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AC Store Room Operation and Maintenance

AC Store Room, Purpose:

AC Store Room, The purpose of this SOP is to define the standard operating and maintenance procedure of AC store room in order to ensure its smooth & trouble-free operation.

AC Store Room, Scope:

This Standard Operating Procedure applies to the AC store rooms of XX Pharmaceuticals Ltd.

Definitions / Abbreviation:

[][]AC: Air Conditioner.

Responsibilities:

[][]The roles and responsibilities are as follows:

Engineering (Validation) Department

[][]Preparing the SOP and revise it when necessary.

Engineering (Maintenance) Department

[][]To provide necessary support for smooth operation & maintenance of AC room.
[][]To ensure that the operators are responsible to carry out the operation and maintenance work and regular checking of the critical components and logbooks.
[][]To develop a list of spare parts based on the manufacturer’s recommendations and to forward the list to the Planning and Procurement department with a request to place order as required.

Operators

[][]To operate the AC room according to the SOP.
[][]To do the maintenance according to the check list and fill up the maintenance log book.

Manager, Engineering

[][]To ensure that the operation and maintenance of air compressor are done properly.
[][]To approve any maintenance/plans related to the compressor.

Manager, Quality Assurance

[][]To ensure overall implementation of this SOP.

Procedure:

Precautions:

[][]All operation and maintenance work must be done safely in accordance with the requirements of the Plant Safety Statement and the safety notices around the plant. Specific attention must be paid to the following:
[][]Use personal protective equipment before doing any kind of maintenance.
[][]Persons switching on the machines shall take adequate precautions to ensure that there is no one doing any kind of maintenance of machine.
[][]Switch off the power before doing maintenance.

[][]Keep the door shut while the AC is running.

System Description:

[][]There are two split type AC in the AC store room to maintain the desired temperature. The capacity of each AC is 2.5 ton. Each cooling unit consists of one indoor unit and one out door unit. The operation of AC is remote controlled. The desired temperature is set using the remote.
[][]Two ACs do not run at a time. While one runs another one stands by.

Operating Procedure:

[][]Starting of AC of AC store room:
[][]Insert the plug of AC into the power socket and switch ON the power.
[][]Press the button on the remote to switch ON the AC.
[][]Set the desired temperature by pressing up and down arrow key.
[][]Select the AUTO or COOL mode by pressing the button.

During Operation:

[][]During operation the temperature of AC store room is controlled automatically in automatic mode.
[][]The AC of AC store room is kept running 24 hrs. When one AC runs another one stands by.

Stopping procedure:

[][]Press button to switch OFF the AC.
[][]Unplug the plug from the power socket.

Maintenance Program:

Monthly Maintenance

[][]Check the current consumption of Compressor.
[][]Clean the filter.
[][]Clean the evaporator coil by blower.
[][]Clean the outdoor unit.
[][]Check and clean the blower.
[][]Check the refrigerant pressure. The pressure should be 50 – 60 psi. If the gas pressure is lower, recharge with new refrigerant.
[][]Check for any icing over the evaporator coil.

Half yearly Maintenance

[][]Overhauling of the whole machine.

Annexure:

Annexure I Equipment Use Log Book
Annexure – II: Maintenance of AC store room

AC Store Room Operation and Maintenance Read More »

Cold Room Operation & Maintenance

Engineering, SOPs

Cold Room, Purpose:

Cold Room, The purpose of this SOP is to define the standard operation and maintenance procedure of Cold room in order to ensure its smooth & trouble-free operation.

Cold Room, Scope:

This Standard Operating Procedure applies to the Cold rooms which are located at General and Cephalosporin Block.

Definitions / Abbreviation:

[][]N/A.

Responsibilities:

[][]The roles and responsibilities are as follows:

Engineering (Validation) Department

[][]Preparing the SOP and revise it when necessary.

Engineering (Maintenance) Department

[][]To provide necessary support for smooth operation & maintenance of cold room.
[][]To ensure that the operators are responsible to carry out the operation and maintenance work and regular checking of the critical components and logbooks.
[][]To develop a list of spare parts based on the manufacturer’s recommendations and to forward the list to the Planning and Procurement department with a request to place order as required.

Operators

[][]To operate the cold room according to the SOP.
[][]To do the maintenance according to the check list and fill up the maintenance log book.

Head of Engineering

[][]To ensure that the operation and maintenance of air compressor are done properly.
[][]To approve any maintenance/plans related to the compressor.

Manager, Quality Assurance

[][]To ensure overall implementation of this SOP.

Procedure:

Precautions:

[][]All operation and maintenance work must be done safely in accordance with the requirements of the Plant Safety Statement and the safety notices around the plant. Specific attention must be paid to the following:
[][]Use personal protective equipment before doing any kind of maintenance.
[][]Persons switching on the machines shall take adequate precautions to ensure that there is no one checking or working on the control panel of the machine.
[][]Keep the door shut during operation.

System Description:

[][]The Cold room of both Cephalosporin and General Block has been manufactured by Frigair.
[][]The raw materials are stored in the room at a temperature of 2 – 8 ⁰C. There is a split type AC of capacity 5 ton to maintain the temperature.
[][]The indoor unit contains evaporator, blower etc.
[][] The outdoor unit contains compressor, condenser, oil separator, filter dryer etc. There is a data logger to monitor the temperature of cold room for 24 hrs.

Operating Procedure:

Starting of Cold room:

[][]Switch ON the main switch. The Yellow and blue indicator will be ON.
[][]Then switch ON the blower by turning the switch to ON position. The blue indicator light will be ON.
[][]After 5 minutes compressor will be ON automatically. The BLUE indicating light will be ON.
[][]To set the required lower temperature, press the SET button. Then press up and down arrow button to set the required temperature.
[][] The temperature band is programmed as 5.5⁰C i.e if the lower temperature is set at 2.5 ⁰C, the higher temperature will be automatically set at 8.0⁰C.

During Operation:

[][]During operation check for any alarm. If the compressor and blower trip then the trip light will be ON and buzzer will give alarm.
[][]If the temperature of cold room becomes very much lower, the CC Heater will be ON and compressor will be OFF.
[][]In that case, the CC heater indicating light will be ON.
[][]In case of icing, the compressor, blower will be OFF and CC heater will be ON. The Defrost indicating light will be ON.
[][]Check the temperature in the display of monitor.
[][]Check the data logger. Change the page once a week because one page is used for a week.

Stopping procedure:

[][]Switch off the compressor by turning the switch to OFF position. The indicating light will be OFF.
[][]Then switch off the blower by turning the switch to OFF position. The indicating light will be OFF.
[][]Switch off the main switch. The Yellow and Blue indicating light will be OFF.

Maintenance Interval/ Maintenance action to be taken

Daily Maintenance

>>Check for any alarm.
>>Check whether all the equipments operate sequentially.

Weekly Maintenance

>>Clean the outdoor unit.
>>Clean the blower.
>>Clean the drain pan of indoor unit.

Monthly Maintenance

>>Check the refrigerant pressure.
>>The pressure should be 50 – 60 psi.
>>If the gas pressure is lower, recharge with new refrigerant.

Annexure:

Annexure I Equipment Use Log Book
Annexure – II: Maintenance log book of Cold room

Cold Room Operation & Maintenance Read More »

Thermal Validation System Operation Procedure

SOPs

Thermal Validation System, Purpose:

Thermal Validation System, The purpose of this SOP is to define the Operation of Thermal Validation system situated at Calibration Lab of XX Pharmaceuticals Ltd.

Thermal Validation System, Scope:

This SOP covers the operating procedure of Thermal Validation System manufactured by Anville Instruments Ltd., UK and located at Calibration Lab of XX Pharmaceuticals Ltd.

Definitions / Abbreviation:

[][]SOP: Standard Operating Procedure.
[][]Pre-calibration: Calibration of thermocouples before performing any qualification.
[][]Post-calibration/Calibration check: Calibration Check of thermocouples after performing any qualification.
[][]USB: Universal Serial Bus.

Responsibilities:

[][]The roles and responsibilities are as follows:

Validation Department

[][]Preparing the SOP and revise it when necessary.

Head of Engineering

[][]To ensure the proper operation of the system following the SOP.

Head Quality Assurance

[][]To approve the SOP.
[][]To ensure overall implementation of this SOP.

Procedure:

Precautions:

[][]Do not touch the thermocouples with bare hands as it might create itching on the skin due to having glass wool insulation.
Do not touch the thermal bath, thermocouples and reference temperature probe with bare hand when working under high temperature.
[][]Ensure that the thermocouples are properly inserted in the thermal bath due to having no erroneous readings while performing pre and post-calibration.
[][]When the thermocouples are inserted or affixed inside the autoclave or Depyrogenation Tunnel, be careful that these do not get stuck with anything. This is because, thermocouples might be torn apart.

System Description:

[][]The thermal validation system is comprised of following components:
[][]Data Logger: This 18 (16 temperature and 02 pressure) channels data logger of model Series 825 is manufactured by Anville Instruments Ltd., UK.
[][]Reference Temperature Probe: This probe, having model no. P750 is manufactured by Dostmann Electronic, Germany, which is used to perform the pre and post-calibration of thermocouples.
[][]Thermal Bath: The thermal bath of model TECAL 425F has been manufactured by TECHNE which is used as a source of temperature while performing the pre-calibration and post-calibration.
[][]Reference Pressure Calibrator: The reference pressure calibrator is used for pre and post-calibration of pressure transducer used in qualification of Autoclave.

[][]Thermocouples and pressure transducer: There are total 16 nos. T type thermocouples which are used to perform any kind of thermal validation.
[][]TQ Software: The software of version 6.1.2 and license number 2265486119 is used to interface the Data logger, Reference Temperature probe, thermocouples as well as pressure transducer. There is a dongle which holds the license for the software.
[][]Laptop: The laptop is used to operate all the components using TQ software.

Operating Procedure:

[][]There are mainly three steps involved in performing any thermal validation using this system such as pre-calibration, qualification as well as post-calibration/calibration check. All of these steps are described below:
[][]Pre-calibration of thermocouples and pressure transducer: All components must be connected to the laptop using USB port. Then, start the TQ soft by double clicking the TQSOFT icon. After that, following screen will be displayed:

[][]Click the Setup and enter electronic ID and password and the specific persons will be logged in the software.

[][]Click the ‘Logger’ option and choose “Calibration”. After that, following screen will be shown:

[][]Enter any suitable Job Ref in the respective box and press OK.

[][]Insert three different temperature values for calibration covering the operating range during validation. For instance, for autoclave validation set the Low point, High point and check point at 900C, 1300C and 121.10C respectively.

Set other parameters as follows:

[][]Stability 0.20C per minute for 3 minutes.
[][]Allowed deviation from reference 0.80C
[][]Reference stability criteria 0.020C for 01 minute.
[][]Report after stability for 1 minute.
[][]Report interval 20 secs.
[][]Report maximum deviation allowed 0.50C
[][]Then press OK and following screen will appear:
[][]Set the temperature of Thermal bath at low point and wait till all the probes are stabled. The “Countdown on Stability Requirements” will be zero for both thermocouples and reference probe when the readings are stable.
[][]Complete the Calibration by pressing “Proceed” and repeating the procedure for High and Check points.

Annexure:
Annexure I Equipment Use Log Book

Thermal Validation System Operation Procedure Read More »

Trimming Machine Operation & Cleaning Procedure

Production, SOPs

Trimming Machine, Purpose :

Trimming Machine, The purpose of this SOP is to describe the operation procedure of Trimming Machine in order to comply with cGMP standard.

Trimming Machine, Scope :

The scope of the procedure is applicable to the Trimming machine at the Dialysis Fluid Production area of XX Pharmaceuticals Limited.

Definitions / Abbreviation:

[][]Trimming machine is a precision machine. It is covered by metal body. This machine consisting of a lever-operated knife and adjustable guides for container surfaces true to required angle.

Operator/Supervisor

[][]Operation and cleaning of the Trimming machine

Executive/ Sr. Executive

[][]Checking and ensuring that the operation and cleaning is performed according to the SOP.
[][]Preparation and timely review of the SOP.

Manager Engineering

[][]Preparation of maintenance schedule and maintenance of the machine.

Manager, Quality Assurance

[][]Ensure that the SOP reflects actual operation, cleaning and maintenance procedure.
[][]Approve the SOP against XX Pharmaceuticals Ltd. Master documents and current regulatory requirements.
[][]Implementation of the SOP.

Procedure :

Precaution(s) :

[][]Ensure that no unauthorized person gains operational access to the machine.
[][]Care must be taken to ensure that the drive units and accessory parts cannot be switched on inadvertently after servicing or maintenance work.

Instruction :

[][]Use Air (1 to 1.5 bar) during operation of Trimming machine.
[][]Keep the machine dry and cool environment.
[][]Keep the air pipe free from any other instrument, naught and coiling during operation and after completion of job.

Machine Assembling :

[][]Setting of in air pipe line of the machine.
[][]Ensure that the air pipe locks are tightly locked and cleaned.

Machine Operation :

[][]Check the machine that there is no abnormal setting of pipe in the machine.
[][]Connect the main electric supply with the socket.
[][]“On” the electric power.
[][]Then “On” the machine control power.
[][]After completion of assembling
[][]Placed the well required position of HPDE Container.
[][]Machine lever-operate HPDE container up the adjustable knife.
[][]Then Knife cutting the container mouth surfaces true to required.

Machine Dismantling :

[][]First “OFF” the air line valve and then remove the pipe from the source and the machine.
[][]“OFF” the machine control power.
[][]Then “OFF” the electric power.
[][]Remove the main power supply form the socket.

Machine cleaning :

Remove dusts from the machine with a dry lint free cloth.
Clean all the machine parts (air pipe and metal parts) with dry lint free cloth.

Annexure:

Annexure I Equipment Use Log Book

Trimming Machine Operation & Cleaning Procedure Read More »

Filter Integrity Test Machine Operation & Cleaning Procedure

Production, SOPs

Filter Integrity Test Machine, Purpose :

Filter Integrity Test Machine, The purpose of this SOP is to describe the operation and sanitization procedure of filter integrity test Machine in order to comply with cGMP standard.

Filter Integrity Test Machine, Scope :

The scope of the procedure is applicable to the filter integrity test machine at the DFU Production area of XX Pharmaceuticals Limited.

Definitions / Abbreviation:

[][]Filter integrity test machine is a high precision machine. It is covered by special sealing profile with metal body, large size (10 inch) of touch PLC windows. This machine is associated with data control unit with networking system. BPT/ DFT/BDT are loaded into the machine by Supplier.

Responsibilities:

[][]The roles and responsibilities are as follows:

Operator/Supervisor

[][]Operation and cleaning of the filter integrity test machine
[][]Maintaining operation and cleaning log book.

Executive, Production

[][]Checking and ensuring that the operation and cleaning is performed according to the SOP.
[][]Checking the log book.
[][]Preparation and timely review of the SOP.

Manager Engineering

[][]Preparation of maintenance schedule and maintenance of the machine.

Head of Quality Assurance

Procedure:

Precaution(s):

Instructions:

[][]Use Nitrogen (7 to 8 bar) during operation of filter integrity testing.
[][]Keep the machine dry and cool environment.
[][]Keep the nitrogen and other silicon pipe free from any other instrument, naught and coiling during operation and after completion of job.

Machine Assembling :

[][]Remove the SS cover of the Upper side of the machine.
[][]Setting of in and out pipe line of the machine.
[][]Ensure that the pipe locks are tightly locked and cleaned.

Machine Operation :

[][]Check the machine that there is no abnormal setting of pipe in the machine.
[][]Connect the main electric supply with the socket.
[][]Open the flap of automatic data controller (which is situated on the Upper side of the machine) & on the UPS switch.
[][]On the control power of automatic data controller.
[][]Login the password.
[][]After completion of assembling,
[][]Fix the recommended test method setting.
[][]Fix the pre-pressure on the nitrogen pressure gauge setting.
[][]Fix the main-nitrogen pressure setting.
[][]Log in by the main user.
[][]Select the “Program Test” on PLC.
[][]Press the “Page Down” on the PLC of machine.
[][]Select the “Test Technique” (Like: BPT, DFT, BDT).
[][]Press the “Page Down” On PLC of machine.
[][]Set the minimum and maximum range of nitrogen pressure (3000mbar to 4000mbar) as per recommendation of filter certificate.
[][]Press the “Page Down” on PLC machine.
[][]Then set the Product Name, Batch No., and Filter Identity No. on the PLC of machine.
[][]Press “Page Down” and press “Save” button.
[][]Then check all the pipe line again and plug on the nitrogen out line to the filter housing.
[][]Placed the well wetted (soaked by purified water) filter (02 micron) at “O” ring of the filter housing.
[][]Cover the filter housing and tightly locked with TC clam.
[][]After obtaining required steps lock the solution “In” line “OFF” with dead valve and TC clam tightly.
[][]Then press the “Start” button to start the filter integrity testing.
[][]During operation if we want to change (increase/decrease) any parameter or batch no. we have to Press “Stop” button and then put the data again.

Machine Dismantling :

[][]First “OFF” the nitrogen line valve and then remove the pipe from the source and the machine.
[][]Remove the nitrogen line from the filter housing.
[][]Press the “Main Menu” on the PLC of the machine.
[][]Remove the main power supply form the socket.

Machine cleaning :

[][]Remove dusts from the PLC of the machine with a dry lint free cloth.
[][]Clean all the machine parts (silicon pipe and metal parts) with dry lint free cloth.

Annexure:

Annexure I Equipment Use Log Book

Filter Integrity Test Machine Operation & Cleaning Procedure Read More »

Laminar Air Flow Machine Operation, Cleaning & Maintenance

Production, SOPs

Laminar Air Flow Machine, Purpose :

Laminar Air Flow Machine, The purpose of this SOP is to describe the operation, calibration and cleaning of Laminar Air Flow used for the Filling Area in the Dialysis Fluid unit (DFU) at XX Pharmaceuticals Ltd.

Laminar Air Flow Machine, Scope :

This procedure describes the application of Laminar Air Flow, for the Filling Area of formulated drug product at the XX Pharmaceuticals Limited.

Definitions / Abbreviation:

[][]SOP: Standard Operating Procedure.
[][]LAF: Laminar Air Flow

Responsibilities:

[][]The roles and responsibility is as follows:

Executive, Production

[][]To ensure that this procedure is followed.
[][]To maintain the records properly as per SOP.

Manager, Production

[][]To ensure that this procedure is kept up to date.
[][]To confirm that the SOP is technically sound and reflects the required working practices.
[][]To arrange training on the SOP to all concerned personnel and to ensure implementation of the SOP after training.
[][]Schedule calibration of the instrument at the defined intervals.

Head of Quality Assurance

[][]Approval of the SOP.

Procedure:

Precaution(s):

[][]Ensure the Safety Precaution.
[][]No Water Contact on the switch Board.

Operation

[][]Ensure that all surface area is clean with PVC curtain.
[][]Check the Electric line ON
[][]Ensure that the Laminar Air Flow is cleaned on the day use.
[][]Plug on the electric line. .
[][]Switch on the power its main.
[][]Power on the Laminar Air Flow Light
[][]Switch ON the LAF operation.
[][]Check Pressure Gauge Meter.
[][]Ensure the Reading of air Differential Pressure 150pa-200pa.
[][]Record the Operational data in the Operation Logbook of Laminar Air Flow as per Annexure – II.
[][]Power off the Laminar Air Flow.
[][]Switch off the power from its main.

Cleaning and maintenance:

[][]Clean the outside case of the Laminar Air Flow using a mild detergent or disinfectant (e.g.75% IPA) if required.
[][]Clean the area around the Laminar Air Flow and wipe immediately. Special care should be exercised when cleaning up IPA 75% (usually).
[][]When required, clean all wires and contacts to avoid corrosion.
[][]Inspect the cables of the LAF for any signs of broken insulation.
[][]Inspect the Light Shade Dry Cleaned Cloth.
[][]Rinse through with Purified Water of PVC Curtain.
[][]Make sure that no water Flow to the HEPA Filter, Light Shade.

Annexure:

Annexure I Equipment Use Log Book
Annexure-II: Logbook for daily Operation of Laminar Air Flow.

Laminar Air Flow Machine Operation, Cleaning & Maintenance Read More »

SUPAC Guideline, Scale Up and Post Approval Changes

Biopharmaceutics, Production, SOPs

SUPAC Guideline Purpose

SUPAC Guideline, This guideline provide recommendation mainly to those sponsors of 1.0 New Drug Applications (NDA’s), 2.0 Abbreviated New Drug Applications (ANDA’S), And 3.0 Abbreviated Antibiotic Applications (AADA’s) who want to change during the post approval period

1.0 The components or composition;

2.0 The site of manufacture of an immediate release oral formulation.

3.0 Scale-up/scale-down of manufacture; and/or(Batch Size Change)

4.0 Manufacturing (Process and Equipment)

This guidance (SUPAC Guideline) has been deprived or resulted from the workshop on scale-up of immediate release drug products directed by AAPS(American Association of Pharmaceutical Scientists) in conjunction with the USPC (United States Pharmacopoeial Convention) and FDA (Drug Administration).

SUPAC Guideline mainly focused on

[][]Levels of change,
[][]Each level of change for recommended chemistry, manufacturing, and controls tests
[][]In vivo bioequivalence tests/or in vitro dissolution tests,
[][]Documentation that should support the changes.

SUPAC Guideline doesn’t comment if compliance/inspection documentation doesn’t affected. Except as specified in this guideline, no post approval changes are affected. These guidelines do not comment on or affect compliance/verification documents issued by the CDER Compliance Office or the FDA Regulatory Authority.

Some useful definitions for SUPAC Guideline

Batch

A certain amount of drug or other ingredient is produced according to a of production order and during the same production cycle, it is intended to maintain consistent character & quality within certain limits.

Dissolution Testing

[][]Case A:
Dissolve Q = 85% in 900 mL (mL) for 15 minutes use of 0.1N Hydrochloride (HCl), USA Pharmacopoeia (USP) <711> Apparatus 1 at 100 rpm or Apparatus 2 at 50 rpm.

[][]Case B:
The multipoint dissolution profile in the application/summary interval is 15, 30, 45, 60, 120 minutes or until the asymptote is reached for the proposed and now accepted formula.

[][]Case C:
Water, 0.1N HCl, And pH 4.5, 6.5 and 7.5 USP buffers (5 separate Profile) Proposed and currently accepted pharmaceutical formulation where Multi-point dissolution profiles performed. Proper sampling should be done in the following locations: Up to 90% of the drug 15, 30, 45, 60 and 120 minutes Resolved from medicines or asymptote Reached. Surfactants can be used with suitable agents Justification.

Validation

Establishing a high level of security with documented evidence Producing a product that consistently meets that requirement for a particular process Given specifications and quality features. Verified the manufacturing process is a process that has been proven to carry out what it claims to be or is represented as. Proof of verification is obtained by If possible, process-based data collection and evaluation from the development phase to the production phase. Verification inevitably involves process certification ( Not only materials, equipment, systems, buildings, personnel) Includes control over the entire process of repeated batches or executions.

1.0 Components and Composition

This section of the guidance focuses on changing pharmaceutical additives. Changes in the amount of active substance are not covered in this guideline. Ingredients or compositional changes that cause the addition of new additives or the removal of additives are defined at Level 3 (defined below), except as described below.

SUPAC Guideline: Levels of change

Level 1 Change

Level 1 changes are unlikely to have detectable impact on product quality and performance.

Level 1 Change, Example

[][]Example 1

Removal or partial removal of an element intended to affect the color or odor of the drug product, Or change printing ink material on another approved material.

Example 2

[][]Changes in excipients, expressed as a percentage of (w/w) Total composition below the next percentage area:
[][]The above mentioned percentage has been demonstrated that the drug substance has been formulated to 100% of label/potency.
[][]Total additive shall not be more than 5%( If a product formulated with Active Ingredient I, Microcrystalline cellulose, lactose, magnesium stearate. Then Microcrystalline cellulose, lactose total quantity shall not be more than 5%.
[][]If any component increases 2.5%, other component shall be decrease at 2.5%; if we increase microcrystalline cellulose 2.5% then Lactose shall be decrease to 2.5% & this is vice versa which is relating to target dosage weight.
[][]Mentioned active and excipients in the formulation shall be multiple targets as it represents the nominal composition for the drug product where any future changes shall be in the dug product based. Based on approved composition allowable changes shall be made.

List of documents required to implement the Level 1 change

Chemistry Documentation
[][]Application / official release requirements and Stability Testing Report.
-Stability test: batch containing long-term stability data Reported in the annual report for one batch

[][]Dissolution Documentation
-Nothing goes beyond the application/official requirements.

[][]n Vivo Bioequivalence Documentation
-None/Nothing else.

[][]Filing Documentation
-Annual report (all information including data on long-term stability).

Level 2 Change

[][]Level 2 changes are changes that can have a significant impact on the quality and performance of the formulation. List of documentation depends on three factors for level 2 documentation. Therapeutic range, solubility and permeability. The range of treatment is defined as narrow or not narrow.

[][]Change in the excipient technical grade (i. e. Avicel PH102 vs. Avicel PH200.)
[][]Excipients changes has been demonstrated as w/w for the respective formulation which is greater than the Level I changes but it shall be equal to or less than the mentioned range demonstrated below.

Table 2: Level 2 Change

[][]The above mentioned percentage has been demonstrated that the drug substance has been formulated to 100% of label/potency.

[][]Total additive shall not be more than 10%( If a product formulated with Active Ingredient I, Microcrystalline cellulose, lactose, magnesium stearate. Then Microcrystalline cellulose, lactose total quantity shall not be more than 10%.

[][]If any component increases 5%, other component shall be decrease at 5%; if we increase microcrystalline cellulose 5% then Lactose shall be decrease to 5% & this is vice versa which is relating to target dosage weight.

List of documents required to implement the Level 2 change

Chemistry Documentation
[][]Application/ official release requirements and batch records.
[][]Stability testing: 1 lot with 3 months accelerated stability data and 1 lot for long-term stability data
[][]Dissolution Documentation
Case A, Case B & Case C required for 1.0 High Permeability, High Solubility Drugs, 2.0 Low Permeability, High Solubility Drugs, 3.0 High Permeability, Low Solubility Drugs.

[][]In Vivo Bioequivalence Documentation
-If the situation is not as described See Case A, Case B, or Case C, the refer to Level 3 Changes.

[][]Filing Documentation
Pre-approval supplement (accelerated stability data with all information) Annual report (long term stability data)

Level 3 Changes

Level 3 changes are those that are likely to have a significant impact on formulation quality and performance. Tests and filing documentation vary depending on the following three factors: Solubility, Permeability and therapeutic range.

Examples: Level 3 Changes

[][]Changes of excipient quantity for a narrow therapeutic drug over the above mentioned Table 1.
[][]Changes of excipient quantity of all drugs beyond those listed in Section Table 2.
[][]Changes of excipient quantity for low solubility, low permeability drug over the above mentioned Table 1.

List of documents required to implement the Level change

Chemistry Documentation

[][]Application/ official release requirements and batch records.
>>Stability test: One batch 3 month accelerated stability data & One batch long-term stability data Reported in one year report.
[][]Dissolution Documentation
>>Case B dissolution profile
[][]In Vivo Bioequivalence Documentation
>>Can be waived with the accepted verified in vivo/in vitro study.
[][]Filing Documentation
>>Pre-approval supplement (accelerated stability data with all information) Annual report (Long term stability data).

2.0 Site Changes

Changes in the site which is owned by company or site of contact manufacturing . No scale up batches, changes in component or composition batch shall not be mentioned/ include here. Selected site shall be possessed cGMP.

Level 1 Changes

Definition of Level
This is really a site to site change where actually no basic changes are made only administrative information are changes all of the control parameter like SOP, Environment, Equipment’s, Facility etc. are same and manpower is fully experienced on the new site in a single facility.

Documentation

[][]Chemistry Documentation
>>No special requirements

[][]Dissolution Documentation
>>No special requirements

[][]In Vivo Bioequivalence Documentation
>>None.

[][]Filing Documentation
>>Only Annual report

Level 2 changes

In the adjacent city blocks where the same equipment’s, environment, SOP’s etc. are used & no change are made except administrative information and the location of the site.
[][]Test Documentation
>>Chemistry Documentation
>>New site Location and updated batch records.
>>Batch long-term stability data reported in annual report.
[][]Dissolution Documentation
>>Official Requirements only
[][]In Vivo Bioequivalence Documentation
>>No issue
[][]Filing Documentation
>>Annual report (long-term stability test data), Changes being effected supplement;

Level 3 changes

[][]Level 3 changes comprise of an adjustment of assembling site to an alternate grounds. An alternate grounds is characterized as one that isn’t on similar unique adjoining site or where the offices are not in contiguous city blocks.

[][]To qualify as Level 3 change, similar Equipment Setup, Environment circumstances SOP’s, and controls should be utilized in the assembling system at the new site, and no changes might be made to the Manufacturing batch records with the exception of regulatory data, area and language interpretation, where required.

Test Documentation

>>Chemistry Documentation
>>New site Location of & updated batch record.
>>Application/compendial release requirements.

Stability:

>>Stability test: One batch 3 month accelerated stability data & One batch long-term stability data Reported in one year report.

Dissolution Documentation

>>Case B: Multi-point dissolution profile ought to be achieved within the utility/compendial medium at 15, 30, 45, 60 and a hundred and twenty mins or till an asymptote is reached. The dissolution profile of the drug product on the contemporary and proposed site must be similar.

In Vivo Bioequivalence Documentation

None.

Filing Documentation

Annual report (long-term stability data).

Level 1 Changes

Change in batch size, as much as and which includes a thing of 10 times the scale of the pilot/biobatch, in which: 1) the system used to produce the take a look at batch is of the identical layout and working concepts; 2) the batch is manufactured in complete compliance with CGMP’s; and 3) the equal well known running processes (SOP’s) and controls, in addition to the same components and production tactics, are used on the take a look at batch and on the overall-scale production batch.

Test Documentation

[][]Chemistry Documentation
>>Similar or as of Application/compendial release requirements.
>>Notification for change & submission of updated batch records in annual report.
>>Long term stability reported in annual report (One batch)
[][]Dissolution Documentation
>>Similar as of application/compendial release requirements.
[][]In Vivo Bioequivalence
>>None.
[][]Filing Documentation
>>long-term stability data (Annual report).

3.0 Batch Size change

Level 1 Changes

Changes in batch length past a aspect of ten instances the scale of the pilot/biobatch, wherein: 1) the machine used to supply the take a look at batch is of the identical design and operating principles; 2) the batch is (are) produced in whole compliance with CGMP’S; and 3) the same SOP’s and controls as well as the identical formulation and manufacturing approaches are used at the take a look at batch and on the full-scale manufacturing batch.

Test Documentation
[][]Chemistry Documentation
>>Similar or as of Application/compendial release requirements.
>>Notification for change & submission of updated batch records in annual report.
>>Long term stability reported in annual report (One batch) & three months accelerated stability data for One batch
[][]Dissolution Documentation
>>Case B testing.
[][]In Vivo Bioequivalence
>>None.
[][]Filing Documentation
>>long-term stability data (Annual report).

4.0 Manufacturing

Manufacturing adjustments/Change might also affect each system used in the production process & the technique itself.

A. Equipment

Level 1 Changes

Definition of Change

This class includes: 1) alternate from non-automated or non-mechanical system to automatic or mechanical equipment to transport elements; and a couple of) trade to opportunity device of the identical layout and working ideas of the equal or of a distinct potential.

Test Documentation

[][]Chemistry Documentation
>>Similar or as of Application/compendial release requirements.
>>Notification for change & submission of updated batch records in annual report.
>>Long term stability reported in annual report (One batch)
[][]Dissolution Documentation
>>Similar as of application/compendial release requirements.
[][]In Vivo Bioequivalence Documentation
>>None.
[][]Filing Documentation
>>Long-term stability data (Annual report).

Level 2 Changes

[][]Definition of Level
>>Equipment Change to a different design & different operating principles.

[][]Test Documentation
[][]Chemistry Documentation
>>Similar or as of Application/compendial release requirements.
>>Notification of change and submission of updated batch records.
>>Long term stability reported in annual report (One batch) with 3 month accelerated stability data.
[][]Dissolution Documentation
>>Case C dissolution profile.
[][]In Vivo Bioequivalence Documentation
>>None.
[][]Filing Documentation
>>long-term stability data (annual report); Prior approval supplement with justification for change;

B. Process

Level 1 Changes

This class includes process adjustments along with adjustments consisting of blending instances and operating speeds within application/validation degrees.
Test Documentation
[][]Chemistry Documentation
Similar as of application/compendial release requirements.
[][]Dissolution Documentation
Similar as of application/compendial release requirements.
[][] In Vivo Bioequivalence Documentation
None.
[][]Filing Documentation
Annual report.

Level 2 Changes

Definition of Level
This category includes process changes including changes such as mixing times and operating speeds outside of application/validation ranges.
Test Documentation
[][]Chemistry Documentation
>>Similar as of Application/compendial release requirements.
>>Change notification & updated batch records to be submit.
>>Stability testing: Long-term stability for One batch.
[][]Dissolution Documentation
>>Case B Study: Dissolution profile.
[][]In Vivo Bioequivalence study
>>None.
[][]Filing Documentation
>>Long-term stability (Annual Report); Changes being affected supplement;

Level 3 Changes

Application/compendial release requirements.
Change Notification & updated batch records submission.
[][]Stability testing:
Significant body of data available:
three months accelerated stability data for One batch reported in supplement; long-term stability data reported in annual report for one batch.
[][]Dissolution Documentation
Case B dissolution profile.
[][]In Vivo Bioequivalence Documentation
May be waived if a suitable in vivo/in vitro correlation has been verified/established.
[][]Filing Documentation
Prior approval supplement with justification; long-term stability data (Annual report).

[][]In Vitro Dissolution
As per USP/NF Section<711>, to be conducted for 12 individual dosages.

In Vivo Bioequivalence Studies

In vivo bioequivalence study has been demonstrated as below. The actual design style may vary as it can be treated as an intended design guide for drug and dosage form.

[][]Objective:
The drug product which manufacture has been changed its rate and extent of absorption shall be compare.
[][]Design:
The study layout must be a single dose, two-treatment, two-period crossover with adequate washout period among the 2 phases of the study.
[][]Selection of Subjects:
The range of subjects enrolled inside the bioequivalence observe need to be decided statistically to account for the intrasubject variability and to satisfy the modern bioequivalence interval.

[][]Procedure:
>>Each subject should obtain the subsequent remedies:
Treatment 1: Product produced with the proposed change.
Treatment 2: Product produced prior to the proposed change.
>>Following an overnight speedy of at least 10 hours, subjects must get hold of both Treatments 1 or 2 above with 240 mL water. Food ought to now not be allowed until four hours after dosing. Water can be allowed after the primary hour. Subjects must be served standardized food beginning at 4 hours at some stage in the look at.
[][]Restrictions:
>>Prior to and at some stage in each observe section, water can be allowed ad libitum except for 1 hour before and after drug administration. The issue ought to be served standardized food and drinks at unique instances.

List of Narrow Therapeutic Range Drugs: SUPAC Guideline

[][]Aminophylline Tablets, ER Tablets
[][]Carbamazepine Tablets, Oral Suspension
[][]Clindamycin Hydrochloride Capsules
[][]Clonidine Hydrochloride Tablets
[][]Clonidine Transdermal Patches
[][]Dyphylline Tablets
[][]Disopyramide Phosphate Capsules, ER Capsules
[][]Ethinyl Estradiol/Progestin Oral Contraceptive Tablets
[][]Guanethidine Sulfate Tablets
[][]Isoetharine Mesylate Inhalation Aerosol
[][]Isoproterenol Sulfate Tablets
[][]Lithium Carbonate Capsules, Tablets, ER Tablets
[][]Metaproterenol Sulfate Tablets
[][]Minoxidil Tablets
[][]Oxtriphylline Tablets, DR Tablets, ER Tablets
[][]Phenytoin, Sodium Capsules (Prompt or Extended), Oral Suspension
[][]Prazosin Hydrochloride Capsules
[][]Primidone Tablets, Oral Suspension
[][]Procainamide Hydrochloride, Capsules, Tablets, ER Tablets
[][]Quinidine Sulfate Capsules, Tablets, ER Tablets
[][]Quinidine Gluconate Tablets, ER Tablets
[][]Theophylline Capsules, ER Capsules, Tablets, ER Tablets
[][]Valproic Acid Capsules, Syrup
[][]Divalproex, Sodium DR Capsules, DR Tablets
[][]Warfarin, Sodium Tablets

SUPAC Guideline, here by apply for the above mentioned & SUPAC Guideline shall be followed for the same.

SUPAC Guideline, Scale Up and Post Approval Changes Read More »

Container Washing and Handling System of Dialysis Fluid Unit

Production, SOPs

Purpose :

The purpose of this SOP is to describe the procedure of container Washing and Handling system of Dialysis Fluid Unit at XX Pharmaceuticals Ltd.

Scope :

This SOP is applicable for the Production and Primary Packaging of Dialysis Fluid Unit at XX Pharmaceuticals Limited.

Definition / Abbreviation :

[][]HDPE: High Density Polyethylene

Responsibilities :

[][]The Roles and Responsibilities are as follows :

Operator

[][]To ensure that this procedure is followed.

Executive, Production

[][]To monitor and check the laid down procedure.

Manager, Production

[][]To implement this correctly.

Head of Quality Assurance

[][]To approve the SOP.

Precautions :

[][]Ensure the Proper Safety Instruction Are Followed.
[][]Ensure that the Supply the Water (Potable, Hot & Purified).

Empty Container Washing Procedure :

[][]Send the ERP Requisition to the ware house, then they Provide QC passed Containers from General Warehouse.
[][]Places the containers (50pcs) at the Plastic Pallet and transfer to the container washing room.
[][]Ensure that all utility lines like compressed air, electric line, potable water (hot & normal) and purified water are in attendance.
[][]Put off the stopper plug.
[][]Placed the container perpendicularly (3Pcs at a time) at the washing machine then flow the potable water for 30 sec (inner & outer elevation).
[][]Supply the hot water (50 to 60o) into the containers for 30 sec (inner & outer elevation).
[][]Concluding Supply of Purified water into the containers for 30 sec (inner & outer elevation).
[][]After that washed container staging at the cage trolley, then transfer to the filling room.
[][]Ensure that area cleaning activity is recorded in Cleaning Log book
[][]Check and ensure that Containers Cleaning activity is recorded in respective ‘Equipment log book’
[][]Ensure that all Containers are labeled as CLEANED.

Annexure

Annexure-I: HDPE Container (10 L) Washing Record.

Container Washing and Handling System of Dialysis Fluid Unit Read More »

Product Changeover of Dialysis Fluid Unit

Production, SOPs

Product Changeover, Purpose :

Product Changeover, To lay down the Procedure of Product Change Over to the Production and Packaging Area during Product to Product changeover and Batch to Batch Changeover for Dialysis Fluid Unit(DFU)

(DFU).

Product Changeover, Scope :

This SOP is applicable for the Concern Personnel of Production and Packaging of DFU Unit at XX Pharmaceuticals Limited.

Definition / Abbreviation :

N/A

Responsibilities :

[][]The roles and responsibilities are as follows :

Operator

[][]To follow the laid down procedure.

Laundry Man

[][]To provide cleaned garments.

Executive, Production

[][]To monitor and check the laid down procedure.

Manager, Production

[][]To implement this correctly.

Head of Quality Assurance

[][]To approve the SOP.

Precautions :

[][]Ensure the proper safety instructions are followed.
[][]Ensure that no previous product is available in the area.

Product to Product Changeover :

[][]Ensure that, all utility lines like compressed air line, steam line, electrical fixtures, air inlet ducts, return air risers, potable water and purified water lines are cleaned and no visible traces of product are present.
[][]Ensure that Outer surface of machine, table, door, floor, walls and ceiling are cleaned.
[][]Ensure that Pre-mixing, Mixing, Storage, Filling Vessel to be clean with plenty of water (First time Potable Water Finally Purified water).
[][]Ensure that area cleaning activity is recorded in ‘Room Cleaning Log Book’
[][]Ensure that all equipments in the area are cleaned according to their respective SOPs and no traces of previous product are visible within the equipment.
[][]Check and ensure that equipment cleaning activity is recorded in respective ‘Equipment Log Book’
[][]Ensure that Span between equipment usage and cleaning is not more than seventy two hours.
[][]Ensure that Balances in the production area are cleaned and accuracy check is done before use.
[][]Ensure that production utensils like scoops, spatula, sieve stand, punch trolley, pallets, BMR table and tool boxes are cleaned as per procedure.
[][]Ensure that all equipments are labeled as ‘CLEANED’.
[][]Ensure that fresh set of gowns are issued to concerned operators.
[][]Ensure that proper environmental condition is maintained in the area and the records of the same are maintained in the specified formats.
[][]Ensure the correctness of Batch Manufacturing Record / Batch Packaging Record.

Batch to Batch Changeover :

[][]Ensure that previous batch material is removed from the production area.
[][]Ensure that all the equipment and their spares are cleaned according to their respective SOPs.
[][]Ensure that equipment cleaning activity is recorded in respective ‘Equipment Log Book’.

Annexure:

Annexure I Equipment Use Log Book

Product Changeover of Dialysis Fluid Unit Read More »

Material and Man Flow of Dialysis Fluid Production Area

Production, SOPs

Material and Man Flow, Purpose :

Material and Man Flow, To lay down the procedure of Material and Man Flow to the Production and Packaging Area for Dialysis Fluid .

Material and Man Flow, Scope :

This SOP is applicable for the Concern Personnel of Production and Packaging of Dialysis Fluid Unit(DFU) of the XX Pharmaceuticals Limited.

Definition / Abbreviation:

[][]BOM = Bill of Material
[][]QAD = Quality Assurance Department
[][]DFU= Dialysis Fluid Unit

Responsibilities:

[][]The roles and responsibilities are as follows:

Operator

[][]To follow the laid down procedure.

Laundry Man

[][]To provide cleaned garments.

Executive, Production

[][]To monitor and check the laid down procedure.

Manager, Production

[][]To implement this correctly.

Head of Quality Assurance

[][]To approve the SOP.

Annexure:

N/A

Precautions :

[][]Do not step on the floor with bare foot.
[][]Rub hands with Disinfectant Solution before entering into the Production Area.
[][]Jewelry, Wrist Watch, Finger Ring & Ear Ring is not allowed to Production Area.
[][]No food is allowed to Production Area.
[][]Shoe>Cover >Cap >Apron >Mask.
[][]After wearing company provided dress, stand in front of the mirror and confirm that, clothing is covering full arms and cap is covering all hairs according to the sample photos displayed.
[][]Proceed towards the DFU Unit.

MAN FLOW ( Starting from D Change ) :

[][]Before entering into the primary change room, Personnel should complete secondary change as per procedure.
[][]Enter into the Primary Change Room.
[][]Rub hands with Disinfectant Solution (70% Iso-Propyl Alcohol).
[][]Open the door of Corridor, turn left side and proceed to the Production as well as Container Washing Area of DFU.

MATERIALS FLOW ( Starting from Ware-House, Solid Block ) :

[][]Collect Materials from Cargo Lobby (less than 25 Kg) for dispensing at the Dispensing Booth (GPR009) of General Block.
[][]Ensure that, around 25 Kgs. in a single Bag / Pack transfers directly to the DF Unit Air-Lock.
[][]Ensure that, all the materials dispensed as per BOM are to be needed to transfer to the Manufacturing Area of the DFU.
[][]Liquid Material (Glacial Acidic Acid) is to be collected from the Flammable Storage Area.
[][]Filled Containers (10L) are to be transferred to the Secondary Packaging Area of General Block by using transfer trolley.
[][]The received Filled Containers (10L) are taken to the Packaging Conveyor for proper Wiping, Labeling and Packaging.
[][]Packed Products as a whole batch are to be taken to the Quarantine Area on Pallets for QA Release.
[][]After getting QA Release Slip, the Finished Goods (as a whole batch) are to be transferred to the Central Ware-House through the Warehouse of Solid Block.

Material and Man Flow of Dialysis Fluid Production Area Read More »