Product Development

Container blender, Purpose:

Container blender, The purpose of this SOP is to define the operation and cleaning procedure of container blender.

Container blender, Scope:

This SOP is applicable for operation and cleaning procedure of container blender in product development of XX Pharmaceuticals Limited.

Definition / Abbreviation:

[][]None

Responsibilities:

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

Operator/Supervisor Product Development

[][]Operation and cleaning of the container blender
[][]Maintaining operation and cleaning log book

Executive/ Senior Executive, Product Development

[][]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, Quality Assurance

[][]Ensure that the SOP reflects actual operation and cleaning procedure.
[][]Approve the SOP against XX Pharmaceuticals Limited master documents and current regulatory requirements.
[][]Implementation of the SOP.

Procedure:

Machine Assembling

[][]Before operation assemble the machine accessories that are necessary for operation.
[][]Place the container at the holding arm of the blender. Then, secure it with the holding arm.
[][]Securely close and lock of inlet ports and outlet port in place.
[][]Test whether container rotates smoothly without any abnormal noise after activation. Check that rotation direction is correct according to the arrow sign.

Machine Operation

[][]Connect the power cable to the socket for power supply.
[][]Turn the machine ON/OFF switch (main switch at the right down corner of the machine) to ON. Control panel light will illuminate and the machine is ON.
[][]Unclamp and open the inlet port cover.
[][]Load raw materials into the chamber. Total material load should not exceed the maximum working volume and the minimum working volume.
[][]Securely close the mixing chamber cover and clamp.
[][]Release the EMERGENCY SWITCH, MIXER STOP SWITCH will light up, indicating that the electricity is supplied to the control system and the machine is ready to perform the process.
[][]Set Timer process according to the timer required for the mixing process.
[][]Activate the mixer.
[][]Observe carefully, there is no abnormal noise generated by the blender.
[][]Ensure that there is no leakage in inlet valve and outlet valve during the mixing.
[][]Check that the timer counts down the time. Once the set time is reaches, the mixer will stop operation accordingly.
[][]Place a collection bin under the outlet port. Plastic or clothing bag might be wrap between outlet port and other collection bin to prevent product dispersion into the room.
[][]Open the outlet valve to discharge the product into a collection bin. Open the inlet port to check whether there is any remaining product inside the container.
[][]Shut the outlet port after all product removed.
[][]In case of manual operation set TIMER OFF/ON selector to OFF. And activate the blender.
[][]Push EMERGENCY SWITCH button to discontinue the electrical supply to the system.
[][]Clean the machine as per above cleaning procedure.
[][]Turn the machine ON/OFF button to OFF. The machine light will be OFF.

Machine Cleaning

[][]If the machine doesn’t used within 15 days after cleaning, then the machine should be cleaned on the 15th day.
[][]Place the drain tank under the discharge port.
[][]Ensure the discharge port is securely closed.
[][]Check again there is no material inside the container.
[][]Fill the container until half of the mixing chamber with normal water.
[][]Securely close the inlet port.
[][]Activate the machine to rotate at low speed first before accelerate the speed.
[][]After a while, check inside the chamber whether machine residue is fully dissolved and suspended or not. If not, start the blender rotation again.
[][]Repeat the procedure until it is done.
[][]Now discharge the water with dissolved materials.
[][]Now hot water is applied inside the chamber to remove materials fixed hardly on the chamber surface.
[][]Wash the machine with wet marking cloth.
[][]Re-wash the machine with purified water as required. Finally rinse with purified water.
[][]Clean inlet ports, discharge port, mixing chamber and external surface with damp cloths.
[][]Wipe the water droplets with cloth, and dry the machine with compressed air.
[][]Fix ‘CLEANED’ label on the machine.
[][]Keep the record of machine operation and cleaning according to the Annexure – I of this SOP.

Annexure:

Annexure – I: Operation and cleaning log sheet of Container Blender

Wet and Dry Granulator , Purpose:

Wet and Dry Granulator , The purpose of this SOP is to define the operation and cleaning procedure of Wet and Dry granulator.

Wet and Dry Granulator , Scope:

This SOP is applicable for operation and cleaning procedure of Wet and Dry granulator in product development of  XX Pharmaceuticals Limited.

Definition / Abbreviation:

[][]None

Responsibilities:

[][]The roles and responsibility are as follows

Operator/Supervisor Product Development

[][]Operation and cleaning of the Wet and Dry granulator
[][]Maintaining operation and cleaning log book

Executive/ Senior Executive, Product Development

[][]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, Quality Assurance

[][]Ensure that the SOP reflects actual operation and cleaning procedure.
[][]Approve the SOP against XX Pharmaceuticals Limited master documents and current regulatory requirements.
[][]Implementation of the SOP.

Procedure:

[][]Machine Assembling
[][]Before operation assemble the machine accessories that are necessary for operation.
[][]Place the appropriate granulator head that is Wet head or Dry head.
[][]Place the appropriate sieve in the head.
[][]Securely lock the main head body to the driving shaft.
[][]Clamp down or tighten each component in place and insert the desired sieve with correct mesh size.
[][]Tightened the blade, hopper and body.
[][]Switch on the machine check that the granulation head rotates smoothly and there is no abnormal noise heard.

Machine Operation

[][]Switch on Main Breaker to supply main power to the system.
[][]Place a product container underneath the granulation head.
[][]Wrap the discharge chute with lint-free cloth which allows air to flow through. This will make the product flow penetrating into the product container without dispersing in the air.
[][]Press Start (Green push button) to activate the granulation head. The head will start rotating.
[][]Gradually load material into the granulation head from the top side.
[][]Observe that material loading rate should synchronize with granules output rate, that granule present through the discharge chute into the product collection bin.
[][]Loading product faster in the granulation head will results finer particles than the desired.
[][]The granulation rate varies depending on sieve size used and product characteristics.
[][]After charging all material into the machine and all are discharged, press Stop (Red push button) to discontinue the granulation process. The main shaft will stop rotating.

Machine Cleaning

[][]If the machine doesn’t used within 15 days after cleaning, then the machine should be cleaned on the 15th day.
[][]For safety purpose, cut off the main breaker that supply electricity to the machine before commencing the cleaning operation.
[][]Removing Granulation head from the main machine and bring it to the cleaning area.
[][]Disassemble each component for cleaning separately.
[][]Clean each component with fresh running potable water, hot water finally Purified water. Spatula (scraper) and cleaning agent might be required to remove sticky material attached on the surface.
[][]Do not submerge Granulation head into water bath. Water will penetrate into the bearing housing and cause rust, bearing service life of bearing will be lessened and machine will not operate smoothly.
[][]Spatula (scraper) or cleaning brush used with the machine must be made of only of plastic, rubber or materials that do not generate scratches or damage to the mirror-polished surface.
[][]Sieve should be thoroughly clean and ensure that no material stuck in the perforated holes and wire net.
[][]Repeat cleaning if necessary until the granulation head is completely cleaned.
[][]Use soaked cloth to clean the main granulation machine. Care must be taken that no water enters the control box and motor housing.
[][]Wipe each component with clean and dry cloth to remove the remaining water. Start wiping the critical area that is product contact parts first, following by non-product contact area.
[][]Apply compressed air or heated air to expedite the drying rate. Otherwise, leave each component to dry up in the clean operating room.
[][]Re-wash the machine with purified water as required. Finally rinse with purified water.
[][]Fix ‘CLEANED’ label on the machine.
[][]Keep the record of machine operation and cleaning according to the Annexure – I of this SOP.

Annexure:

Annexure – I: Operation and cleaning log sheet of Wet and Dry granulator

Stability Study, Purpose:

Stability Study, The purpose of this SOP is to define the procedures to be followed in the management of stability studies throughout the stability study lifecycle from study initiation to study completion.

Stability Study, Scope:

[][]This procedure is applicable for
[][]Development of New Product.
[][]Reformulation of existing products.
[][]Routine study of commercial batches.
[][]Change of specification of raw and primary packing material.
[][]Process change.
[][]Change of batch size.
[][]Rework reprocess and investigational batches.
of all pharmaceutical products  at XX Pharmaceuticals limited.

Definitions / Abbreviation:

Stability Studies:

[][]Long-term and accelerated (and intermediate) studies undertaken on Development and/or production batches according to a prescribed stability protocol to establish the shelf-life of an finished pharmaceuticals product.

Accelerated Testing:

[][]Studies designed to increase the rate of chemical degradation or physical change of an active substance or pharmaceutical product by using exaggerated storage conditions as part of the formal stability studies.

Long Term Testing:

[][]Stability studies under the recommended storage condition for the re-test period or shelf life proposed (or approved) for labeling.

Development-scale Batch:

[][]A batch of an FPP manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a Development scale is generally, at a minimum, one-tenth that of a full production scale or 100 000 tablets or capsules, whichever is the larger; unless otherwise adequately justified.

Specification:

[][]A list of tests, references to analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges or other criteria for the tests described. It establishes the set of criteria to which an FPP should conform to be considered acceptable for its intended use.

Release Specification:

[][]The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of an FPP at the time of its release.

Shelf-life Specification:

[][]The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that an FPP should meet throughout its shelf life.

Shelf-life:

[][]The period of time during which an FPP, if stored correctly, is expected to comply with the specification as determined by stability studies on a number of batches of the API or FPP. The shelf-life is used to establish the expiry date of each batch.

Expiry Date:

[][]The date given on the individual container (usually on the label) of a product up to and including which the API and FPP are expected to remain within specifications, if stored correctly. It is established for each batch by adding the shelf-life to the date of manufacture.

Bracketing:

[][]The design of a stability schedule such that only samples at the extremes of certain design factors, e.g. strength and package size, are tested at all time points as in a full design. The design assumes that the stability of any intermediate levels is represented by the stability of the extremes tested.

Matrixing:

[][]The design of a stability schedule such that a selected subset of the total number of possible samples for all factor combinations is tested at a specified time point. At a subsequent time point, another subset of samples for all factor combinations is tested. The design assumes that the stability of each subset of samples tested represents the stability of all samples at a given time point.

Container Closure System:

[][]The sum of packaging components that together contains and protects the dosage form. This includes primary packaging components and secondary packaging components, if intended to provide additional protection to the pharmaceutical product.

Responsibilities:

The roles and responsibility are as follows:

Senior Executive, Product Development

[][]Reporting and generation of stability protocol and stability report for new products
[][]Identify the need for stability study
[][]Sample storage and withdrawal.
[][]Compile and review the trend of analytical test results.
[][]Time to time revision of the SOP.
[][]Prepare Monthly Stability Schedule of new products.

Senior Executive, Quality Control

[][]Prepare, generate & Review Master Stability Schedule
[][]Timely analysis of stability sample and analytical report generation.
[][]Development and validation of finished products analytical method.

Senior Executive, Quality Assurance

[][]Sampling of the commercial batches for real time stability study.
[][]Schedule, reporting and generation of stability protocol and stability report for commercial products.

Head of Quality Assurance

[][]To approve the stability protocol and stability report.
[][]To approve the shelf life and packing instruction of the products to be marketed.

Procedure

Precaution:

All concerned persons have to follow the SOP. Keep The Stability Samples according to instruction and maintain Stability Schedule of individual Product.

Stability study of Development batches

Stability study protocol of Development batches

[][]Executive product development will generate he stability study protocol after completion of the trial batch of the products according to the Annexure I of this SOP
[][]Individual protocol will be used for individual products. In case of any change in the protocol, due to any stability problem, new version of the protocol will be issued, defining change history at the revision details section of the protocol.
[][]Each protocol will have a unique identification number of 20 digits. As following
GPD/SSP/001/XX/01
Where,
GPD stands for General Product Development. In case of Cephalosporin unit, the code will be CPD which indicates cephalosporin Product Development.
SSP stands for Stability Study Protocol.
001 in the numerical serial number, first protocol of the year will bear number 001, second one 002 and continue till the end of the year.
XX stands for the year 20xx, in case of the following years
01 stands for the version number. Second version will bear the number 02 and so on.
/ stands for separator in all case.

[][]Executive, Product Development will maintain a log Book according to Annexure II of the SOP to record the Protocol Number. Specific protocol shall be used for specific products and same number shall never be issued for two products.
[][]Senior executive, product development will check the protocol and Manager, Quality Assurance will approve the protocol.

Determining Batch Size

[][]Executive, Product Development will determine the batch size of the products. Batch size of the Development batches will be one tenth of the commercial batch. Commercial batch size will be determined from the yearly sales forecast. Depending on the sales volume, the commercial batch size will be either 50 kg or 30 kg. Therefore, Development batch size will be either 5.0 kg or 3.0 kg respectively.

Design of stability Study

For new product stability study, one trial batch and two Development batches will be stored for stability study, also optimization and validation batches will be stored for stability testing.

[][]1 Trial batch
(batch size: Below 1 kg or decided batch size)

[][]2 Development batches
(batch size: 1/10th of Commercial batches)

[][]Commercial Batches (Ongoing)

Reformulation manufacturing / Process change / Specification Change (API / Excipient) , one trial batch and two Development batch will be stored for stability study, also optimization and validation batches will be stored for stability testing.

[][]1 Trial batch
(batch size: Below 1 kg or decided batch size)

[][]1 Development batch
(batch size: 1/10th of Commercial batches)

[][]Commercial Batches (Ongoing)
(Accelerated & Long Term)

New Source Development (Primary Packaging Material) / Equipment Change

[][]Trial run with new packing material / equipment

[][]Accelerated Stability study on Commercial batches

Number of sample to be stored

Executive, Product Development will store required quantity of sample according to the dosage form .In case of matrixing number of sample to be stored will be generated from the protocol.

Storage condition

[][]Storage condition of stability sample should be as per WHO assigned climatic Zone which is mentioned below:

Climatic Zone	Accelerated	Long term
Zone I	40°C ± 2°C/75% R.H. ± 5% R.H.	21°C ± 2°C/45% R.H. ± 5% R.H.
Zone II	40°C ± 2°C/75% R.H. ± 5% R.H.	25°C ± 2°C/60% R.H. ± 5% R.H.
Zone III	40°C ± 2°C/75% R.H. ± 5% R.H.	30°C ± 2°C/35% R.H. ± 5% R.H.
Zone IVA	40°C ± 2°C/75% R.H. ± 5% R.H.	30°C ± 2°C/65% R.H. ± 5% R.H.
Zone IVB	40°C ± 2°C/75% R.H. ± 5% R.H.	30°C ± 2°C/75% R.H. ±5% R.H.

[][]In case of storage in refrigerator (2°C – 8°C) indicated products storage condition and minimum testing time should be maintained as

Study	Storage condition	Minimum time period
Long term	50 C ± 30 C	12 months
Accelerated	250C ± 20C / 60 ± 5% RH	06 months

[][]In case of storage in freezer (-20°C ± 5°C) indicated products storage condition and minimum testing time should be maintained as  Long term storage condition shall be  (-20⁰ C ± 5⁰ C) for 12 months.

[][]As per WHO guideline Bangladesh is in Zone IVA. So, the stability study shall be done as per Zone IVA for the products marketed in Bangladesh only.
[][]Executive, Product Development will store the sample in the following conditions and for mentioned time period (at minimum) for initial submission to drug authority.

Study	Storage condition	Minimum time period covered by data at submission to Regulatory
Long term	30°C ± 2°C/65% R.H. ± 5% R.H.	12 months
Accelerated	40°C ± 2°C/75% R.H. ± 5% R.H.	6 months

[][]If 30°C ± 2°C/65% R.H. ± 5% R.H. or 30°C ± 2°C/75% R.H. ±5% R.H. is the long term condition there is no intermediate condition.

Bracketing

[][]Bracketing can only be done if the following criteria is meet
[][]Three or more strength of the products are to be stored for stability.
[][]Products are prepared by the same blend or same pellets by only varying the final weight.
[][]Packing materials for all strength are same.
[][]If all the above mentioned criteria are met, Executive, Product development will specify the bracketing design in the section 10 of the stability protocol.
[][]If applied shelf life for all strength will be declared by only assessing the minimum and maximum strength of the product. For example, if a tablet dosage form has three different strengths like 20 mg, 40 mg and 80 mg, only 20 mg & 80 mg strength may be selected for conducting stability study at all time points. The intermediate strength will then be represented by the stability of the extremes tested.

Matrixing

[][]The following factors can typically be matrixed
Strength (same formulation)
Container size
Container fill sizes
Intermediate time points
[][]The following factors should not be matrixed
Initial and final time points
Test parameters e.g. assay, related substances, pH
Dosage forms
Strength of significantly different formulation
Storage condition

[][]Bracketing and matrixing should not be applied together.
[][]Accelerated storage condition should not be matrixing, only long time test frequency may be matrixed.
Matrixing can be done in batches of the same formulation that are manufactured using same process and same machineries.
[][]Certain batches will be exempted from analysis at certain time point. but following time points must be considered for full scale analysis
Initial time point
06 Month time point
24 month time point with 18 month time point in case of the products with 18 month shelf life.

[][]Executive, Product Development will define the matrixing design at the section 10 of stability protocol.

Storage of stability sample

[][]A sample will be considered for stability storage if it meets the following criteria
[][]Batches prepared by same formulation using API from the same source
[][]Batches prepared using same manufacturing process and machinaries
[][]Batches meeting all specification as outlined in section 11 of the stability protocol
[][]Batches packed in the same container closer system

[][]After approval of the stability protocol, executive, product development will store the necessary quantity of sample  in the stability chamber.
[][]Executive product development will maintain the log book of stability sample storage log book (Annexure III).
[][]Individual log book would be maintained for individual stability chamber.
[][]Chamber number, tray number and position of sample stored must be mentioned clearly in the log book.
[][]Stability chamber tray is numbered numerically from 1 to 8 from top to bottom.

Tray and position number like 1A denotes that the sample is stored in 1st tray and in the rear left position of the tray.

Monthly stability schedule

[][]After storing sample in the stability chamber, executive, product development will entry the product name in the stability schedule. (Annexure IV)
[][]Stability schedule will be printed monthly from the live data, and will be stored in the stability chamber room at the beginning of the month.

Withdrawal of stability sample

[][]Based on the stability schedule, operator, product development will withdraw sample from the specific stability chamber.
[][]Sample will be withdrawn on due date whenever possible, but in case of any circumstance sample may be withdrawn within 7 days after the storage date. No sample will be withdrawn before the expected sample withdrawal date.
[][]After withdrawal of every sample, operator, product development will sign in the sample storage log book.
[][]Executive, product development will assign unique lab control number in every sample and maintain the stability sample analysis register (Annexure V) of this SOP.
[][]Executive, product development will analyze the sample and put the report in product master file, he will also put the data in stability trend.(Annexure VI)
Stability study report of Development batches.
[][]After completion of both the accelerated and long term stability testing executive, product development will generate a stability study report according to the Annexure VII of this SOP.
[][]Each report will have a unique identification number of 20 digit. As following
GPD/SSR/001/15/01
Where,
GPD stands for General Product Development. In case of Cephalosporin unit the code will be CPD which indicates cephalosporin Product Development.
SSR stands for Stability Study Report.
001 in the numerical serial number, first protocol of the year will bear number 001, second one 002 and continue till the end of the year.
15 stands for the year 2015, in case of the following years 16, 17 etc will be used.
01 stands for the version number. Second version will bear the number 02 and so on.
/ stands for separator in all case.

[][]Executive, Product Development will maintain a log Book according to Annexure VIII of the SOP to record the Report number. Specific report shall be used for specific products and same number shall never be issued for two products.
[][]Senior executive, product development will check the report and manager, Quality Assurance will approve the report.
[][]One copy of the report will be provided to quality compliance department for assigning shelf life to the commercial batches.
[][]One copy of the stability report will be generated to the regulatory department for regulatory submission.

Stability study of market sample

[][]A comparative study with the market sample will be done in case of all new products.
[][]Executive, product development will raise requisition for the amount of market sample required to supply chain department.
[][]Executive, product development will store the market sample in stability chamber with the stability batches.
[][]Only accelerated stability study will be done for comparison with the market sample.

[][]Executive, product development will send the sample of market products with the SAF along with the stability batches.
[][]Executive, product development will assign a unique lab control number to the SAF and analyze the sample.
[][]After analysis the analytical reports will be stored in the market products file and the analytical data will be entered in the stability trend (Annexure VI)
[][]After completion of the accelerated stability study a comparative result of the Development batch and market sample will be provided with the accelerated stability report.

Stability study of commercial batches

[][]Stability study protocol of commercial batches

[][]Commercial batches that will undergo stability study are as follows

Batches	Accelerated study	Long term study
Optimization batches	Y	--
Validation batches	Y	Y
Change in the source of active raw materials: First three batch	Y	Y
Change in the source of major excipients: First batch. (Only if the excipients constitute more than 70 % of the total mix)	Y	--
Change in manufacturing process: First three batch after change	Y	Y
Change in manufacturing equipment: First three batches after change.	Y	Y
Change in manufacturing formula: First three batches after change.	Y	Y
Change in batch size.	Y	Y
Reprocess / Rework batch: Specific batch.	Y	--

Y indicates the type of stability study to be conducted. Indicates no stability will be done for this storage condition.

[][]Executive, quality compliance will generate stability study protocol (Annexure I) of commercial batches
[][]Each protocol will have a unique identification number of 20 digit. As following
QCOM/SSP/001/15/01
Where,
GQCOM stands for G Block Quality Compliance.
SSP stands for Stability Study Protocol.
001 in the numerical serial number, first protocol of the year will bear number 001, second one 002 and continue till the end of the year.
15 stands for the year 2015, in case of the following years 16, 17 etc will be used.
01 stands for the version number. Second version will bear the number 02 and so on.
/ stands for separator in all case.

 

[][]Assistant manager, quality Assurance  will check the protocol and manager, quality compliance will approve the protocol.
[][]The protocol will be generated by keeping the batch number portion of the protocol blank. Executive, quality compliance will fill the portion while he will store certain batches in stability.
[][]Long term stability testing will continue for shelf life plus one year, for example if the product is assigned with 24 month shelf life tehn the study will be designed for 24 plus 12 that is for 36 month.

Storage of stability sample

[][]After approval of the stability protocol, executive, quality compliance will send the required quantity of sample to product development department along with the protocol and stability sample.
[][]Executive, product development will receive the sample and store the sample in the stability chamber after filling the log book (Annexure III)

Monthly stability schedule

[][]After storing the stability samples, executive, product development will fill the stability schedule (Annexure IV).
[][]At the beginning of the month executive, product development will print the schedule for the specific month and after signing from the department in charge send the schedule to quality compliance department.

Withdrawal of stability sample

[][]Executive, Quality Assurance will generate a Sample Advice Form (SAF) to product development department, based on the stability schedule.
[][]The SAF should be sent on due date, but due to any circumstance it may be sent after the expected date, no sample will be withdrawn before the schedule date.

[][]After receiving the Sample Advice Form from operator, product development will withdraw the sample and provide the sample to quality compliance department. He will sign in the logbook for sample withdrawal.
[][]Executive, quality Assurance will send the Sample Advice Form from along with the sample to quality control department.
[][]Executive, quality control will receive the sample and assign a unique lab control number and analyze the sample. After analysis executive, quality control will store the data in quality control department and put the result in stability trend.

Stability study report of commercial batches

[][]After completion of the accelerated and long term stability study executive quality compliance will generate the stability study report according to Annexure VII of this SOP.
[][]Each report will have a unique identification number of 20 digit. As following
QA/SSR/001/XX/01
Where,
QA Quality Assurance
SSR stands for Stability Study Report.
001 in the numerical serial number, first protocol of the year will bear number 001, second one 002 and continue till the end of the year.
XX stands for the year 20XX, in case of the following years
01 stands for the version number. Second version will bear the number 02 and so on.
/ stands for separator in all case.
[][]Senior executive, product development will check it and assistant manager quality compliance will review. Manager quality assurance will approve the report.
Significant change criteria“Significant change” for an Finished Pharmaceutical Products are:
[][]A change from the initial content of API(s) of 5% or more detected by assay, or failure to meet the acceptance criteria for potency when using biological or immunological procedures.
[][]Any degradation product exceeding its acceptance criterion.
[][]Failure to meet the acceptance criteria for appearance, physical attributes and functionality test
[][]Also, as appropriate for the dosage form:
[][]Failure to meet the acceptance criterion for pH; or
[][]Failure to meet the acceptance criteria for dissolution for 12 dosage units.

Data evaluation procedure

[][]In general, a provisional shelf-life of 24 months will be established provided the following conditions are satisfied:
[][]The API is known to be stable (not easily degradable).
[][]Stability studies, of API, have been performed and no significant changes have been observed.
[][]Supporting data indicate that similar formulations have been assigned a shelf-life of 24 months or more.
[][]Long-term studies to be continued until the proposed shelf-life has been covered, and the results obtained will be submitted to the national medicines regulatory authority.
[][]Alternatively, after the availability of sufficient long term data, shelf life will be declared following any of the following process:
[][]If the Accelerated stability data shows no significant change, the long term data shows little or no variability and the accelerated data also shows little or no variability then shelf life will be declared as double the time of available long term data but, it should not exceed long term data availability time + 12 month (Y = 2X, but should not exceed Y = X + 12 Month, Where Y = proposed shelf life, and X = period covered by long term data). Such as if a product meets all the above criteria with 12 month long term data, then shelf life will be 2 x 12 = 24 Month. If 24 month long term data will be available, shelf life will be 24 + 12 = 36 month but not 24 x 2 = 48 month.

[][]If accelerated data shows significant change, but long term data shows no significant change and shows little or no variability, a statistical analysis will be performed with graphical representation with 5% upper and lower acceptance criteria. Available data will be then extrapolated to figure out time to attain the lower acceptance criteria.

[][]If backed by the above graphical representation shelf life will be declared as 1.5 time of available long term data but, it should not exceed long term data availability time + 6 month (Y = 1.5X, but should not exceed Y = X + 6 Month Where Y = proposed shelf life, and X = period covered by long term data). Such as if a product meets all the above criteria with 12 month long term data, then shelf life will be 1.5 x 12 = 18 Month. If 24 month long term data will be available, shelf life will be 24 + 6 = 30 month but not 24 x 1.5 = 36 month.

[][]If the Accelerated stability data shows no significant change, the long term data shows variability and the accelerated data also shows little or no variability a statistical analysis will be performed with graphical representation with 5% upper and lower acceptance criteria. Available data will be then extrapolated to figure out time to attain the lower acceptance criteria.

[][]If backed by the above graphical representation, shelf life will be declared as double the time of available long term data but, it should not exceed long term data availability time + 12 month (Y = 2X, but should not exceed Y = X + 12 Month Where Y = proposed shelf life, and X = period covered by long term data). Such as if a product meets all the above criteria with 12 month long term data, then shelf life will be 2 x 12 = 24 Month. If 24 month long term data will be available, shelf life will be 24 + 12 = 36 month but not 24 x 2 = 48 month.

[][]If sufficient data are not available to perform the statistical analysis shelf life will be declared as 1.5 time of available long term data but, it should not exceed long term data availability time + 6 month (Y = 1.5X, but should not exceed Y = X + 6 Month Where Y = proposed shelf life, and X = period covered by long term data). Such as if a product meets all the above criteria with 12 month long term data, then shelf life will be 1.5 x 12 = 18 Month. If 24 month long term data will be available, shelf life will be 24 + 6 = 30 month but not 24 x 1.5 = 36 month.

[][]If the Accelerated stability data shows no significant change, the long term data shows variability and the accelerated data also shows variability a statistical analysis will be performed with graphical representation with 5% upper and lower acceptance criteria. Available data will be then extrapolated to figure out time to attain the lower acceptance criteria.

[][]If backed by the above graphical representation, shelf life will be declared as double the time of available long term data but, it should not exceed long term data availability time + 12 month (Y = 2X, but should not exceed Y = X + 12 Month Where Y = proposed shelf life, and X = period covered by long term data). Such as if a product meets all the above criteria with 12 month long term data, then shelf life will be 2 x 12 = 24 Month. If 24 month long term data will be available, shelf life will be 24 + 12 = 36 month but not 24 x 2 = 48 month.

[][]If sufficient data are not available to perform the statistical analysis shelf life will be declared as 1.5 time of available long term data but, it should not exceed long term data availability time + 6 month (Y = 1.5X, but should not exceed Y = X + 6 Month Where Y = proposed shelf life, and X = period covered by long term data). Such as if a product meets all the above criteria with 12 month long term data, then shelf life will be 1.5 x 12 = 18 Month. If 24 month long term data will be available, shelf life will be 24 + 6 = 30 month but not 24 x 1.5 = 36 month.

Labeling statement for finished product

[][]As the accelerated storage condition is 40°C ± 2°C/75% R.H. ± 5% R.H, and the long term storage condition is 30°C ± 2°C/65% R.H. ± 5% R.H. then the storage condition in final pack should include “ Do not store above 30°C”.
[][]Semi-finished and ready to fill materials
[][]In case of semi-finished and ready to fill material shelf life will be based on manufacturers declared shelf life regardless of date of dispensing.

Photostability Testing

[][]Selection of product/batch
[][]Photostability testing will be conducted for the finished products of which photo sensitivity is known. Products that are not photosensitive will not fall under the criteria of photo stability testing Photostability will be done for the Development batches and the validation batches only.
[][]Photostability will be conducted in following cases
[][]For new products
[][]Any change in the formulation
[][]Any change in the immediate pack
[][]Any change in the marketing pack
[][]From the three Development and trial batch, one Development batch will be stored for photostability, if the result from one batch is not conclusive then two other batch will be stored for photostability.
[][]From the three validation batch, one batch will be stored for photostability, if the result from one batch is not conclusive then two other batch will be stored for photostability.

Design of photostability

[][]Products will be stored in three following types
[][]Fully exposed products (products without any packing, coated if coating is incorporated)
[][]Products in immediate pack (eg. Blister or glass bottle or vial, ampoule)
[][]Products in the marketing pack (eg. Inner carton)
[][]Along with a controlled sample, this will be covered with aluminum foil to assure complete protection light.

Photostability testing protocol of Development batch

[][]Executive, product development will generate photostability testing protocol of Development batch according to Annexure IX of this SOP
Individual protocol will be used for individual products. In case of any change in the protocol, due to any stability problem, new version of the protocol will be issued, defining change history at the revision details section of the protocol.
[][]Each protocol will have a unique identification number of 20 digit. As following
PD/PSP/001/XX/01

Where,
PD stands for Product Development.
PSP stands for photo stability protocol.
001 in the numerical serial number, first protocol of the year will bear number 001, second one 002 and continue till the end of the year.
XX stands for the year 20X, in case of the following years
01 stands for the version number. Second version will bear the number 02 and so on.
/ stands for separator in all case.
[][]Executive, Product Development will maintain a log Book according to Annexure X of the SOP to record the Protocol Number. Specific protocol shall be used for specific products and same number shall never be issued for two products.
[][]Senior executive, product development will check the protocol and Manager, Quality Assurance will approve the protocol.

Number of sample to be stored

Number of sample stored will follow the following criteria

[][]Sample type/Number of sample
[][]Fully exposed sample /60 pcs
[][]Sample in immediate pack /60 pcs
[][]Sample in marketing pack /60 pcs
[][]Controlled sample /60 pcs

Sample storage procedure

[][]Executive, product development will store sufficient sample in the stability chamber after approval of the protocol
[][]He will provide input in the photostability sample storage log book (Annexure XI), he will provide input regarding the sample withdrawal time at the same time.
[][]Time requirement for sample to be stored should be calculated based on the procedure outlined

Withdrawal of sample

[][]Executive, product development will input the required time in photostability sample storage log book, in case of withdrawal time falling in the off time sample will be withdrawn at next possible time, no sample will be withdrawn before the schedule time.
[][]Operator, product development will OFF the light and withdraw the sample at scheduled time, and after wraping the sample with light protected barrier provide the sample for analysis.

Storage condition and procedure

[][]Executive, product development will define the position number in the tray, the tray is divided in supplied  position
[][]Executive, product development will define the position of each sample in the protocol from the above figure.
[][]He will ON the flurosence lamp and the UV lamp and take three reading of the flurosence light and UV light and from the average data will calculate the time required to attain the sufficient exposure time from the following equation

[][]Time required for flurosence light (H) = 1.2 x 1000000 / average data
[][]Time required for UV light (H) = 200 x 1000000 / average data x 10000
[][]After estimating the required time, executive, product development will determine when UV light will be kept OFF and when the sample will be withdrawn.
[][]Executive, product development will take reading of the both light twice daily, within the scheduled time at 8.30 AM in the morning and 4.30 PM in the evening, to figure out the actual values of light during sample stored.
[][]He will note the values daily in the photostability testing protocol.

Analysis of sample

[][]Executive, product development will analyze the samples along with the controlled sample after the end of the exposer time.
[][]In case of Tablet or Capsule a composite sample of 20 pcs will be analyzed.
[][]In case of other samples (eg. Suspension or vial/ampoule) homogeneous sample must be used for determination.
[][]Following test parameters will be tested after the exposed time
[][]Appearance
[][]Assay
[][]Degradants
[][]Clarity or color of solution (for suspension and vial/ampoule)
[][]Disintegration and dissolution for tablet and capsules.
[][]After completion of the analysis, executive, product development will submit the analytical result for evaluation.

Photostability testing report of Development batch

After completion of both the accelerated and long term stability testing executive, product development will generate a stability study report according to the Annexure II of this SOP.

[][]Each report will have a unique identification number of 20 digit. As following
PD/PSR/001/XX/01
Where,
PD stands for Product Development.
PSR stands for photostability study report.
001 in the numerical serial number, first protocol of the year will bear number 001, second one 002 and continue till the end of the year.
15 stands for the year 20XX
01 stands for the version number. Second version will bear the number 02 and so on.
/ stands for separator in all case.
[][]Executive, Product Development will maintain a log Book according to Annexure X of the SOP to record the report number. Specific report shall be used for specific products and same number shall never be issued for two products.
[][]Senior executive, product development will check the report and manager, quality assurance will approve the report.
[][]One copy of the report will be provided to quality compliance department for assigning shelf life to the commercial batches.
[][] Photostability study protocol of commercial batch
[][]Executive, quality compliance will generate photostability testing protocol of commercial batch according to Annexure VIII of this SOP
[][] Individual protocol will be used for individual products. In case of any change in the protocol, due to any stability problem, new version of the protocol will be issued, defining change history at the revision details section of the protocol.
[][]Each protocol will have a unique identification number of 20 digit. As following
QA/PSP/001/XX/01
Where,
QA stands for Quality Assurance
PSP stands for photo stability protocol.
001 in the numerical serial number, first protocol of the year will bear number 001, second one 002 and continue till the end of the year.
XX stands for the year 20XX.
01 stands for the version number. Second version will bear the number 02 and so on.
/ stands for separator in all case.
[][] Executive, Quality Assurance will maintain a log book according to Annexure XIII to record the report number. Specific protocol shall be used for specific products and same number shall never be issued for two products.
[][]Assistant manager, Quality Assurance will check the protocol and Manager, Quality Assurance will approve the protocol.
[][]Quantity of sample stored will be same as the section 7.7.4 of this SOP, storage conditions will be same as the section 7.7.5 of this SOP
[][]Storage of stability sample
[][]After approval of the stability protocol, executive, quality compliance will send the required quantity of sample to product development department along with the protocol and stability sample.
[][]Executive, product development will receive the sample and store the sample in the photo stability chamber after filling the log book.
[][] Withdrawal of stability sample
[][]Executive, quality compliance will generate a Sample Advice Form (SAF) to product development department, based on the stability schedule.
[][] The SAF should be sent on due date, but due to any circumstance it may be sent after the expected date, no sample will be withdrawn before the schedule date.
[][]After receiving the SAF operator, product development will withdraw the sample and provide the sample to quality compliance department.
[][]Executive, quality assurance will send the SAF along with the sample to quality control department.
[][] Executive, quality control will receive the sample and assign a unique lab control number and analyze the sample. After analysis executive, quality control will store the data in quality control department and put the sample in stability trend.

Photostability study report of commercial batch

[][]After completion of the photostability study executive quality compliance will generate the stability study report according to Annexure – IX of this SOP.
[][]Each report will have a unique identification number of 20 digit. As following
QA/PSR/001/XX/01
Where,
QA stands for General Quality Assurance.
PSR stands for Photostability study report.
001 in the numerical serial number, first protocol of the year will bear number 001, second one 002 and continue till the end of the year.
15 stands for the year 20XX
01 stands for the version number. Second version will bear the number 02 and so on.
/ stands for separator in all case.
[][] Senior executive, product development will check it and assistant manager quality compliance will review. Manager quality assurance will approve the report.
[][]Evaluation of data
[][]Sample data will be evaluated against the data of the controlled sample for any change in samples.
[][] Depending on the extent of change special labeling or packaging will be designed to mitigate exposure light.

Labeling information

Depending on the extent of change storage information like “Protect from light” will be incorporated in the marketing pack.

Annexure:

Annexure – I : Stability study protocol.
Annexure – II : Stability study protocol log book for Development batch.
Annexure – III : Stability sample storage log book.
Annexure – IV : Monthly stability schedule.
Annexure – V : Stability Sample analysis register.
Annexure – VI : Stability trend.
Annexure – VII : Stability study report.
Annexure – VIII : Stability study report log book for Development batch.
Annexure – IX : Photostability study protocol of Development batch.
Annexure – X : Photostability protocol logbook of Development batch.
Annexure – XI : Photostability sample storage log book.
Annexure – XII : Photostability study report of Development batch.
Annexure – XIII : Photostability report log book of Development batch.

Correspondence with regulatory affairs , Purpose:

Correspondence with regulatory affairs , The purpose of this SOP is to describe the procedures of the following activities related with the regulatory affairs, Namely
[][]Recipe preparation
[][]Annexure Preparation
[][]Sample sending procedure to DGDA for INN Products.
[][]Annexure amendment as and when necessary.
[][]To comply with the cGMP as well as DGDA requirements.

Correspondence with regulatory affairs , Scope:

This procedure is to be followed for recipe preparation, Annexure preparation, sample sending to DGDA for INN products and Annexure amendment procedure in of XX Pharmaceuticals Limited.

Definition of Terms:

[][]SOP: Standard Operating Procedure
[][]DA: Drug Administration
[][]INN: International Nonproprietary Name
[][]cGMP: Current Good Manufacturing Practice.
[][]QA: Quality Assurance
[][]QC: Quality Control
[][]PD: Product Development
[][]RA: Regulatory Affairs
[][]SCM: Supply Chain Management
[][]COA: Certificate of Analysis
[][]MOA: Method of Analysis
[][]W/S: Working Standard

Responsibilities:

The roles and responsibility are as follows:

Executive / Sr. Executive, PMD

[][]Generation of recipe.
[][]Generate pack size and brand name of the products.

Executive / Sr. Executive, Product Development

[][]Recipe and Annexure Preparation after completion of stability study
[][]Provide sample and stability data of INN products for submission to DA
[][]Provide Annexure amendment form and other related documents for Annexure amendment

Manager, Regulatory Affairs

[][]Recipe, Annexure, INN product sample and Annexure amendment form Submission to DA and provide approved recipe to QA
Update to QA, PD about any changes or requirements of DA

Executive / Sr. Executive, Quality Control

[][]Analysis of INN product sample send to DA

Head of Plant Operation

[][]Review Recipe and Annexure prior send to DGDA

Head of Quality Assurance

[][]Review the Recipe and Annexure prior send to DGDA.
[][]Approve the SOP against XX Pharmaceuticals Ltd. master documents and current regulatory requirements.
[][]Implementation of the SOP

Precaution(s):

[][]All concerned persons have to follow the SOP.
[][]Any deviation from the stated procedure should be documented and reported to the supervisor for corrective measure.

Procedure:

[][]Procedure for product proposal and feasibility testing
[][]PMD will generate the Recipe after finalization of product brief and based on technical feasibility.
[][]Recipe will be submitted according to the Annexure – I of this SOP
[][]Executive / Sr. Executive, PMD will fill the product data sheet and the section 6 and 7 of the Annexure and send to Product Development Department.
[][]Executive / Sr. Executive, Product development will fill the technical data section of the Recipe carefully and send the Recipe to GM Plant for further checking and signing in the particular section.
[][]After signing Product development will send the recipe to Head of QA for checking and signing in the particular section.
[][]After approval of the Recipe regulatory affairs shall conform to QA about the approval.
[][]Procedure for Annexure Preparation
[][]Necessary documents to be provided for product inclusion includes
Application for new product inclusion to the director of DA
Recipe approval form from DA
Product Inclusion fee
For INN products necessary quantity of sample (as described by DA) and analytical method of the product.
Text of the packing materials
Accelerated Stability data of the product.
Annexure.
[][]Regulatory Affairs will provide the application, Recipe approval form and product inclusion fee.
[][]PD will generate the Accelerated Stability Data of the product after completion of six month stability
[][]PD will prepare the Annexure after completion of six month accelerated stability.
[][]Annexure for Non Biological drugs will be filled through Annexure I and for Biological drugs will be filled through Annexure II of DA.
[][]Manufacturing License no for Biological and Non Biological License will be checked before filling the corresponding Annexure.
[][]Brand name and blister/bottle/ampoule/vial per pack must be checked before filling the Annexure
[][]Formulation of the product must be filled according to the Stable pilot batch formulation after completion of six month stability.
[][]Compendial reference must be checked for active materials and excipients while filling the Annexure.
[][]Annexure must be filled as Quantity per tablet/capsule for tablet and capsule dosage forms, Quantity per 100 ml for PFS/Syrup/Suspension/ampoules, Quantity per vial for injectable vials.
[][]After completion of Annexure, Manager QA shall check the formulation according to the stable pilot batch formulation and send it to the RA along with other documents.
[][]Regulatory Affairs will arrange for submission and approval of the Annexure from DA.
[][]After approval of the Annexure ,RA will send copies of the Annexure to QA and PD.

Procedure for Sample Sending of INN Products

Required documents for sample sending to the DA are
[][]Application for approval of INN products to director of DA.
[][]Recipe approval form from DA
[][]Fees for analysis
[][]Required quantity of sample of different dosage forms as required by DA
[][]Method of analysis of the active materials as supplied by the manufacturer.
[][]Certificate of Analysis of the active materials.
[][]Working Standard/ Reference Standard of the active materials.
[][]Method of analysis of the finished product
[][]Sample Chromatogram of the active materials.

[][]Regulatory Affairs will arrange for the submission of application, Recipe approval form and fees for analysis to the DA

[][]Quality control will arrange the MOA supplied by the manufacturer, COA and WS and the sample chromatogram after the initial analysis of the sample to be sent to DA.
[][]Manager, QA will check all the documents and arrangement to send to Regulatory Affairs
[][]Regulatory Affairs will arrange the submission to the DA and after the approval will send copies to QA, PD and QC.

Procedure for Annexure amendment

An Annexure can be amended in following cases (not limited to)
[][]Any change in the formulation than the approved Annexure after the process validation.
[][]Inclusion or exclusion of any excipients than the approved Annexure.
[][]Increase or decrease in the quantity of Excipients than the approved Annexure
[][]After any reformulation work.
[][]PD will arrange the justification of Annexure amendment form according to the Annexure – III

[][]In case of inclusion or exclusion of excipients corresponding row will be left blank.
[][]Head of QA and GM plant operation will check the requirements of the justification of Annexure amendment and the formulation and sign for approval.
[][]PD will generate the revised Annexure following step .
[][]Manager, QA will check the revised Annexure according to the revised formulation (pilot batch or validation batch) and documents to RA.
[][]RA will submit and amend the Annexure accordingly and send approved copies to QA.
[][]QA will send revised approved Annexure to PD and SCM and obsolete the previous Annexure.

Annexure:

Annexure – I: Recipe format
Annexure – II: Annexure format
Annexure – III: Format of Annexure amendment form.

New Product Development Purpose:

New Product Development, To detail the standard operating procedure for the manufacturing of new products by Product Development Department.

New Product Development Scope:

This SOP is applicable for new product of  XX Pharmaceuticals Limited.

Definitions / Abbreviation:

[][]Preformulation: Preformulation is the basic study of the physical and chemical properties of the product prior to start the formulation procedure. Generally, preformulation are conducted to get necessary information to optimize formulation of the products.
[][]Trial Batch: Trial batches are the batches that are conducted in small scale to finalize the formulation of the product in terms of physical feasibility and cost effectively.
[][]Batch: Batches are the Batch that will be prepared to conduct the full physical and chemical stability of the product.
[][]Development Batch: Development batches are the batches that are manufactured and packed using production machinery, for which full physical and chemical accelerated stability will be conducted. The batch size for Development batch should be at a minimum of one tenth of the commercial batch.
[][]Stability Study: Studies conducted to ensure that finished dosage form with excipient will exert to produce its intended effects over the shelf life.
[][]SAF: Sample Advice Form
[][]PB: Pilot Batch
[][]PV: Process Validation
[][]PD: Product Development
[][]DB: Development batch
[][]BMR : Batch manufacturing Record

Responsibilities:

The roles and responsibility are as follows:

Executive/ Sr. Executive PMD

[][]Issue of Product Proposal, Product Brief, Technical Feasibility Analysis Report.

Executive/ Sr. Executive Product Development

[][]Development of new products following this SOP.
[][]Preparation and periodic revision of the SOP
[][]To ensure that the documents technically are accurate and reflects the required working practice

Manager, Supply Chain Management

[][]To ensure availability of all necessary raw materials (active and excipients) for new product purpose

Executive/ Sr. Executive, Quality Control

[][]Analysis of samples of raw materials, trial batches, batches, Development batches, process validation batches.

Manager, Regulatory Affairs

[][]To provide all necessary information on regulatory requirements for new products.

Head of Quality Assurance

[][]Approve the SOP against XX Pharmaceuticals Ltd. master documents and current regulatory requirements.
[][]Ensure effective implementation of the SOP

Procedure:

[][]After getting Product Proposal, Product brief and Feasibility study report from PMD, start information collection about that product from all possible sources; i.e. BP, USP, BNF, Physicians’ Desk Reference (PDR), The Electronic Medicines Compendium, Mark Index, Martindale, Patent manufacturer of the API, Internet etc.
[][]Summarize or highlight that information vital for formulation in the preformulation Study (Annexure-I) & discuss with the members of team through a meeting, if required.
[][]Inform Quality control department to collect sample of the specific product, mention any specific requirement of the product and sample quantity through mail.
[][]Collect the sample of the product from market, preferably from patent manufacturer or of leading Brand Company. Check the physical parameters of the market products to set specifications of our final product.
[][]To get preliminary idea about formulation, make trial of minimum units of each dosage form and record on the Trial Batch (TB) Manufacturing Sheet (Annexure-II). Send the trial batch for QC analysis and figure out best probable formulation.
[][]Based on the information collected in preformulation study and considering trial batch formulation confirm product formula and issue manufacturing instruction for batches (DB). Total manufacturing procedure of batches should be noted properly in to the batch manufacturing record (Annexure – III)
[][] Submit the sample for analysis & compare the results with set specification previously set by the quality control department.
[][]After getting satisfactory results send the batch (DB) sample to production department along with ERP generated packing material requisition for primary packing.
[][] Store the finally packed samples in the accelerated and long term condition according to SOP/PD/003/02 & store the batch manufacturing record in to the product master file. It should be insured that for comparative study, market leading brands, preferably of patent manufacturer is being studied simultaneously.
[][] Analyze and evaluate the stability study results periodically submitted by Quality Control department. Discuss with the head of the department for further proceeding.
[][] After getting satisfactory batch (DB) results, take necessary action for scaling up in to Development batch (PB). Manufacture the Development batch according to the manufacturing formula and instruction of the batch, maintaining all GMP requirements for commercialization of the batch.
[][]Batch size of Development batch should be preferably equivalent to commercial batches and optimization of machine capacity should be considered properly.
[][]Total manufacturing procedure for Development batch should be noted in the Optimization batch manufacturing record (Annexure V), Critical process parameters be justifies and optimized for validation.
[][] For solid oral dosage forms the Development batch size is generally taken to be, at a minimum one tenth that of full commercial batch, or 100000 tablets or capsules whichever is larger, This quantity can be compromised only in case of machine capacity constrain.
[][] Check the analytical results in each & every steps of Development batch. Ensure that the results are within specifications. Then proceed to next step.
[][] Submit the sample of Development batch (PB) to QC laboratory for analysis and stability study following the same procedure as like batch (DB).
[][] To standardize the commercial batch size and to set all the process parameters, first Development batch will be manufactured as optimization batch under the direct supervision of concerned PD Executive. If more than three optimization batches are required for setting all process parameters then it should be justified through risk assessment.
[][] Satisfactory Development batch (PB) result should be informed to all concerned departments to pack as commercial batch according to launching forecast.
[][] Prepare Batch Manufacturing Record (BMR) for a particular product, based on the manufacturing record of Development batches. Finally hand over all related documents of a new product e.g. BMR, Batch formula etc. to Quality Compliance departments for start up the Process validation activities.
[][] On the basis of the approved BMR, next three consecutive commercial batches will be considered as process validation batches.

Reformulation Procedure

[][]A product will be reformulated for any or all of the following causes.
[][]A failure in the evaluation of validation program.
[][]In case of a deviation of a specification that cannot be trouble shoot.
[][]For changing the manufacturing process.
[][]A root cause analysis will be done by the Quality Compliance Department in case of the deviations.

Annexure:

Annexure – I: Preformulation Study Sheet.
Annexure – II: Trial Batch Manufacturing Sheet.
Annexure – III: Batch Manufacturing Record.
Annexure – IV: Optimization batch Manufacturing Record.