IN-PROCESS CHECK DURING VARIOUS MANUFACTURING STAGES IN SVP SECTION

IN-PROCESS CHECK DURING VARIOUS MANUFACTURING STAGES IN SVP SECTION

PURPOSE

To define the procedure for in-process check during various manufacturing stages in SVP Section.

SCOPE                                   

This SOP covers the in-process check procedure during various manufacturing stages of SVP Section

CROSS REFERENCE DOCUMENTS

Monitoring of temperature/humidity, differential pressure

Monitoring of non-viable particle count in classified area of SVP section

CIP & SIP of manufacturing tank, holding tank, product line, filter assembly & FFS machine

Cleaning & operation of visual inspection table

Cleaning, operation, monitoring & challenge of vacuum leak test machine

Filter integrity of product filter (Bubble point test)

Filter Integrity of vent filter

Handling of non-sterilized filled & sealed ampoules

DEFINITION & ABBREVIATION(S)

DEFINITION 

In-Process check refers to the checks performed during an activity (it can be manufacturing or packing) in order to monitor and if necessary to adjust the process and/or to ensure that the intermediate or finished product confirm to its specification.

This may include control of equipment & environment also. In-process quality control may be performed at regular interval during a process steps.

The objective of in-process to monitor, control & improve effectively the whole applied operation at every stage of finished pharmaceuticals product.

In-process control check designed to provide early warning for quality or other problems arising during production, in other words it is intended to provide a snap shot of the quality of the product manufactured at the factory.

ABBREVIATION(S)

SVP :Small Volume Parenteral

BMR : Batch Manufacturing Record

WFI: Water for Injection

BOM : Bill of Material

CIP  :  Cleaning in Place

SIP  :  Sterilization in Place

IPQA :  In-process Quality Assurance

HMI  : Human Machine Interface

RESPONSIBILITY

Production department shall be responsible:

Initiating, preparation, review and revision of SOPs.

To perform the in-process as per the SOP.

To make entry in concern BMR, BPR & log books.

To provide training of the SOP to concerned personal SOPs.

To follow described here in.

Production Head shall be responsible for:

To verify the procedural &  technical content of SOP.

To get the SOP approval from Head Quality Assurance or designee.

To provide the training of SOP to the concerned personnel in between issue date & effective date.

To check whether the activity is performed as per the SOP.

Quality Assurance department shall be responsible for:

To check the draft sops for regulatory and cGMP compliance.

To maintain the approved master copy of the SOP of all department for document control.

To verify the content of SOP.

To verify that originated department performing task as per concern sop.

Head Quality Shall be responsible for:

Review of draft SOP for regulatory and cGMP compliance.

Final approval of new or revised SOP by signing off as approved by.

To ensure the implementation of defined system.

To ensure all the employees are trained before performing any task.

Plant head shall be responsible for:

To approve new or revised SOP.

To ensure the implementation of defined system.

PROCEDURE

SAFETY/PRECAUTION/EHS 

During in-process of CIP & SIP of tanks, don’t touch the tanks directly.

Always follow entry/exit procedure during entry in mfg. or filling room to avoid particle & microbial load.

Always wear sterilized gowning & gloves for clean area.

6Don’t take non-sterilized items in side filling room.

Don’t use non calibrated measuring cylinder & balance during in-process.

Don’t use rusted blade or seizure for in-process.

Don’t use back in-process solution again in filling.

Don’t open both door of dynamic pass box during in-process.

Initial discarded ampoules should not mix with good ampoules.

IN-PROCESS CHECK DURING MANUFACTURING & FILLING

During in-process check of manufacturing & filling be sure area should be clean & verify the environmental condition(temperature, humidity, differential pressure and particle count) as per SOP

Production & IPQA will check & verify that before start the manufacturing & filling there should be no other product or previous product or product container should be there.

Verify that all the person entering in manufacturing & filling has wear clean & sterilized gowning & gloves.

All the pallets, tray, carets, bin are properly clean.

Check & verify that BMR of concern product & batch no. is available at site.

Check proper CIP/SIP of tanks, filter assembly, filling machine as per SOP & graph of SIP properly complies as per specification & attached in BMR.

Verify that filter integrity of product & vent filter is performed & report is attached in BMR as per SOP

Check the availability of RM, PPM (granules) of concern batch & BOM sheet of same attached in BMR.

Check that dispensed RM is in day store room in good condition & with proper status label & cross verify the weight of same with BOM sheet.

check the dispensed granules bag, all are clean & intact before charging in granule tank. Before charging verify that vertical LAF above tank is running properly & both granule tank & LAF are properly clean.

Verify that before batch preparation WFI is freshly prepared & release by QC in chemical & BET.

Verify that production person is performing batch preparation as per SOP.

Before starting filling production & IPQA person will be sure product is release from qc department & the SAP generated bulk COA attached in BMR.

Verify that status board of filling is maintained with product name, batch no., mfg. date, exp. Date, batch size, filling date & time.

Before start filling machine verify machine is properly clean, solution is filtered & all the utilities are ready & machine LFR is running before operation.

During startup of the machine check all the parameters of filling machine (extruder temperature, mold cooling temperature, hydraulic oil pressure & temperature, air pressure, buffer air pressure etc.) it should be within limit as per machine specification.

Check the in-process balance is working properly & calibrated and same should be record in log book.

Check the availability of measuring cylinder, it should be properly clean and calibrated by qc & should be of grade “A” only.

Verify that measuring cylinder should not be damaged or broken condition.

Check the status board is maintained for particular product, batch no. mfg. date, exp. date & stage.

Filling machine operation will start as per SOP & as the machine starts discard first  three empty cycles, then take next empty cycle, check physically each container shape for proper forming of cavity.

Check & verify the empty weight, thickness, twisting, cutting, surface & embossing of cavity number (if available) of each container.

To check the thickness during startup of machine collect empty cassette & get all the ampoules.

Cut each ampoule from vertically from the middle & measure the wall thickness with Vernier caliper as per defined location (L1, L2, L3, L4, L5, L6).

If any of deformities found inform to operator to rectify and again verify.

As the empty cycle parameter found satisfactory, allow to start filling.

Discard initial validated cycle as per assay/pH & take next cycle for filled weight/volume verification as per the specification mentioned in BMR & as per the following table.

Every hours production person will check the weight, volume, physical appearance of the empty and filled container & will record in the BMR.

IPQA person will cross verify the production person by checking complete cassette/card of 20 ampoules (for 5 ml & 10ml containers) & 16 ampoules (for 20 ml & 30 ml containers).

Fill volume of the ampoules/respules to be measure by both volume/weight method.

In this method In-process production/QA person after collection of filled ampoules from filling line, first check the filled weight of each ampoules on calibrated balance, the value subtracting the empty weight of container from filled weight, will be divided by specific gravity (will provide by qc) as per the below formula.

(Filled wt. of ampoule)- (Empty wt. of ampoule) Volume (ml)  =  ————————————— Specific gravity of solution

Afterwards the same ampoule after opening from the neck & by collecting the solution of same in calibrated measuring cylinder & verify the volume in filled container.

After verification the solution of measuring cylinder is discard.

During in-process if  any defective container or rejection like volume variation, weight variation, twisting problem, leakage, surface particles, deform ampoules or container found that will be collected in the red colour rejection crate.

After batch completion production person will count the rejected ampoules in presence of IPQA person and mention in BMR & transfer in scrapyard.

If during operation any minor break down create due to any reason happens will be notify in the BMR & log book of machine, if break down is major then inform to QA & take incident & CAPA for same.

IN-PROCESS CHECK DURING TERMINAL STERILIZATION

After filling of terminally sterilized product, arrange all the ampoules in ss trays & trolleys as per SOP & mention the label “TO BE STERILIZED” & load

all trolleys in terminal sterilizer for terminal sterilization.

Before loading check & verify that terminal sterilizer is clean & there is no previous product in it & sump water is clean.

Check & verify that  all the temperature sensors are working properly & pressure gauges are calibrated & get the line clearance before loading of containers & record the data in BMR.

Maintain terminal sterilization status board with information of product name, batch batch size/no. of containers, mfg. date, exp. Date & lot number etc.

Before start the cycle verify the batch detail & parameters of autoclave, detail of loaded quantity, check door gasket is good & greased.

Check all utilities (raw steam, compressed air, purified water) are ready for operation of sterilizer.

Run the cycle as per the designed specification of cycle.

After completion of autoclave cycle production & IPQA person will verify the sterilization graph for hold time, hold temp., F0 value temperature & pressure etc.

Make entry of load cycle in log book as we as in BMR.

After completion of terminal sterilization cycle production & IPQA will check the sterilized ampoules or containers for proper shape & attach green colour “ STERILIZED” status on each crate after unloading from trolleys.

If some ampoules found rejected (leak, deform or empty) count them & make entry in BMR as a part of sterilization rejection.

After cooling ampoules will be transfer to further stage in blue plastic crates with status label in presence of production & IPQA person.

For non-terminally sterilized products the filled ampoules will be directly transferred to leak test & visual inspection in separate close box to avoid chance of cross contamination.

 IN-PROCESS CHECK DURING LEAK TEST, VISUAL INSPECTION & PACKING

Before start leak test operation check the leak test machine is clean & no previous product is there.

Check the status board is maintained.

Check the vacuum gauge, sensor, door gasket, vacuum pump is properly working.

Load the ampoules in leak test machine as per loading pattern SOP

During operation mention batch detail in HMI & run the machine as per SOP

After leak test operators will verify the containers for leak tested ampoules properly In presence of IPQA & mention the rejected leak and good quantity in BMR & log Book.

Transfer the ampoules for visual inspection.

Before transferred the leak tested good ampoules for visual inspection& packing Production & QA person will be ensure that there should be no previous product ampoules or batch running there.

After previous batch or product or ampoules completion operator will clean the line Properly in presence of production & IPQA.

Production person will maintain the status board of packing room bearing product name batch no., mfg. exp. date quantity & packing start time, date etc.

After getting line clearance from IPQA will transfer the next batch for inspection, labeling & packing.

Ensure that lights of visual board are properly working, production, engineering & QA person will verify the same as per SOP it should not be below 2000 lux.   

Verify that all the visual inspector are qualified & trained as per SOP

Ensure that all the packing material of batch on the packing line as per BOM, before transfer the packing material, production person & IPQA will verify the packing material.

Production & IPQA person will verify the printed packing material detail as per BPR.

Before start labeling & packing printed label specimen will be attached in BPR & IPQA will verify the same.

During visual inspection as per SOP, IPQA person will select 50 ampoules cassette from inspected ampoules & cross verify the visual inspectors for proper visual inspection.

Check & verify the over printing detail during labeling & verify that there should be no any defected container, without label, torn label, any visual defected container should be transferred for final packing.

IPQA person will cross verify the packed shipper randomly during packing & verify that there should not be any defective ampoules should be there in final packed shipper, if any of abnormality observe then instruct to production to check the complete batch again in presence of QA.

Check the quantity/ weight of final shipper is within limit & as per the packing specification.

After packing all remaining unprinted packing material to be reconcile in presence of QA.

All printed packing material will destroyed in presence of QA & mentioned in BPR.

IPQA person will collect the finish product sample as per specification & transfer to QC & micron for complete analysis & control sample will transfer to retain sample room against the requisition slip & mention the quantity of same in BMR.

After complete batch packing production person will transfer the finish goods to FGS room against the SAP generated transfer ticket.

After verifying the finish product IPQA person will duly signed TT & production person will send one copy of TT to warehouse person & another copy will be attached in BMR.

After complete analysis of particular batch, finish product will send for commercialization in presence of QA.