope: This SOP is applicable for retesting of raw material for material lying in warehouse for longer period.

Responsibility: Chemist or above of QC Department.

Accountability: Head – Quality Control.

Procedure: Material shall be transferred to Quarantine area by warehouse personnel as soon as retesting period is due.

Approved label shall be defaced and new Quarantine label shall be affixed alongside defaced approved label on each container of the material by warehouse personnel.

Intimation for re-sampling shall be sent to Quality control department by warehouse for the material to be retested.

QC personnel shall enter the material details in Retest raw material control register and sampling shall be done as per SOP.

A.R. No. shall be allotted by adding suffix ‘/ Rn’ where ‘/’ is for separation, R is for retesting and n is the no. of times of retesting. For example, if intimation for retesting of raw material is received first time and its previous A. R. No. is RM/25/0051 then A. R. No. of material to be retested shall be RM/25/0051/R1.

Retesting period of active and inactive raw materials having microbiological analysis shall be six months. Inactive raw material, not having microbiological analysis shall have retest period of one year.

Retesting can also be carried as per any directive from Quality Assurance Department.

If Expiry date of material is coming before the in-house retest date then retest date shall not be applicable and material shall be considered expired as per expiry date given by vendor.

Raw material shall be retested five times, after that material shall be sent to FR & D for further investigation and decision shall be taken, based on the investigation done by FR & D.

Analysis and approval of retest raw material shall be done as per SOP.

Expired or rejected raw material shall be destroyed by Ware house as per SOP.

Retesting parameters of raw material has been mentioned in respective raw material specification.

Annexure – Retest raw material Control

Quality Control

SOP On Entry, exit and gowning procedure in Quality Control Department

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SOP On Entry, exit and gowning procedure in Quality Control Department

Objective: To lay down a procedure for entry, exit and gowning procedure in quality control department.

Scope: This SOP is applicable to entry, exit and gowning procedure in quality control department.

Responsibility: Every person entering in QC department.

Accountability: Head – Quality Control & Head – Quality Assurance

Procedure:

Entry procedure for company employees and visitors:

Company employees shall take company apron and cap from almirah, wear apron, cap and enter into the department.

Visitors shall take disposable apron and cap from almirah dedicated for visitors, wear the disposable apron and cap and enter into the department.

Entry procedure for laboratory helpers and housekeeping persons:

Laboratory helpers shall take their white colour dedicated uniform from almirah, wear it and enter into the department.

Housekeeping persons shall take their orange colour uniform from almirah, wear it and enter into the department.

Exit procedure for company employees and visitors:

Company employees shall remove apron and cap in change room, hang the on hangers, and leave the change room.

Visitors shall remove the disposable apron and cap in change room and put in bin dedicated for used apron and cap and leave the change room.

Exit procedure for laboratory helpers and housekeeping persons:

Laboratory helpers and housekeeping persons shall remove their uniform in change room and keep in almirah then leave change room.

List of Annexure / Formats: Not applicable.

References (if any): Sop on SOP .

Quality Control

SOP On General Laboratory Practices

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SOP On General Laboratory Practices

Objective: To lay down a procedure for General Laboratory Practices in the QC laboratory.

Scope: This SOP describes the procedure for General Laboratory Practices in the QC laboratory.

Responsibility: Chemist or above of Quality Control laboratory.

Accountability: Head – Quality Control.

Procedure: In Quality Control department, there shall be separate wings for wet lab, instrument lab, GC lab, stability room, microbiology etc. and each wing shall be interconnected.

Lightning, Temperature and Ventilation shall be appropriate.

Working temperature shall be 15ºC to 25º

Temperature monitoring of Instrument Lab, Wet Lab, GC Lab and Chemical store room shall be done at least twice daily and record shall be maintained.

Working area should be clean and tidy at all time.

All entries shall be done online.

If any mistake has been occurred during entry in logbook or other document then make single strikethrough on wrong entry with initial and date.

All instrument calibration and preventive maintenance record shall be done periodically and documented as per schedule.

All instruments operation, calibration and cleaning SOPs and other SOPs shall be displayed near by the relative instruments.

SOPs training shall be given by QC Head or nominee to all laboratory personnel and their training record shall be maintained as per SOP.

Before using instrument analyst shall check the status label / calibration label of instrument then start analysis.

All QC persons are responsible to maintain the laboratory safety rules and discipline as per SOP.

During analysis any laboratory incident observed SOP shall be followed.

Points to be kept in mind while doing analysis:

Class ‘A’ glassware received with calibration certificate shall be used for quantitative analysis.

While using class ‘B’ glassware be sure that they are properly calibrated.

Always use balances, which are calibrated periodically against absolute standard weights.

Never leave balance doors open.

While weighing, the quantity actually used must not deviate by more than 10 % from that stated in the test procedure of the individual.

Operating range shall be affixed on each balance.

Do not weight beyond the operating range for quantitative analysis. Incase of qualitative analysis or preparation of system suitability solution, which is not used for calculation of results, might be weight less than operating range.

During pipetting if sample is colourless / slightly colored and clear, slowly drop the lower meniscus of the sample to the mark of the pipette and if it is highly coloured then slowly drop the upper meniscus of the sample to the mark of the pipette.

Keep the pipette in a vertical position and then touch against the wall of the receiving vessel to drain the tip.

While observing the meniscus always keep the pipette in vertical position at the level of eyes.

Never blow out the tip of the pipette while draining.

For non-viscous samples, allow the pipette to drain for about 15 sec. after the liquid has been dispensed.

For viscous samples, allow the pipette to drain for about 45 sec. after the liquid has been dispensed.

While doing dilutions, be careful not to lose sample during transfer, such as liquid dripping out of a pipette tip before the tip is in the receiving vessel

When the combination of two substances is either exothermic or endothermic, allow the mixture or solution to come to room temperature prior to achieving final volume.

While using microlitre pipettes, be sure that they are properly calibrated.

While doing filtration following precautions should be taken:

For gravity filtrations choose an appropriate size of filter paper (as per requirement) from an approved vendor. Fold it in cone shape and place it into a suitable clean funnel.

Place the funnel stem into the receiving vessel such that the bottom tip of the stem touches the wall of the receiving vessel.

Pour few ml of sample to be filtered on the filter paper and discard the filtrate.

Continue the filtration by pouring sample in portions, allowing each portion to filter before adding the next.

Do not fill the funnel (with filter paper) to more than about 90 % of its capacity.

For vaccum filtration take a clean vaccum filtration cup.

Place the membrane filter in the filtration cup.

Wet the membrane filter with appropriate solvent.

Place the filter assembly on a clean vaccum filter flask and connect the sidearm of the flask to a source of vacuum.

Filter the sample portions, adding each subsequent portion after the previous one has been approximately 80 % filtered. Do not allow the filter media to go dry between portions.

On completion of filtration, break the vaccum by releasing the vacuum from the flask sidearm slowly and gradually.

Remove and disassemble the filter funnel assembly, discard the membrane filter, and clean the filter assembly for subsequent use.

During centrifuging place the tube in the centrifuge head’s tube holders, always use an even number of tubes, such that they are placed across each other so that the weight of material in the centrifuge is evenly balanced. If only one sample is to be centrifuged, then counterbalance it with a tube containing water.

Make sure that the centrifuge cover is closed.

During titration fill the burette with the titrant up to the 0 ml mark.

Always use standardized titrant for titration.

Perform the titration slowly, drop by drop towards the end point.

Continuously swirl the sample/blank containing flask while performing titration.

Basic Techniques for performing TLC:

Always use a TLC plate 1.5-2.0 inch more in length than the distance to be developed.

Always prepare fresh mobile phase sample and standard solutions and spraying reagents.

Always spot at a distance of 1.0- 1.5 cm above the baseline of the plate.

The mobile phase level in the chamber should not be more than the application line of the spots on the plate.

Place the plate straight or with the least angle, in the TLC chamber for faster and better development.

Special Precautions while using vacuum oven:

Close the vacuum inlet and turn off the vacuum pump. Then bleed off the vacuum gradually over a period of a minute or two so as not to disturb samples contained within the oven.

When pulling vacuum on vessels containing volatile or corrosive solvents, place a cold trap or scrubber between the vacuum source and the vessel to which vacuum is being applied. Whenever vacuum is being applied to glassware, be sure that the glassware used is rated for use with vacuum. Failure to do so may result in serious injury due to glassware implosion.

Handling Precautions during Instrumental analysis:

Before starting the analysis of HPLC, ensure that respective solvents and inlets inserted as per the requirement given in the respective STP’s.

Sequence shall be prepared by the analyst as per the respective STP.

Sequence shall be verified by the supervisor before starting the analysis a day shift. Incase any sequence started after day shift, analyst shall verify the sequence himself and start the sequence and attached the sequence with raw data.

During analysis, analyst shall verify each and every injection. If any discrepancy observed, ‘Handling of lab incident’ SOP shall be followed.

If any sequence is running in night shift and finish in next shift or if samples are being loaded in long sequence then next shift analyst shall verify the sequence for its authenticity. If any discrepancy observed then followed the SOP (Handling of lab incident).

System suitability procedures shall be followed wherever required.

After running the sequence, if any discrepancy is found (for e.g. absence of vial, system suitability failure etc.) then, SOP for lab incident shall be followed.

For analysis on GC, before starting the analysis, ensure that the pressure of gases is within limits.

No leakage of gases should be there.

If any malfunctioning is occurs in any instrument, deviation shall be raised as per SOP on Handling of deviations.

Desiccants like silica gel and molecular sieves shall be dried and in proper working condition.

Volumetric solution bottles, reagents bottles, mobile phase / diluents bottles and other solution bottles should be properly labeled.

During analysis analyst shall be labeled or marked the glassware with initial and date and write the sample details like sample name, batch no. etc.

Analysis shall be done as per respective specification and STP.

Not more than one entries shall be allowed in one row in log book and one line shall be left blank in to instrument and inward log book to ensure readability of each entry.

Maintain the record of operational activity of instruments in instrument logbook as per SOP.

Inject the sample immediately after preparation, not hold it more than 15 minutes in case of related substances test.

Reporting procedure for related substances test:

In related substances test, if % impurity is less than Quantitation Limit or reporting threshold then result shall be reported as BQL (Below Quantitation Limit) or BRT (Below reporting threshold), which ever is given in the STP.

Incase if known impurity does not elute then it shall be reported as ND (Not Detected).

Quality Control

SOP on Chromatographic Practices and Documentation for Instrumental analysis

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SOP on Chromatographic Practices and Documentation for Instrumental analysis

Objective: To describe the procedure to be followed in Chromatographic Analysis and Documentation for instrumental analysis and to ensure that good laboratory practices are followed during instrumental analysis in the Quality Control laboratory.

Scope: This procedure is applicable to Chromatographic analysis through HPLC & GC and instrumental analysis documentation, in Quality Control laboratory..

Responsibility: Chemist or above of QC laboratory

Accountability: Head – Quality Control & Head – Quality Assurance

Procedure:

General Cleaning: Ensure that the electrical power supply to the instrument is switched off. Clean daily the outer surface of the instrument with a clean dry cloth. If necessary, clean the instrument using a cloth wetted with 70 % IPA. Remove the moisture, if any, with a tissue paper or a dry cloth.

Mobile phase / Diluent preparation: The mobile phase / diluent shall be prepared as per the procedure described in the respective STP and the same shall be recorded in the current version of mobile phase preparation record Format as per current version of SOP.

Chromatographic grade solvents shall be used for mobile phase preparation.

The Mobile phase shall be degassed (Passing through a 0.45 µm µm membrane or sonication) adequately to avoid flow rate inconsistencies, column equilibration, etc. which eventually results in change in retention time & failures in system suitability requirements.

The degassed mobile phase / diluent shall be transferred into a glass bottle closed with polypropylene (GL45) screw cap and labelling shall be done as per current version of SOP.

Shelf life of mobile phase / diluents shall be assigned as per current version of SOP

If mobile phase shelf life is more than 48 hours in STP then same shelf life shall be assigned for that mobile phase.

Analysis:

System suitability / Standard / Sample preparation control:

The standard / sample preparation shall be made as per the STP taking into consideration the analyte stability and storage requirement.

System suitability: In case where the resolution solution / peak identification solution / marker solution required for establishing system suitability is to be stored for longer duration it shall be assigned a shelf life based on the actual study conducted.

QC analyst shall download required instrument method and verify it with respective STP.

After instrument method verification a trial injection (RT check) of standard / blank / system suitability shall be injected before starting the injection sequence to check the retention time / baseline interference, if retention time is more than 10 minutes than 10 % variation is acceptable and for upto 10 minutes retention time, 1 minute variation is acceptable. If system suitability parameter fails to meet the acceptance criteria, then perform necessary adjustment in the mobile phase / cleaning / conditioning of the column to meet the requirement.

QC analyst shall prepare the sequence as per the respective STP

Sequence shall be verified by the supervisor before starting the analysis in a day shift. Incase any sequence started after day shift, analyst shall verify the sequence himself and start the sequence and attached the sequence with raw data.

QC analyst shall take print out of instrument method with processing method immediately after starting the sample set.

Note: Some of the commonly observed problems are peak tailing, front tailing, peak broadening, peak splitting, blank peaks and retention time shifting. These characteristics of chromatographic peak directly impact the quality of results.

The system suitability (once established) shall be valid for a maximum of 24 hours or 5 times the total time required for establishing the method system suitability, whichever is higher or as described in respective STP.

The system suitability shall be demonstrated throughout the run by intermittent evaluation. The intermittent system suitability shall be performed by the current version of SOP.

In case of unstable analyte, freshly prepared analyte standard solutions shall be injected and the area response (area/weight) shall be used for calculating a co-relation against the earliest standard area response.

Where STP requires use of more than one concentration of standard, the standard with the lowest concentration shall be used for demonstration of intermittent system precision.

Where the sample is required to be injected in duplicate / triplicate the area ratio of the main peak between the successive injections shall lie between 0.98 and 1.02 from the mean area.

In case of sample injections, involving concentrations of equal or less than 10 ppm the area ratio between duplicate / triplicate shall lie between 0.95 and 1.05 from their mean area.

Where the STP does not specify any RSD limits for standards. RSD limit shall not be more than 1.0 %

In case of unstable analyte, freshly prepared analyte solutions shall be injected and the area response (area/weight) shall be used for calculating the correlation against earlier standard area response.

During assay and related substances analysis involving isocratic runs, the flow rate of mobile phase shall be kept constant for the entire run, after the system suitability is established. If the flow rate of the system is changed, system suitability shall be established again.

During assay and related substances analysis involving gradient run, if there is delay (exceeding the run time) in injecting the next sample, the blank run with gradient operation shall be continued. The chromatograms for blank injections shall be recorded.

Incase whenever sample set is completed, further samples shall be analyzed after some time and within the system suitability time.

Flow rate shall be kept constant for the required time for isocratic mode. Blank injections shall be injected for gradient mode.

System suitability / standard injection shall be injected followed by blank before injecting the sample to ensure the system suitability. In case, there is delay of more than a single run time before injecting a sample, a bracketing standard is added in the sequence before injecting the sample preparation to ensure the system suitability.

In case the above mentioned acceptance criteria are not met, all the data collected during the time period shall be properly identified and reviewed by QC Supervisor. The system suitability with fresh standard preparations shall be carried out all over again before injecting any test samples.

If any sample set fails during run due to any reason i.e. system malfunctioning / instrument error / communication error / vial missing or bracketing standard does not meet acceptance criteria etc, same shall be handled by as per current version SOP.

Recording Chromatograms:

All chromatograms for the establishment of system suitability and up to entire analysis run shall be maintained properly.

The raw data emerging from such chromatograms shall be recorded as per current version of SOP on Preparation, Review & Approval of worksheet). Appropriate remarks (where required) shall be recorded on these chromatograms by the QC Chemist / QC Supervisor.

Each chromatogram shall be duly signed off by the analyst only for the work done by him / her and reviewed and signed off by the checker. No other person shall sign for the work done by others.

The name of analyst shall not be entered in lieu of the analyst’s signature for the work done.

However, in case the analyst does not turn up for duty for next few days, the supervisor can review the raw data for accuracy and compile the test report and sign on the test report. Necessary remarks shall be recorded by the supervisor about the accuracy of data. However, the raw data shall be signed by the original analyst upon resumption of duty.

In case of long absence or leaving the company by the original analyst, the supervisor shall then close the raw data after review for accuracy and necessary remarks and signatures.

No chromatogram shall be ever discarded or destroyed by anyone.

The chromatograms which are disregarded and not considered for calculations shall be stamped as “DISREGARDED”. The reasons for disregarding the chromatogram could be printing error, variation in area count / inconsistent area, faulty integration, abnormal drift in baseline, ghost peak or any other reason considered by the supervisor.

The analyst performing the analysis shall assign the reason for disregarding a chromatogram on the chromatogram itself, with signature and date. This shall also be counter-signed by the supervisor with date. The disregarded chromatogram shall be preserved along with the test chromatograms.

For the system generated chromatograms, the necessary information shall be printed on each chromatogram.

Analyst-1 performing the analysis shall process the chromatograms with suitable integration parameters and use the chromatogram for calculating / reporting results. However, in the absence of Analyst-1 for rational reasons, processing shall be done by the Analyst-2 with due signature and date. This shall also be counter-signed by the supervisor with date. Further, raw data so generated, shall not be kept unprocessed for more than two working days.

Reprocessing of chromatograms, if necessary, at a later date/time shall be documented with reason(s) for reprocessing and certified by the QC Manager. However, during reprocessing of chromatogram, no raw data shall be altered or deleted or modified or added.

The entire record of chromatograms shall be part of the sample evaluation test protocol.

Calculations: The calculations shall be performed as per the respective STP. All calculations shall be done as per the area count / values obtained for the standard injected in the beginning. Area counts of in-between injections of standard shall not be considered for calculations

Monitoring the Lamp Energy (Shimadzu / Waters HPLC):

Let the deuterium lamp initialize for 15 minutes before starting the analysis.

The energy of deuterium lamp shall be verified to ensure its performance for the analysis on weekly basis.

HPLC grade water shall be used as mobile phase and the flow cell shall be rinsed for 5 minutes at a flow of 1 ml/min.

For Shimadzu HPLC lamp energy shall be checked at 220 nm by pressing VP key on the instrument touch panel and record the lamp energy.

For Waters HPLC press diagnostic key and check the Sample Reference Energy at 220 nm and record.

The deuterium lamp energy shall be recorded in format.

Acceptance Criteria:

The lamp energy shall not be less than 800 mV for Shimadzu HPLC and 15 nanoamps for Waters HPLC.

Audit Trail:

What is an audit trail: Audit trails maintain a record of system activity both by system and application processes and by user activity of systems and applications.

Audit trail secures computer generated and time-stamped electronic record that allows reconstruction of the course of events relating to creation, modification and deletion of an electronic record.

Purpose of Audit trail: The purpose of an audit trail for Electronic Record systems is to provide assurance of the integrity of the Electronic Record and the associated Raw Data.

The administrator / manager shall hold the primary responsibility for ensuring computerized systems used in generating analytical data in the Quality Control laboratory are in compliance with applicable regulations, as regards design and validation. QC Manager shall ensure that the Instrument vendor shall provide 21 CFR Part 11 compliance certificate for the chromatographic software.

Audit trail features of the software shall be enabled at the time of preparation of project for each month of chromatographic hardware and software and never shall be disabled / blocked.

Verification of audit trail shall be done monthly by administrator shall be completed with in 10 days. Audit trail shall be verified to check whether there is any change in Instrument method parameter such as flow rate, gradient program, detector wavelength, run time, column oven temperature, sample compartment temperature, change in processed data such as alteration in processing parameter like change in peak width, threshold, peak naming, change in system date and time.

Verification if any abnormality found same shall be informed to QC head and shall be investigated through sop on deviation and a formal report shall be prepared. Verification of audit trail shall be recorded as per format.

Electronic data and user management shall be done as per current version SOP of Electronic data and user management).

Creation, modification and deletion of electronic users account shall be as per current version of SOP of Electronic data and user management)

Backup, restore and archival of analytical data from computer system of Instruments shall be as per current version of SOP of Backup, restore and archival of analytical data from computer system of Instruments).

Safety Precautions: Ensure that personal shall use appropriate personal protective equipment like hand gloves, safety shoes, safety goggle, apron etc. while working.

List of Annexure

Deuterium lamp energy record

Audit Trail Verification Record

Quality Assurance

SOP ON INPROCESS CONTROLS

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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.

Quality Assurance

SOP ON GAP ASSESSMENT

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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.

Quality Assurance

SOP FOR REPORTING OF INVESTIGATION

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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

Quality Assurance

SOP ON BATCH CONVERSION

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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

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