SOP For Operation, Maintenance And Calibration Of Ultrasonic Water Bath

The purpose of this Standard Operating Procedure (SOP) is to lay down the procedure for Operation, maintenance and Calibration of Ultrasonic Water Bath.

  • PROCEDURE:
    1. PRELIMINARY CHECK:
      1. Fill the Water bath with water up to height of minimum 7cm from bottom of tank. Whenever the Ultrasonic Water Bath is required with specific temperature then heater to be kept “ON”.
      1. Ensure that there is no leakage of water from water bath.
      1. Do not put any heavy objects on the bottom of the tank as it can damage the transducers. Always use tray supplied with ultrasonic bath.
      1. Ensure that liquid does not splash on the controls and switches.
  • Basic Operation :Connect the Ultrasonic Water Bath to the main power supply with the connecting plug the cleaner into grounded outlet after power on the temperature displays the actual environment temperature time and temperature default as the last setting ones.( 3 minutes default time for initial use temperature display 0°C)Press + Button adjustable for timer working time increase 1 minute hold the key the time raised by 10 minutes continuous in the contrary.Press – Button adjustable for timer working time reduce 1 minute hold the key the reduced by 10 minutes continuous the cleaning stops when the counts down 00:00.Press Button for heating key for temperature setting with the range 0°C-80°C.Press + Button adjustable for heating a time temperature will rise 1°C holding the key temperature will rise continuously with 10°C in the contrary.Press – Button temperature reduce 1°C holding the key temperature reduced continuously with 10°C usually the best results are with 40°C-60°C.When setting the temperature if the setting temperature exceed the environment temperature Press button heating key the heating working and indicator light up below the environment temperature heating can’t start and the indicator light turn off.Heating won’t shut off automatically when the environment temperature below the setting press Button heating key in to stop heating (heating can’t stop if you don’t press Button heating key).After time and temperature setting press Button heating key en press any other keys Degas,Soft, Normal Machine start to work indicator light up if need to stop heating or ultrasonic press corresponding key again then corresponding indicator lights turn off.Machine stop working after 8hours working time (power saving mode) in this made machine restored to the standby state once you press any key.Three ultrasonic working mode:Degas mode: Press Degas Button intermittent operation of ultrasonic power for rapid removal of entrained air from liquids ultrasonic work 6 seconds and stop 2 seconds same cycle to be proceed & press Degas key again to stop it.Normal mode: Press Normal Button to start the normal faction strong ultrasonic power with large current press again to stop it.Soft mode: Press Soft Button to start soft function continuous slight variation of ultrasonic frequency to eliminate hot spots dead zones and standing waves press again to stop it. During working you will hear the “sizzling“ voice that means the cleaner running properly.
  • MAINTENANCE  : Ensure system is off and disconnect the power cable from the main socket before cleaning.Clean the water bath and replace the water on daily basis or as and when the water gets turbid.
  • CALIBRATION PROTOCOL:

            Calibration Frequency: Yearly

  • Carry out the Calibration of temperature indicator controller with sensor and time by an approved external party.

SOP for Handling of Laboratory Reagents

Standard Operating Procedure (SOP) for Receipt, Storage, and Handling of Laboratory Reagents, Buffers, Solvents, Glasswares and other consumables in QC.

Receipt, Storage, and Handling of Laboratory ReagentsPurpose :

  • The purpose of this SOP ( Standard Operating Procedure) is to describe the procedure for the receipt, storage, and handling of laboratory reagents.

Scope :

  • This procedure is applicable to laboratory reagents used at Quality Control Department in the pharmaceutical manufacturing plant.

Responsibilities : (Laboratory Reagents)

  • Analyst :
  • To provide information about chemical/reagent for procurement and follow the procedure as per the SOP.
  • To maintain the related documents as per the SOP.
  • Quality Control Head or Designee :
  • To procure the required chemical/reagent.
  • Receiving of procured chemicals in proper condition.
  • Store the received chemicals as per their required storage condition
  • Handling of Chemicals with proper safety as per the respective SDS.
  • Perform the documentation as per the SOP.
  • Provide training to the concern persons before the implementation of the SOP.
  • Quality Assurance :
  • To check the SOP.
  • The implementation of the system as per the SOP.
  • Regulatory Affairs Quality Head and Plant Head :
  • To review and approve the SOP.

Abbreviations and Definition of Terms : (Laboratory Reagents)

  • Abbreviations :
  • ETP: Effluent Treatment Plant.
  • PPE: Personal Protective Equipments
  • SDS: Safety Data Sheet.
  • SOP: Standard Operating Procedure
  • NA: Not Applicable
  • Definition of terms: NA

Procedure for Handling of Laboratory Reagents :

  • Laboratory Reagents Procurement Procedure :
  • The analyst shall inform the designated QC person in case of the requirement of any Laboratory reagent /chemicals.
  • The analyst shall mention the details of the required Laboratory chemical/ reagent in the Reagent requirement register as per  Annexure-2.
  • The designated QC person shall inform the supplier about the desired chemical and its required quantity for its procurement.
  • Laboratory Reagents Receiving Procedure :
  • On receipt of the reagents/chemicals, the designee from QC shall verify it against the reagent requirement /issuance register.
  • The designed QC person shall observe the physical condition of the container/bottles/packs before receiving the reagent/ chemicals.
  • If any discrepancy is observed (e,g damaged container, improper storage condition, quantity mismatch, etc.) the QC person shall immediately inform to Head QC or designee and return the material to the supplier.
  • After the required laboratory reagent/chemical is received. its receipt and stock details shall be maintained as per Annexure- 3 by the designed QC person.
  • After receipt of Laboratory glasswares, its receipt and stock details shall be maintained as per Annexure- 4 by the designed QC person.
  • QC person shall paste the label on the laboratory reagent/container as shown in Annexure -1 and put the details of  “Date of Receipt along with the signature.
  • The analyst shall put the date of “First time opened on” along with the sign and assign an expiry date to the chemicals.
  • The expiry date for solid laboratory reagents, solvents and acids shall be as provided by the manufacturer.
  • In case the expiry date is not provided by the manufacturer, then the expiry date shall be assigned as three years from the date of opening.
  • The designated person shall arrange SDS and certificate of analysis if required.
  • Storage of Laboratory Chemicals / Reagents :
  • Store the chemicals/reagents as per the manufacturer’s instructions on the container considering safety precautions.
  • If the manufacturer does not mention any recommended storage condition, store the chemicals/reagents in a designated reagent/chemical storage room controlled at 25°C ± 2°C.
  • In the case of general reagent, where specific storage condition is not required, shall be stored at ambient temperature.
  • If the recommended storage condition of any laboratory reagent is below 15°C, it shall be stored in the refrigerator.
  • In the case where the recommended storage condition of any laboratory reagent is below 0°C, store in a deep freezer.
  • Handle the chemical/ reagent with proper precautions as per its SDS.
  • Acid corrosive chemical bottles/containers shall be opened after wearing proper PPE’s.
  • General Usage Procedure of Laboratory Reagents / Chemicals:
  • The analyst shall take the required reagent for usage from its designed storage place/ chemical store.
  • The analyst shall put the date of opening with signature and expiry date on the label affixed at the time of receipt.
  • If the label is not affixed, Do not use such reagents.
  • The analyst shall codify the reagents and arrange them in alphabetical order on the cupboard of the working table of the respective location.
  • Do the coding of reagents coding at the time of its receipt, the Designated person shall give the specific code to the reagent and maintain the list of reagents with code.
  • Code: the first alphabet of the reagents with serial number
    • e.g. 3-Aminopyridine Code: A01
    • Aluminum GR Code: A02
    • Barium chloride 2-hydrate GR Code: B01
    • Zinc Acetate extra Pure Code: Z01
  • After opening the reagent bottle, if any abnormal observation is found in the physical appearance of reagent, the analyst shall immediately inform to Head QC or designee.
  • Discard such reagents/chemicals as per the procedure defined in the SOP for  “ Disposal of waste generated in Quality control” by taking proper precautions as per its respective SDS.
  • The analyst shall use a new chemical/reagent bottle.
  • After using the required reagent/ chemical, Keep the bottle/container back to its designed place.
  • Maintain the minimum stock of laboratory reagents/chemicals to prevent any delay in the analysis.
  • Precautions during Handling of Laboratory Reagents:
  • Always assure the intactness of the reagent bottle before use.
  • Always check the physical condition and appearance of the reagent before use
  • Ensure the expiry date of a particular reagent before using it. Do not use any reagents after the expiry date as mentioned on the label of the bottle/container.
  • Tighten the mouth of the reagent container both before and after use.
  • Always use suitable PPE’s (like hand gloves, mask, goggle, etc.) required as per the SDS of the chemical/reagent.
  • Always refer to SDS and handling precautions while handling poisonous and toxic chemicals/reagents.
  • Consumption of Acetic Anhydride :
  • Controlled usage of  Acetic Anhydride.
  • Keep Acetic Anhydride under control and secured with lock and key.
  • Destruction Procedure of Laboratory Reagents:
  • If the reagents are left after the expiry date is over, Destroy the remaining quantity as per the procedure mentioned in the SOP for “ Disposal of waste generated in Quality Control.
  • Destruction of Acids :
  • Take plenty of water in a container and add the acid slowly with stirring through sides of the beaker.
  • If the temperature is observed in the container, add more water, cool it and drain it.

Note: Some reagents/chemicals/acids may be reactive when treated with water.  Hence, it mandatory to refer to the SDS of the particular reagent before following any discardation procedure. 

Sticker Label at the time of receipt (Annexure -1)

Sticker - Laboratory Reagents

Reagent Requirement and Issuance Register (Annexure -2)

Annexure 2

Receipt and Stock detail of Chemical/Reagent (Annexure -3)

Name of Material:

Code No.:                                                                                                                     Sr.

No. Date of

Receipt Received

Qty. Withdraw

Qty. Withdrawal

By and Date Balance

Qty. Checked

By

Remark

Receipt and Stock detail of Laboratory Glasswares (Annexure -4)

Name of Glassware :

The volume of Glassware:

Sr. No. Date of Receipt Received qty. Received by. Checked By

Remark

References and Annexures:

  • References :
  • In House.
  • SOP for Disposal of waste generated in Quality Control
  • Annexures :
  • Sticker Label at the time of receipt (Annexure -1)
  • Reagent Requirement and Issuance Register (Annexure -2)
  • Receipt and Stock detail of Chemical/Reagent (Annexure -3)
  • Receipt and Stock detail of Laboratory Glasswares (Annexure -4)

Acceptable Quality Level (AQL) – SOP and Chart

OBJECTIVE:

  • To define the procedure for Acceptable Quality Level sampling for Tablets and Capsules during bulk approval.

SCOPE:

  • This procedure is applicable to bulk approval of manufactured Tablets and Capsules at pharmaceutical product manufacturing location.

    REFERENCES:

  • SOP for Event Reporting and Investigation.

DEFINITIONS OF TERMS:

  • Inspection by attributes:
  • Inspection whereby either the unit of product is classified simply as defective or no-defective or the number of defects in the unit of product is counted, with respect to a given requirement or set of requirements.
  • Acceptable Quality Level (AQL):
  • The AQL is a percent defective that is the baseline requirement for the quality of the producer’s product. The producer would like to design a sampling plan such that there is a high probability of accepting a lot that has a defect level less than or equal to the Acceptable Quality Level (AQL).
  • Sampling Plan:
  • A lot sampling plan is a statement of the sample size or sizes to be used and the associated acceptance and rejection numbers.
  • Representative Sampling:
  • When appropriate, the number of units in the sample shall be selected in proportion to the size of sub-lots or sub-batches, or parts or the lot or batch, identified by some rationale criterion. When representative sampling is used, the units from each part of the lot or batch shall be selected at random.
  • Defects:
  • A defect is any non- conformance of the unit of the product with the specified requirement.
  • Critical Defect:
  • A critical defect is one which is likely to result in a hazardous or unsafe condition for individual using, maintaining or depending upon that product.
  • Major Defect:
  • A major defect is one, other than critical, that is likely to result in failure or to reduce materially and usability of the unit of product for its intended purpose..
  • Minor Defect:
  • A Minor defect is one that is not likely to reduce considerably the usability of the unit of product for its intended purpose or is a departure from established standards having little bearing on the effective use or operation of the unit of product.
  • Part Lot:
  • Distinct portions of a whole lot, i.e. a whole lot of core tablets divided into an equal portion for the purpose of coating – each portion of the coated tablets is a distinct lot. I
  • Inspection Levels:
  • The standards provide for three general inspection levels (i.e. Level I-Reduced Inspection, Level II- Normal/General Inspection, Level III- Tightened Inspection) and four special inspection levels. These levels permit the user to balance the cost of inspection against the amount of protection required.

PROCEDURE FOR ACCEPTABLE QUALITY LEVEL (AQL):

  • Acceptable Quality Level (AQL) checks shall be performed semi-finished for commercial batches of tablets and capsules.
  • QA shall perform the Acceptable Quality Level (AQL) checks in the respective area and based on findings,
  • QA shall decide the need & extent of inspection for the subjected batch and details shall be recorded.
  • In the case of Process validation batches, 100% visual inspection shall be performed and the same shall be addressed in the Batch record.
  • During Process validation, Segregate the visual inspection rejection and evaluate the type of rejection i.e. Critical, Major and Minor.
  • If the visual inspection trend of process validation is satisfactory, then based on process validation (report) recommendations, Acceptable Quality Level (AQL) sampling shall be performed in commercial batches.
  • Selection of Containers for Acceptable Quality Level (AQL) Sampling of Tablets/Capsules:
  • Production Officer shall submit duly filled and signed BMR to QA for review and intimate for visual inspection of the bulk product as per Acceptable Quality Level (AQL).
  • QA shall ensure Product name, Batch No, Manufacturing date, Expiry date and select the containers of product for Acceptable Quality Level (AQL).
  • The samples to be withdrawn for the bulk approval from the number of the container shall be based on the following criteria :
  • Determine the “total number of containers to be sampled” per part lot (for coated tablets) or per batch (for capsules and uncoated tablets) by using the formula  10+√n +1, Where “n” is the total number of containers per part lot/Batch.
  • If the total number of the container is less than or equal to 10 Nos (per batch/lot), then samples shall be checked from all the containers.
  • In case of the total number of the container is more than 10, then for Acceptable Quality Level (AQL) sampling of 10 containers shall be done 100% and the remaining container shall be AQL as per formula √n+1.
  • For Example Number of the container is 35 then AQL of 10 (Frist 5 + Last 5) container is 100% and for remaining (35-10=25) 5 containers, as per formula (√25+1=5+1), 6 containers shall be checked.
  • If any value of √n is above the whole number, the number shall be rounded off to the next whole number).
  • For coated tablets, if coating performed in multiple lots then individual lot size shall be considered as batch size and accordingly Acceptable Quality Level (AQL) samples shall be withdrawn.
  • E.g. If 1 part lot contains 28 containers ( e.g. coating is performed in two lots) then the number of containers to be sampled shall be 10+√18+1 = 10+4.24+1 =15.24 Therefore the total number of containers to be sampled shall be 16 from each lot.
  • If one batch contains 50 containers (e.g. uncoated tablets/capsules) then the number of containers to be sampled will be 10+√40+1 = 10+6.32+1 = 17.32, therefore, the total number of containers to be sampled shall be 18 from the whole batch.
  • Collection of samples and acceptance criteria for Acceptable Quality Level (AQL)
  • Collect the samples from each selected container in equal quantity in a duly labeled polyethylene bag.
  • Check each collected tablet (coated and uncoated) or capsule for the quality attributes specified as per Acceptable Quality Level (AQL) on the inspection trolley.
  • e.g. In case of uncoated tablets/ capsules if Acceptable Quality Level (AQL) sample quantity requirement is 1250 and no. of containers to be sampled is 9 then from each container 1250/9 i.e. 138.9=139 samples (Withdrawn of samples = No. of Sample X Avg. weight of sample or by Manual Counting) shall be withdrawn and composite sample of 1250 bulk units shall be prepared.
  • In case of coated tablets if the coating is performed in two lots and lot size is 500000 then 800 tablets from each part lot shall be withdrawn.
  • If samples are to be withdrawn from 5 containers then from each container 800/5=160 coated tablets (Withdrawn of samples = No. of Sample X Avg. weight of sample or by Manual Counting) shall be withdrawn.
  • For the purpose of the Acceptable Quality Level (AQL). Consider the sampling standard weight of tablets as average weight.
  • QA Officer shall check the bulk product for visual defects as per the below-mentioned procedure. ( Check the visual defects on both the sides of tablets in case of tablet products ).
  • Collect the sample quantity from each selected container in equal quantity and inspect on the inspection trolley.
  • The acceptance criteria for Acceptable Quality Level (AQL) shall be as given below based on the classification of the defect.
Sr. No.Classification of defectAcceptance criteria
01Critical0.010%
02Major0.40 %
03Minor1.50  %
  • The sampling quantity for bulk approval and number of defects observed against acceptance criteria to determine whether batch passes or fails shall be as per the below table.
  • The below table is equivalent to the General Inspection Levels -LEVEL II.

Table-1

Table 1 - Accepted Quality Level (AQL)
  • In case batch size is more than 10,00,000 Tablets/Capsules sample size quantity is doubled as compared to if batch size is between 5,00,001 to 10,00,000 Tablets/ Capsules.
  • This is Sun in-house stringent criteria with respect to sample quantity in order to increase sample size in proportion to batch size.
  • Note: If batch/part lot fails in Acceptable Quality Level (AQL) acceptance criteria then 100 % inspection of the part lot/batch shall be performed. Raise the event to find out the root cause.
  • The classification of defects as per the nature of dosage forms as given below:
  • Classification of core tablets defects are as follows:
(1) Critical
A. Wrong appearance
Foreign productPharmaceutical material is either a component, powder on the finished dosage that is not a normal part of the batch being processed
Foreign materialAnything other than Pharmaceutical material that is not a normal part of the batch being processed.
Wrong appearanceProduct appearance is not as per product specification.
Tablets not in  uniform size /Wrong punch shapeThe tablet that is notably thinner, thicker, larger, smaller or a different shape than the other in the sample.
Abnormal discoloration of productsDiscolored tablets
  Note: Broken tablets are considered as critical criteria and 100% inspection shall be performed prior to loading bulk units into the hopper for primary packaging.
(2) Major :
Chipping or Minor breakingIt is the breaking of tablet edges, while the tablet leaves the press or during subsequent handling and coating operations.
Illegible de-bossingCharacters in the de-bossing are not legible.
Illegible embossingCharacters in the embossing are not legible.
Layer separationIn the bilayer tablet, one layer is separated from the other layers.
LaminationIt is the separation of a tablet into two or more distinct horizontal layers.
Cracking/broken tabletSmall, fine cracks observed on the upper and lower central surface of tablets, or very rarely on the sidewall are referred to as ‘Cracks’.
Double impression‘Double Impression’ involves only those punches, which have a monogram or other engraving on them.
Soft tablets The tablets are susceptible to hydrolysis will develop soft nature.
PickingThe small amount of material from a tablet is sticking to and being removed off from the tablet-surface by a punch face.
StickingThe tablet material adhering to the die wall. Filming is a slow form of sticking and is largely due to excess moisture in the granulation
Dark Spot/Blackspot/Colour particlesStains or spots will appear on the tablet surface. Migration of coloring agent upon storage.
CappingCapping happened when the upper or lower segment of the tablet separates horizontally, either partially or completely from the main body of a tablet and comes off like a cap, during ejection from the tablet press, or during subsequent handling.
BindingTablets adhere, seize or tear in the die. A film is formed in the die and ejection of the tablet is hindered. With excessive binding, the tablet sides are cracked and it may crumble apart
(3) Minor :
Mottling‘Mottling’ is the term used to describe an unequal distribution of color on a tablet, with light or dark spots standing out in an otherwise uniform surface.
Rough surfaceThe tablet surface is rough.
Shade variationThe tablet that is visibly a different shade or color than the others in the sample.
Dust on TabletThe powder found on the tablet.
De-bossing or score is not well definedCharacters in the de-bossing / crease have slight imperfections but are legible.
  • Classification of Coated tablets defects are as follows:
(1) Critical :
A. Wrong appearance
Foreign productPharmaceutical material is either a component, powder on the finished dosage that is not a normal part of the batch being processed.
Foreign materialAnything other than Pharmaceutical material that is not the normal part of the batch being processed.
Tablet not in uniform sizeThe tablet that is notably thinner, thicker, larger, smaller or a different shape than the other in the sample.
Missing debossingDebossed characters are missing from the tablet.
Abnormal discoloration of productsDiscolored tablets
Large dark staining on productStains found on the products
  Note: Broken tablet is considered as critical criteria and 100% inspection shall perform prior to loading bulk units into the hopper for primary packaging.
(2) Major :
BloomingIt is a defect where the coating becomes dull immediately or after prolonged storage at high temperatures.
BridgingThis occurs when the coating fills in the lettering or logo on the tablet and is typically caused by improper application of the solution, poor design of the tablet embossing, high coating viscosity, a high percentage of solids in the solution, or improper atomization pressure.
ChippingIt is a defect where the film becomes chipped and dented, usually at the edges of the tablet.
Colour VariationA defect which involves variation in the colour of the film.
CrateringIt is a defect of film coating whereby volcanic-like craters appears exposing the tablet surface.
FlakingFilm flakes off exposing the tablet surface
Mottling‘Mottling’ is the term used to describe an unequal distribution of color on a tablet, with light or dark spots standing out in an otherwise uniform surface.
Orange Peel/RoughnessIt is a surface defect resulting in the film being rough and nonglossy. Appearance is similar to that of an orange
SplittingThe film splits usually around the edges of the tablet
StickingAn indentation in the surface of the tablet that can cause a dimple resulting in weight variation.
TwinningWhen two tablets stick tighter. It usually happens with capsule-shaped tablets.
(3) Minor :
BlisteringThe film becomes detached from substrate forming a blister
Blushing It is a defect best described as whitish specks or haziness in the film.
Cracking/SplittingIt is a defect in which the film either cracks across the crown of the tablet (cracking) or splits around the edges of the tablet (Splitting)
Peel offThe film peels off exposing the best tablet surface
PickingIt is a defect where isolated areas of the film are pulled away from the surface when the tablet sticks together and then part.
PittingIt is a defect whereby pits occur in the surface of a tablet core without any visible disruption of the film coating
Shade variationThe tablet that is visibly a different shade or color than the others in the sample.
InfillingIt is a defect that renders the integrations indistinct.
  • Classification of Capsules defects are as follows:
(1) Critical :
A. Wrong appearance
Foreign ProductPharmaceutical material is either a component, powder on the finished dosage that is not a normal part of the batch being processed.
Foreign MaterialAnything other than Pharmaceutical material that is not a normal part of the batch being processed.
Missing Imprint On Cap & BodyAll imprint characters are missing from the cap & body of the capsule that precludes product identification. Wrong imprint.
Capsule EmptyCapsules with little or no contents or the body & cap are disengaged.
Partially filled capsuleCapsule not properly filled.
(2) Major :
Capsule not free of cracks, breaks, notching, V notch cap, pinholes or splits.The surface of the capsule is not intact & the contents of the capsule may fall out or have already fallen out.
Capsules not free of embedded surface spots.Clearly defined particles embedded in the surface or the capsule.
Capsule not properly closedCapsule not completely closed & the cap may slip off of the body.
Crushed CapsulesTranslucent capsules with a crimped or smashed top. Content leaking/ missing.
Imprint illegibleCharacters in the imprint are not legible.
(3) Minor :
Capsule not free of dentsIndentation in the surface of the capsule.
Capsule not free of surface blemishesClearly defined bumps, porous areas or lighter color areas prone to breakage.
Capsule cap & body cutting into one another (Telescoping)A portion of the cap & body cutting the other, without loss of contents.
Blurred imprintCharacters in the imprint have a slight imperfection, including ink splatters, but are legible.
InkspotsTwo or more ink spots on the capsule away from the imprint.
Double CapThe additional cap also observed on the body

Note: Refer annexure-5 for flow chart of Acceptable Quality Level (AQL) procedure.

  • If the bulk is meeting the acceptance criteria, production shall precede for weighing of the bulk, shall record batch reconciliation and yield data in the BMR and release the bulk for further processing.
  • After completion of Acceptable Quality Level (AQL) sampling, the double polyethylene bag of sampled containers selected for AQL shall tie with fastener immediately.
  • If the bulk is not meeting the acceptance criteria. QA shall ask the production Officer for visual inspection and raise the event to investigate the Acceptable Quality Level (AQL) failure.
  • After visual inspection, again Acceptable Quality Level (AQL) shall be performed. Based on AQL results, Further proceed the bulk.
  • If 3 consecutive batches fail in Acceptable Quality Level (AQL). Perform the investigation and Stop the subsequent manufacturing of drug products.
  • The Acceptable Quality Level (AQL) inspection shall be performed in inspection cubical and if the Acceptable Quality Level (AQL) meets as per acceptance criteria then after the completion of AQL inspection inspected good Tablets / Capsules shall add to the last container of good Tablets / Capsules.
  • 100% Inspection (By production department) and Acceptable Quality Level (AQL) inspection (By QA department) shall perform in the same condition i.e. area and inspection trolley etc.
  • In the case of an event that may impact visual inspection, a 100% inspection shall be performed.
  • In case of repetitive market complaints related to visual inspection defects based on investigation findings AQL shall be discontinued and 100% visual inspection shall be performed.
  • After completion of Acceptable Quality Level (AQL) inspection, QA Officer shall fill the AQL inspection result in annexure-1 in case of core Tablet, annexure-2 in case of Coated Tablet, annexure-3 in case of Capsules, and handover BMR to Production Officer for final yield and accountability reconciliation.
  • QA shall send the finished samples of the core, Coated Tablet, and Capsules along with test requisition cum report to QC after AQL inspection.
  • Production Officer shall submit duly filled and signed BMR to QA for the final release.
  • QA shall check final yield, test requisition cum report and sign in reviewed by column in BMR and release the bulk in ERP as per location SOP.
  • During the visual inspection in case of any abnormality observed investigation shall be triggered (like higher % of rejection for specific defect………etc.) to find out the root cause and initiate appropriate corrective and preventive action.
  • Issue the AQL inspections annexure along with each BMR.
  • Concerned Production Officer shall prepare the Acceptable Quality Level (AQL) Product list and QA shall check it as per Annexure-5.
  • Perform AQL  only for those products mentioned in the AQL List and remaining products which have problems as per their trend shall not be considered under AQL Product List and 100% visual inspection shall be performed for those products.
  • In case Acceptable Quality Level (AQL) inspection is discontinued and 100% inspection started due to any failure then only upon implementation of CAPA. Start the AQL inspection in the particular drug product.

 DISTRIBUTION OF ACCEPTABLE QUALITY LEVEL (AQL) SOP:

  • Quality Assurance
  • Production

ANNEXURES OF ACCEPTABLE QUALITY LEVEL (AQL) SOP:

Bulk release format for core Tablets (Annexure 1).

AQL bulk release format for Coated Tablets (Annexure 2)

AQL bulk release format for Capsules (Annexure 3).

Bulk Approval Procedure of Acceptable Quality Level (AQL) for Tablets & Capsules (Annexure 4).

Flow Chart - Acceptable Quality Level (AQL)

Acceptable Quality Level (AQL) Product List (Annexure 5).

SOP for Polarimeter

Purpose:

  • The purpose of this SOP is to describe the procedure for operation, cleaning, and calibration of the polarimeter.

   Scope:

  • This SOP  is applicable to the polarimeter available in the Quality control laboratory at the pharmaceutical drug manufacturing plant.
  • Make: …
  • Model:….

Responsibilities – SOP for Polarimeter:

  • The Analyst shall be responsible for:
  • Operate the instrument as per SOP.
  • Calibrate the instrument as per SOP.
  • Maintain the calibration records.
  • Head QC or Designee shall be responsible for:
  • Check the SOP.
  • Impart the training to all concerned persons before the implementation of SOP.
  • Ensure that Operation & Calibration of the instrument is carried out as per SOP.
  • Execute the Out of Calibration (OOC) in case of calibration failure and breakdown and intimate the same to Quality Head.
  • Initiate repairs or breakdown and to make alternative arrangements during the status of under maintenance.
  • Ensure proper documentation as per SOP.
  • Quality Assurance shall be responsible for:
  • Check the SOP.
  • Ensure the implementation of the system as per SOP.
  • Quality Head shall be responsible for:
  • Review and approve the SOP.
  • Authorize the Out of Calibration investigation.
  • Ensure that the system is implemented.

Procedure for Handling and Calibration of Polarimeter:

  • Definition of terms :
  • Optical Rotation :
  • The optical rotation of a substance or liquid is the angle through which the plane of polarization is rotated when polarized light passes through the substance or liquid/solution of the substance.
  • Such substances are said to be optically active.
  • If the plane of polarization is rotated to clockwise direction then it is called dextrorotatory (+) and if it is anticlockwise then called levorotatory (-).
  • Specific Optical Rotation (SOR) :
  • For solid samples :  
  • A specific optical rotation of a substance is defined as the angle of rotation of the plane of polarization at the wavelength of the D line of Sodium (λ=589.3 nm)measured at 25°C (unless otherwise specified)calculated with reference to a 1-dm thick layer of a solution containing1g of a substance per ml.
  •  For liquid sample: A specific optical rotation of a liquid substance is defined as the angle of rotation of the plane of polarization at the wave-length of the D line of sodium (λ=589.3 nm) measured at 25°C (unless otherwise specified), calculated with reference to a 1-dm thick layer of a solution and its density.
  • General Procedure – Polarimeter:
  • For the entry of usage of the instrument, follow the SOP on “Instrument/equipment usage logbook.
  • In case of any maintenance of the polarimeter instrument, follow SOP on “Maintenance of laboratory instrument.
  • Maintain the internal and third-party calibration schedule for the instrument as per SOP.
  • In case of noticing any calibration result out of the specified limit, follow the SOP of “Handling Out of Calibration.
  • Precautions during handling of Polarimeter:
  • Allow sufficient time to warm up the lamp before use
  • Optical rotation should be determined within 30 minutes of preparation, unless otherwise specified.
  • Maintain the required temperature during the optical rotation analysis.
  • Before start of the analysis this shall be conform that the instrument, and polarimeter tube is clean and no spillage or residues of the previous product, if present then need to clean.
  • Polarimeter tube should be clean with the diluent and then rinse with the small amount of sample.
  • Then fill it with the required solution in such a way that no air bubble remains in the path of polarized light.
  • Maintain the cleanliness of glass tube and avoid over-tightening of end screw caps.
  • Set the bubble at the center (curvature) to align the instrument properly.
  • The temperature probe shall keep clean after analysis to avoid the contamination which may affect the result.
  • Make sure that the sample chamber is empty and its lid is closed during the analysis and after completion of analysis.
  • The sample shall be measured using the same angular orientation of the cell as that of the blank.
  • While changing samples from one to another, wash the sample cell 2-3 times with the sample to remove any previous sample residue.
  • To hold the sample cell in the cell holder, set it in the same position facing the same direction. The data cannot be reproduced if the position/direction is changed.
  • Before shutting, make sure that the sample chamber is empty.
  • Turn OFF the power switch on the rear panel of the polarimeter.
  • Clean and air dry the sample cell for storage.
  • Allow sufficient time to warm up the lamp before use.
  • Maintain the required temperature during the optical rotation measurement of blank and sample solution.
  • Liquid and solutions of solids must be clear.
  • Cleaning procedure of Polarimeter:
  • The Analyst shall clean the Polarimeter and its surrounding with the dry cloth before and after use.
  • If the solution spills on the instrument then clean it immediately with the dry cloth.
  • If required clean the instrument with approved detergent (e.g. 1% Hemtop) followed by purified water and wipe with the dry cloth.
  • Lens cleaning shall be done by using lint-free tissue paper.
  • After every analysis cleaning of the glass tube and temperature probe shall be done by using the solvent in which the test solution prepared and then wash with purified water and finally rinse with methanol.
  • Operation Procedure of Jasco make Polarimeter:
  • Check the polarimeter calibration status of the instrument.
  • Press the power switch “ON” located on the front panel.
  • The power lamp located on the front right side of the instrument lights.
  • Now double click on the “Polarimeter” icon on the desktop.
  • Enter the user name and password and click on the login button.
Polarimeter - Login Page
  • After the login, click on the standard measurement option.
  • The system begins to initialize which requires about five minutes.
  • Click on the ‘parameter’ short cut or select it from the measure tab and enter the measurement parameters accordingly.
  • Enter the integration time in seconds.
  • If the time entered is 5 sec then the test shall be performed for 5 seconds.
  • Enter the repeat time by using the keyboard in numbers.
  • If the repeat time is given 5, then the instrument will perform the test 5 times.
  • Enter the interval time in seconds. If the time entered is 5 seconds then it will take 5 sec interval after every repeat reading.
  • Enter the cell length in mm.
  • The default value is 100 mm.
  • Enter the sample name, comment and save the parameter.
  • To zero set open the sample compartment and check that it is empty and then close it, select ‘zero clear’ from the measurement menu.
  • To take the blank reading, open the cover of the instrument.
  • Fill the blank (diluent) in the cell tube and hold the cell in the sample chamber by opening the lid of the instrument.
  • Dip the temperature sensor in the sample cell.
  • The temperature of sample or blank to be measured should be within the specified range, make sure that the mode is selected as ‘Optical rotation’ for ‘Blank’ in the parameters, click on the ‘Blank’ button and select ‘measure’.
  • For taking the measurement of the sample click on the parameters and select the mode as required, if Specific Optical Rotation (SOR), Concentration or Optical Rotation (OR) value is required then select accordingly and save the parameters.
Polarimeter - Parameter Setup
  • Click on the ‘Sample’ button and enter the sample name and comment if any, and select measure after the measurement is over, then save the data.
  • For printing the data, go to the ‘Spectra Manager CFR’ window and select ”Polarimeter Analysis’ on the left -hand side of the window.
  • Select the sample file by double-clicking on it, select print.
  • Filter Changing (Wavelength Set):
  • Normally, the Sodium (Na) lamp is used, the wavelength set (filter) is 589nm.
  • To check or change the wavelength, open the lid of the filter unit as shown in the figure below, to the left of the sample chamber.
  • Remove the filter (589nm) and place it safely.
  • Insert the filter having wavelength set 436nm to the filter unit.
  • In some cases, Use the Mercury (Hg) lamp as per the requirement of product.
  • The wavelength set (filter) required is 436nm.
  • To replace the wavelength set (filter) 436nm to wavelength set (filter) 589nm, follow the same procedure.
  • Light Source Change:
  • To change the light source select the ‘light source’ button on the standard measurement window.
  • Click on the Hg or the Na lamp with yellow mark first to deactivate the lamp and select the lamp which is required for analysis, the status of the lamp is indicated by the yellow color, the yellow color indicates that the lamp is activated.

Calibration Procedure of Polarimeter

  • Polarimeter Calibration Methods:
  • Calibration can be done either by preparing calibration solutions of sucrose/ fructose or by using Quartz plates.
  • Polarimeter Calibration frequency and standard :
  • Quarterly ± 7 days or immediately after maintenance.
  • Temperature sensor (If applicable) shall be calibrated yearly once with an accuracy of ± 0.5°C.
  • Calibration shall be carried out after the following maintenance.
    • Change in lamp
    • Replacement
  • Calibration shall be carried out after relocation
  • For the Calibration of Polarimeter, it is recommended to use the certified standard like sucrose and fructose.
  • Alternatively, Polarimeter Calibration can be checked by using a polarization reference standard which consists of a plate of quartz (This standard is available, traceable to NIST, from Rudolph research analytical or from Rudolph Instrument).
  • Polarimeter Calibration check using Quartz Plate :
  • Calibration with the Quartz Plate is done by mounting the quartz plate in a holder perpendicular to the light path.
  • Polarimeter Calibration shall meet the value supplied by the manufacturer(traceable to NIST) for that applicable wavelength.
  • The observations of calibration using quartz plate shall be recorded in Annexure-1
  • Polarimeter Calibration check using the Sucrose solution ( Dextrorotatory range)for Mercury and Sodium Lamp :
  • Frequency: Quarterly± 7 days
  • Follow the calibration procedure for Mercury (Hg) lamp having wavelength set (filter) 436nm as well as Sodium(Na) lamp having wavelength set (filter) 589nm.
  • The acceptance criteria for SOR at 20.0°C for Mercury lamp and 25.0°C for sodium lamp are mentioned in the Polarimeter calibration template as per Annexure-2.
  • Dry the sucrose at 105°C for 2 hours.
  • Prepare a series of solutions having the concentration of 10.0%, 20.0% 30.0%, 40.0% and 50.0% w/v solution of anhydrous sucrose in purified water as specified in calibration template i.e Annexure-2.
  • Condition the sucrose solutions and the blank solution (diluent) at 20°C±0.5°C while using Mercury (Hg) lamp
  • Condition the sucrose solutions and the blank solution (diluent) at 25°C±0.5°C while using Sodium (Na) lamp.
  • Take the reading of purified water (diluent) as a blank and auto-zero the instrument.
  • Fill the tube with the sample solution of the specified concentration of sucrose.
  • Measure the SOR of all five solutions using 1-dm Polarimeter tube, by following the operation procedure.
  • Take five readings of each solution. Each reading should meet the acceptance criteria as per the manufacturers COA
  • Tabulate the results in the Polarimeter calibration template.
  • Note 1: If the visual polarimeter is employed, the average of five determinations, corrected for the reading of the same tube with a solvent i.e. purified water, is used.
  • Note 2: If the automatic polarimeter is employed then blank to be performed before sample analysis, to avoid the interference of blank in the sample result.
  • Plot a linearity curve of component concentration vs corresponding optical rotation. The coefficient of correlation shall be not less than 0.992.
  • Polarimeter Calibration check using Fructose solution (Levorotatory range) for Mercury and Sodium Lamp:
  • Frequency: Quarterly ± 7 days
  • Note: If the location does not have any sample with the specification in the Levorotatory range then calibration in the Levorotatory range is not required to be performed.
  • Follow the calibration procedure for Mercury (Hg) lamp having wavelength set (filter) 436nm as well as Sodium(Na) lamp having wavelength set (filter) 589nm.
  • The acceptance criteria for SOR at 20.0°C for Mercury lamp and 25.0°C for sodium lamp shall be as per manufacturer COA.
  • Polarimeter Calibration shall be performed as per Annexure-2.
  • In-general the observed optical rotation at 436 nm is about double that at 589 nm (Ref. USP <781> ).
  • Dry about 5 gm of Fructose in the vacuum oven at 70°C for 4 hours.
  • Solution Preparation for Polarimeter Calibration:
  • 10% w/v Fructose Solution: Weigh accurately (5gm, it should be as accurate as possible) of previously dried fructose and transfer it in a clean and dry 50 ml volumetric flask, dissolve it in 25 ml of purified water.
  • Make up the volume (50 ml) with purified water.
  • Follow the above calibration steps with fructose solution.
  • Re-calibration of Polarimeter:
  • If the equipment is subjected to severe mechanical shock or vibration.
  • If the equipment is relocated.
  • When there is any suspicion about the accuracy of the numbers measured when any of the optical components like bulb, PMT, filter, polarizer or analyzer shall be changed or replaced.

ANNEXURE 1

Format for Polarimeter Calibration Template (by Quartz Plate)

Instrument NameTemplate Issuance No.
ID No.Make /Model
LocationCalibration frequencyQuarterly ± 7 days
Calibrated onNext calibration due on

TABLE -A

Quartz Rotatory Plate ( Dextro rotatory range )Make/ Model :
Sr. No.TemperatureWavelengthActual ValueObserved ValueAcceptance Range (Actual value ± 0.5 %)
1589 nm
2436 nm

TABLE -B

Quartz Rotatory Plate ( Levo rotatory range )Make/ Model :
TemperatureWavelengthActual ValueObserved ValueAcceptance Range (Actual value ± 0.5 %)
589 nm
436 nm

(Note :- The Limits shall be as per the calibration certificate provided by the manufacturer.)

Remarks: The instrument is calibrated & qualified/ Out of calibration & not qualified for use.

Calibration type: Scheduled / Not scheduled (Reason: _________________________)

Calibrated by:Checked by:
Date:Date:

ANNEXURE 2

Format for Polarimeter Calibration Template (Chemical Test)

Instrument NameTemplate Issuance No.
ID No.Make /Model
LocationCalibration frequencyQuarterly ± 7 days
Calibrated onNext calibration due on

Mercury Lamp : By Sucrose Solution (Dextro-rotatory range)

  • Calibration Requirements:-
  • Lamp used _________ Mercury (Hg)
  • Filter (wavelength set) used ______________ 436 nm
  • Analytical Balance Code No.______________ Valid upto _________
  • Vacuum Oven Code No.______________ Valid upto _________
ChemicalsBatch No.Cal.Std.No.Make/GradeUse Before
Sucrose anhydrous
  • Procedure – Polarimeter Calibration:
  • Sucrose Solution Preparation:
  • Take the required quantity of ____________________________ sucrose anhydrous and dry it in an oven at ___________ 105°C for _________ 2 hours.(From ________ to ________ ).
  • Prepare a series of solutions having the concentration of 10.0%, 20.0%, 30.0%, 40.0% and 50.0% w/v solutions of sucrose in purified water as specified below:
  • 10% w/v Sucrose Solution:
  • Weigh accurately _________ 5.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in cleanand dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • 20% w/v Sucrose Solution:
  • Weigh accurately _________ 10.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in clean and dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • 30% w/v Sucrose Solution:
  • Weigh accurately _________ 15.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in clean and dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • 40% w/v Sucrose Solution:
  • Weigh accurately _________ 20.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in clean and dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • 50% w/v Sucrose Solution:
  • Weigh accurately _________ 25.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in clean and dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • Measurement – Polarimeter Calibration:
  • Condition the sucrose solutions and the blank solution (diluent) (________________ purified water) at ____________ 20°C±0.5°C.
  • Take the reading of ____________________ purified water (diluent) as a blank and make it to auto zero.
  • Take the readings of all samples within 30 minutes of sample preparation.

Sodium Lamp : By Sucrose Solution

  • Calibration Requirements:
  • Lamp used _________ Sodium (Na)
  • Filter (wavelength set) used ______________ 589 nm
  • Analytical Balance Code No.______________ Valid upto _________
  • Vacuum Oven Code No.______________ Valid upto _________
ChemicalsBatch No.Cal.Std.No.Make/GradeUse Before
Sucrose anhydrous
  • Procedure for Polarimeter Calibration:
  • Sucrose Solution Preparation:
  • Take the required quantity of ____________________________ sucrose anhydrous and dry it in an oven at ___________ 105°C for _________ 2 hours (From ________ to ________ ).
  • Prepare a series of solution having the concentration of 10.0%, 20.0% , 30.0%,40.0% and 50.0% w/v solutions of sucrose in purified water as specified below:
  • 10% w/v Sucrose Solution:
  • Weigh accurately _________ 5.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in cleanand dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • 20% w/v Sucrose Solution:
  • Weigh accurately _________ 10.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in clean and dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • 30% w/v Sucrose Solution:
  • Weigh accurately _________ 15.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in clean and dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water
  • 40% w/v Sucrose Solution:
  • Weigh accurately _________ 20.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in clean and dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • 50% w/v Sucrose Solution:
  • Weigh accurately _________ 25.000gm (as accurate as possible) of ___________________ previously dried sucrose and transfer it in clean and dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • Measurement – Polarimeter Calibration:
  • Condition the sucrose solutions and the blank solution (diluent) (________________ purified water) at ____________ 25°C±0.5°C.
  • Take the reading of ____________________ purified water (diluent) as a blank and make it to auto zero.
  • Take the readings of all sucrose solution within 30 minutes of sample preparation.
  • Fill the tube with the sample solution of the specified concentrations of sucrose respectively.
  • Measure the Specific optical rotation of all five solutions using 1-dm Polarimeter tube.
  • Take ________ five readings of each solution.
  • Each reading should meet the acceptance criteria as specified in the observation table.
  • Tabulate the results in the observation table.
  • Plot a linearity curve of component concentration vs corresponding optical rotation.
  • The coefficient of correlation shall be not less than 0.992.
Sr. No.Concentration of Sucrose (dried) (in %)Specific Optical Rotation at 25 °C ± 0.5°CSpecific Optical Rotation, SOR (in %) at 25°CCorrelation of coefficient (NLT 0.992)
Lamp  ______             SodiumFilter _________               589nm
12345Mean SOR (in %)
110+66.15° to +67.15°
220+66.03° to +67.03°
330+65.93° to +66.93°
440+65.83° to +66.83°
550+65.73° to +66.73°

Remarks: The instrument is calibrated & qualified/ Out of calibration & not qualified for use.

Calibration type: Scheduled / Not scheduled (Reason: _________________________)

Calibrated by:Checked by:
Date:Date:

Attachments (if any) :-

Mercury Lamp : By Fructose Solution

  • Calibration Requirements:
  • Lamp used _________ Mercury (Hg)
  • Filter (wavelength set) used ______________ 436 nm
  • Analytical Balance Code No______________ Valid upto _________
  • Vacuum Oven Code No______________ Valid upto _________
ChemicalsBatch No.Cal.Std.No.Make/GradeUse Before
Fructose
  • Procedure for Polarimeter Calibration:
  • Fructose Solution Preparation:
  • Take the required quantity of ____________________________ fructose and  dry it in a vacuum oven at ___________ 70ºC for _________ 4 hours. (From ________ to ________ ).
  • 10% w/v Fructose Solution:
  • Weigh accurately _________ 5.000 gm (as accurate as possible) of ___________________ previously dried fructose and transfer it in cleanand dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • Measurements – Polarimeter Calibration :
  • Condition the fructose solution and the blank solution (diluent) (________________ purified water) at ____________ 20°C±0.5°C.
  • Take the reading of ____________________ purified water (diluent) as a blank and make it to auto zero.
  • Fill the tube with the fructose solution of the specified concentration of fructose.
  • Measure the Specific optical rotation of the solution using 1-dm Polarimeter tube.
  • Take ________ five readings of solution.
  • Reading should meet the acceptance criteria as specified in the observation table.
  • Tabulate the results in the observation table.

Observation Table : Polarimeter Calibration

Sr. No.  Concentration of Sucrose (dried) (in %)  Specific Optical Rotation at 20 °C ± 0.5°CSpecific Optical Rotation, SOR (in %) at 20°C
Lamp _________ MercuryFilter _________ 436 nm
12345Mean SOR (in %)  
110

Note:- The limits shall be as per the COA provided by the manufacturer.

Remarks: The instrument is calibrated & qualified/ Out of calibration & not qualified for use.

Calibration type: Scheduled / Not scheduled (Reason: _________________________)

Calibrated by:Checked by:
Date:Date:

Attachments (if any) :-

Sodium Lamp : By Fructose Solution

  • Calibration Requirements – Polarimeter:
  • Lamp used _________ Sodium (Na)
  • Filter (wavelength set) used ______________ 589 nm
  • Analytical Balance Code No.______________ Valid upto _________
  • Vacuum Oven Code No.______________ Valid upto _________
ChemicalsBatch No.Cal.Std.No.Make/GradeUse Before
Fructose
  • Procedure for Polarimeter Calibration:
  • Fructose Solution Preparation:
  • Take the required quantity of ____________________________ fructose and dry it in a vacuum oven at ___________ 70ºC for _________ 4 hours. (From ________ to ________ ).
  • 10% w/v Fructose Solution:
  • Weigh accurately _________ 5.000 gm (as accurate as possible) of ___________________ previously dried fructose and transfer it in cleanand dry _________ 50 ml volumetric flask.
  • Dissolve it in 25ml of __________ purified water and dilute up to the volume with _________ purified water.
  • Measurement – Polarimeter Calibration:
  • Condition the fructose solution and the blank solution (diluent) (________________ purified water) at ____________ 25°C±0.5°C.
  • Take the reading of ____________________ purified water (diluent) as a blank and make it to auto zero.
  • Fill the tube with the sample solution of the specified concentration of fructose.
  • Measure the Specific optical rotation of the solution using 1-dm Polarimeter tube.
  • Take ________ five readings of solution.
  • Reading should meet the acceptance criteria as specified in the observation table
  • Tabulate the results in the observation table.
Sr. No.  Concentration of Sucrose (dried) (in %)  Specific Optical Rotation at 25°C ± 0.5°CSpecific Optical Rotation, SOR (in %) at 25°C  
Lamp ____________                    SodiumFilter _________                 589 nm
12345Mean SOR (in %)  
110   

Note :- The limits shall be as per the COA provided by the manufacturer.

Remarks: The instrument is calibrated & qualified/ Out of calibration & not qualified for use.

Calibration type: Scheduled / Not scheduled (Reason: _________________________)

Calibrated by:Checked by:
Date:Date:

References

  • Operation manual supplied by the manufacturer
  • Maintenance of laboratory instrument/equipment
  • SOP for Instrument/Equipment usage log book.
  • SOP for Preparation of Internal and External (Third-party) calibration schedule and calibration practices
  • Indian Pharmacopoeia Chapter-2.4.22
  • Annexures:
  • Annexure – 1: Format for Polarimeter calibration template ( by Quartz  plate )
  • Annexure – 2: Format for Polarimeter calibration template

SOP on Operation and Calibration of Melting Point Apparatus

Standard Operating Procedure (SOP) for Operation and Calibration of Melting Point Apparatus used for analysis / identification  of starting materials (Raw Material – API & Excipient) in Quality Control Laboratory.

Operation and Calibration of Melting Point Apparatus

1.0   PURPOSE:

  • The purpose of this SOP is to describe the procedure for operation, calibration and maintenance of Melting Point Apparatus.

2.0   SCOPE:

  • This SOP is applicable to the following Melting point apparatus at Quality Control Department in pharmaceutical for Make : Polmon and Model MP-96.

3.0   REFERENCES – SOP FOR MELTING POINT APPARATUS:

  • Operation Manual supplied by the manufacturer
  • SOP for  Maintenance of Laboratory Instruments
  • SOP for Preparation of internal and external (Third Party) Calibration schedule and  calibration practices   

4.0   RESPONSIBILITY – SOP FOR MELTING POINT APPARATUS:

  • Analyst shall be responsible for:
  • To operate the instrument as per the SOP.
  • Calibrate the instrument as per the SOP.
  • To carry out the documentation as per the SOP.
  • Quality Control Head or Designee shall be responsible for :
  • To approve the calibration of instrument verifying against SOP.
  • To provide training to all the concerned persons before implementing the SOP.
  • Execute the out of calibration in case of calibration failure and in case of breakdown, intimate to Quality Head.
  • To ensure the operation and calibration of the instrument is carried out as per the SOP.
  • To ensure proper documentation as per the SOP.
  • Quality Assurance shall be responsible for:
  • To ensure the implementation of the system as per the SOP.

5.0   PROCEDURE – MELTING POINT APPARATUS:

  • General Procedure for handling of Melting Point Apparatus
  • Follow the SOP on Instrument/Equipment usage log book, for the entry of usage of the instrument. 
  • In case of any maintenance of instrument, follow SOP on Maintenance of Laboratory Instrument.
  • Maintain the third party calibration schedule and the internal calibration schedule for the instrument as per SOP, Preparation of internal and external (Third Party) calibration schedule and calibration practices.
  • Operational procedure
  • Check the calibration status of the instrument.
  • Switch ON power supply by switching on the main supply and switch provided on backside of the instrument.
  • Press the “FUNCTION” Key to set initial temperature. The “INI TEMP” LED blinks and parameter is displayed in the display.
  • Use “↑ ” or “ ↓ “ keys to set the initial temperature.
  • Set the initial temperature to 10°C below the expected melting point and the initial temperature should be (15 – 25 )°C above the bath temperature to overcome undershoot or overshoot of temperature, the maximum melting range for the operation of the instrument is 350°C.
  • Press the “FUNCTION” key to set “°C/min”, “°C/min” LED blinks and the parameter is displayed in the display.
  • Use “↑” or “↓” keys to set the rate of heating.
  • Press “FUNCTION” key. The bath temperature is displayed.
  • Press “START” key. The “INI TEMP” and “°C/min” LED blinks one after another displaying the corresponding setting with an interval of 2.5 sec.

NOTE: Be sure about the settings (initial temperature and °C/min) as they cannot be viewed or changed while heating process is ON.

  • Press “START” key. The oil bath temperature is raised to the initial   During this period “INI TEMP” LED glows continuously and “HEATER” LED glows continuously or blinks.
  • Insert the capillaries in the bath.
  • Press “FUNCTION” key to start Rate of heating (i.e. °C/min). During this period “°C/min” LED glows continuously and “HEATER” LED blinks.
  • Watch the sample through magnifying lens.
  • Press “STORE” key at the beginning of Melting point, “T1” LED glows continuously indicating that initial melting temperature is stored.
  • Press “STORE” key again to store final melting point. “T2” LED glows continuously indicating that final melting point temperature is stored.
  • To view initial and final melting point temperatures press “STORE” key to view initial melting point temperature, “T1” blinks to indicate that the displayed temperature is initial melting point.
  • Press “STORE” key again to view final melting point temperature, “T2” LED blinks to indicate that the displayed temperature is final melting point  
  • Calibration Procedure of Melting Point Apparatus
  • Calibrate by using Melting Point reference standard.
  • Calibration Frequency: Monthly ± 3 days.
  • The four Melting Point standards Vanillin, Caffeine, Acetanilide and Sulfanilamide shall be used.
  • Reduce the reference standard to very fine powder.
  • Treat the reference standards as given below:
  • Vanillin: Do not dry.
  • Caffeine: Dry portion over silica gel for 16 hours.
  • Sulfanilamide: Dry portion over silica gel for 16 hours.
  • Acetanilide: Dry portion over silica gel for 16 hours.
  • Charge the capillary, one end of which is sealed with sufficient quantity of reference standard to form a column in the bottom of the tube 2.5 mm to 3.5 mm height when packed down as closely as   possible by moderate tapping on a solid surface. Surface. (There should not be gap in the column).
  • Heat the block until the temperature is about 10°C below the expected melting point and continue heating at a rate of temperature increase of about 1° C per minute.
  • Insert the capillary tube in the melting point apparatus when the temperature is about 5° C below the lower limit of the expected   melting range and continue heating until melting is complete. 
  • Follow the above steps given in the procedure part.
  • Note the melting point of the reference substance.
  • Record the same in the calibration record.

6.0   ANNEXURES – MELTING POINT APPARATUS:

Annexure -1 : Format for Calibration Record of Melting Point Apparatus

Instrument NameMelting Point Apparatus
Instrument CodeMake/Model  
LocationCalibration frequency  Monthly ± 3 days
Calibration DateNext Calibration due on

Procedure

  • Reduce the standard to very fine powder or as recommended on the label of respective reference standard.
  • Treat the reference standards accordingly.
  • Charge the capillary, one end of which is sealed with sufficient quantity of reference standard to form a column in the bottom of the tube 2.5 mm to 3.5 mm height when packed down as closely as possible by moderate tapping on a solid surface. (There should not be gap in the column.)
  • Heat the block until the temperature is about  10° C  below the expected melting point and continue heating at a rate of temperature increase of  about 1° C per minute.
  • Insert the capillary tube in the melting point apparatus when the temperature is about 5°C below the lower limit of the expected melting range and continue heating until melting is complete.
  • Record the temperature at which the last particle passes into the liquid phase.
  • Remove the capillary tubes care fully and dispose it off after cooling.

Observation Table:

Sr.No.Melting Point StandardCalibration Standard No.Observed Melting RangeLimit
1Vanillin81°C to 83°C
2Acetanilide112°C  to 115°C
3Sulfanilamide163°C to166°C
4caffeine235°C to 239°C

Remarks : The instrument is calibrated & qualified / Out of calibration & not qualified for use.               

Calibration : Scheduled / Not scheduled ( Reason : ______________________

Annexure -2 : Format for Calibration Status label

CALIBRATION STATUS
Instrument :       ___________________________           ___________ Code :     ___________________ Model:  ______________________ Frequency______________________________________________ Done on :  ____________________________ Due on :____________ Status : Instrument found satisfactory for analytical use Done By : __________________________  Checked By :  __________ Date :    ___________________________   Date : ________________

SOP for BMR & BPR Review

Standard Operating Procedure (SOP) for Review of Batch Manufacturing Record (BMR) and Batch Packing Record (BPR) in the pharmaceutical manufacturing plant. A detailed checklist for review of BMR and BPR for Draft Copy as well as  Filled Copy of Batch Manufacturing/Packing Records. 

Procedure for BMR & BPR Review

1.0       PURPOSE:

  • The purpose of this SOP is to define the procedure to review the draft Batch Manufacturing Record (BMR) and Batch Packing Record (BPR) prior to final approval. Also, this SOP shall be applicable for a review of executed BMR/BPR prior to the final release of batches.

2.0      SCOPE:

  • Scope of this SOP covers for the review of the draft as well as filled Batch Manufacturing Record (BMR) and Batch Packing Record (BPR) at the pharmaceutical manufacturing plant.

3.0      REFERENCES:

  • In-house

4.0        RESPONSIBILITY:

  • The user department shall be responsible for the preparation of draft BMR/BPR and shall handover toBMR – BPR – REVIEW QA for review along with the intended supporting documents
  • QA designee shall be responsible for the review of draft Batch Manufacturing Record (BMR) as well as Batch Packing Record (BPR) as per Annexure-1 and Annexure-2.
  • QA/Production shall be responsible for the review of filled Batch Manufacturing Record (BMR) as well as Batch Packing Record (BPR) as per Annexure-3 and Annexure-4.
  • HOD of Production and HOD of Packing shall be responsible for the review of draft BMR/BPR and subsequent approval of BMR/BPR.
  • QA Head shall be responsible for final approval of master BMR/BPR as well as compliance of SOP.

5.0      ABBREVIATIONS USED IN SOP FOR BMR, BPR REVIEW:

  • AR. No. : Analytical Report Number
  • ADD: Analytical Development Department
  • BMR: Batch Manufacturing Record
  • BOM: Bill of Material
  • BPR: Batch Packing Record
  • COA: Certificate of Analysis
  • Dept: Department
  • ERP: Enterprise Resource Planning
  • FDD: Formulation Development Department
  • IH: In House
  • IMO: Issue Material Order
  • MPS: Master Product Specification
  • PDD: Packaging Development Department
  • QC: Quality Control

 6.0      PROCEDURE FOR REVIEW OF BMR AND BPR:

  • Review of Draft Batch Manufacturing Record (BMR) and Batch Packing Record (BPR):
  • Concern production officer/Packing officer shall handover draft BMR/BPR to QA for review along with the intended supporting documents.
  • QA shall review draft BMR/BPR as per Annexure-1 and Annexure-2 respectively and shall return to concern production officer for correction.
  • Concern production officer/Packing officer shall correct the BMR/BPR and shall return to QA for the final review. After satisfactory review of draft copy, final print shall be taken for approval
  • All persons involved in the review of draft BMR/BPR shall ensure to compliance against the checkpoints as per subsequent Annexure-1 and Annexure-2.
  • All concerns involved in the review shall go through the checkpoints as a part of training and shall provide the acknowledgment as per Annexure-1 and Annexure-2 for their understanding and future compliance.
  • QA shall issue a working copy of Annexure-1 and Annexure-2 to the respective person involved in draft BMR/BPR review as a ready reference.
  • The master copy shall be kept with QA and filed with a master copy.
  • Any amendment to the checklist shall be done with the help of change control and the revised checklist for review of draft BMR/BPR shall again reissue to the concerned person.
  • QA shall also ensure the retrieval of issued Annexure-1and Annexure-2 controlled copy and the same shall be destroyed.
  • A retired signed copy shall be retrieved by QA prior to the issuance of the checklist.
  • Review of Filled Batch Manufacturing Record (BMR):
  • Production officer shall handover filled BMR to QA after proper checking and signing in place of approved production chemist in BMR.
  • QA shall review filled BMR as per Annexure-3 & in case of any discrepancies to checklist or some other discrepancies observed and shall be documented in Executed Batch Record Review Sheet as per Annexure-5.
  • If any discrepancies observed against standard/limit as per BMR shall be recorded in the history sheet of respective BMR and shall be investigated prior to the further course of action.
  • Review of Filled Batch Packing Record (BPR) :
  • The packing officer shall handover filled BPR to QA after proper checking and signing in place of approved Packing Head/ Approved Production Head in BPR.
  • QA person shall review filled BPR as per Annexure-4 and in case of any discrepancies to checklist or some other discrepancies observed and shall be documented in Executed Batch Record Review Sheet as per Annexure-5.
  • If any discrepancies observed against standard/limit as per BPR shall be recorded in the history sheet of respective BPR and shall be investigated prior to the further course of action.
  • Review of Batch Manufacturing Record (BMR) and Batch Packing Record after Packing:
  • Ensure the first page of BMR/BPR is filled and ensure that the data/information provided on the cover page of BMR/BPR is correct.

7.0      ANNEXURES / CHECKLIST FOR BMR REVIEW:

Annexure 1: Checklist for Draft BMR Review.

Sr. No.Check PointsReference Documents
STEP 1: INTRODUCTION OF  NEW PRODUCT (BMR Review)
1Ensure that the availability of Approved MPS.Approved MPS
2Ensure that the availability of Approved Change Control.Approved Change Control
3Ensure that the availability of the Approved Bill of Material Master.Approved BOM
4Ensure that the availability of Risk Assessment Report of Granulation/ Compression and Coating (as required).SOP Approved MPS
5License no, Form no, Generic name, Product name (Brand name) and Label Claim/Category, product strength and type of dosages form.FDA License copy
6Product Code, Description, Batch Size, BOM Code, Unit, Item Code, Item Ref. Lot, Item Name/Manufacturer Code, Quantity (Lot Wise), Material Potency, Minimum potency, Adjust potency, BOM valid up to and BMR version No.Approved MPS Approved BOM
7Product Shelf Life.Approved MPS
8Product stability data.Approved MPS
Product description (core tablet /coated tablet /finished product specification).Approved MPS
9Grade (Pharmacopoeial status) of API and Excipients.Approved MPS Master BOM
10Overages in Raw materials added, (if any)Approved MPS
11Product manufacturing and packing special precautions (if any).               (e.g. Light Sensitive and Hygroscopic)Approved MPS
12Stage wise yield limits.IH
13Bill of Material/Work order, pages, and space for entries/ instructions and UOM (Unit of Measurement)NA
14Details of product equipment’s/utensils are used for manufacturing.IH
15Equipment equivalency and occupancy as per batch sizeIH/SOP
16Item codes for raw materials as per regulated /non- regulated market requirementApproved BOM
17Details of environmental conditions for product stage wise.Approved MPS
18During Sifting and Milling process checks and ensures Mesh size/ Screen size/ Co-sifting / Pre-mixing/Qty. and Ingredients used.Approved MPS
19During Binder Preparation process checks and ensures Sieve/Binder preparation time and Temperature of Purified Water.Approved MPS
20During Mixing and Granulation processes checks and ensure Material sequence/ Mixing time/ Agitator -Chopper speed and Ampere load.Approved MPS
21During Drying process checks and ensure Operating parameters/ LOD/Total drying time.Approved MPS
22During Sizing and Milling checks and ensure Screen size/Mesh size/ Direction of blades / Speed and Milling time.Approved MPS
23During Lubrication (Blending) checks and ensure Blending time / Speed and LOD.Approved MPS
24During Compression and Inspection checks and ensure Physical parameters / Operating parameters/ Punch description (Drawing) /Tablet description, dimension / Machine type/ Machine speed/ Qty. of defected tablets and Quantity of good tablets.Approved MPS
25During Coating and Inspection checks and ensure Physical parameters/ Operating parameters /Quantity/ Stirrer RPM / Time for milling/ Homogenization/ Qty. of defected tablets and Quantity of good tablets.Approved MPS
26Coating specifications like Appearance, Weight, Thickness, Diameter, DT, etc. shall be the part of BMR.Approved MPS
STEP 2: SITE TRANSFER PRODUCT (BMR Review)
1Ensure that the availability of Site Transfer BMR.Approved BMR
2Ensure that the availability of Approved Change Control.Approved Change control
3Ensure that the availability of the Approved Master Bill of Material.Approved BOM
4Ensure that the availability of Risk Assessment Report of Granulation/ Compression and Coating (as required).IH/SOP
5License no, Form no, Generic name, Product name (Brand name) and Label Claim/Category, product strength and type of dosages form.FDA License
6Product Code, Description, Batch Size, BOM Code, Unit, Item Code, Item Ref. Lot, Item Name/Manufacturer Code, Quantity (Lot Wise), Material Potency, Minimum potency, Adjust potency, BOM valid up to and BMR version No.Approved BOM Approved BMR
7Product Shelf Life.Approved BMR
8Product Stability Data.Transfer Site
9Product description (core tablet /coated tablet /finished product specification).Approved BMR FP Specification
10Batch size (Kg/No. of units), unit dosage weight/Lot division as per batch size/ Overages in Raw materials added, (if any)Approved BOM Approved BMR
11Grade (Pharmacopoeial status) of API and Excipients.Approved BOM Approved BMR
12Product manufacturing special precautions (if any). (e.g. Light Sensitive and Hygroscopic)Approved BMR
13Stage wise yield limitsIH
14Bill of Material/Work order pages and space for entries/ instructions and UOM (Unit of Measurement)NA
15Details of product equipment’s/utensils are used for manufacturing.IH
16Equipment equivalency and occupancy as per batch sizeIH/SOP
17Item codes for raw materials as per regulated /non- regulated market requirementApproved BOM Approved BMR
18Product-related Stage wise Environmental ConditionApproved BMR
19Ensure that the availability of Tooling Drawing/Change PartIH
20Ensure that the availability of the Site Product History/Flow Chart.From Site
21During Sifting and Milling process checks and ensures Mesh size/ Screen size/ Co-sifting / Pre-mixing/Qty. and Ingredients used.Approved BMR
22During Binder Preparation process checks and ensures Sieve/Binder preparation time and Temperature of Purified Water.Approved BMR
23During Mixing and Granulation processes checks and ensure Material sequence/ Mixing time/ Agitator -Chopper speed and Ampere load.Approved BMR
24During Drying process checks and ensures Operating parameters/ LOD/Total drying time.Approved BMR
25During Sizing and Milling checks and ensure Screen size/Mesh size/ Direction of blades / Speed and Milling time.Approved BMR
26During Lubrication (Blending) checks and ensure Blending time / Speed and LOD.Approved BMR
27During Compression and Inspection checks and ensure Physical parameters / Operating parameters/ Punch description (Drawing) /Tablet description, dimension / Machine type/ Machine speed/ Qty. of defected tablets and Quantity of good tablets.Approved BMR
28During Coating and Inspection checks and ensure Physical parameters/ Operating parameters /Quantity/ Stirrer RPM / Time for milling/ Homogenization/ Qty. of defected tablets and Quantity of good tablets.Approved BMR
29Coating specifications like Appearance, Weight, Thickness, Diameter, DT, etc. shall be the part of BMR.Approved BMR
STEP 3: FORMULATION CHANGE
A.       MAJOR CHANGE (E.G. GRANULATION PROCESS CHANGE)
1Ensure that the availability of Approved MPS.Approved MPS
2Ensure that the availability of the Approved Master Bill of Material.Approved BOM
3Ensure that the availability of Approved Change Control.Approved Change control
4Ensure that the availability of Risk Assessment Report of Granulation/ Compression and Coating (as required).IH/SOP
5License no, Form no, Generic name, Product name (Brand name) and Label Claim/Category, product strength and type of dosages form.FDA License
6Product Code, Description, Batch Size, BOM Code, Unit, Item Code, Item Ref. Lot, Item Name/Manufacturer Code, Quantity (Lot Wise), Material Potency, Minimum potency, Adjust potency, BOM valid up to and BMR version No.Approved MPS Approved BOM
7Overages in Raw materials added, (if any)MPS
8Product Stability Data.Approved MPS
9Product Shelf Life.Approved MPS
10Grade (Pharmacopoeial status) of API and Excipients.Approved BOM
11Equipment equivalency and occupancy as per batch sizeIH/SOP
12Product description (core tablet /coated tablet /finished product specification).Approved BMR
13Bill of Material/Work order pages and space for entries/ instructions and UOM (Unit of Measurement)NA
A.    MINOR CHANGE (E.G. CHANGE IN QUANTITY)
1Ensure that the availability of Approved MPS or Availability of supportive documents.Approved MPS Supporting documents
2Ensure that the availability of the Approved Master Bill of Material.Approved BOM
3Ensure that the availability of Approved Change Control.Approved Change Control
4License no, Form no, Generic name, Product name (Brand name) and Label Claim/Category, product strength and type of dosages form.FDA License
5Product Code, Description, Batch Size, BOM Code, Unit, Item Code, Item Ref. Lot, Item Name/Manufacturer Code, Quantity (Lot Wise), Material Potency, Minimum potency, Adjust potency, BOM valid up to and BMR version No.Approved BOM
6Overages in Raw materials added, (if any)Approved MPS Existing BMR
7Product Shelf Life.Approved MPS Existing BMR
8Grade (Pharmacopoeial status) of API and Excipients.Approved BOM
9Bill of Material/Work order: pages and space for entries/ instructions and UOM (Unit of Measurement)NA
STEP 4: OTHER TYPE OF CHANGES
A.    PHARMACOPOEIAL CHANGE
1Ensure that the availability of the Approved Master Bill of Material.Approved BOM
2Ensure that the availability of Approved Change Control.Approved Change Control
3BMR version No. Master Bill of Material Code No.Approved BOM
4Pages and space for entries/ instructions /quantities and UOMNA
B.     BATCH SIZE CHANGE
1Ensure that the availability of the Approved Master Bill of Material.Approved BOM
2Ensure that the availability of Approved Change Control.Approved Change Control
3FDD Approval required.Supporting Document
4Ensure that the availability of the Risk Assessment Report of Granulation/Compression/Coating stage.NA
5BMR version No. Master Bill of Material Code No.Master BOM
6Pages and space for entries/ instructions /quantities and UOMNA
A.    PUNCH SPECIFICATION CHANGE
1Ensure that the availability of Approved Change Control.Approved Change Control
2FDD Approval required.Supporting Document
3BMR version No.NA
4Pages and space for entries/ instructions /quantities and UOM.NA
B.     COMPRESSION SPECIFICATION CHANGE
1Ensure that the availability of Approved Change Control.Approved Change Control
2FDD Approval required.Supporting Document
3BMR version No.NA
4Pages and space for entries/ instructions /quantities and UOMNA
C.    CRITICAL PROCESS PARAMETER FREEZE
1Ensure that the availability of Approved Change Control.Approved Change Control
2Approved Trend Data required.NA
3BMR version No.NA
4Pages and space for entries/ instructions /quantities and UOMNA
ACKNOWLEDGEMENT: I______________________has read the above checkpoints which are required to ensure during review of draft BMR and understood the same.
Name:
Emp. Code:
Department:
Sign/Date:

Annexure 2: Checklist for Draft BPR Review.

Sr. No.Check PointsReference Documents
STEP 1: INTRODUCTION OF  NEW PRODUCT
1.                       Ensure that the availability of Approved MPS.NA
2.                       Ensure that the availability of Approved Change Control.NA
3.                       Ensure that the availability of the Approved Master Bill of Material (PM).NA
4.                       Ensure that the Risk Assessment Report (Packing)MPS
5.                       Product name: Generic name, Brand name.FDA License
6.                       Packing code, BPR version No.Master BOM
7.                       Product strength, Type of dosage form & label claim/CategoryFDA License
8.                       Stability Data/Finished Product Shelf LifeMPS
9.                       Description as per Finished Product Specification.MPS
10.                   Product-related special precautions (if any) (e.g. Light Sensitive and Hygroscopic)MPS
11.                   Environmental ConditionMPS
12.                   Product-Related Pack ProfileMPS
13.                   Packing Area for the product: Equipment’s used for PackingIH
14.                   In-process test (Leak test, Morpholine test)IH
15.                   Bill of Material/Work order: pages and space for entries/ instructionsNA
16.                   Yield limits (To be established)IH
STEP 2: SITE TRANSFER PRODUCT
1.       Ensure that the availability of Site Transfer BPR.NA
2.       Ensure that the availability of Approved Change Control.NA
3.       Ensure that the availability of the Approved Master Bill of Material (PM).NA
4.       Ensure that the availability of the Risk Assessment Report (Packing)Transfer BPR
5.       Product name: Generic name, Brand name.FDA License
6.       Packing code, BPR version No.Master BOM
7.       Product strength, Type of dosage form & label claim/CategoryFDA License
8.       Stability Data/Finished Product Shelf Life/DescriptionTransfer BPR
9.       Product-related special precautions (if any) (e.g. Light Sensitive and Hygroscopic)Transfer BPR
10.   Environmental Condition/Pack ProfileTransfer BPR
11.   Packing Area for the product: Equipment’s used for PackingIH
12.   In-process test (Leak test, Morpholine test)IH
13.   Bill of Material/Work order: pages and space for entries/ instructionsNA
14.   Yield limits (To be established)IH
15.   Ensure that the availability of Change PartFrom Site
STEP 3: CHANGE IN PACK STYLE
1.       Ensure that the availability of stability data.FDD
2.       Ensure that the availability of Pack Profile.PDD
3.       Ensure that the availability of Approved Change Control.NA
4.       Ensure that the availability of the Approved Master Bill of Material (PM).NA
5.       Ensure that the Risk Assessment Report (Packing)NA
6.       Ensure that the availability of the Approved Master Bill of Material (PM).NA
7.       Ensure that the Risk Assessment Report (Packing)NA
8.       Packing code, BPR version No.Master BOM
9.       Bill of Material/Work order: pages and space for entries/ instructionsNA
10.   Yield limits (To be established)IH
STEP 4: PARAMETER FREEZE (Forming Roller Temp./Sealing Rolling Temp./Machine RPM/Compressed Air Pressure/ Yield data)
1.       Ensure that the availability of Approved Change Control.NA
2.       Department Approved Trend Data required.NA
3.       BPR version No.NA
4.       Pages and space for entries/ instructions /quantities and UOMNA
ACKNOWLEDGEMENT: I______________________has read the above checkpoints which are required to ensure during review of draft BPR and understood the same.
Name:
Emp. Code:
Department:
Sign/Date:

Annexure 3: Checklist for Filled BMR Review.

Stage Of ProcessingGranulation/ Compression / Coating
Sr. No.CheckpointsComplies/Not Complies/NA
1Check all entries mentioned on the cover page of BMR.
2Check that the wash water analysis reports (if required) is attached to BMR.
3Check METIS generated fresh batch confirmed IMO (Issue Material Order) and deviated IMO attached with the BMR.
4Check the Raw Material issue coupons for completeness e.g. A.R. No., Batch No., Qty. dispensed against IMO and BMR and checked by sign and are attached with BMR.
5Check that the environmental conditions (temperature & RH) are within the limit as per BMR.
6Check line clearance checklist and cleaned/ partially cleaned card at each and every stage attached with the BMR.
7Check that the procedure, process parameter & equipment /Accessories is followed as per BMR and recorded properly.
8Check that all in-process records is attached to the BMR.
9Any planned or unplanned deviation like Change Control/Event in the process is properly documented and authorized (Refer CC No /Event No) and their photocopy attached to the BMR.
10Check the status of Shop Floor Observation.Closed/Not closed
11Check that the batch yield calculation and batch reconciliation are within the limit as per BMR.
12Check that all entries have done properly with sign and date and approved chemist has signed.
13Ensure that the batch is released by QA for further processing and the AQL sheet shall be attached to BMR.
14Check finished /micro/ validation sample/hold time has been withdrawn and its quantity documented properly and test requisition cum report attached with the BMR.
15All the observation listed in executed batch record review sheet is corrected by Production officer.
16Check the BMR history sheet comment.
17Check all the page number sequence in the executed BMR.
  • NOTE :
    • Check Legible, Complete Set of BMR & Correctness Of entries (all stages) and then sign in  BMR.
  • Put tick mark (√) at Stage (At which stage BMR to be reviewed) and at the status of Shop floor Observation mentioned above.
  • Annexure 4: Checklist for Filled BPR Review.
Sr. No.CheckpointsComplies/Not Complies/NA
1Check that all entries are filled at the cover page of BPR.
2Check that the BPR is authorized for Packing.
3Check that the METIS generated confirmed IMO (Issue Material Order) and the deviated IMO attached to the BMR.
4Check that the environmental conditions (temperature & RH) are within the limit as per BMR.
5Check line clearance checklist and cleaned/ partially cleaned card at each and every stage and attached with the BPR.
6Check packing material issue order against batch packing record.
7Check that printed and plain overprinted packing material specimen is attached and checked by the concerned packing officer and verified by QA.
8Check that the pack profile complies as per BPR.
9Check that the distribution of batch size matches with standard batch size.
10Check that the procedure, process parameter & equipment /Accessories are followed as per BPR and recorded properly.
11Check that the all in process records are attached to the BPR.
12Any planned or unplanned deviation like Change Control/Event in the process is properly documented and authorized (Refer CC No /Event No) and their photocopy attached with the BPR.
13Check that the primary packing material, secondary packing material and batch reconciliation are within limit as per BPR.
14Check that the Hold time/validation/ control sample / micro / stability samples are withdrawn and its quantity documented properly and test requisition cum report attached with the BPR.
15Check that the material return note for excess printed packing material is attached with the BPR.
16Check that the destruction of stereos & non- recoverable recovery is documented properly.
17Check that the Final Inspection Report and COA are attached with BPR.
18Check the quantity to be dispatched against the Material Transfer Note and its quantity documented properly in the BPR.
19Ensure that the Approved Packing Head/ Production Head have signed.
20Check status of Shop Floor Observation.Closed/Not closed
21All the observation listed in executed Batch Record Review Sheet is corrected by Production officer/ Packing Officer.
22Check BPR history sheet comment.
23Check all the page number sequence in the executed BPR.
  • Note:
    • Check Legible, Complete Set of BPR & Correctness Of entries (all stages) and then sign in BPR.
  • Annexure 5: Executed Batch Record Review Sheet.

Put tick (√ ) wherever it is applicable:    (BMR/BPR)

Product:                                                                                                 Batch No:

Sr. No.Page No.ObservationStageCorrected By ProductionChecked By QA

SOP OF GOOD CHROMATOGRAPHY PRACTICES

Chromatography is a laboratory technique for the separation of a mixture. The mixture is dissolved in a fluid called the mobile phase, which carries it through a structure holding another material called the stationary phase. The various constituents of the mixture travel at different speeds, causing them to separate.

GOOD CHROMATOGRAPHY PRACTICES

1.0   PURPOSE :

  • The purpose of this Standard Operating Procedure (SOP) is to describe the procedure of Good Chromatographic Practices.

2.0   SCOPE :

  • This SOP shall be used as such for “Good Chromatographic Practices” in Quality Control Laboratory.

3.0   RESPONSIBILITY – GOOD CHROMATOGRAPHY PRACTICES

  • The Executive/Officer QC shall be responsible;
  • To carry out the analysis and record the findings as per SOP.
  • To intimate the Head QC / designee in case of any deviation from the SOP.
  • The Section head / Manager  QC shall be responsible;
  • Ensure implementation and adherence to the system as per the SOP.
  • Evaluate proper documentation.
  • Provide training as and when required.
  • The Head QA/his or her designee shall be responsible for;
  • To ensure implementation and adherence to the system as per the SOP.

4.0   PROCEDURE – GOOD CHROMATOGRAPHY PRACTICES

  • Precautions during Chromatography:
  • Indicate on the status board, the name of product/ material, batch number / A.R.No., Stage, Test, Start time, and Analyst (Sign/Date) prior to starting the chromatography.
  • Make the relevant entry in the chromatography instrument logbook.
  • Handle the chromatography column with extreme care.
  • Always keep both ends closed after usage.
  • Increase/ decrease the mobile phase flow rate stepwise and slowly.
  • Use always filtered degassed Chromatography (HPLC) grade solvents/ mobile phases.
  • Do not overtighten fittings of the injector, column, pump, or detector.
  • Ensure that the date and time of data acquisition appear on each chromatogram and the chromatograms are compiled in succession.

Related: SOP for Waters HPLC system with Empower Software

  • System suitability parameters shall be checked by the analyst before proceeding with the sample analysis.
  • All solutions shall be clear homogeneous and free from particulate matter.
  • Filter the solutions before use.
  • While going through change over from reverse phase to normal phase and normal phase to reverse phase follow the changeover steps.
  • Use High-Performance Liquid Chromatography (HPLC) grade solvents
  • In case of non-availability of Chromatography, grade solvents use AR grade solvents
  • Use Elga/MilliQ or any high purity water (suitable for chromatography) for the preparation of the mobile phase.
  • Never mix the aqueous phase and organic phase portion in measuring cylinder as it can give erroneous composition.
  • Column shall be washed pre and post running of the sample set.
  • It should be part of the Sample set/sequence.
  • Flush the High-Performance Liquid Chromatography (HPLC) system with hot water (Approx. Temp 50-600C or as per the suitability of tubing) by using union in place of Column at least by weekly.
  • Preparation of mobile phase and usage of solvent for Chromatography :
  • If the mobile phase contains a buffer solution, first calculate the quantity of the mobile phase required for complete analysis (including quantity required for dilution) and prepare the buffer solution as per the procedure.
  • Set the pH (If required) and do not use concentrated acid/alkali directly for pH adjustment,
  • Use diluted acid/alkali solution for pH adjustment.
  • Filter the buffer solution through 0.45µ nylon filter or as mentioned in respective STP.
  • The filter also can be done at the time of the final mobile phase composition, if applicable.
  • Measure the aliquot of buffer solution required in the mobile phase composition.
  • Transfer to a clean and dried stoppered bottle.
  • Measure the required quantity of organic solvents separately and
  • Add to the stoppered bottle containing a buffer solution and mix well.
  • If the mobile phase contains a small amount (5% or less) of solvents,
  • use a volumetric flask/pipette/measuring cylinder of appropriate size for the measurement.
  • Degas by sonication or vacuum for 4-5 minutes.
  • Do not degas the mobile phase for a longer time containing organic solvents.
  • It may alter the composition while sonication ensures that the bottle cap is loosened to avoid the pressure built up.
  • If the mobile phase is reverse-phase then rinse the filtration assembly and
  • Collection vessel with water before filtration followed by the mobile phase.
  • If the mobile phase is a normal phase then rinse the filtration assembly and collection vessel with the water-miscible component of the mobile phase before filtration followed by the mobile phase.
  • Do not sonicate the buffer solution prepared by using acetate and phosphate buffer since on sonication it forms the complex which may interfere with the analysis.
  • Usage of the chromatography column, System set-up, and Sample analysis:
  • Physically check the column intactness and then Connect the column on HPLC.
  • Wash the column with appropriate solvents and
  • Saturate the column with the mobile phase for about 30 minutes or more until the baseline gets stabilized.
  • The injection sequence (sample set) shall be prepared by the analyst for the respective tests.
  • The injection sequence shall contain the following but not limited to:
    • Vial No.
    • Injection volume.
    • Sample name (sufficient details to link each chromatogram with the sample, like Product name, B. No./AR No., Stage).
    • Method set name.
    • Chromatogram No./Data No./ Injection No. etc.
  • Before starting the sequence, the reviewer or section head shall ensure that the sequence (sample set) parameter and respective instrument method parameters are as per STP/GTP.
  • There shall not be any trial injection run to check the suitability of the system (except System Suitability run defined in respective STP/GTP).
  • All injections shall be run as a part of the main sequence.
  • Check that the
    • Peak shape,
    • Retention time,
    • Relative retention time
    • Resolution,
    • Asymmetry,
    • System pressure and theoretical plates, etc. from the system suitability run / First run of Standard preparation and
  • If required to make necessary modification in the system as per “Allowable modification in chromatography system”,
  • The modification shall not be made prior to Authorization.
  • After satisfactory system suitability run (if applicable) inject blank (i.e. diluents, mobile phase, etc.) standard solution, check the system suitability parameters, and if it meets then start sequence.
  • If peak splitting or broadness of peak occurs during the analysis stop the analysis, then after proper washing of column bracketing standard injection/system suitability solution shall be injected.
  • If it meets with the system suitability then analysis shall be carried on from that sample where peak splitting or broadness took place.
  • Fill the details of system suitability parameters in the respective analytical template/worksheet.
  • After completion of the analysis, wash the column with an appropriate solvent for the appropriate time (e.g. Column shall be washed with water for a long time if the buffer concentration is more in the mobile phase and/or if the column is used for a long time), rinse/ purge auto-injector and make necessary entry in the “Column usage log” and in “Instrument usage logbook”.
  • All chromatograms shall be part of the final reports.
  • Ensure the pressure graph/run shall be enabled while creating/modifying the instrument method.
  • Handling of chromatography column change while analysis :
  • If the peak shape is not satisfactory system suitability parameters are not achieved as per the limit even after making necessary modifications in the system, the column can be changed with the following documentation.
    • Make entry of previously used column in the column usage log with the reason of discontinuation and keep for washing.
    • Take the print of all chromatograms generated on the previous column and put the reason for column change on the Chromatogram checklist along with the previous column no.
    • Attach all chromatograms with the relevant document / Template / Analytical report/worksheet.
  • Handling of mobile phase change while chromatography analysis:
  • If the peak shape is not satisfactory or resolution is not achieved or the theoretical plate and/or tailing factor is not within the limit even after making necessary modifications in the system mobile phase can be changed with the following documentation.
    • Make an entry in the instrument usage logbook with the reason for discontinuation of the mobile phase.
    • System suitability check is a must for every new mobile phase and column.
    • The mobile phase cannot be added in between the analysis of the running mobile.

Note A) ± 10% flow rate adjustment in RT shall be considered during the analysis.

B) ± 1-minute tolerance shall be considered for retention time up to 10 minutes, ± 10% tolerance shall be considered for retention time more than 10 minutes.

  •   Allowable modification in Chromatography system:
  • Adjustments to the specified chromatographic system may be necessary in order to meet system suitability requirements.
  • Chromatographic systems adjustments performed in order to comply with system suitability requirements are not to be made in order to compensate for column failure, Analytical error, and system malfunction.
  • Adjustments are permitted only when suitable standards (including Reference Standards / Working Standard) are available for all compounds used in the suitability test; and
  • The adjustments or column change yields a chromatogram that meets all the system suitability requirements specified in the official procedure.
  • If adjustments of operating conditions are necessary in order to meet system suitability requirements,
  • Each of the items in the following list is the maximum variation that can be considered unless otherwise directed in the ATP.
  • Multiple adjustments can have a cumulative effect on the performance of the system and are to be considered carefully before implementation.
  • In some circumstances, it shall be desirable to use an HPLC column with different dimensions to those prescribed in the official procedure (different length, internal diameter, and/or particle size).
  • In either case, changes in the chemical characteristics (“L” designation) of the stationary phase will be considered a modification to the method and will require full validation.
  • Adjustments to the composition of the mobile phase in gradient elution may cause changes in selectivity and are not recommended.
  • The adjustments are allowed only to improve the quality of the chromatography unless otherwise directed in the respective pharmacopoeial monograph/GTP/STP.

Note: Modification in the allowable chromatographic system shall be within the raggedness study performed during the method validation study.

  • Any adjustment done shall be part of the reporting.
  • The dis-positioning of the batch/sample will be subject to the approval of this report.
  • Alternate columns (Different make) can be used in case of column fails to meet the system suitability requirement.
  • But it should be defined in respective GTP/STP and also covered under AMV / Pharmacopoeial evaluation study.
  • The following are the general criteria, which provide the extent of allowable variation to get the system suitability.
  • The pH of Mobile phase:
  • The pH of the aqueous buffer used in the mobile phase preparation can be adjusted to within ±2 pH units.
  • Example: If the specified pH is 7.0 then the allowable limit for adjustment is 6.80 – 7.20.
  • The concentration of Salts in Buffer:
  • The concentration of salts used in the preparation of aqueous buffer used in the mobile phase can be adjusted within ±10%
  • (Ex.: If the specified concentration is 1.0% then the allowable limit for adjustment is 0.90 % – 1.10 %).
  • Stationary phase in chromatography :
  • Column length: ±70%.
  • (Ex.: If specified length is 25 cm then allowable limit for adjustment is 7.5 cm – 42.5 cm).
  • Column internal diameter: ±25%
  • (Ex.: If specified internal diameter is 4.6 mm then allowable limit for adjustment is 3.45 – 5.75 mm.).
  • Particle size :
  • A maximum reduction of 50%, no increase permitted.
  • (Ex.: If specified particle size is 5 micron then the allowable maximum reduction is 2.5 micron).
  • Flow rate: When column dimensions have been modified, the flow rate can be adjusted using
  • F2= F1 (L2 D2/ L1d2 )
  • Where,
  • F1:     Flow indicated in the monograph in ml/min,
  • F2:     Adjusted flow rate, in ml/min,
  • L1:     Length of column indicated in the monograph,
  • L2:     Length of column used,
  • d:     Column inner diameter of the column indicated in the monograph
  • D:     Internal diameter of the column used
  • Additionally, the flow rate can be adjusted ± 50 %.
  • Column temperature: ±10%
  • (Ex.: If specified column temperature is 40°C then allowable limit for adjustment is 36° – 44°C).

Note: If the column temperature and sample temperature are not mentioned in the ATP/STP, or it is mentioned to keep it “Ambient”, then in both cases the column temperature shall be set to 25°C and sample temperature to 15°C.

  • Detector wavelength:
  • Deviations from the wavelengths specified in the method are not permitted.
  • Injection volume:
  • The injection volume can be reduced/increased as far as is consistent with accepted precision and detection limits.
  • Mobile phase composition can be changed in chromatography as follows:
  • The following adjustment limits apply to minor components of the mobile phase (specified at 50% or less).
  • The amount(s) of these component(s) can be adjusted + 30% relative.
  • However the change in any component cannot exceed + 10% of absolute (i.e. in relation to the total mobile phase), nor can the final concentration of any component be reduced to zero.
  • Examples of adjustments are given below.
  • The specified ratio of 50:50:
  • Thirty percent of 50 is 15% absolute, but this exceeds the maximum permitted change of + 10% absolute in either component.
  • Therefore, the mobile phase ratio may be adjusted only within the range of 40:60 to 60:40.
  • The specified ratio of 60:35:5:
  • For the second component, 30% of 35 is 10.5% absolute, which exceeds the maximum permitted change of + 10% absolute in any component.
  • Therefore the second component may be adjusted only within the range of 25% to 45% absolute.
  • For the third component, 30% of 5 is 1.5% absolute.
  • In all cases, a sufficient quantity of the first component is used to give a total of 100%.
  • Therefore, a mixture range of 50:45:5 to 70:25:5 or 58.5:35:6.5 to 61.5:35:3.5 would meet the requirement.
  • Duplicate standard / Similarity Factor calculation 
  • The duplicate standard shall be applied for the Assay test (irrespective of sample category).
  • 2nd Standard shall be injected in duplicate after System suitability run (After completion of 5/6 replicate standard injection and prior to the sample run).
  • Assay analysis shall be performed using duplicate standard preparation.
  • The second standard shall be prepared by the same/different analyst.
  • The first standard (Initial standard) shall be injected as per the above schedules, while the second standard shall be injected in duplicate.
  • The correlation between two standards shall be calculated as per the below formula.
    • Mean area of std -2 x Weight of std -1
    • Mean area of std -1 x Weight of std -2
  • Acceptance criteria: Between 0.98 -1.02
  • In case of correlation does not fall within acceptance criteria,
  • log the Lab Incident/Event as per the current version of SOP – Lab Incident, investigate and repeat the analysis by preparing the standard and establish the similarity factor prior to sample injection.
  • For calculation mean area of the first standard shall be considered.
  • Bracketing standard procedure in Chromatography:
  • System suitability shall be established as per the test procedure.
  • After every defined sample injections or after every test (Club analysis or individual analysis) standard preparation in single shall be injected (Called as Bracketing standard preparation).
  • Bracketing Standards shall be injected after 12 injections or 3 hrs after the last standard injection injected whichever is earlier.
  • Bracketing standard can be injected other than the above conditions (Completion of Test, After 3 Hrs, After 12 sample injection), It should be justified and documented.
  • To meet the system suitability criteria of method %RSD of last five injections (including Bracketing Standard) area to be considered,
  • the average area including bracketing standard preparations shall be used in the calculations.
  • For e.g. If System suitability is established by five injections of standard injection (1st, 2nd, 3rd, 4th, and 5th ).
  • After testing the sample (A) preparations (6th and 7th ) and one bracketing standard preparation injection (8th ) shall be injected.
  • Then further sample (B) preparation injections ( 9th and 10th ) followed by bracketing standard (11th ).
  • To calculate the result (A)
  • Standard Avg. Area = Avg. Area of std (2nd, 3rd, 4th 5thand 8th).
  • Sample(A) Avg. Area = Avg. Area of Sample (6th and 7th)
  • To calculate the result (B)
  • Standard Avg. Area = Avg. Area of std (3rd,4th,5th, 8th, and 11th ).
  • Sample(B) Avg. Area = Avg. Area of Sample (9th and 10th).
  • The analysis is valid only if the %RSD of Bracketing Standard preparations are within the limit.
  • If the RSD of bracketing standard is failed, stop the analysis,
  • The analyst shall log the Lab Incident (as per the current version of SOP for Lab Incident) and investigate the reason for failure, adopt the strategy as follows.
  • If the failure in RSD is because of system instability, bracketing standard RSD shall be considered up to last bracketing standard till it meets the criteria of system suitability and analysis of remaining samples shall be carried after reestablishing the system suitability as per the GTP.
  • If there is a significant change in one of the injection area of bracketing standard and analysis is continued.
  • Additional injections of bracketing standard shall be done and reason for variation in the previous injection of bracketing standard shall be justified.
  • In case of vial missing/solution volume inside the vial is less than required, area variation between replicate injection, additional peak observed, re-injection from the same vial, or from the same solution shall be done, with proper scientific justification.
  • Additional injection of the Blank-mobile phase and/or diluent, placebo preparation, and impurity standard can be injected to verify the elution pattern and peak identification of Blank, placebo, and impurity.
  • Data shall be attached to the Analytical Report with scientific rationales.
  • Chromatogram set up for integration, review, Calculation, and Documentation:

Note1: Chromatograms shall be processed within one working day from the completion of the sequence. If exceeds, Log the Lab incident, Investigate / Justify and then process the acquired data.

Note 2: No single chromatogram shall remain unprocessed irrespective of Blank, Placebo, System check, standard, sample, etc.

  • Analysts shall ensure the peak shape and system suitability parameters for all chromatograms in a sequence (i.e.Up to the last chromatogram) before the set up of integration parameters.
  • Set the integration parameters like width, threshold, peak area, peak height, scale are selected appropriately for proper peak marking and detection and inhibit all others peaks except the principal peak in all tests except for related substance test and degradation product, Chromatography purity (but not limited to).
  • Integration parameters shall be the same for all chromatograms generated in a sequence or test.
  • Manual Integration is not allowed.
  • In case of the integration of peak is not possible by software, manual integration can be done for the proper peak integration with justification (Only in RS test).
  • If different processing methods (Integration parameters) used in the same sequence then it shall be properly justified.
  • In the system, suitability chromatogram identifies the peaks, its RRT, System suitability parameters, peak shape, and report the values as applicable.
  • Identify each peak for RS test e.g.
    • Blank-Diluent,
    • Placebo,
    • Principal peak,
    • Unknown impurity,
    • Known impurity (mention the name of impurity), etc. and
  • Inhibit those peaks in the sample whose responses are similar in placebo and blank.
  • If the response of an unknown peak in sample chromatogram is greater than the response of that peak in blank or placebo chromatogram then integrate that peak in both (sample and blank or placebo) chromatograms and consider area for calculation after (area of peak in sample-area of the peak in blank or placebo).
  • In the case of the RS test, attach the overlay chromatogram of the sample, blank, and placebo for clarity of peaks.
  • In-case of In-house product/ material if system suitability parameters ( theoretical plates, resolution, and tailing, etc.) do not comply as per acceptance criteria but peak shape or peak elution pattern is good then send all relevant data to the analytical method development team for to review and revise the system suitability acceptance criteria.
  • Chromatography Report Format :
  • The custom report shall cover the following information but not limited, which is for information and can be modified as per the specific need.
    • Name of Product / Raw Material
    • Test performed
    • Sample ID -B. No. / A.R. NO.
    • Data Path
    • Injection volume
    • Vial no.
    • Column number / ID
    • WaveLength.
    • Date of acquisition
    • Date processed
    • Acquired by /Analyst
    • Instrument ID
    • Chromatogram No / Data No / Injection No.
    • Instrument method ID
    • Processing method ID
    • Print date / Time & Time Zone
  • The peak table in the custom report shall cover the following data (But not Limited to), however other data as per requirement.
    • Peak Name
    • Retention time
    • Area / Height
    • Area% / Height%
    • Tailing factor or Asymmetry
    • Theoretical plates / Plate count
    • Integration type
    • Other system suitability parameter as per requirement
  • Take the print out of integration parameters and all chromatograms.
  • If Degradation / Related substances are to be calculated from Assay, take the separate print out of the first injection of each sample chromatogram by setting the width and threshold appropriately to detect all peaks along with blank or placebo.
  • Report the system suitability data (theoretical plate, tailing factor, capacity factor, etc.) in the respective analytical template.
  • In cases where reintegration is necessary, all the chromatograms from the previous integration or multiple integrations shall be identified, assessed, justified and shall be part of the raw data and set of chromatograms (previous Processing method print out, audit trail (for that specific change) and the print out shall be attached with the sequence of record).
  • For related substances and similar low content test.
  • The analyst shall be zoomed the chromatograms on the baseline and shall check that all the peaks are integrated and the integration of all interested peaks are properly marked.
  • Peaks that are not separated completely shall be integrated valley-to-valley extrapolation (tangential skim).
  • The integration parameters shall set in such a way that the peak of at least half of the disregard limit must be integrated, and shall be documented in the Chromatogram checklist.
  • The scale of chromatograms shall be set properly so that the peak shape of all interesting peaks and their integration can be seen clearly.
  • In the chromatogram peak shall be identified by RT only and other detail like peak identification, etc. shall be part of the peak table.
  • The sample chromatogram shall overlay with diluent and placebo chromatograms to identify the interested peak properly.
  • For Assay, Content uniformity, dissolution, preservative content:
  • Integration shall be set appropriately for the principal peak.
  • The scale of chromatogram shall be such that the response of principal peak is at least 70% of the full-scale deflection or Autoscale of the chromatograms.
  • In the related substances/chromatographic purity/degradation test exclude the area of diluent/placebo peak in the impurity calculation.
  • Where disregard peak/area is mentioned in GTP (based on LOQ performed during AMV), those peak/ peaks area shall be ignored in the calculation.
  • In the calculation of impurity disregard the peak of response below 0.03% with respect to the principal peak where LOQ is not available.
  • Calculate the area equivalent to 0.03% as follows :
  • For area normalization method :
    • = 0.03 x  area of the principal peak in sample preparation-1
    •    100
  • For the external standard method :
    • = 0.03  x X x Z
    •          Y x P
  • Where,
    • X= Concentration of drug substance (Theoretical) in sample preparation.
    • Y= Concentration of external standard in standard preparation.
    • Z= Area of external standard in standard preparation.
    • P= Potency of an external standard.
  • In the calculation of known and unknown impurity disregard the peak of response below LOQ level.
  • Calculate the area equivalent to LOQ as follows.
    • = L x A
    •     C x P
  • Where,
    • L= LOQ of impurity in ppm
    • C= Concentration of impurity in ppm from Standard preparation
    • A= Area of impurity from standard preparation
    • P = Potency of impurity standard
  • In the calculation of known and unknown impurity disregard the peak of response below LOQ level.
  • Where impurity standard is not injected and LOQ and RF are mentioned in GTP/Protocol.
  • Calculate the area equivalent to LOQ as follows :
    • L x A x RF
    • C
  • Where,
    • L= LOQ of impurity in ppm
    • C= Concentration of drug substances (theoretical) in ppm from Sample preparation-1
    • A= Area of drug substances from Sample preparation-1
    • RF= Response factor of impurity.
  • In the case where RF is mentioned in the GTP corrected area of respective impurity shall be used in the calculation.
  • Chromatogram Checklist (Chromatography Review) : (Annexure 2)
  • Fill the detail like Product / Sample, Test, Reference (GTP/Protocol No./Template No.), Bach No., A.R.No.,  in Chromatogram checklist.
  • Put the “ √ ” mark against the applicable point and ‘NA’ against the not applicable points.
  • If any parameter in the Chromatogram checklist is not complying or not carried out writing the justification under the head “Remark” or if the deviation is filled mention the deviation no.
  • Make a bunch of “Chromatogram checklist”, “Mobile phase preparation “Sequence print out”, instrument method, processing method, and all chromatograms and attach with the template/worksheet or protocol.
  • Put all chromatograms together and attach them with the relevant Batch No./ A.R.No. Document.
  • In case of analysis discontinuation, mention the reason for discontinuation in instrument usage Log and on the “Chromatogram checklist”.
  • Take the print out of all generated chromatograms put the canceled on each chromatogram with proper justification and attaches with the relevant document.
  • General Guideline and instructions for Chromatography:
  • Chromatographic systems shall be reviewed by the reviewer for events, such as,
    • Unprocessed chromatograms,
    • Single injections,
    • system check injections,
    • system suitability injections,
    • Partially run sequences or complete run sequences,
  • Which are not part of the original sequences on a weekly basis and
  • Document the review observations as per the current version of SOP for Analytical Data Review.
  • Any of the above events are observed, log the lab incident as per the current version of the SOP-Lab Incident.
  • Chromatographic run shall be identified, processed, justified and impact assessment shall be performed w.r.t. original sequence. Prints out shall be attached to the original sequence.
  • For any chromatographic run incident, such as incomplete run, discontinued run or run for system suitability check (or for any other reason ) and not considered for evaluation shall be marked as “Not Used” with proper justification, signature, date, and shall be made part of main sample sequence set attached with the batch analytical documentation.
  • “Printed on date and time” of chromatograms shall be part of the chromatogram report format.
  • Chromatograms shall be processed within one working day from the completion of the sequence.
  • QC head shall identify instruments that are not in compliance with 21 CFR part 11.
  • Derive an action plan with a timeline to make all such instrument compliant (refer current version of SOP for Data Integrity).
  • For experimental analysis sample shall be selected from,
    • Expired lots of finished products.
    • Lots prepared from working standard.
    • Retention Sample (subject to Approval of Head QA)
  • All the activities performed by the service technician shall be recorded in the report and the same shall be reviewed and approved as per respective report approval procedure.
  • For related substances test / Degradation product, New cleaned vial shall be used.
  • Run time and replicate injection. 
  • In the test for Assay, run all Standard and Sample chromatograms about 5 minutes extra after the principal peak elution is over and the peak is properly integrated or as per the GTP / STP.
  • Chromatography Purity/ Degradation/ Related Substances/Stability samples analysis, run the chromatogram 2.5 times the RT of principal peak or as specified in individual GTP / STP.
  • In case of specific impurity analysis, run the chromatogram about 5 minutes extra after the principal peak elution is over and the peak is properly integrated.
  • In case the HPLC system is running in the mobile phase (subject to sufficient mobile phase volume available) and the further sample is supposed to inject,
  • It can be injected as per the following strategy.
    • If the time gap is 2 hrs. or less further samples can be injected directly.
    • If there are more than 2 hrs. time-gap inject bracketing standard.
  • Calculate the RSD of bracketing standard (i.e. last two injections of initial system suitability standard and injections of bracketing standard made after time gap) and if this is satisfactory further sample analysis shall be continued.
  • In the end of the sample sequence a different method for “D2 lamp off and flow rate change to 0.2ml/min (or suitable)” shall be submitted to keep the system stabilize in the mobile phase.
  • If any carryover in the chromatogram is not affecting the interested peak analysis shall be considered after proper justification and authorization.
  • The concentration of any unknown peak in assay, dissolution, and content uniformity test, shall not be more than the concentration of unknown impurity peak in related substances test. (As related substances unknown impurity limit is derived based on ICH daily dose criteria.)
  • Any unknown peak detected above this concentration shall be investigated.
  • During analysis, an additional injection of blank-mobile phase and/or diluent can be made to verify the elution pattern of the blank.
  • Additional injection of placebo solution and impurity solution with or without spiking can be made where ever necessary with proper justification.
  • In case, if during analysis any failure in established system suitability, peak splitting, area variation shall be rectified on line by altering the same sequence with justification.
  • In the case of the sample if any abnormality is observed during analysis then a freshly prepared sample can be injected with proper justification.
  • If the system is required to be discontinued for rectification then it shall be handled as per SOP on Lab Incident.
  • Preparation and use of specimen chromatograms
  • To verify the reproducibility in chromatography and
  • To notice any change in chromatograms online during analysis and also
  • At the verification stage during raw data review by comparing the chromatogram against specimen chromatograms, the laboratory shall maintain a file of “Specimen Chromatograms “for each HPLC test ( product wise).
  • Reproducibility can also be verified by AMV data.
  • To prepare the specimen chromatogram and ensure its usage the below procedure to be followed.
  • If the reference chromatogram is available from the manufacturer, Source laboratory STP/ Data, the chromatogram of first analysis/ analytical method transfer (or method validation) shall be compared against the reference chromatogram to check the following but not limited to,
    • Peak shape
    • Retention time
    • Baseline (Baseline pattern is very important particularly in HPLC gradient analysis)
    • Scale of chromatogram
    • Additional peak
    • Other system suitability parameters as per the requirement of STP / ATP.
  • Make a photocopy of one chromatogram each of
    • Blank (diluent),
    • Resolution solution,
    • Standard solution,
    • Placebo solution,
    • Sample solution, etc. as per the requirement of the test,
  • Put “Specimen chromatogram” on individual chromatogram and sign/date of Head QC.
  • File all the “ Specimen chromatograms” product and test wise for the comparison of all future analyses.
  • During routine analysis, the analyst shall verify the chromatogram against Specimen Chromatograms.
  • In case of any abnormality observed in the chromatographic pattern analyst shall immediately inform QC -Head or designee.
  • QC-Head or designee shall suggest an analyst for allowable modification to get the chromatography that is comparable with the “ Specimen chromatogram”.
  • During raw data review, the reviewer shall verify the chromatograms against the “specimen chromatogram”, in case of any abnormality observed.
  • Whenever there is any change in method of analysis, the impact on the “Specimen chromatogram” shall be evaluated.
  • Cancellation of Chromatograms :
  • Each cancellation of chromatograms due to system failure, system suitability parameters failure, poor chromatography or due to any other reason, shall be canceled by section head only.
  • Section head shall put the canceled stamp on each canceled chromatograms with proper justification with sign and date.
  • HPLC change oversteps from reverse phase to Normal phase chromatography
    • Step 1:
  • After proper washing of the previously used column remove the column from the column compartment and connect the Union.
  • Keep all tubing reservoirs in the bottle containing HPLC water/Solvent (degassed) and proceed following steps.
  • Step 2: Dry Prime:
  • Take 100 % HPLC water in Mobile phase reservoirs, and execute the dry prime 5 minutes individually for each channel (line) at flow rate 5ml/minutes during the dry prime outlet valve shall be opened.
  • Step 3: Wet  Prime: 
  • Execute the wet prime 3 minutes individually for each channel (line) at flow rate 5ml/minutes during the dry prime outlet valve shall be opened.
  • Note: Degasser shall be off during priming (preferably in Quaternary pump)
  • Step 4: Needle Wash, Seal Wash, Injector Wash:
  • Perform these activities for the time as per default settings subsequently.
  • Step 5:
  • Flush the HPLC system for 20 minutes by gradually increase the flow 1ml/minute to 5ml/minute, 25% flow from each channel / Pump (line).
  • Step 6 :
  • Repeat wet prime, needle wash, seal wash, and injector wash as per procedure mentioned above in steps 2, 3, and 4 by using 100% HPLC grade methanol.
  • Step 7 :
  • Repeat wet prime, needle wash, seal wash, and injector wash as per procedure mentioned above in step 2, 3, and 4 by using 100 %HPLC grade IPA.
  • Step 8 :
  • Use 100% IPA or other non-polar solvents as per GTP or template for seal wash or needle wash during the analysis.
  • After proper washing of the previously used column remove the column from the column compartment and connect the Union.
  • Keep all tubing reservoirs in the bottle containing HPLC water /solvent (degassed) and proceed following steps.
  • Step 2: Dry Prime:
  • Take 100 % Isopropyl Alcohol (IPA) in Mobile phase reservoirs, and execute the dry prime 5 minutes individually for each channel (line) at flow rate 5ml/minutes during the dry prime outlet valve shall be opened.
  • Step 3: Wet  Prime: 
  • Execute the wet prime 3 minutes individually for each channel (line) at flow rate 5ml/minutes during the dry prime outlet valve shall be opened.
  • Note: Degasser shall be off during priming (preferably in Quaternary pump)
  • Step 4: Needle Wash, Seal Wash, Injector Wash:
  • Perform these activities for the time as per default settings subsequently.
  • Step 5:
  • Flush the HPLC system for 20 minutes by gradually increase the flow 1ml/minute to 5ml/minute, 25% flow from each channel (line).
  • Step 6:
  • Repeat wet prime, needle wash, seal wash, and injector wash as per procedure mentioned above in step 2, 3, and 4 by using 100% HPLC grade methanol.
  • Step 7:
  • Repeat wet prime, needle wash, seal wash, and injector wash as per procedure mentioned above in step 2, 3, and 4 by using 100 %HPLC grade water.
  • Step 8:
  • Flush the HPLC system for 20 minutes by gradually increase the flow rate 1 ml/min to 5 ml/minutes, 25% flow from each channel (line), (In case of the Quaternary pump).

5.0   Reference & Annexure – Good Chromatography Practices :

  • References :
  • 21 CFR Part 11: Electronic Records ; Electronic Signatures
  • Schedule L1: Drug and Cosmetic Act (Good Laboratory Practices)
  • USP – NF: USP 40, NF -35, Chapter <621>

Annexure 1: Mobile Phase Preparation Record

Product / Material : ………………………………………………………………………………………… B. No.  / A.R. No. : 1. ………………….. 2. ………………..3. …………………. 4. ………………… Tests : 1. ………………….     2. ……………………      3. …………………….. 4. …………………… Mobile Phase Quantity: …………………………………ml Date of preparation: ………………………………… Prepared by: ………………………………… Date of Usage: ………………………………… Quantity Used: …………………………………. Quantity Destroyed: ………………………………… Destroyed by (Sign/Date): …………………………………

Annexure 2: Chromatogram Checklist

Product / Sample: _______________ A.R. No.: ________________ Test :_____________________ Batch No.:_____________________ 1. Integration Parameters printed on the last Standard chromatogram of System suitability / Processing Method printout attached.
2. Chromatograms in serial of Blank, Standard, and Sample from the first Injection. 3. Cancellation of any chromatogram justified (Justification attached).
4. Each chromatogram properly identified.
5. Chromatograms checked for the proper peak shape and baseline and identify Peaks.
6. System Suitability Parameters filled in the respective template/worksheet and should be within the limit.
7. In Chromatographic Purity/ Degradation/ Related Substances/Stability samples analysis, run the chromatogram 2.5 times the RT of principal peak or as specified in individual GTP/Pharmacopoeial Monograph.
8. The method and integration parameters the same throughout the analysis.
9. Any type of Reintegration authorized.
10. Samples bracketed by Standards as per the system. If not, justification Remarks (If any):

SOP of Maintenance, Storage and Usage of the Primary Standards

The purpose of this SOP is to describe the procedure for the maintenance storage and usage of the Primary standards.

This SOP is applicable for all primary standards, used in Quality Control Department at manufacturing facility of Pharmaceutical Industry

PROCEDURE:

Whenever any primary standard received from supplier, check whether the sealing of the bottle is proper, and that particular material is having proper Certificate of analysis.

File the Certificate of analysis of the supplier properly.

Record the ‘date received and the ‘quantity received’ in the format as per Annexure-I.

Primary standards may be used for standardization of volumetric solutions, calibration of analytical Instruments, performance checking and for routine analysis as applicable in a quality control laboratory.

Whenever the material is needed for analysis, record the quantity of the material taken for analysis, in the concerned format as per Annexure-I.

Seal the material properly after use and keep it in the original position. Each primary standard shall be kept in laboratory condition i.e. 25°C + 2°C in original pack.

Expiry date of the primary standard shall be five years from the date of opening, or as per manufacturer’s certificate of analysis.

It shall be labeled as per Annexure- II.

Primary standard control number shall be assigned as follows

i.e.  XX/PS/001

    Where ,

                        XX=Company Name

PS= Primary Standards

                        001= stands for an incremental number

Refer Annexure-III for list of primary standards and primary standard shall be dried        before use wherever applicable as per (Refer Annexure-IV).    

TRAINING:

As per SOP of Employee Training

DISTRIBUTION:

As per SOP on SOP  

ANNEXURE:

Annexure-I         : Primary Standard usage record.

Annexure-II       : Primary standard usage label.

Annexure-III      : List of Primary standard.

Annexure-IV      : Drying Condition For Primary Standard.

REFERENCES:

Nil

SOP of Reference Standard Management

The purpose of this SOP is to lay down a procedure for entry and exit in laboratory in Quality control department.

  • PROCEDURE:

  Reference standards :

Receive the Reference substances check current lot, material safety data sheet and certificate (If available). Allot a reference number to it as illustrated below. USPRS/A1/1.

In this, ‘USPRS’ stands for the pharmacopoeial body from which the RS is received. ‘A1’ stands for the unique number for a particular product in the alphabetical series and ‘1’ stands for the version number.

Make sign and date on original container of reference substance/ standard.
Maintain a reference substance register (Annexure I) and enter the details like item, RS number, Lot/Batch number, date of receipt, quantity received, direction for storage and use.

Maintain an index of all reference substances/standards and attach it to the register.  
      Place the reference substance container in a self-sealing polythene bag, along with a silica gel pouch, which is kept in a small stainless steel container with the label (Annexure II) indicating item, RS number, lot/batch number, date of receipt and direction for storage and usage.

Replace the silica gel pouch of the container every six months and record the same.  Refer Annexure III.

Prepare a usage log for each reference substance indicating its usage and maintain a record  of the same.

Check the validity of lot No./Batch No. of reference substances/ standard from official catalogue of pharmacopoeial bodies every two months or whenever a new catalogue is received whichever is earlier.
  Reference substance should be up to the lot/Batch No. is valid Whenever a new lot is received or a new container of same lot is received, replace old lots/batches of reference substances with the new lots.

Retain the same reference number  but revise a version number e.g. USPRS/A1/2 and so on.

Assume the potency to be 100% if the same is not specified on the original reference substance container or catalogue of respective pharmacopoeial bodies.

Where drying of reference substance is specified, dry only the minimum required quantity of the reference substance.

Do not dry the original container under any circumstances.

Do not transfer the dried/ weighed substance back to the container.

In case the instructions for use mention determination of moisture content by Karl Fischer apparatus, use the bare minimum quantity by diluting the Karl Fischer reagent three to four times with methanol or using diluted Karl Fischer reagent (water equivalence factor 1 to 2 mg/ml) or determine moisture content using coulometer.

After withdrawing reference substance vial from refrigerator, allow it to attain ambient temperature before proceeding with testing.

Make relevant entries in the usage log every   time the reference standard is used.

Unless otherwise mentioned, store all the reference substances at temperature between 2 to 8°C.

Allow it to attain ambient temperature before use. Destroy the old reference standard and mention the details of destruction in usage log.  

Reference substance solutions :   Prepare the RS solution only whenever it is required.

Allot a reference number to it as illustrated below:  RSSoln/A1/1.

In this, ‘RSSoln’ stands for Reference Substance Solution,  ‘A1’ stands for the unique number for a particular solution in the alphabetical series and ‘1’ stands for the version number of reference solution.

Store reference substance solutions in tightly closed bottles with proper labeling) and protect them from light Maintain a register and enter the details like item, solution number, source number of material used, test name, validity (6 months) .
Maintain an index and attach it to the register. Prepare a “Solution Preparation and Usage Log” indicating name of solution, date of preparation, RS No. For which RS solution prepared, dilution, direction for use.

Unless otherwise mentioned, store all the reference solutions at a temperature between 2 to 8°C.

Allow it to attain ambient temperature before use.

Check the solution for colour, clarity and foreign particles, before use. 

Carry out the periodic checks for colour, clarity and foreign particles once in every 3 months and record the observations.

If change is observed, discard the RS solution.

Prepare fresh solution, Retain the same solution number but revise version number. e.g. Solution/A1/2 and so on.

If the Lot No. / B.No. of the reference substance (used for the preparation of reference solution) is changed, discard the reference solution and replace with fresh solution.

After initial analysis, maintain the records of data related to the solution used e.g. copy of HPLC/GC chromatograms or in case of TLC, observation of TLC pattern (i.e. number of spots observed) and attach with the usage log..

After every analysis, compare the data obtained related to RS solutions used with the data of initial analysis.

If any significant change is observed (like major degradation peaks observed in case of chromatographic tests) discard the solution and prepare the fresh solution.

Record the observations and comparison in preparation and usage log.
 
   
  • TRAINING:

As per SOP of Employee Training

  • DISTRIBUTION:

As per SOP on SOP

  • ANNEXURE:

Annexure I     :  Reference standard vial Register

Annexure II   :  Label of Reference standard Container / bag

Annexure III :  Reference standard consumption Record

Annexure IV :  List of Reference standard.

Annexure V :  Silica gel Change record

Annexure VI :  Reference solution Label

Annexure VII:  Reference solution index

Annexure VIII : Reference solution Preparation and usage log

  • REFERENCES(S):

Nil

SOP On Disposal of Waste Generated in Quality Control Lab

The purpose of this SOP is to lay down a procedure for disposal of waste generated in Quality control department. This SOP is applicable to Quality Control Department in Quality Control Department at manufacturing facility of Pharmaceutical Industry.

PROCEDURE:

All used chemicals, Reagents and analyzed products shall be stored in HDPE containers after making slurry with suitable solvents. The container shall be properly sealed and labeled as “Disposal waste from QC”.

Such containers shall be stored only in the washing room of quality control department under proper covering.

Cyanide waste shall be detoxified using 10% w/v Sodium hypo chloride solution and transferred to the container.

Analyzed Bromine shall be detoxified using 5% w/v Sodium thiosulfate solution and transferred to the disposal container.

Proper care shall be taken while making slurry and disposal. Appropriate Personal Protective Equipment (PPE) shall be used at the time of disposal.

The collected slurry shall be disposed to ETP equalization point with the prior permission from Environmental Management Representative.

The waste shall be disposed & documented in collection and disposal records under the supervision of wet lab In charge.

TRAINING:

As per SOP of Employee Training

DISTRIBUTION:

As per SOP ON SOP

ANNEXURE:

Annexure –I                 : Disposal of Waste

REFERENCES(S):

Nil