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 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 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 For FTIR

FTIR Spectrometer

Standard Operating Procedure (SOP) for Operation, Calibration, Cleaning, and Maintenance of FTIR (Fourier Transform Infrared Spectrometer).

Procedure for Operation and Calibration of FTIR

1.0   PURPOSE:

  • The purpose of this Standard Operating Procedure (SOP) is to describe the start-up, operation, calibration, and maintenance procedure of the FTIR – Fourier Transform Infrared Spectrophotometer.

2.0   SCOPE:

  • This SOP is applicable to the Shimadzu make and model IRAffinity-1 FTIR- Fourier Transform Infrared Spectrometer of the quality control department at the pharmaceutical drug manufacturing plant.

3.0   REFERENCES:

  • Instrument manual of Fourier Transform Infrared Spectrophotometer (FTIR).
  • SOP for Handling of out of Calibration results (OOC)
  • SOP for Analytical Instrument Qualification.
  • European Pharmacopoeia
  1. SOP for -Instrument/Equipment usage log book.
  • SOP for –Maintenance of Laboratory Instruments.

4.0   RESPONSIBILITY & ABBREVIATIONS

  • The Analyst shall be responsible for the operate the instrument as per SOP,
  • Calibrate the instrument as per SOP and Recording all the document related to the operation, calibration, and maintenance.
  • Quality Control Head or Designee shall be responsible for give training to all the concerned persons before the implementation of SOP,
  • To ensure proper documentation as per SOP and initiate the maintenance activity white breakdown.
  • QA shall be responsible for check and ensure the implementation of the system as per SOP.
  • Quality Head and Plant Head shall be responsible for the review, approve the SOP.
  • ABBREVIATIONS:
  • FTIR: Fourier Transform Infrared Spectrophotometer.
  • KBr: Potassium Bromide
  • NA: Not Applicable
  • QA: Quality Assurance
  • QC: Quality Control
  • SOP: Standard Operating Procedure

4.0   PROCEDURE FOR OPERATION AND CALIBRATION OF FTIR:

  • Startup of FTIR Software
  • Clean the Instrument and surroundings.
  • Connect the instrument with the power supply.
  • Switch on the instrument and Computer system.
  • Double click on “IR Solution” Icon.
  • After No. of internal operation.
  • Select the “Measure” and select Measurement from the main menu, further select “ initialize” from the measurement tab.
  • Press “Yes” then following screen will appear:
  • Select File to load standard method for analysis or fill the desired parameter of the method.
  • Click on file,
  • Select the above option to enter the main window and select the standard method for analysis or prepare new method as per STP.
  • After selecting the standard method, double click on method or Open it from main window. A dialog box will appear and ask about downloading parameter of Method.
  • Press “OK” to download the method parameters
  • After completion of method downloading,
  • Click on “BKG” for background correction. A dialog box will appear.
  • Press “OK” if the Sample compartment is ready for Background.
  • Select measure from the above screen window, fill all the required (sample/standards information) in comment/Date file and select sample for sample analysis.
  • For the Sample Analysis click on the Data path file and give the appropriate file path for saving the data.
  • Copy the file name and paste the data in the comment and click on the sample tab.
  • After scanning the sample click on “Calculate” and then “OK” on the Peak Table.
  • The number of peaks in the Peak Table must be between 15 to 25.
  • To adjust the number of peaks click on “Calculate” and then increase or decrease the “Min Area” and then click on “OK”.
  • Click on “Window” from the main menu bar and select “Join Visible”.
  • Then click on “Manupulation 2” and select Purity.
  • Rightclick on the sample and select send to source similarly right click on the reference and select send to reference.
  • Send to reference
  • Click on “Calc”, then “OK”, select the print command from the main window.
  • Click on “OK” and select the desired report template for the Peak purity Graph as shown bellow.
  • Select the Report format and click on “Open” or double click on Report format. Press ‘OK’ for printing the document.
  • For Peak table : select the Manipulation 1 and select Peak table.
  • After selecting the peak table,
  • Click on “Calc” then “OK”.
  • Select “Print” from the above screen.
  • Select the report format as ‘peak table’ and print. As per the above described procedure.
  • Sample Preparation for FTIR Analysis:
  • Sample Preparation for solid Sample for FTIR Spectrometer:
  • Dry the KBr (Potassium Bromide –IR Spectroscopy grade) at 105°c for about 1 hour, cool it in the desiccator before use.
  • Crush the dried KBr in mortar.
  • Clean the sample holder with carbon tetrachloride or acetone to remove grease.
  • Take crushed KBr in the  “Sample Cup” and plain the surface by using sample-pressing bar.
  • Clean the excess powder that fall on the sides of the sample cup using a tissue paper and put the cup on “Sample Cup Holder” in the sample compartment of the instrument.
  • Take the background IR.
  • Weigh about 300 mg of previously dried KBr and transfer it to a clean mortar.
  • Weigh about 2 to 4 mg of previously dried sample or as per the specified specification (to make sample concentration about 1.0% w/w) and transfer to the mortar, which contained the KBr.
  • Mix the sample with KBr for homogeneous.
  • Use this sample for the sample spectrum.
  • Sample preparation (For Liquid sample) for FTIR Spectrometer:
  • Select fixed thickness cell as per the requirement or use sodium chloride cell.
  • Put the cell in cassette and take the background (Air background) or as per the requirement.
  • Suck up the liquid sample by syringe.
  • Inject the liquid sample into the cell through the one hole of cell until the liquid came out from another hole of cell and become a thin film and insert the plugin both the holes.
  • Clean the cell with tissue paper.
  • Use this sample for sample spectrum.
  • Sample Preparations – Films.
  • Use this technique for liquids or semisolids or low melting solids.
  • Put the cell in cassette and take the background (Air background) or as per the
  • A thin film can be made by dissolving a semisolid or a highly viscous liquid (such as polymers) in a minimum volume of a volatile solvent (such as chloroform, carbon tetrachloride) or the sample can be taken as such.
  • Using a clean glass capillary, place a drop or a small portion of the sample onto a clean sodium chloride cell.
  • Hold the other sodium chloride cell’s edge on the top of the sample and slide horizontally applying slight pressure so as to form a thin film on the cell.
  • In case film is to be made with a solution, evaporate the solvent to dryness using a hot air gun. Align the cell edges and assemble the two sodium chloride cells.
  • Run a Background Scan as an air blank
  • Cut the film cassette size and insert a cassette.
  • Use this sample for the sample spectrum.
  • If the sample preparation is specified in the STP/ATP or individuals monograph follow the same.
  • Calibration (Verification of the wave-number scale) of FTIR Spectrometer:
  • Follow the operational procedure and record the Spectrum of the Polystyrene film over the range of 3800 cm-1 to 650 cm-1.
  • Record the wave number in attachment no. 01.
  • The spectrum should show the Transmission minima (absorption maxima) at the wave-number given in the attachment no. 01.
  • Frequency: (Monthly± 3 days)
  • Validation Procedure of FTIR Spectrometer:
  • Ensure that, the instrument is ready for calibration and the start-up procedure is followed.
  • Calibrate the instrument for power spectrum, resolution, wave number accuracy, repeatability of wave-number and repeatability of absorbance.
  • Ensure that the Instrument is ready for the calibration and start-up the procedure is followed.
  • Initialized the instrument.
  • Click on the icon Measurement, select “EP5.0 validation”.
  • After selecting “EP 5.0 validation”.
  • Click on “Measurement”.
  • Verify the necessary information or change the details as per requirements.
  • Click on “OK” to start the background.
  • After background validation completion,“ Set polystyrene film into the sample chamber” is displayed in the screen.
  • Set the polystyrene film accordingly and click on “OK”, scanning will start.
  • After completion of the validation the report will be generated and printed automatically.
  • Compare the results for its compliance against limits given in validation format and put remark regarding validation status.
  • Make entry of the usage into the Instrument usage logbook.
  • Calibration report shall come in form of validation format at the time of printing.( Annexure-2)
  • File the validation report duly signed and checked.
  • Affix calibration label on the instrument.
  • Frequency: Monthly ± 3 days
  • Precautions/Maintenance Program of FTIR Spectrometer:
  • Precautions during FTIR Calibration :
  • Use only spectroscopic grade KBr for the sample preparation and store a dry box.
  • Clean and dry mortar and pestle immediately after the usage.
  • Check silica bag of the dry box as well as sample compartment for its effectiveness.
  • When not in use Polystyrene film should be kept in its accompanying protective cover.
  • The exposed film surface should never be touched by fingers or any other objects and Dust should be removed by blowing with clean and dry air.
  • Breakdown Maintenance of FTIR Spectrometer :
  • Put “UNDER MAINTENANCE” label on the instrument when it is under breakdown maintenance / not functioning and intimate to Head quality or designer.
  • Head quality or desginee informs to the Instrument service engineer or Utility dept.
  • Keep instrument UNDER MAINTENANCE between breakdown and service period.
  • After maintenance, calibrate the instrument to check its satisfactory functioning and record the readings. (Note: Calibrate the instrument as per the calibration schedule, this calibration is additional)
  • Retain service report copy attached in the Instrument Maintenance History File.

5.0   ANNEXURES – SOP OF FTIR SPECTROMETER:

Annexure 1: FTIR Calibration Record.

Instrument Name: FTIR
Instrument NoMake/Model
LocationCalibration frequencyMonthly±3 days
Calibrated onNext calibration due on
Sr.NoDateTransmission minimum/absorption maximum (cm-1)Observed wave number (cm-1)Calibrated byChecked byRemarks
3059-3061
2848.5-2850.5
1941.9-1943.9
1600.2-1602.2
1582.0-1584.0
1153.5-1155.5
1027.3-1029.3

Annexure 2: FTIR Validation Record.

Instrument Name: FTIR
Instrument NoMake/Model
LocationCalibration frequencyMonthly±3 days
Calibrated onNext calibration due on
1. Power Spectrum3. Wave Number Accuracy
Wave numberMeasuredStandard Not less thanWave numberMeasuredErrorTolerance
4600.03060.0±1 cm-1
4000.02849.5±1 cm-1
3000.01942.9±1 cm-1
At maximum1601.2±1 cm-1
700.01583.0±1 cm-1
500.01154.5±1 cm-1
403.01028.3±1 cm-1
351.0
2. Resolution4. Repeatability of Wave Number
Wave numberMeasuredStandardWave numberNo.1No.2ErrorTolerance
Between 2870.0-2850.0Greater than 0.332849.5±5 cm-1
1601.2±1 cm-1
Between 1589.0-1583.0Greater than 0.081028.3±1 cm-1
5.Repeatability of absorbance :
Wave numberNo.1No.2ErrorTolerance
2849.5±0.03%
1601.2±0.05%
1028.3±0.03%

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

Calibration : Scheduled/Not scheduled (Reason : _________________________)
Done By: Date :Checked By: Date :Approved By: Date:

Annexure 3: Calibration Status label.

Quality Control

CALIBRATION STATUS

INSTRUMENT:

MAKE: 

MODEL  :

CALIBRATION ON :

CALIBRATION BY :

NEXT CALIBRATION DUE ON :

SOP For Computer System Control Policy

Standard Operating Procedure (SOP) for Physical and Logical Control Policy of Computer system to fulfill the requirement of 21CFR Part 11 under the cGMP activity in the pharmaceutical drug manufacturing unit.

Computer System Control Policy

1.0   Purpose:


To define the process of the physical and logical security policy of the computer system.

2.0   Scope:


This applies to all computer systems used in GxP environments pharmaceutical plant.

3.0   References:

Good Automated Manufacturing practices V5 (GAMP 5)

21 CFR Part 11

4.0   Responsibilities – Computer System Policy:


IT Designee:

Prepare the security plan with the consultation of the functional owner or assignee.

Prepare security administration SOP (Computer System Policy) with the consultation of the functional owner or assignee.

Approve security plan and security admin SOP.

Functional Owner:

To approve the security plan and security admin SOP reviewed by I.T. designee.

5.0   Abbreviations and Definition of Terms – Computer System Policy :

Abbreviations:

GxP: Good (x) Practices, where x: L= Laboratory, M=Manufacturing, C= Clinical, D=Distribution, Q=Quality

GAMP 5: Good Automated Manufacturing Practices v5

IT: Information Technology

OSS: Open Source Software

UPS: Uninterrupted Power Supply

Definition of Terms:

Logical Security – Computer System Policy:

Logical Security consists of software safeguards for an organization’s systems, including user identification and password access, authenticating, access rights, and authority levels.

These measures are to ensure that only authorized users are able to perform actions or access information in a network or a workstation.

It is a subset of computer security/control policy.

Physical Security – Computer System Policy:

Physical security describes security measures that are designed to deny unauthorized access to facilities, equipment, and resources, and to protect personnel and property from damage or harm (such as espionage, theft, or terrorist attacks).

Computer system policy for physical security involves the use of multiple layers of interdependent systems which include CCTV surveillance, security guards, protective barriers, locks, access control protocols, and many other techniques

6.0   Procedure – Computer System Control Policy:

Process Overview – Computer System Policy:

Security management is the process that ensures the confidentiality, integrity, and availability of an organization’s regulated systems, records, and processes.

Implement the measures to ensure that GxP regulated computerized systems and data are adequately and securely protected against willful or accidental loss, damage, or unauthorized change.

Implement the appropriate physical and logical controls.

The extent of the controls shall be based on risk, which includes but not limited to the following factors:

1. Regulatory and business requirements associated with the intended use of the computer system.

2. Impact on product quality, safety, and record integrity

3. The complexity of the computer system

4. Number of users

5. Potential for breach of security

Maturity of technology A security plan and Security Administration SOP are required to support the validation policy of the computer system.

Security Planning – Computer System Policy:

Security planning involves defining and documenting the physical as well as logical control policy for the computer system.

Keep the security planning document current.

Description of data security Model:


The data security model describes the planned/actual security mechanisms used for the system.

The description shall include but not limited to:

1. Type of data handled by the system

2. Type of user

3. Identity and authentication mechanisms used?

4. Authorization mechanisms used?

5. Confidentiality mechanisms used?

6. Integrity mechanisms used?

7. Availability required and how will it ensure?

Physical Controls Policy of Computer System:

Keep in place the Physical controls policy to protect the computer system from willful or accidental loss, damage, or unauthorized change.

These shall include but not limited to:

1. The building or Room Access

2. Fire Protection

3. Mechanism use for controlled access

4. Temperature and humidity control

5. Electrical backup and Uninterrupted Power Supply

Logical Controls Policy of Computer System:

Establish appropriate logical controls to protect information assets and limit access to authorized users across the computer system life cycle.

Items in scope include hardware, software (including source code), documentation, and data.

These controls must include, but not limited to:

Define the Logical/Role-based access levels, Including any special access Privileges.

Different types of groups, third-party access, and supplier access.

This shall also include access privileges and control.

For Example:

Group/Role 

User RoleAccess Privilege                                                    Responsibilities
System AdministratorManageResponsible for adding/deleting users from the system, monitoring system logs
SupervisorRead, Write                                Must be able to read and write analysis datasets for a specified study
AnalystAdd                  Allowed to add new analysis datasets for a specified study

                                                    


Access privileges and control

Access PrivilegeControl Limit
Read or View only (R)Allows read-only access to <specify granularity as described above>
Write or Modify (W)Allows read and write access to<specify granularity as described above>
Add (A)Allows new <objects> to be added to the system
Delete (D)Allows <objects> to be deleted from the system
Manage (M)Allows a system administrator to manage <objects>within the system





Define the elevated/Additional access privileges.

Groups or individuals to be given elevated access privileges, such as system administrators, must be identified.

For Example:

Apart from default access if someone needs additional accesses like analyst has view rights but due to some reasons he also needs review rights.

Mitigate appropriately the conflicts of interest.

Identify the potential conflicts of interest (e.g. the ability for same individual to request, grant, and approve access for themselves) along with the mitigations in place to address those conflicts.

Assign the accounts to an individual and not shared.

Any accounts that are not assigned to an individual person (i.e. accounts established for other computer systems, batch job accounts, and administrative accounts) must be described.

User IDs and passwords or other credentials (e.g. pins, biometrics) should strong.

Describe the requirement for system-enforced user IDs and passwords, including the minimum number of characters and complexity.

Adequately protect the Data to ensure its integrity.

Describe the methods used to protect the confidentiality and/or integrity of data stored/transmitted internally.

Restrict the Re-use of the recent password.

Describe the system control related to password re-use.

Fix the password age.

Describe the frequency of any system enforced password changes.

Configure the session time.

Describe the Time outs with unattended use.

Restrict the access to the system clock to appropriate personnel.

Describe the method used to restrict access to the system clock to appropriate individuals.

Implement the protection against Viruses and other malware. Describe this protection.

Accounts shall be locked out/deactivated, where appropriate based on security-related triggers.

Triggers for any security-related deactivation of accounts must be described, along with any requirements for resetting the account. E.g. Security Breaches, Exceeding a maximum number of access attempts, etc.

Password Storage and transmission – Computer System Policy:

Do not store the password or transmitted using plain text in any system or media.

All passwords should encrypt using an appropriately strong algorithm.

Default Accounts and Passwords – Computer System Policy :

Disable the Default Accounts, if Possible.

If the account cannot be disabled. Change the default passwords immediately upon installation and configuration of the system.

Unique User Identification – Computer System Policy :

Establish the processes to ensure the uniqueness of the ID throughout the retention period of the records maintained by the system.

All users shall have a unique user ID.

A user ID shall never reassign to any user other than the one to whom it’s originally assigned.

Describe/Refer to ensure the uniqueness of the User ID.

Software Security Updates – Computer System Policy :


Whenever a critical security-related patch/service pack available, Evaluate carefully to determine the potential impact on the system.

Based on the risk, Make a decision for implementation of security/Service pack.

Virus Protection – Computer System Policy :

Install and enable the Virus protection software on all computer systems connected to the network.

Any system on which anti-virus is not installed (Exceptions) needs to be documented, approved with rationale justifying why such software is not installed.

For such exceptions, Document a process for ensuring that they are protected from viruses, worms, Trojan horses, and malware.

Use of Public Domain Software – Computer System Policy :

Any use of software in the public domain (e.g. OSS, Shareware, Freeware) must include controls to ensure that introduction of this type of software, not a negative impact.

Approval Requirement – Computer System Policy :

Security planning document must be agreed by IT owner and Functional owner to signify that:

All appropriate persons have reviewed the document.

Any security risks or limitations and risk mitigation procedures associated with the system are understood and accepted.

IT Owner to signify that:

All appropriate persons have reviewed the document.

The plan is accurate and complete.

Security Administration Processes – Computer System Policy :

Security administration processes, including computer system account and password management, must be determined and document to protect and limit access to the system, documentation, and to authorized users.

The processes shall address access review, physical security, Logical security, and electronic signature devices (if applicable).

Access Review – Computer System Policy :

Access to each secured physical location and computer system accounts must be periodically reviewed to ensure that only authorized personnel has access and that access levels are appropriate.

The security administration access review process must outline the steps for conducting and documenting the review, including the resulting actions.

Physical Security – Computer System Policy :

Access to secure physical locations should be controlled.

The security administration processes must describe the process of access management.

This description shall include, but not necessarily limited to:

– Process of requesting access.

– Verification Process that the access requested is appropriate (i.e. Privileges are consistent with job function and responsibilities.)

– Process and responsibility for documenting and approving the creation, change, and cancellation of access authorizations.

– Process for ensuring that the access is removed from those who no longer require it (e.g. When an individual leaves the company or the area or there is the change in Roles).

Describe a process signing out for issuance of keys at the time of use.

This process shall include documenting who issued the key, who received the key, the specific key issued, date, and time the key was issued and date and time key were returned.

Temporary Access – Computer System Policy :


The security administration processes must describe a process for controlling temporary physical access to controlled areas.

For Example- Access needed by supplier etc.

Logical Security – Computer System Policy :

Establishing and modifying access (including Temporary and Special)

Authorization for access to computer systems.

The Security administration process must describe not to establish and modify access accounts, including how to grant special access privileges.

The account access management process shall include, but not necessarily limited to the following:

Define the process for requesting access.

The process shall include the means for verifying that the access requested is appropriate (e.g. privileges are consistent with required functionality).

The process and responsibility for documenting and approving the creation of access authorizations must be defined.

Related: SOP for Electronic Data Management

Access that no longer required, remove them in a timely manner.

The process and responsibility for documentation and timely changes/cancellation of access authorizations must be described.

Complete the required training to receive access prior to granting access.

Define a process for ensuring the completion of required training prior to establishing access.

Generate the passwords with appropriate strength and communicated securely.

The process for initially creating or resetting passwords and communicating to the owner must be defined.

Grant the temporary access for only the period of time that access required.

The time period that the temporary access will be in place, as well as the means to ensure the temporary access is removed when the time period has expired, shall be defined.

Deactivating Access – Computer System Policy :

The security Administration Process must describe how to deactivate access.

Accounts that no longer needed shall deactivate permanently and not deleted.

Un-Authorized access attempts – Computer System Policy :

The security administration processes shall address the monitoring of unsuccessful access attempts and the reporting of unauthorized access attempts when they are detected.

Enable this during the use of electronic signatures.

This unauthorized access monitoring process shall include, but not necessarily limited to the following:

– Method of monitoring.

– Frequency of monitoring.

– Description of the appropriate triggers or events to initiate a review.

– Triggers, methods, and processes for notifying the appropriate individuals of unauthorized access attempts or account deactivation.

– Appropriate measures to address any instances of unauthorized access attempts.

SOP For Batch Release of Finished Product


Standard Operating Procedure (SOP) for approval and release of Finished Product Batch for moving from the manufacturing site to supply chain/distributors or C&F warehouses. 

Procedure for Finished Product Batch Release

1.0   PURPOSE:


To lay down the procedure for approval and release of the finished product batch.

2.0   SCOPE:

This Standard Operating Procedure is applicable for all batches of finished products manufactured at the pharmaceutical drug manufacturing plant.

3.0   RESPONSIBILITY – SOP FOR BATCH RELEASE:

Officer / Executive, QA / Production: responsible for reviewing the batch record for its completeness and accuracy.

Head-Production: For completion and review of BMR/ BPR for adequacy.

Head, QC / QM: For completion and review of analytical / microbiology records for adequacy.

QA (QC Compliance): For the review of Analytical / Microbiology Data (Hard copy / Soft Copy) along with COA.

Related: SOP for Analytical Data Review

Plant Head: Approval of requisition in case of conditional transfer of product.

Head – QA: Responsible for approval and release of the batch. Responsible for Approval of batch for conditional transfer.

DEFINITION (S)

Conditional transfer: The transfer of finished product from the manufacturing location to   Macleod’s Finished Goods Warehouse or Carrying and Forwarding Agents (C&F) prior release of the batch but not for sale and distribution.

4.0   PROCEDURE – SOP FOR BATCH RELEASE


Production shall submit Batch Manufacturing Record and Batch Packaging Record after review and approval by Production Officer/ Executive and final review of Head, Production to QA for onward review by Quality Assurance.

Related: SOP for BMR & BPR Review

IPQA personnel shall ensure that the control samples and other samples like stability /microbiology/ validation samples in a product have been collected as applicable.

Batch records Review:

On receipt of the batch records (both batch manufacturing and batch packing records), Officer/ Executive Quality assurance shall review the documents for any discrepancy or deficiency, which impacts the product quality/ customer safety or licensing compliance or marketing authorization.

The discrepancies shall be categorized as given below:

Critical Discrepancies:

Any discrepancies which have a direct impact on the quality of the product or safety of the consumer and any discrepancy which leads to batch rejection/ failure/ serious non-compliance to approved procedures shall be classified as a critical discrepancy…

These discrepancies shall be brought to the notice of Head-Quality Assurance.

These discrepancies may arise from a failure to carry out GMP / GLP, etc. in some form or another.

All critical discrepancies observed shall be investigated or corrected in consultation and agreement of Head, QA with Head- Production / QC. SOP titled “Corrective and Preventive Actions” shall be referred for detailed CAPA for such cases.

The release of a batch shall be based on the investigation findings/ closure of CAPA/ corrective action and the final decision shall be taken by Head, Quality Assurance.

Major Discrepancies:

These discrepancies may or may not have direct impact on the quality of the product or customer safety or the licensing commitment or marketing authorization.

These can be rectified in consultation of the QA / Production / QC / QM personnel.

All major discrepancies observed shall be investigated or corrected in consultation and agreement of Head, QA with Head- Production / QC. Any major deficiency prior to batch release.

Minor Discrepancies:

These discrepancies do not have direct impact on the quality of the product or customer safety or the licensing commitment or marketing authorization.

These can be rectified in consultation of the QA / Production / QC personnel.

The discrepancies are listed in Annexure-I (Review Record for BMR (Orals)), Annexure-II (Review Record for BPR (Orals)), Annexure-IV (Review Record for BMR (Injections)), Annexure-V (Review Record for BPR (Injections)), Annexure-VII (Review Record for Analytical / Microbiology Data).

During the review of Analytical / Microbiology data, QA (QC Compliance) shall review the Soft Copies along with the Hard Copies of the data.

Prior to batch release, BMR/ BPR/ analytical/ Microbiology data shall be scrutinized by Officer/ Executive QA for appropriateness and adequacy of the rectifications/ corrections made and shall make entries in the ‘Batch Review Checklist (Orals)’ (Annexure-III) and ‘Batch Review Checklist (Injections) (Annexure-VI)’.

Head-QA or his designee shall check the batch review checklist for any kind of critical or major or minor discrepancies.

If found acceptable, Head-QA or his designee shall release the batch for sale or distribution.

Head, QA, while certifying a batch for release, shall ensure that the batch of the concerned product complies with the requirements of the product registration/ registration dossier/ marketing authorization/license and all other requirements regarding the manufacture, quality control and batch release of pharmaceutical products for sale.

The batch release shall be done through Enterprise Resource Planning (ERP) Batch Release Module.

Relevant Batch documents and Finished Product Analytical data (stored AR No. wise) and shall be archived in the document storage room under the custody of QA.

If the conditional transfer of a batch is required, production shall raise the “Conditional Batch Transfer Initiation Slip” (Annexure- IX).

The initiator shall provide the reason for the conditional transfer.

The request shall be approved by HOD and Plant Head. Head, Quality Control shall provide the tentative date for the clearance of the batch.

Based on the reason for conditional transfer and the date provided head QC, conditional transfer evaluated by Head, Quality Assurance.

If approved, the consignment shall be transferred to warehouse/ C&F agents. 

The distribution of batches approved for conditional transfer shall be controlled by means of restricting the preparation of the sale invoice in ERP Module on Batch Hold/ Unhold (Refer to print screen of the module as Annexure-XI and Batch Release Module: Annexure-X).

The process shall be controlled by Head, Quality Assurance

Following the clearance of batch from QC and completion of batch release procedure Head, QA shall “UNHOLD” the batch in the ERP/another Software module (Annexure-X).

Conditional Release of Batch:

Conditional Transfer shall be permitted for batches manufactured and sold by the company for the India region only.

Products sold by another party (in India region) shall not be allowed for conditional transfer.

Conditional Transfer for such products shall be allowed through a planned deviation (refer SOP for “Handling of Deviations”) after approval from the contract giver.

Conditional Transfer is not permitted for products to be sent for export markets.

Transfer (conditional) for such products shall be allowed through a planned deviation (refer SOP for “Handling of Deviations”) after approval from the contract giver or distribution department of Macleods Pharmaceuticals Limited, as and where applicable.

Product recall shall be initiated in case of failure of a batch transferred on a conditional basis as per SOP for Product Recall.

5.0   ABBREVIATION (S) :

ERP: Enterprise Resource Planning

OOS: Out of Specification           (SOP for Handling of OOS)

CAPA: Corrective and Preventive Action

6.0   ANNEXURE (S) – SOP FOR BATCH RELEASE :



Annexure-I:   Review Record for BMR (ORALS)

Product Name: B. No.:                        Batch Size :                   

Market: Checking of Documents

Manufacturing Records

Categories of Discrepancies: (Batch Release)

1. Critical:  (SOP for Batch Release)

Line clearance from QA for any manufacturing stage is completed.

Yes / No/ NA

Any process deviations carried out without formal approval of Head, Quality Assurance.

Yes / No/ NA

Failure to carry out the cleaning of equipment/ area as per the approved procedure.

Yes / No/ NA

Unexplained or unapproved addition/deletion of extra/ required ingredients.

Yes / No/ NA

Calculation of API done as per the requirement of the Batch record

Yes / No/ NA

Any other discrepancy observed

Observation: Critical discrepancy are observed / not observed in BMR

2. Major:  (SOP for Batch Release)

Checking of weight for the active ingredients/ excipients and their addition is recorded.

Yes / No/ NA

Missing entries such as relative humidity, temperature, pH, QC results, LOD/ moisture/water activity, etc.

Yes / No/ NA

All dispensing labels/ in-process weight labels duly checked at each stage of processing by the Production and QA executives.

Yes / No/ NA

Missing signatures of production chemist/operators for critical activities such as dispensing, blending, mixing, drying, lubrication, compression, coating, filling, inspection, etc.

Yes / No/ NA

Yield reconciliation at various stages of processing areas requirements of BMR

Yes / No/ NA

Any other discrepancy observed:

Observation: Major discrepancy are observed / not observed in BMR

3. Minor:  (SOP for Batch Release)

One of the signatures missing, other than those referred under “Critical” category

Yes / No/ NA

Missing date in a sequential flow.

Yes / No/ NA

Overwriting.

Yes / No/ NA

Error due to the transcription of entries.

Yes / No/ NA

Leaving blank spaces instead of striking out the area or writing ‘NIL’ / ‘NA’.

Yes / No/ NA

Missing ancillary documents that are found later.

Yes / No/ NA

The omission of date at the start and end of processing.

Yes / No/ NA

Sample entry missing in the BMR

Yes / No/ NA

Any other discrepancy observed

Observation: Minor discrepancy faults are observed / not observed in BMR

  Name of the reviewer (QA):                                                                          Sign & Date:        

Discrepancy Correction Form

FROM

QUALITY ASSURANCE                                          DATE:

To

PRODUCTION

Subject

Discrepancies observed in the Batch Manufacturing Record

Product

:

Batch No.

:

Observations

Reviewed by QA (Sign & Date)

 

FROM

:  PRODUCTION                                                        DATE:

To

:  QUALITY ASSURANCE

Subject

:  Actions are taken

Head- Production (Sign & Date)

 

Critical / Major/ Minor discrepancies reviewed and found corrected/ not corrected or No Discrepancies observed BMR accepted/ rejected Head-QA (Sign & Date):

 

Annexure-II:   Review Record for BPR (ORALS)


Product Name             :_________________________ Batch No.                     :_________________________ Batch Size                   : _________________________ Market                          : _________________________  Checking of Documents

Batch Packaging Records

Categories of Discrepancies:

1. Critical: (SOP for Batch Release)

Line clearance from QA for any packing stage is completed.

: Yes / No/ NA

Any process deviations carried out without formal approval of Head, Quality Assurance.

: Yes / No/ NA

Failure to carry out the cleaning of equipment/ area as per the approved procedure.

: Yes / No/ NA

Un explained or unapproved addition/deletion of extra/ required packaging material.

: Yes / No/ NA

Specimen of labels, foils, cartons, catch covers, overprinted material, shipper proofs, etc. duly signed by Production and QA taken at the time of each step of the packaging process.

: Yes / No/ NA

Any other discrepancy observed

Observation: Critical discrepancy are observed / not observed in BPR

2. Major: (SOP for Batch Release)

The discrepancy in the printed packaging material reconciliation.

: Yes / No/ NA

Missing entries such as relative humidity, temperature, leak test, pH, volume, etc.

: Yes / No/ NA

All in dispensing labels/ process weight labels duly checked at each stage by the Production and QA executives.

: Yes / No/ NA

 Missing signatures of production chemist/operators for critical activities overprinting/ coding, stereo reconciliation, batch reconciliation, packaging, etc.

: Yes / No/ NA

Yield reconciliation at various stages of packing areas requirements of BPR

: Yes / No/ NA

Any other discrepancy observed

Observation: Major discrepancy are observed / not observed in BPR

3. Minor: (SOP for Batch Release)

One of the signatures missing, other than those referred under “major” category

: Yes / No/ NA

Missing date in a sequential flow.

: Yes / No/ NA

Overwriting.

: Yes / No/ NA

Error due to the transcription of entries.

: Yes / No/ NA

Leaving blank spaces instead of striking out the area or writing ‘NIL’ / ‘NA’.

: Yes / No/ NA

Missing ancillary documents that are found later.

: Yes / No/ NA

The omission of date at start and end of processing.

: Yes / No/ NA

Control sample/ other sample entry missing in the BPR

: Yes / No/ NA

Any other discrepancy observed

Observation: Minor discrepancies are observed / not observed in BPR

 

Annexure-III: Batch Review Checklist (ORALS)

Product Name:                                  Batch No.:                                Market:

Sr. No.

Documents

Available

Not available

1.     

Manufacturing Record

2.     

Packaging Record

3.     

COA

4.     

Completed “discrepancy correction form”

MANUFACTURING RECORD

Sr. No.

Document Details

Satisfactory

Not satisfactory

1.     

Batch details (Batch No., Mfg. date, Expiry date, batch size, etc.)

2.     

Line Clearances

3.     

Bill of material entry details

4.     

Temperature and humidity records

5.     

Stage wise reconciliation

6.     

Deviation records, if any

7.     

Weight cards at each stage of processing

8.     

Cleaning Swab/rinse Reports, if applicable

9.     

Cleaned Labels, if applicable

  PACKAGING RECORD

Sr. No.

Document Details

Satisfactory

Not satisfactory

1.     

Batch details (Batch No., Mfg. date, Expiry date, batch size, etc.)

2.     

Packaging material entry details

3.     

Line clearances

4.     

Dispensing labels

5.     

In-process approval for coding, overprinting, etc.

6.     

Temperature and humidity records

7.     

Stage wise reconciliation

8.     

Reconciliation of packaging material

9.     

Deviation records, if any

10.   

Finished goods transfer note

11.   

Control Samples/ Stability Sample/ Miscellaneous Samples (…………………………..) collected and records

ANALYTICAL / MICROBIOLOGY DOCUMENTS

Sr. No.

Document Details

Satisfactory

Not satisfactory

1.

In-process Data & Reports

2.

COA and Finished product reports

3.

Microbiology report, if any

  Checked By (Sign & Date):

Discrepancy observed/ Not observed in Batch Manufacturing Record/ Batch Packaging Record/ Analytical / Microbiology Documents. The Batch documents have been reviewed for Critical, major and minor discrepancies and found satisfactory/ not satisfactory. Reviewer (QA) (Sign/ Date)

 

Annexure-IV: Review Record for BMR (Injections)

Checking of Documents Manufacturing Records

Categories of Discrepancies:

1. Critical: (SOP for Batch Release)

Line clearance from QA for the manufacturing or packaging stage is complete.

: Yes / No/ NA

Checking of weight and no. of containers of API and its addition is recorded.

: Yes / No/ NA

Any process deviations carried out without formal approval of authorized persons.

: Yes / No/ NA

Missing entries such as humidity, temperature, pressure differentials, QC results, area conditions, etc.

: Yes / No/ NA

Failure to carry out cleaning and sanitization of done as per the approved procedure.

: Yes / No/ NA

Un explained or unapproved addition/deletion of extra/ required ingredients.

: Yes / No/ NA

Addition of drug substances without checking the quantity as per calculation in BMR.

: Yes / No/ NA

Machine logs filled as per progress of operations.

: Yes / No/ NA

Autoclave record including charts and indicator records available.

: Yes / No/ NA

In-process checks like leaking test, weighting variation, etc. as applicable done.

: Yes / No/ NA

Any other discrepancy observed:

Observation: Critical discrepancy are observed / not observed in BMR

2. Major: (SOP for Batch Release)

Missing signatures of production chemist/operators for critical activities such as dispensing, washing of vials, autoclaving procedures, visual inspections, filling, sealing, etc.

: Yes / No/ NA

All in-process weight labels duly checked at each stage of processing by the production and QA executives.

: Yes / No/ NA

Yield reconciliation at various stages of processing

: Yes / No/ NA

Any other discrepancy observed

Observation: Major Discrepancies are observed / not observed in BMR

3. Minor: (SOP for Batch Release)

One of the signatures missing.

: Yes / No/ NA

Missing date in a sequential flow.

: Yes / No/ NA

Overwriting.

: Yes / No/ NA

Error due to the transcription of entries.

: Yes / No/ NA

Leaving blank spaces instead of striking out the area or writing ‘NIL’ / ‘NA’.

: Yes / No/ NA

Missing ancillary documents that are found later.

: Yes / No/ NA

The omission of date of start and end of processing.

: Yes / No/ NA

Sample entry missing.

: Yes / No/ NA

Any other discrepancy observed

Observation: Minor faults are observed / not observed in Batch Record

Annexure-V:  Review Record for BPR (Injections)

Checking of Documents Packaging Records

Categories of Discrepancies:

1. Critical: (SOP for Batch Release)

Line clearance from QA for the packaging stage is complete.

: Yes / No/ NA

Any process deviations carried out without formal approval of Head, QA

: Yes / No/ NA

Failure to carry out cleaning and sanitization of equipment/ area is done as per the approved procedure.

: Yes / No/ NA

Unexplained addition/deletion of extra/ required packaging component.

: Yes / No/ NA

Specimen of labels, cartons/ catch covers, overprinted material, WFI label, etc. duly signed by Production and QA taken at each step of the packaging.

: Yes / No/ NA

Any other discrepancy observed 

Observation: Critical discrepancy are observed / not observed in BPR

2.  Major :(SOP for Batch Release)

All dispensing/ in-process weight labels duly checked at each stage of processing by the production and QA executives.

: Yes / No/ NA

Missing entries such as humidity, temperature, area conditions, etc.

: Yes / No/ NA

The discrepancy in the printed packing material reconciliation

: Yes / No/ NA

Machine logs filled as per progress of operations.

: Yes / No/ NA

Yield reconciliation at various stages of packing as per requirements of the BPR

: Yes / No/ NA

Missing signatures of production chemist/operators for critical activities overprinting/ coding, stereo reconciliation, batch reconciliation, packaging, etc

: Yes / No/ NA

Any other discrepancy observed

Observation: Major discrepancy are observed / not observed in BPR

3. Minor: (SOP for Batch Release)

One of the signatures missing, other than those referred under “major” category

: Yes / No/ NA

Missing date in a sequential flow.

: Yes / No/ NA

Overwriting.

: Yes / No/ NA

Error due to the transcription of entries.

: Yes / No/ NA

Leaving blank spaces instead of striking out the area or writing ‘NIL’ / ‘NA’.

: Yes / No/ NA

Missing ancillary documents that are found later.

: Yes / No/ NA

The omission of date of start and end of processing.

: Yes / No/ NA

Control sample/ other sampling entry missing in the register.

: Yes / No/ NA

Any other discrepancy observed

Observation: Minor discrepancy are observed / not observed in BPR

 

Annexure-VI:  Batch Review Checklist (Injections)

Sr. No.

Documents

Available

Not available

1.     

Manufacturing Record

2.     

Packaging Record

3.     

COA

4.     

Completed “discrepancy correction form”

MANUFACTURING RECORD

Sr. No.

Document Details

Satisfactory

Not satisfactory

1.     

Batch details (Batch No., Mfg. date, Expiry date, batch size, etc.)

2.     

Line Clearances

3.     

Bill of material entry details

4.     

Temperature, differential, humidity records

5.     

Equipment/Instrument print outs

6.     

Pressure differential records

7.     

Stage wise reconciliation

8.     

Deviation records, if any

9.     

Cleaning Swab / Rinse Reports, if applicable

10.   

Cleaned Labels, if applicable

11.   

Microbiology Report attached            Date of filling





Active Air Sampling Reports              Date :

Passive Air Sampling Reports            Date :

Sr. No.

Document Details

Satisfactory

Not satisfactory

Personnel monitoring Reports (aseptic area) Name :

i.              ……………………………. ii.             ……………………………. iii.            ……………………………. iv.           ……………………………. v.            …………………………….

d. Surface Monitoring Report                          Date:

12.   

Airborne non-viable particle count      Date:

PACKAGING RECORD

Sr. No.

Document Details

Satisfactory

Not satisfactory

1.     

Batch details (Batch No., Mfg. date, Expiry date, batch size, etc.)

2.     

Packaging material entry details

3.     

Line clearances

4.     

Dispensing labels

5.     

In-process approval for coding, overprinting, etc.

6.     

Temperature and humidity records

7.     

Stage wise reconciliation

8.     

Reconciliation of packaging material

9.     

Deviation records, if any

10.   

Finished goods transfer note

11.   

Control Samples/ Stability Sample/ Miscellaneous Samples (…………………………..) collected and records

ANALYTICAL / MICROBIOLOGY DOCUMENTS

Sr. No.

Document Details

Satisfactory

Not satisfactory

1.

In-process Data & Reports

2.

COA and Finished Product reports

3.

Microbiology report, if any

4.

Sterility report

 

Annexure-VII: Review Record for Analytical / Microbiology Data

Review of Quality Control and Microbiology Data

Categories of Discrepancies:

1. Critical

Product tested as per Approved Specification of the product.

: Yes / No/ NA

Product tested according to approved Standard test procedures.

: Yes / No/ NA

All results are within specification.

: Yes / No/ NA

All instruments used within defined calibration period

: Yes / No/ NA

COA is available and correct.

: Yes / No/ NA

Analytical / Microbiology data Hard copy is complying with Soft Copy

Any other discrepancy observed

Observation: Critical faults are observed / not observed in analytical reports

2. Major

 

Balance print outs, IR graphs/ UV, chromatographs attached with reports.

: Yes / No/ NA

Overwriting in weight and calculations adequately authorized.

: Yes / No/ NA


Multiple entries without the signature of the doer or checker

: Yes / No/ NA

All instruments identification nos. available on the analytical data sheet.

: Yes / No/ NA

Multiple entries / missing date in a sequential flow.

: Yes / No/ NA

Any other discrepancy observed

Observation: Major discrepancies are observed / not observed in analytical reports

3. Minor

Single signature missing

: Yes / No/ NA

Missing date in a sequential flow.

: Yes / No/ NA

Overwriting or error due to transcription of entries.

: Yes / No/ NA

Leaving blank spaces instead of striking out the area or writing ‘NIL’ / ‘NA’.

: Yes / No/ NA

Missing ancillary documents that are found later.

: Yes / No/ NA

The omission of date at start and end of the analysis.

: Yes / No/ NA

Any other discrepancy observed:

Observation: Minor faults are observed / not observed in analytical reports

 

Annexure- IX:  Conditional Batch Transfer Intimation Slip


Section A: Request Initiation 

From: Production                                                      

   To Quality Assurance Date of Initiation:                                                          Initiated by (Sign/ Date):                                

The following product is required for conditional transfer

Product name:

Batch no.:

Batch size:

Market:

Mfg. Date:

Expiry date:

FGTN No.:

FGTN Date :

Reason:

 Request Approved by  Head of Dept. (initiator Dept) (Sign/ date)                                              Plant Head (Sign/ Date): Comments from QC

  Sign/ Date (Head, Quality Control)

  Section B: Approval of Conditional Transfer  

From: Quality Assurance                                         

To Finished Goods Store The above-mentioned batch is approved/ Not approved for conditional transfer.

Tentative date of release:  Head -Quality Assurance (Sign & Date)

Annexure-X:    Print Screen Batch Release ERP Module



Annexure-XI:   Print Screen Batch Release ERP Module (HOLD/ UNHOLD)

 

   

HVAC System Qualification Protocol (Validation)

Protocol for Qualification and Re-Qualification or Validation of Heating Ventilation and Air Conditioning (HVAC) system for Clean Room.

HVAC System Qualification Protocol (Validation)

Table of Content – HVAC System Qualification Protocol

   S.No.Table of ContentsPage
1.0Protocol Approval
2.0History Sheet
3.0Objective
4.0Scope
5.0Responsibilities
6.0Equipment Description
6.1System Specification
7.0Requalification tests
7.1Air velocity/airflow measurement and calculation of air changes:
7.2Integrity Test Of HEPA Filter
7.3Differential Pressure Measurement
7.4Temperature And Humidity Control Test
7.5Air Flow Pattern Test
7.6Non- Viable Particle Count
7.7Recovery Study
7.8Passive Air Sampling
7.9Active Air Sampling
7.10Re-qualification Criteria
8.0Deficiency and corrective action report
9.0Requalification summary report
10.0Approval of requalification report
11.0List of forms/Annexure
12.0References
13.0Abbreviations

1.0   Approval Sheet of Protocol:

Prepared by:
DepartmentNameDesignationSignatureDate
Quality Assurance

Related: SOP for Qualification of HVAC System

Reviewed by:
DepartmentNameDesignationSignatureDate
Engineering
Concern
Quality Control /Microbiology
Quality Assurance
Approved by:
DepartmentNameDesignationSignatureDate
Head Quality Assurance   

2.0    History Sheet :

Rev. No.Effective dateNature of change/ reason for revisionApproved by QA

3.0   Objective –HVAC System Qualification Protocol :

  • The objective of this protocol is to provide an outline for the qualification of the HVAC system and to establish documentary evidence to demonstrate that the Air Handling Units (AHU’s) are qualified to perform well within the predetermined acceptance criteria of performance as per guideline outlined in this protocol.    

4.0   Scope –HVAC System Qualification Protocol :

  • The scope of this protocol is applicable for the requalification of Air handling unit (AHU) system, 

5.0   Responsibilities –HVAC System Qualification Protocol :

Department Responsibilities
Quality Assurance:Responsible to ensure the overall re-qualification of the HVAC system. Preparation, review, and approval of protocol and report. Handling of deviations. To impart training of the team involved in HVAC requalification. Compile and review of reports.
User department:To provide execution support during requalification. To review the protocol and report.
Quality Control / Microbiology:To review the protocol and report. To perform and provide environmental monitoring reports of the manufacturing area for the microbial load as per schedule to record all the observations.
Engineering:To review the protocol and report. To provide execution support and ensure proper operation of the system.
External agency:Execution of tests as per protocol. Collection of data and preparation of final test certificates.

Execution Team –HVAC System Qualification Protocol :

Execution team shall comprise of the representative from the following functions:

DepartmentNameDesignationSignatureDate
External agency    
Engineering    
 Concern    
Microbiology    
Quality Assurance    

Pre Requisite:

  • Daily cleaning of the area.
  • Availability of area
  • Required materials and instruments are available.
  • Calibration and Preventive Maintenance of equipment.
  • The gowning procedure of plant personnel and external agency shall be done as per the respective SOP for Entry and exit to the Aseptic area.
  • Personnel qualification of the external party shall be done as per the respective SOP “Qualification of personnel for working in the aseptic area”.
  • Personnel hygiene of personnel.
  • Fogging cleaning shall be done prior to performing the requalification activity.
  • External party agreement, respective valid SOP, and traceability certificates of instruments. Please elaborate. These are the bullet points.
  • Training records of the external parties.
  • Calibration of instruments or equipment used for testing like Anemometer, Aerosol photometer, Non-viable particle counter, etc.

6.0   Equipment Description / Specification:

  • System Specification:
  • Details of AHU’s are as follow:-
Sr. No.AHU NO.Area (In m2)Room IDRooms CateredGrade / ISO GradeNo. of HEPANo. of Return RisersCapacity CFMACPH (NLT)Temp. (NMT) (In oC)RH (NMT) (In %)DP(In Pa)
Design Parameters
 

7.0   Requalification Tests:-

Detailed below-mentioned parameters shall be performed in the requalification of AHU’s.

 Sr. No.TESTSRE-QUALIFICATION FREQUENCY
01Air Velocity Measurement and Calculation of Air ChangesOnce every six months. At Every Filter replacement.
02Integrity Testing y HEPA FilterOnce every six months. At Every Filter replacement.
03Pressure Differential TestFor 3 days (Every six month) Continuous monitoring
04Temperature and Relative Humidity TestFor 3 days(Every six month) Continuous monitoring
05Air Flow Pattern TestOnce in a year.
06Cleanliness Class Verification Non Viable Particulate count. At-rest condition and in operation for ISO class 5, 6, 7, and 8Once in every six months for three consecutive days at a defined location. At Every Filter replacement
  07Microbial monitoringOnce in every six months for three consecutive days for ISO classes 5, 6, 7, and 8 at defined location. Continuous monitoring in critical / core areas.
08Recovery TestOnce in a year.
  • Air velocity, the Air volume, and Air Changes Per Hour (ACPH) measurement:
    • The test shall be performed by the external party as per their respective SOP, reviewed, and accepted by the plant.  Refer the Attachment for SOP
  • Reference SOP’s and results should be enclosed with the report.
  • The formula to calculate the ACPH is as follows-
  • Air changes per hour (ACPH) =    Total CFM X 60                                                     
  •                                                                     Room volume
  • Apparatus Required:- Anemometer, Capture hood. A calibrated instrument should be used for measurement.
  • Acceptance criteria:- Air velocity and Air Change Per Hour (ACPH) shall be within the design specification. A variation in air volume shall not be ±20% from the design CFM
  • Result:- Refer enclosed file named FORM-A of respective AHU requalification report. Traceability certificates should be enclosed along with the requalification report.
  • Integrity test Of HEPA Filter:
  • The test shall be performed by the external parties as per their respective SOP, reviewed, and accepted by the plant. Refer the Attachment for SOP Reference SOP’s and results should be enclosed with the report.
  • Apparatus Required:- Aerosol Photometer. A Calibrated instrument should be used for measurement.
  • Acceptance Criteria:-The leakage rate is NMT 0.01%. Ensure zero (0 %) leakage at joints.
  • Result:-
  • Refer enclosed file named FORM-B of respective AHU requalification report.
  • Traceability certificates to be enclosed along with the report.
  • If any leakage is detected in the joints of filter it shall be repaired with the food-grade silicon and leak site shall be rescanned.
  • Upstream concentration should be 100%.
  • Differential Pressure Measurement:-
    • Differential pressure of the room shall be recorded using the calibrated instrument, once in two hours and it shall be continued for 72 hours.
  • Acceptance criteria:- Pressure differentials should meet the requirement as specified in the system specifications.
  • Result:- Record the differential pressure in the FORM-C of the requalification report.
  •  Temperature And Humidity Control Test:-
  • The air handling system shall be in operation for at least 15 minutes prior to performing this activity.
  • In the case of manual recording, record the data for 72 hours at an interval of 2 hours frequency.
  • If data loggers are using, record the date for a period of 72 hrs at 5 minutes interval.
  • All lights in the critical and controlled areas should be ON during the testing.
  • Observe the temperature and relative humidity use calibrated thermo hygrometer.
  • Temperature and RH in the area shall be checked and recorded in dynamic conditions.
  • Acceptance criteria:-
  • Temperature and relative humidity should meet the requirement as specified in the system specifications. Refer point No. 6.1 system specification for predetermined acceptance criteria.   
  • Result:-
  • Measure and record temperature and RH using sling psycho meter, thermo hygrometer, or data logger. Record the observations on FORM-D of the AHU requalification report.
  •     Air Flow Pattern Test:-
  • The test shall be performed by the external party as per their respective SOP, reviewed, and accepted by the plant.
  • The test shall be performed in Rest as well as Dynamic condition.
  • Reference SOP’s and results should be enclosed with the report.
  •  
  • Video recording shall be performed for the airflow pattern test.
  •  
  • Enclose the unedited CD of flow pattern along with the re-qualification report.
  •  
  • Apparatus required:-
  •  
  • Fog generator, water generated fog, and digital video camera.
  •  
  • Acceptance criteria:-
  •  
  • Air should flow from the higher-pressure zone to the lower pressure zone in the room to room.
  •  
  • The air should flow unidirectionally from supply towards the return air filter or grill within the room.
  •  
  • In videography show the exact area name and supply return grill’s ID.
  •  
  • Videography shall be carried out to demonstrate the airflow pattern.
  •  
  • Result recording:-
  •  
  • Observe the airflow pattern as per the procedure mentioned above and record in the FORM-E in the requalification report.
  • Non-Viable Particle Count (NVPC) – HVAC Qualification Protocol:-
  •  
  • The test shall be performed by the external party as per their respective SOP, reviewed, and accepted by the plant.
  •  
  • Reference SOP’s and results should be enclosed with the report.
  •  
  • The test shall be performed at rest and in operation both the condition.
  •  
  • Attach the print out original and one photocopy of original with the qualification report and data shall also be recorded and compiled in the report.
  •  
  • The no. of sample locations shall be calculated according to the below-mentioned table.
  •  
  • Refer annexure No.: ­­­­­­­_________ for location details of area.
  •  
  • Apparatus Required: Particulate Counter. A calibrated instrument should be used for measurement.
  •  
  • Acceptance Criteria:- The average particle concentration at each of the particle measuring locations should fall the below-mentioned class limit.
Class /Grade SizeAT RESTIN OPERATION
Maximum number of permitted particles per cubic meter equal to or above
0.5 mm 5.0 mm0.5 mm5.0 mm
A / 53,50003,5000
B / 63,50003,50,0002,000
  1. Result Recording
  2. Data shall be collected in the datasheet.
  3. Measure and Record the particulate count at various locations as the attached sheet.
  4. The recording shall be done in FORM-F of the re-qualification report
  5. Attach the calibration certificate of Particle Counter.
  6. Recovery Study:
  7. The test shall be performed by the external parties as per their respective SOP.
  8. Reference SOP’s and results should be enclosed with the report.
  9. Attach the print outs, original and photocopy provided by the external agency of particle form of clean room from the initial stage of contaminated area till recovery.
  10. Ensure that the master instrument is calibrated and enclose the calibration certificate along with the re-qualification report.
  11. Recovery study should be performed for Temperature, RH, and Differential pressure.
  12. Record the readings and evaluate them with the design specification.
  13. Recording frequency should be 02-minute time interval by manual entries or using data loggers.
  14. Recovery test for viable counts should be checked on 15 minutes time interval 15 minutes, 30 minutes, 45 minutes, and 1 hour
  15. Apparatus: Particulate Counter, Hygrometer, differential pressure gauge.
  16. Acceptance criteria:  The recovery time should not be more than 15 minutes excluding viable count.
  17. Result Recording: Record the observations in FORM-G of the re-qualification report.
  18. Microbial Monitoring:
  19. To determine the viable particle count test by exposing the settle plate and air sampling in the defined areas.
  20. The procedure shall be followed as per the respective SOP.
  21. PASSIVE AIR SAMPLING:-
  22. Procedure:
  23. Plates shall be exposed on plate exposure stand at the pre-defined locations mentioned in individual format for each stream for not less than 4 hrs.
  24. Keep the plates on the upper platform of plate exposure stand, lift, and slide open the lid of the media plate and keep on the lower platform of the plate exposure stand.
  25.  
  26. Exposed plates shall be recovered after 4 hrs. of exposure and incubate at specified conditions; SCDA plates: 20-25ºC for 72 hrs. Then 30-35ºC for 48 hrs.
  27.  
  28. Plates shall be observed for any microbial growth after 5 days.
  29.  
  30. Frequency:
  31.  
  32. Microbial monitoring shall be done for three consecutive days once every six months.
  33.  
  34. Acceptance criteria:
Class / GradeLimit (CFU/Plate)Alert LimitAction Limit
Grade A / 5<1<1<1
Grade B / 6534
Grade C / 7503040
Grade D / 81006080
  •  
  • Result recording: Record the observations in FORM-H of the re-qualification report.
  • Active Air Sampling:
  • Procedure :
  • Battery of the Air Sampler shall be ensured for fully charged. Sterilized sieve shall be used during every monitoring exercise in case of an aseptic area.
  • Active sites of the sampler shall be sanitized properly with filtered 70% IPA before each sampling
  • The pre-incubated media plate shall be placed after opening the lid. The perforated lid shall be placed above the plate & the sampler shall be switched on with feed parameter of 1000 liters of air
  • 1000 liters of the air shall be withdrawn.
  • The plate shall be removed by taking care; not to touch the surface of the media & re-place the lid of the plate.
  • After each sampling Air Sampler perforated lid shall be moped with 70% IPA
  • The plate shall be recovered after sampling and incubate at specified conditions; SCDA plates: 20-25ºC for 72 hrs. then 30-35ºC for 48 hrs.
  • Frequency: Microbial monitoring shall be done for three consecutive days once every six months.
  • Acceptance criteria:
Area (Grade)Limit (CFU/m3)Alert LimitAction Limit
A<1<1<1
B1068
C1006080
D200120160
  • Result recording: Record the observations in FORM I of the re-qualification report.
  • Re-qualification criteria:
  • The system should be re-validated under the following conditions.
  • If any major changes or modification in the system is done.
  • Any major changes have been done in the respective room or module, which is affecting the environmental condition.
  • If any major maintenance has taken place in the system which can affect the performance of the air handling system.
  • Periodic re-qualification.

8.0   Deviation (If any):  

Any deviation observed during re-qualification shall be recorded and investigated

A)  Description of deficiency and date observed.

B)  The person responsible for corrective action and date assigned.

C)  Corrective actions are taken and the date conducted.

9.0   Re-qualification Summary :

  • The re-qualification report shall consist of a summary document, in narrative form, which shall briefly describe the activity performed along with the observations recorded in relevant exhibits. 
  • This report shall also include the related documents and attachments/annexures which were completed at the time of re-validation activity.

10.0   Approval of re-qualification Report:

  • The report shall be evaluated and proper references/conclusions/recommendations shall be recorded by Quality Assurance.
  • The report shall be evaluated and finally approved by Quality Assurance.

11.0  List Of Form/Annexure:

  • List Of Form:
Form Title
AAir velocity/airflow measurement and calculation of air changes.
BFilter integrity test.
CDifferential pressure measurement.
DTemperature and humidity measurement.
EAirflow pattern test
FNon-viable particle count test.
GRecovery
HViable particle count- Passive air sampling
IViable particle count- Active air sampling
  • List of Annexure:
  • Requalification report shall include the following annexure:-
S. No.Annexures
01Report of Air velocity and ACPH.
02Report of filter integrity.
03Report of Temperature and Relative Humidity.
04Report of Differential pressure.
05Report of Non-viable particle count.
06Environment Monitoring Report for Passive air sampling.
07Environment Monitoring Report for Active air sampling.
08Recovery study test report.
09CD of Airflow pattern test.
10Calibration certificate of Differential pressure gauge.
11Calibration certificate of data loggers.
12Calibration certificate of Anemometer.
13Calibration certificate of the aerosol photometer.
14Calibration certificate of a particle counter.
15Training Records.
16SOP of an external agency.
17Personal Monitoring report.
18Traceability Certificates

12.0   References:

13.0   Abbreviations:

AbbreviationDefinition
AHUAir Handling Unit
SOPStandard Operating Procedure
RCRegulatory Compliance
QAQuality Assurance
IDIdentification
CFMCubic Feet per Minute
PProtocol
m2Meter Square
HEPAHigh-Efficiency Particulate Air
HVACHeating Ventilation and Air Conditioning
ISOInternational Organization for Standardization
MOCMaterial Of Construction
ACPHAir Changes Per Hour
%Percentage
QAQuality Assurance
Temp.Temperature
RHRelative Humidity
WHOWorld Health organization
DPDifferential Pressure
CDCompact Disc
NVPCNon-viable particle count
SCDASoya bean casein digest agar
NLTNot Less than
NMTNot more than
HODHead of Department
Ltd.Limited
NoNumber
Rev.Revision
Sign.Signature
A/LAirlock
H.P.Himachal Pradesh
µMicron
Cu.Cubic

A Complete Guide on HPLC Calibration – Part 3

A Complete Guide on HPLC Calibration – Part 3 (Continued…)

In the HPLC Calibration – A complete guide article series, we have discussed about Monthly & Quarterly Calibration parameters, rest of the parameters are described below, in the end of the article all the relevant links has mentioned, in this article there are total 3 blogs, for complete Calibration process must read out all three blogs

11.  HPLC Calibration : Auto sampler for RI detector by linearity measurement.

  • Calibration requirements:
    • Column : Symmetry C18 , 3.5 µm , (4.6 mm x 7.5 cm) column.
    • Caffeine
    • Balance
    • HPLC grade water or equivalent.
    • HPLC grade Methanol or equivalent.
  • Mobile phase preparation:
    • Water : Methanol (75:25) Mix 750 ml of HPLC grade water and 250 ml of methanol and filter through 0.45 micron nylon filter, degas for 10 min by sonicator.

Note: This Auto sampler calibration parameter shall be performed when HPLC system consist only with RI detector.

  • System requirements:
Testing conditionsApplied conditions
Column: Symmetry C18, 3.5 µm, (4.6 mm x 7.5 cm) or equivalent.Column No.:
Flow rate : 1.0 ml/min
Column oven temperature : 35°C
Flow cell temperature: 35°C
Injection volume : As per table -1
Run time: 5 min (Retention time: About 2.8 min)
Sensitivity for Waters make HPLC
Polarity + (positive)
*Sensitivity :64
*Response: 5
Rinsing solvent: HPLC grade water : methanol (20 :80)
  • Diluent preparation:
    • Mix 80 ml of HPLC grade water and 20 ml of methanol and filter through 0.45 micron nylon filter, degas for 10 min by sonicator.
  • Sample/standard preparation:
  • Preparation of stock solution (Conc. 2000 ppm):
    • Weigh accurately about 200 mg of caffeine in a clean and dried 10 ml volumetric flask, dissolve in and dilute up to the mark with Diluent. Take 1.0 ml of above solution in 10 ml volumetric flask and dilute up to the mark with diluent.
  •     Calibration procedure :
    • Inject the sample preparations in duplicate and record the area of the principal peak in the given table.
    • Plot a linearity curve of Injection volume Vs corresponding mean area, using least square method. Calculate the squared correlation coefficient (r2), and record the observations in given table.
  • Observation table:
Sr. noInjection volume.AreaMean Area
15 ml
210 ml
320 ml
450 ml
5100 ml
Note:

Location shall decide the calibration range for loop capacity and injection volume based on there working range for the calibration of Auto sampler.

Acceptance criteria :

Linearity – squared correlation coefficient (r2) = NLT 0.99

12.  HPLC Calibration : RI Detector by linearity measurement.

  • Calibration requirements:
    • Column : Symmetry C18 , 3.5 µm , (4.6 mm x 7.5 cm) column.
    • Caffeine
    • Balance
    • HPLC grade water or equivalent.
    • HPLC grade Methanol or equivalent.
  • Mobile phase preparation:
    • Water : Methanol (75:25) : Mix 750 ml of HPLC grade water and 250 ml of methanol and filter through 0.45 micron nylon filter, degas for 10 min by sonicator.
Note:

This Auto sampler calibration parameter shall be performed when HPLC system consist only with RI detector.

  • System requirements:
Testing conditionsApplied conditions
Column: Symmetry C18, 3.5 µm, (4.6 mm x 7.5 cm) or equivalent.Column No.:
Flow rate : 1.0 ml/min
Column oven temperature : 35°C
Flow cell temperature: 35°C
Testing conditionsApplied conditions
Injection volume : 20 µl
Run time: 5 min (Retention time: About 2.8 min)
Sensitivity for Waters make HPLC
Polarity + (positive)
*Sensitivity :64
*Response: 5
Rinsing solvent: HPLC grade water : methanol (20 :80)
  • Diluent preparation:
    • Mix 80 ml of HPLC grade water and 20 ml of methanol and filter through 0.45m nylon filter, degas for 10 min.
  • Sample/standard preparation:
    • Preparation of stock solution (Conc. 1000 ppm) : Weigh accurately about 100.0 mg of caffeine in a clean and dried 100 ml volumetric flask, dissolve in and dilute up to the mark with diluent.
  • 100 ppm-Linearity Solution 1: Dilute 1 ml of stock solution to 10 ml with diluent and mix well.
  • 200 ppm-Linearity Solution 2: Dilute 2 ml of stock solution to 10 ml with diluent and mix well.
  • 400 ppm-Linearity Solution 3: Dilute 4 ml of stock solution to 10 ml with diluent and mix well.
  • 500 ppm-Linearity Solution 4: Dilute 5 ml of stock solution to 10 ml with diluent and mix well.
  • 1000 ppm-Linearity Solution 5: Stock solution of 1000 ppm.
  • Calibration procedure :
    • After stabilization of the system and column inject the diluent as blank.
    • Inject the all five linearity preparations in duplicate and record the areas of the principal peak in the observation table
    • Plot a linearity curve of concentrations Vs corresponding mean area, using least square method. Calculate the squared correlation coefficient (r2) and record the observations in given table.
  • Observation table: Refer SOP for HPLC Calibration
  • Acceptance criteria :
    • Linearity – squared correlation coefficient (r2) = NLT 0.99

13.  HPLC Calibration :  fluorescence detector by linearity measurement .

  • Calibration requirements:
    • HPLC grade water or equivalent.
    • Anthracene
    • Column
    • HPLC grade acetonitrile & HPLC grade water or equivalent.
    • Balance
  • Mobile phase preparation:
    • Water: ACN ( 30:70): Mix 300 ml of HPLC grade water and 700 ml of acetonitrile and filter through 0.45 micron filters and degas about 10 min by Sonicator.
  • System requirements:
Testing conditionsApplied conditions
Column : C18 (3.5 mm,4.6 mm x 75 mm) , Symmetry column or equivalent.Column No.:
Flow rate : 1.0 ml/min.
Injection volume : 20 ml
Run time :10 min
Wavelength : Ex=249 nm,Em=402 nm
Polarity :+
Testing conditionsApplied conditions
Attenuation : 64
Response : STD
Gain :1, Unit: mv
Bandwidth :18
Column temperature : 30°C
  •       Sample/standard preparation:
    • Preparation of stock solution (Conc. 100 ppb):
      • Prepare the standard by weighing, accurately about 50 mg of anthracene and transfer into clean dried 50 ml volumetric flask, dissolve in and dilute up to the mark with acetonitrile (stock solution). Take 1.0 ml of the stock solution in 100 ml volumetric flask and dilute up to the mark with acetonitrile. Further Take 5.0 ml the solution in 500 ml volumetric flask and dilute up to the mark with mobile phase.
    • Linearity Solution Preparation
      • 20 ppb-Linearity Solution 1: Dilute 2 ml of stock solution to 10 ml with mobile phase and mix it well.
      • 40 ppb-Linearity Solution 2: Dilute 4 ml of stock solution to 10 ml with mobile phase and mix it well.
      • 60 ppb-Linearity Solution 3: Dilute 6 ml of stock solution to 10 ml with mobile phase and mix it well.
    • 80 ppb-Linearity Solution 4: Dilute 8 ml of stock solution to 10 ml with mobile phase and mix it well.
    • 100 ppb-Linearity Solution 5: Stock solution of 100 ppb .
  • Calibration procedure
    • Ensure that, the column is conditioned before injecting the solution.
    • Set the instrument as per system requirement.
    • Inject the all five sample preparation in duplicate.
    • Record the area due to anthracene peak. Calculate mean area and record the results in the observation table.
    • Plot a linearity curve of concentrations Vs corresponding mean area, using least square method. Calculate the squared correlation coefficient (r2), and record the observations in observation table.
  • Acceptance criteria
    • Linearity – squared correlation coefficient (r2) = NLT 0.99

14.  HPLC Calibration : fluorescence detector by wavelength accuracy measurement .

  • Calibration requirements:
    • HPLC grade water or equivalent.
    • Column: NA
  • Mobile phase preparation: NA
  • System requirements:

Table

Parameters for emission wavelength calibration.Parameter’s Setting for emission wavelength calibration.
TypeSample scan
Grating to scanExcitation scan
Scan wavelength range340 to 360
Emission wavelength397
Gain1
EUFS100000
Pace100
Mark each nmOff

Table 

Parameters for excitation wavelength calibration.Parameter’s Setting for excitation wavelength calibration.
TypeSample scan
Grating to scanEmission scan
Scan wavelength range375 to 430
Excitation wavelength350
Gain1
EUFS100000
Pace100
Mark each nmOff
  • Calibration Procedure:
    • Connect the restricted capillary to Fluorescence detector in place of column.
    • Keep the HPLC grade water in reservoir.
    • Purge the measuring cell of Fluorescence detector with water and allow to run the water through cell about 10 min.
    • Fill the water in measuring cell of Fluorescence detector.
    • Scan the sample (water fill in flow cell) from 340 nm to 360 nm and measure the emission wavelength (for emission wavelength 397 nm ). Record the observation in table.
    • For excitation wavelength calibration scan the sample (filled water in flow cell) from 375 nm to 430 nm and measure the highest peak listed first (for excitation wavelength 350 nm) peak. Record the observation in table.
Calibration ParameterAcceptance CriteriaObserved value
Emission wavelength397 ± 3 nm
Excitation wavelength350 ± 3 nm

Note:   If the excitation wavelength and emission wavelength test fails, then there may be something other than pure water in flow cell or flow cell may be dirty . Therefore rinse the flow cell with water again and repeat the test.

Acceptance criteria :

Emission wavelength 397 ± 3 nm.

Excitation wavelength 350 ± 3 nm.

—————————————————–Completed Part 3 of 3———————————————————

Kindly visit below articles for Complete HPLC Calibration Procedure.

  1. First Part
  2. Second Part
  3. Third Part

In the First article  HPLC Calibration we have covered following parameters.

  • Pressure Test.
  • Drift and Noise
  • Column oven and sample cooler
  • Pump by flow rate accuracy measurement.
  • Pump by gradient flow measurement.

In the Previous article on HPLC Calibration we have covered following parameters.

  • UV-Vis / PDA detector by reference energy check.
  • UV-VIS/PDA detector by linearity measurement.
  • Auto sampler by carry over check.
  • Auto sampler by linearity check.
  • UV-VIS/PDA detector by wavelength accuracy measurement.
  • Auto sampler for RI detector by linearity measurement.

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