Inprocess Control

QC General SOP,S

1.  Purpose

To ensure that the product in-process about to subject to the next step is according to the specifications.

2.  Scope

It is applicable to In-process control.

3.  Responsibility

QA Officer

QC Analyst

Production pharmacist

Production manager

Quality Control Manager

4. Introduction

“In-process control” means checks performed during production in order to monitor and if necessary to adjust the process to ensure that the product conforms to its specifications.  The control of the environment or equipment may also be regarded as a part of in-process control.

Any materials that must undergo further manufacturing steps before it becomes a bulk product called intermediate product and stage is called the intermediate or in-process stage.  That intermediate product must undergo further manufacturing before it becomes a bulk product.

During the in-process of intermediate product sampling at different stages is performed and then monitor in-process checking during production to ensure that the product conforms to its specification.

5.             General Procedures

5.1          Written Procedures Deviations

There should be written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.  Such procedures shall include all requirements in this subpart.  These written procedures including any changes, shall be drafted, reviewed, and approved by the appropriate organizational units and reviewed and approved by the quality control unit.

Written production and process control procedures should be followed in the execution of the various production and process control functions and should be documented at the time of performance.  Any deviation from the written procedures should be recorded and justified.

5.2          Charge in of components

5.2.1       Written production and control procedures should include the following, which are designed to assure that the drug products have the identity, strength, quality, and purity; they purport or are represented to possess

5.2.2       The batch should be formulated with the intent to provide not less than 100 percent of the labeled or established amount of active ingredient.

5.2.3       Components for drug product manufacturing should be weighed, measured, or subdivided as appropriate.  If a component is removed from the original container to another, the new container should be identified with the following information.

  • Component name or item code
  • Receiving or control number.
  • Weight or measure in a new container.
  • Batch for which component was dispensed

 

5.2.4       Weight measuring or subdividing operations for components should be adequately supervised.  Each container of component dispensed to manufacturing should be examined by a second person to assure that

  • The quality control unit released the component.
  • The weight or measure is correct as stated in the batch production records
  • The containers are properly identified.

5.2.5       Each component should be added to the batch by one person and verified by a second Person.

5.3          Calculation of Yield

Actual yields and percentages of theoretical yield should be determined at the conclusion of each appropriate phase of manufacturing.  Processing, packing, or holding of the drug product.  Such calculations should be performed by one person and independently verified by a second person.

5.4          Equipment Identification

5.4.1       All compounding and storage containers, processing lines, and major equipment used during the production of a batch of a drug product should be properly identified at all times to indicate their contents and when necessary the phase of processing of the batch.

5.4.2       Major equipment should be identified by a distinctive identification number or code that should be recorded in the batch production record to show the specific equipment used in the manufacturing of each batch of a drug product.  In cases where only one of a particular type of equipment exists in a manufacturing facility, the name of the equipment may be used in lieu of a distinctive number or code.

5.5          Sampling and Testing of In-Process Materials and Drug Products

5.5.1       To assure batch uniformity and integrity of drug products, written procedures should be established and followed that describe the in-process controls and tests or examinations to be conducted on appropriate samples of in-process materials of each batch.  Such control procedures should be established to monitor the output and to validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product.  Such control procedures should include but are not limited to the following where appropriate.

  • Tablet weight variation
  • Disintegration time
  • Adequacy of mixing to assure uniformity and homogeneity.
  • Dissolution time and rate
  • Clarity completeness or pH solutions

5.5.2       Valid in-process specifications for such characteristics should consistent product’s final specifications and should be derived from previous acceptable process average and process variability estimates where possible and determined by the application of suitable statistical procedures where appropriate.  Examination and testing of samples should assure that the drug product and in-process material conform to specifications.

5.5.3       In process materials should be tested for identity, strength, quality, and purity as appropriate and approved or rejected by the quality control unit during the production process, e.g. at commencement or completion of significant phases or after storage for long periods.

5.5.4       Rejected in-process materials should be identified and controlled under a quarantine system designed to prevent their use in manufacturing or processing operations for which they are unsuitable.

5.6          Time Limitations on Production

Appropriate time limits for the completion of each phase of production should be established to assure the quality of the drug product.  Deviation from established time limits may be acceptable if such deviation does not compromise the quality of the drug product.  Such deviation should be justified and documented.

5.7          Control of Microbiological Contamination

Appropriate written procedures designed to prevent objectionable microorganisms in drug products, should be established and follow SOP.

 

5.8          Reprocessing

5.8.1       Written procedures should be established and followed by prescribing a system for reprocessing batches that do not conform to standards or specifications and the steps to be taken to insure that the reprocessed batches will conform with all established standards specifications and characteristics.

5.8.2       Reprocessing should not be performed without the review and approval of the quality control unit.

5.9          Labeling Issuance

5.9.1       Strict control should be exercised over labeling issued for use in drug product labeling.

5.9.2       Labeling materials issued for a batch should be carefully examined for identity and conformity to the labeling specified in the master or batch production records.

5.9.3       Procedures should be used to reconcile the quantities of labels issued, used, and returned and should require evaluation of discrepancies found between the quantity of drug product finished and the number of labels issued when such discrepancies are outside narrow preset limits based on historical operating data.  Such discrepancies should be investigated in accordance with.

5.9.4       All excess labels bearing lot or control numbers should be destroyed.

5.9.5       Returned labels should be maintained and stored in a manner to prevent mix-ups and provide proper identification.

5.10        Packaging and Labeling Operations

There should be written procedures designed to assure that correct labels, labeling, and packaging materials are used for drug products. Such written procedures should be followed.  These procedures should incorporate the following features.

 

5.10.1    Prevention of mix-ups and cross-contamination by physical or spatial separation from operations on other drug products.

5.10.2    Identification and handling of filled drug product containers that are set aside and held in unlabeled condition for future labeling operations to preclude mislabeling of individual containers, lots or portions of lots.  Identification need not be applied to each individual container but sufficient to determine the name, strength, the quantity of contents, and lot or control number of each container.

5.10.3    Identification of the drug product with a lot or control number that permits determination of the history of the manufacturing and control of the batch.

5.10.4    Examination of packaging and labeling materials should be done for suitability and correctness before packaging operations and documentation of such examination in the batch production record.

5.10.5    Inspection of the packaging and labeling facilities immediately should be done before use to assure that all drug products have been removed from previous operations.  Inspection should also be made to assure that packaging and labeling materials not suitable for subsequent operations have been removed.  The results of the inspection should be documented in the batch production records.

5.10.6    Printing devices, or associated with manufacturing lines used to imprint labeling upon the drug product unit label or case should be monitored to assure that all imprinting conforms to the print specified in the batch production record.

 

5.11        Drug Product Inspection

5.11.1    Packaged and labeled products should be examined during finishing operations to provide assurance that containers and packages in the lot have the correct label.

5.11.2    A representative sample of units should be collected at the completion of finishing operations and should be visually examined for correct labeling.

5.11.3    Results of these examinations should be recorded in the production or control records.

 

5.12        Check Points for giving Line Clearance

Before starting the operation, the production area and machines must be clean.  The production supervisor will inform Q.C. Inspector for getting the line clearance for the batch startup.  The Q.C. Inspector will check the following points in the related section if the general area and machines are clean, then Q.C. Inspector will give the clearance certificate.

5.12.1    Dispensing Section

  • Wear gloves and check the cleaning of the scoops with tissue paper. it must be clean.
  • Check the balances, they must be clean and calibrated.
  • Check the cleaning of cabins and their doors with tissue paper. The material storage cabin specified for placement of material of batch, which is to be dispensed, must be properly labeled and empty.
  • Empty bags of the previous batch must be removed.
  • Check the cleaning of pallets, it must be clean.
  • Check the cleaning of the floor and ceiling visually.
  • The BPR sheet must be signed by QCM, Prod. Manager and dispensing officer

5.12.2    Dust collector assembly

  • Check cleaning of the exhaust hood with tissue paper. It must be free of any kind of power.
  • Check external cleaning of suction pipes and dust collector chamber.
  • When the dust collector assembly is thoroughly cleaned, check cleaning of
  1. Fine filters
  2. Dust collecting tray
  3. Filter hoses

 

5.13        Injectable Area

  Equipments

 

Instruments Capacity Room
Manufacturing Tank 01

 

1000L

 

Inj. Mfg

 

  • Check the tank when it is labeled “Ready for use”.
  • Wear the gloves and then check the cleaning of the inner surface of the tank with tissue paper. It must be free of any particle.
  • Check the temperature sensor rod and mixing rod cleaning with tissue paper, It must be particle-free.
  • Take purified water in a clean SS container and pour it alongside of walls and mixing rods. Then drain it through the nozzle into another clean SS container.  The water must be free of particle and any kind of smell.
  • Check the screws there must not be any traces of previous products in its grooves.
  • Check cleaning of the outside of the tank with tissue papers, the motor must not contain any dust particle

 

5.14        General Area

5.14.1    There should not be any material or recovery of the previous batch on shelves of S/S tables and they must be properly maintained.

5.14.2    Check cleaning of walls with tissue papers it must be dust-free.

5.14.3    Check cleaning of ceiling and floor visually.

5.14.4    Check working area and equipment they must be clean and free from any starting materials, products, product residues, labels, or documents not required for the current operation.

5.14.5    Check the cleaning of containers for placing rejected bottles.

5.14.6    Electrical bulb for checking empty bottles must be properly working.

 

5.15        Liquid Section

5.15.1    Tanks

 

Instruments Capacity
Manufacturing Tank 01 2000L

 

  • Check the tank when it is labeled “Ready for use”.
  • Wear the gloves and then check the cleaning of the inner surface of the tank with tissue paper. It must be free of any particle.
  • Check the temperature sensor rod and mixing rod cleaning with tissue paper, It must be particle-free.
  • Take purified water in a clean SS container and pour it alongside of walls and mixing rods. Then drain it through the nozzle into another clean SS container.  The water must be free of particle and any kind of smell.
  • Check the screws there must not be any traces of previous products in its grooves.
  • Check cleaning of the outside of the tank with tissue papers, the motor must not contain any dust particle.

 

5.15.2    Colloidal Mill

  • Check cleaning of hopper and outlet with tissue paper it must be clean.
  • Rinse purified water through it and check it, the water must be clear.

5.16        Liquid Filling Section

5.16.1    Filling Machine

  • Wear gloves and check the cleaning of its nozzles with tissue paper.
  • Rinse IPA through its pipes and check it visually it must be clear.
  • Check cleaning of the belt with tissue paper.

5.16.2    Washed Empty Bottles Ready for Filling

Empty bottles ready for liquid filling are checked visually and with tissue paper for contamination with filth, insect infestation, or another extraneous adulterant.

 

5.16.3    General Area

  • There should not be any material or recovery of the previous batch on shelves of S/S tables and they must be properly maintained.
  • Check cleaning of walls with tissue papers it must be dust-free.
  • Check cleaning of ceiling and floor visually.
  • Check the working area and equipment they must be clean and free from any starting materials, products, product residues, labels, or documents not required for the current operation.
  • Check the cleaning of containers for placing rejected bottles.
  • The electrical bulb for checking empty bottles must be properly working.

 

5.17        Packing Hall

 

5.17.1    Labeling Machine

  • Check the cleaning of the machine when labeled “Ready for use”
  • Check the cleaning of the following parts of the machine with tissue paper.
  1. Electrical panel.
    • There must not be any label of the previous batch on the shelves of the S/S table.

 

5.18        Washing Area

5.18.1    Vial washing machines

  • Check cleaning of the following parts of the machine with white tissue paper when labeled “Ready for use”.
  1. Nozzles
  2. Springs
  3. Nozzle plates
  4. Base of machine
  5. External side of the machine
    • There must not be any dust or any broken glasses in the machine.
    • Be sure that washing of bottles is done with purified water.

5.18.2    Dryer/ Sterilization oven

  • Check cleaning of the dryer with tissue paper it must not contain any particle of the previous product.
  • Check cleaning of trolley walls, floor & door of the dryer with tissue paper it must be clean.

5.18.3    General Area

  • There should not be any material or recovery of the previous batch on shelves of S/S tables.
  • The shelves of the S/S table should be properly maintained.
  • Check cleaning of walls with tissue papers it must be dust-free.
  • Check cleaning of ceiling and floor visually.
  • There must not be any packing material of the previous batch on the belt.
  • The area must be free of packing material, products, product residues, labels, or documents not required for the current operation.
  • The waste bin must be clean.

5.19        Procedure for Sampling

Due to the great variability of formulations to be analyzed proper sampling is extremely important for meaningful results.  One should ensure that the selected portion of the sample is the true representative of the whole lot/batch or container the method to be followed for sampling is as under:

 

5.19.1    A sample advice sheet of the product is sent by a production supervisor of the concern section.  This has complete information about a batch i.e.:

  1. Product name
  2. Batch #
  3. Batch size
  4. Stage
  5. Released for or purpose
  6. # of containers
  7. Time and date
  8. Signature of production supervisor

 

5.19.2    After getting intimation from the production supervisor, Quality Control Inspector takes the approximate quantity of samples from each container, which is different for different types of products e.g.

  1. Liquid 150-200ml

*500-600ml for products whose viscosity has to be determined

 

5.19.3    Sample of dried granules, compressed cores, and coated tablets are taken by S.S. spoons in polyethylene bags while the sample of the final mix and cream is taken by aluminum sampler in polyethylene bags.

5.19.4    The liquid sample is drawn by opening value in the container in a glass beaker and closed by polyethylene bags to avoid contamination.

5.19.5    Check volume makes up of tank with a meter rod before taking a sample.  It must be according to batch size.  After taking samples cover the beaker with a polyethylene bag to avoid the contamination.  During manufacturing syrup check the reading of the water meter, it must be according to the BPR.

5.19.6    Note down the product name batch no. date and stage on the polyethylene bags or the beaker and paste under test label on each container.

5.19.7    At different stages different tests are performed as per SOP given in the tabular form. Details are to be found in the particular test instructions for each product.

5.19.8After analysis of the product a release label is pasted on the machine or container.  Labels are of one type and have full information on the batch record.

5.19.9    During in-process checking Q.C. Inspector randomly checks different parameters from time to time and notes the readings in the in-process sheet of every section.

5.19.10   On final packing finish product unit packs are drawn for keeping samples and for finished product testing.

 

 

IN-PROCESS CONTROL OF LIQUID /INJECTION

 

S. No. Stage Test Performed Method
1 PH adjustment

 

pH checking By pH meter
2 Bulk a)       Description

b)       Color

c)       Odor

d)       Assay and identification

e)       pH

f)         Specific gravity

As per SOP

 

IN-PROCESS CONTROL OF PACKING SECTION

 

S. No. Stage Test Performed Method
 

I

 

Labeling

 

 

 

 

 

 

 

 

a)       Overprinting of

b)       M. R .P. Rs.

c)       B #

d)       Mfg. date

e)       Exp. date

i)      Pack size

Proper pasting of labels

 

As per SOP

 

II

 

Cartoning

 

 

 

 

 

 

 

 

 

 

f)         Overprinting of

g)       M. R .P. Rs.

h)       B #

i)         Mfg. date

j)         Exp. date

ii)     Pack size

iii)   Leaflets

iv)   Proper pasting of carton

 

As per SOP

 

III

 

Final packing

 

 

 

 

 

 

Outer carton

Printing on carton

Quantity of unit pack per carton

 

As per SOP

 

 

5.20        In-Process Checking of Liquid Filling/Injection Filling Section

5.20.1    Measuring cylinder and bucket must be cleaned.  Rinse the measuring cylinder with purified water after each checking of volume.  Be sure that there is not any contamination in the syrup stored in the bucket than it may be reprocessed.

5.20.2    Check cleaning of the empty bottle it must be clean and have not any cracks in the glass and any kind of smell.

5.20.3    At the start of filling, check the volume from each nozzle five times in the volumetric cylinder.  After checking, pour the syrup in the bucket placed on the table specified for its volume must be within the range.

5.20.4    Check capping of bottles. Invert capped bottle on the table and after 5minutes, checks it.  There must be not any leakage.

5.21        In-Process Checking during Dispensing

The following points should be checked during dispensing.

5.21.1    Check the name of raw materials placed on a pallet in the area from the list of ingredients required in BPR.  There must not be any extra containers.  Be sure that every raw material container has a released label.

5.21.2    Cross check the raw material name, Q.C. #, G.R. # written by the dispensing officer on the raw material sheet from the “Released” label for raw material.

5.21.3    There must not be the contact of helper with raw material, he must wear the gloves.

5.21.4    Separate scoops must be used for dispensing of each material.

5.21.5    Check the tare wt + net wt.  the net wt. must be according to BPR.

5.21.6    If two or more active materials have to be dispensed helper must change their uniform & gloves before dispensing of each active material.