In-process control in Pharmaceuticals

1. OBJECTIVE:

1.1 To lay down a procedure for describing the details on How and When to perform in process    controls during processing of a batch from dispensing till dispatch of finished goods. 

2.SCOPE:

2.1 To ensure compliance and adherence to laid down procedures, specifications, manufacturing / processing at XXX, Company 

3.RESPONSIBILITY: 

3.1 In charge - IPQA       

4.ACCOUNTIBILITY 

4.1 In charge – QA 

5.PROCEDURE: 

5.1 Manufacturing operations: 

DISPENSING OF RAW MATERIAL 

5.1.1IPQA chemist shall ensure line clearance as per the SOP No. QA102 and  shall make the entries in the BPCR. 

5.1.2 Raw materials are dispensed under reverse laminar air flow bench at   approved raw material store in Helmut Block by warehouse personnel as per the quantity mentioned in the BPCR and details of issuance are entered in the BPCR, which is verified by IPQA. 

5.1.3 Before starting dispensing operation stores and IPQA personnel shall check the following and ensure that they are within the parameters.

Differential pressure of LAF, % RH and temperature.

i. Filters are adequately cleaned.

ii. Nitrogen control.

iii. Balance is calibrated. 

5.1.4 Verify each container before weighing for Q.C Ref. No, Approved label details and grade of the raw material. Stores department issues the exact quantity of each ingredient from container with “UNDER USE” label. The issued quantity shall be entered in the bin card, Q.C Ref. No shall be recorded on the pink colored RM dispensing labels and in the column provided in BPCR.

5.1.5 The IPQA chemist verifies approved label, weighed quantity, Q.C Ref.No and calculation as per the BPCR and signs on the pink colored RM dispensing labels and in the column provided in BPCR. While dispensing the raw materials FEFO, FIFO shall be maintained.

5.1.6 The dispensed material is kept in a S.S bin secured with a pilfer proof self-locking plastic string. The bin shall be identified with the product name, Batch No., Batch Size, Mfg. Dt., Exp.Dt., and shall be signed by stores and production personnel. Mfg. chemist takes this material under his control and signs as receiver on the BPCR.

5.1.7 BPCR is taken along with the raw materials to manufacturing area for recording of various steps by production during processing.

BATCH COMPOUNDING 

5.1.8 IPQA chemist shall verify the cleanliness of the manufacturing and makeup vessels. Rinse water clearance shall be verified for product changeover. The pooled sample of WFI shall be collected from manufacturing and makeup vessel and sent to Q.C for chemical and BET analysis.

5.1.9 The Mfg. Chemist and IPQA chemist shall visually inspect all equipment’s/containers for cleanliness and the absence of active ingredient of previous product will be confirmed by rinse water analysis report. Equipment’s/containers bear a tag for cleanliness, duly signed by production and IPQA chemist.

5.1.10 IPQA chemist shall ensure that the WFI collected shall be used with in 3 hrs from the time of collection. The WFI collected shall be discarded if not used within 3 hrs.                    

5.1.10 The IPQA chemist shall monitor all the steps as per the BPCR. He shall sign on the BPCR after verification of each activity / stage. Temp, pH and dissolved oxygen content shall be checked by calibrated equipments at all the relevant stages. Any unusual observation or deviation shall be immediately recorded and brought into the notice of In charge-Production and in charge – Q.A. 

5.1.11 The pH shall be verified before and after volume makeup. The bulk sample shall be drawn by IPQA chemist and sent to QC lab for analysis as per SOP . Sample to estimate bioburden in bulk products also shall be drawn as per SOP . 

ASEPTIC FILTRATION 

5.1.12 The filter used for filtration shall be as per BPCR. Check the integrity as per    the SOP . Enter the details of filter pre and post integrity test details in the BPCR.

5.1.13 Verify and record the filtration process, for any filter change because of choking of membrane or failure to comply filter integrity test. Change of filter shall be recorded in BPCR and separate lot shall be maintained for solution filtered through other filter membrane. Filtration of the products belonging to Fulford India shall be completed with in 8 hours after completion of compounding. 

5.1.14 Solution shall be filtered directly in to a presterilized filling vessel (which is flushed with sterile nitrogen as per the validated flushing time and flow rate such that the vessel has Oxygen less than 1% from compounding vessel by pressurizing the compounding vessel using sterile nitrogen.

5.1.15 In case of Nitrogen sensitive products Argon shall be used for flushing and overlaying of the filling vessel.

5.1.16  Sterilized filling vessels shall be identified with status label giving product details and shall be stored in sterile storage area under LAF till taken for filling, the aseptically filtered bulk shall be stored for not more than 48 hours or as per specified in the BPCR i.e., the vessel containing the filtered solution to be taken up for filling  before 48 hours or as per the hold time specified in the BPCR. If the time is exceeded the solution should be refiltered. 

5.1.17  For storage of oxygen sensitive bulk, continuous overlaying of sterile nitrogen/ argon shall be given until the vessel is taken for filling. Ensure that the vent filters are in place for filling vessels.

COMPONENT PREPARATION 

5.1.18 The washing operation of vials, rubber stoppers and PFS are carried out as per respective SOP. The IPQA/Production chemist maintains record in the respective formats of BPCR 

5.1.19 The IPQA chemist monitors and verifies the washing procedure as per the validated washing / siliconization cycle.     

5.1.20 The IPQA shall verify the cleaning and preparation of filling vessels, filling   items, mar components, disinfectant items and washing and siliconization of Needle shields, Syringes and rubber stoppers as per SOP.

5.1.21 The IPQA verify that the sterilization of vials, ampoules, syringes, rubber stoppers and all other components done as per respective SOP’s and records the details in the BPCR and also attaches the thermograph with BPCR. 

5.1.22   The IPQA chemist monitors and verifies the sterilization procedure as per the validated load patterns and procedure as per sop. 

5.1.23   The IPQA chemist shall check the sterilisation indicator on the outer packing of the presterilized stoppers and shall ensure that they are sanitized by wiping on each side with 70% IPA and shall be subjected to U.V sanitization as per SOP  and shall be stored in sterile storage under LAF.                       

5.1.24   The IPQA chemist shall ensure that the outer packing of the pre washed rubber stoppers is clean free of dust, shall be subjected to sterilization as per the validated cycle. Rubber stoppers shall be unloaded in sterile storage and stored under LAF till taken for filling. Rubber stoppers shall be used within 48hrs of sterilization for FULFORD products. Rubber stoppers shall be discarded if not used within 48 hrs.

FILLING OPERATION

5.1.25 The IPQA chemist before giving line clearance as per SOP No. QA102 shall check the parameters like set temperatures of the tunnel, conveyor speed, room temperatures, On line non viable particulate monitoring results, relative humidity, sterilization cycle of all items.  Record the compliance report on line clearance format for filling in the BPCR. 

5.1.26 Before filling operation starts the IPQA chemist shall ensure the room pressure of filling room should be more than that of the adjacent rooms (washing, sealing, sterile storage).  Check for the continuous overlaying of sterile Nitrogen to filling vessel, check for the working conditions of Nitrogen alarms used for Nitrogen flow meter for overlaying of vessels and for pre & post flushing of vials/Ampoules. 

5.1.27 The IPQA chemist shall cross check the room pressures and the differential pressures of LAF recorded. 

5.1.28 The IPQA chemist shall ensure the disinfectant currently in use is as per the standard cycle mentioned in the disinfectant cycle chart. 

5.1.29 The footwear cleaning and sterilization record and Aseptic area cleaning record shall also be verified on periodic basis.  

5.1.30 The IPQA chemist shall ensure the validated personnel are entering into the filling area as per the list displayed at entry to ante room. 

5.1.31 The IPQA chemist shall ensure that the vials coming out from the tunnel on to the filling turn table do not fall on the conveyor The IPQA chemist shall ensure that incase of any break down in the LAF unit/ Power break down for longer time the vials from the filling machine turn table should be removed and discarded as per the SOP on power failure.  

5.1.32 The IPQA chemist ensures that the lots for sterility testing are adequately determined as per the relevant SOP. Finished product sampling shall be done as per the standard quantities mentioned on the list enclosed it shall be recorded lot wise into the finished product-sampling format of the BPCR. 

5.1.33 The IPQA chemist shall ensure the volume filled in the vials as per the SOP. The balance used for volume check shall be checked for calibration. IPQA chemist ensures that the filling starts only after the start up activity for volume check and other parameters are performed. The volume check is recorded in the BPCR

5.1.34 The volume adjustment shall be made and recorded only after stopping the machine (Frequency of Volume check: Every 30 min/After Major interruption or any vessel change).

5.1.35 The IPQA chemist shall take care that the microbiologist shall carry out the environmental monitoring as per the written procedures.

5.1.36 The conveyor falls and MAR (stoppering), machine rejects shall be verified and entered on the relevant Format on hourly basis by IPQA chemist. 

5.1.37 The IPQA chemist shall ensure that the FMS is working and the status of 0.5µm and 5.0µm particulate matter is within limits.  

SEALING OPERATION 

5.1.39 The IPQA chemist shall ensure that the sealing room is free from vials of previous product as per SOP.                   

5.1.40 The IPQA chemist shall ensure that LAF pressure is recoded in the respective format and room pressure recorded The IPQA chemist shall ensure the seal parameters (embossing, colour) with the approved specimens displayed in the sealing room.                 

5.1.41 The IPQA chemist shall check the quality of sealing and the same is recorded in the BPCR. The sealing room should not have the vials of the other lot (Frequency: every one hour/after major interruption).

5.1.42 The IPQA chemist shall ensure that no vial shall be resealed / pressed once the vial leaves the LAF in the sealing room.

5.1.43 Production & IPQA chemists shall ensure the transfer of sealed vials & ampoules and stoppered PFS to the packing block as per SOP.  

OPTICAL INSPECTION

5.1.44 The IPQA chemist shall give the line clearance for each lot under optical inspection as per SOP No. QA102 There shall not be more than one lot till optical testing. Only one product will be taken for inspection at any given time.

5.1.45 For Ampoules that are terminally sterilized no lot identification shall be maintained. After completion of terminal sterilization and the entire batch shall be treated as a single lot. A label indicating the product name and batch number shall be pasted on the terminally sterilized Ampoules for identification. 

5.1.46 The IPQA chemist shall ensure the optical testing is carried out by validated operators as per the approved list displayed in the optical operation area. 

5.1.47 The IPQA chemist shall ensure that the spot check is done as per the SOP. 

5.1.48 The IPQA chemist shall verify the quantity and the type of rejects classified by the production operators. The rejects classification shall be done as per the relevant SOP. Defects viz. Black, white, fibres, glass and others, etc. shall be recorded. Eye break record shall be verified on periodic basis. 

5.1.49   The details of optical inspection shall be verified and recorded in the BPCR The unusually high levels of particles if detected shall be brought to the notice of In charge - production and In charge – Q.A for the investigation of the source so that preventive measures can be taken. 

LABELLING OPERATION (for cut labels and Roll labels)

5.1.50 The IPQA chemist shall ensure the labelling machine is free from the previous batch/lot vials/PFS/Ampoules labels (Cut Labels and Roll labels) as per SOP. The line clearance shall be part of the BPCR. 

5.1.51 The IPQA shall follow SOP ensure the over printing details on the label (Mfg. Lic.No, Mfg. Dt., Exp. Dt., MRP) before start of the operation. The start & end specimen of every Roll shall be checked by the operator & production/Q.A. chemist which should be a part of BPCR. 

5.1.52 The IPQA chemist shall ensure the correctness and legibility of overprinting quality and approves the usage of stereo by giving clearance. Production and IPQA chemist shall sign on the label with date and time at the start of operation and at the end of the operation on daily basis. Specimen shall be a part of BPR.

5.1.53 All the labelled PFS shall be checked by the operators for the text matters, clarity of overprint, alignment of labels & plunger rod fixing.

5.1.54 The spot check of the inspected labelled PFS shall be done magazine wise by production/Q.A. before giving for blister packing.10 – 15 % of the quantity from the magazine shall be checked. If any rejects found the entire magazine shall be re inspected. The details are recorded in PFS labelling spot check record.

5.1.55 The IPQA chemist shall ensure the lot wise labelled vials/Ampoules/PFS are collected in appropriate containers and tagged properly.  

5.1.56 Operation of same batch on the next day shall require line clearance for remnants of the previous days activity and recorded in the BPCR. Follow the same steps from 5.1.51 and retain the specimen as mentioned by pasting on the relevant records (Frequency of In process checks for labelling/over printing Every 30 min). 

PACKING OPERATIONS

5.1.57 The IPQA chemist shall follow the SOP and the lot wise packing of labelled vials/ PFS. There shall not be any remnants of the previous operations / product. Not more than one product / batch shall be packed at given time in packing hall. 

5.1.58 IPQA chemist shall ensure the exact packed quantity of vials/ Ampoules/ PFS mentioned in standard pack size should refer in pack profile as per the master. This in process check covers the both first pack and last pack of the batch for correctness of quality and quantity.

5.1.59 All the blisters are inspected by the operators for holes, hair, fibres, black particles, overprinting clarity, without labels, syringe breaks, N/S bend and improper labelling. 

5.1.60 The PFS blisters shall be independently checked by production & Q.A. No single blister should show any defects. If any defects are found the entire crate shall be re inspected. The details of inspection shall be entered in PFS blister spot check record.

5.1.61 The IPQA chemist shall collect the finished product control samples lot wise as per the SOP. After completion of batch packing control samples shall be sent to quality control samples storage room. 

5.1.62 For different type of packs viz. Trade pack, physician sample, government supply, export, separate line clearance and printed packaging material approval shall be taken and recorded in separate format.

5.1.63 Shipper weighing data shall be checked which shall be a part of BPR. 5.1.64  Reconciliation of good quantities and rejected quantities, unused / online rejects shall be done by production verified by Q.A and reconciled on format as per SOP. 

5.1.65 Quantities of the material intended for destruction shall be verified and documented in the BPCR.

5.1.66 The disposal of primary packaging material, leftover printed packaging material shall be authorised by production manager and Manager – Q.A. The disposal shall be performed and documented as per the relevant SOP.

5.1.67 The finished goods transfer record (FGTR) shall be prepared by production and signed by IPQA. Material shall be transferred to bonded store room UNDER QUARANTINE status till the batch is released by Q.A. 

5.1.68 The completed batch record shall be checked for correctness of all the attached formats and information mentioned therein. Record shall be submitted to Manager – Q.A for review and subsequent release of the batch for distribution into the market.

5.1.69 The BPCR is compiled and preserved in QA documentation room for rapid retrieval by QA. 

6.0 ANNEXURES:

NIL

7.0 CHANGE HISTORY