SOPs

BMR and BPR Preparation Standard Procedure

BMR and BPR Preparation, Purpose:

BMR and BPR Preparation, The purpose of this SOP is to define those details that need to be specified in, BMR & BPR to enable consistent routine manufacture and Packaging.

BMR and BPR Preparation, Scope:

This SOP is applicable for preparation of BMR and BPR of XX Pharmaceuticals Limited.

Definition of Terms:

[][]BMR: Batch Manufacturing Record
[][]BPR: Batch Packing record

Responsibilities:

The roles and responsibility are as follows:

Senior Executive, Product Development

[][]Preparation of BMR and BPR following the SOP.
[][]Preparation and revision of validated BMR and BPR after completion of validation
[][]Preparation and timely review of the SOP.

Assistant Manager, Production

[][]Review of the BMR and BPR
[][]General manager, Plant
[][]Review of the BMR and BPR

Manager, Quality Assurance

[][]Approve the BMR and BPR
[][]Approve the SOP against XX Pharmaceuticals Ltd. master documents and current regulatory requirements.
[][]Implementation of the SOP.

Procedure:

[][]Procedure for preparation of Batch Manufacturing record (BMR)
[][]Select and confirm that the name and strength of the product and all the parameters related to BMR is correct.
[][]Follow the following procedure while preparing BMR
[][]A4 size paper
[][]Page orientation will be landscape
[][]Keep the top margin 0.2”, bottom margin 0.2”, Left margin 0.5”, Right margin 0.5”, gutter 0 and gutter position at left
[][]Keep the header and footer 0.2” from the edge
[][]Use Arial font
[][]Font size will be 10 unless or otherwise specified.
[][]Use Bold Capital letters inside third bracket for headings like Dispensing, Granulation etc
[][]Use Bold Capital letters for heading like Check before dispensing, Check before sieving, manufacturing instruction etc. Roman numerical numbers should be followed with the heading.
[][]Use normal Bold letters for any highlighting process
[][]Use arithmetic numerical numbers for all manufacturing instructions
[][]Use border line of two horizontal lines at every page.
[][]Include a table for prepared by, checked by and verified by after completion of all checking steps.
[][]Follow the following for header and footer
[][]Company logo will be standard sized at the top left corner of the page.
[][]Company Name will at the middle with all Capital letter, Bold and with font size 14.
[][]Company address will be at the middle with bold letters of font size 10.
[][]Place Batch Manufacturing Record at the middle in between company name and logo and signatory separated by two double lined horizontal line.
[][]Batch Manufacturing Record will be at the middle with all capital bold letters of font size 12.

Heading on the header will be

[][]Product Name
[][]Product Code
[][]Batch Size
[][]Version No
[][]Batch No
[][]Mfg Date
[][]Exp Date and
[][]Page number.
[][]With normal bold letters of font size 10.
[][]Product name will be normal bold letters of font size 12
[][]Signatory will have one prepared by, one checked by, three reviewed by and one approved option with normal, bold letters of font size 10.
[][]Designation, Department and date option of signatory will be of font size 10.
[][]Use effective date, revision date and revision history in first page.
[][]State a precaution (where applicable) and checking step prior to starting of any processing steps.
[][]Give a title for each stage such as room condition, machine setup etc. Title will be normal Bold letters with font size 10.
[][]Write all the instruction chronologically, sequentially, logically and in a clear way so that everyone can understand easily.
[][]Provide IPC parameters specification and checking sheet where applicable
[][]Provide a container summary record space at the end of the steps like compression and coating.
[][]Keep a reconciliation stage after each processing steps (eg. Granulation, compression etc.)
[][]Provide documents checking option of production and quality assurance head after completion of all stages.

Procedure for preparation of Batch Packing record (Primary Packing)

[][]Select and confirm that the name and strength of the product and all the parameters related to BPR is correct.
Follow the following procedure while preparing BPR
[][]A4 size paper
[][]Page orientation will be landscape
[][]Keep the top margin 0.2”, bottom margin 0.2”, Left margin 0.5”, Right margin 0.5”, gutter 0 and gutter position at left
[][]Keep the header and footer 0.2” from the edge
[][]Use Arial font
[][]Font size will be 10
[][]Use Bold Capital letters inside third bracket for headings like Primary Packaging
[][]Use Bold Capital letters for heading like material requisition, line clearance etc. Roman numerical numbers should be followed with the heading.
[][]Use normal Bold letters for any highlighting process
[][]Use arithmetic numerical numbers for all checking parameters
[][]Use bullet point for all checking options
[][]Use border line of two horizontal lines at every page.
[][]Include a table for performed by, checked by and verified by after completion of all checking steps.
[][]Follow the same procedure as described for header for BMR in case of BPR also
[][]Keep effective date, revision date and revision history in the first page of the BPR
[][]Put the following option in the BPR
[][]Material requisition sheet
[][]Line clearance record
[][]Machine setup section
[][]Record keeping action for setting up the machine
[][]In process checking parameters and record keeping option
[][]Destruction record keeping option
[][]Reconciliation stage after Packaging
[][]Provide documents checking option of production and quality assurance head after completion of all stages.
[][]Procedure for preparation of Batch Packaging Record (Secondary Packing)
[][]Select and confirm that the name and strength of the product and all the parameters related to BPR is correct.
[][]Follow the same page margin specification as were in the batch packaging record
[][]Follow the same procedure as described for header and footer for BMR in case of BPR also
[][]Keep effective date, revision date and revision history in the first page of the BPR
[][]Put the following option in the BPR
[][]Material requisition option
[][]Line clearance option
[][]Item checking before packaging option
[][]Machine setup option with record
[][]In process checking parameters and record keeping option
[][]Item check after packing
[][]Sampling summary
[][]Packaging material destruction record
[][]Reconciliation record
[][]Yield calculation option
[][]Batch reconciliation option
[][]Finished product transfer record

[][]Provide documents checking option of production and quality assurance head after completion of all stages.

Procedure for preparation of Batch Packaging Record (Physicians Sample)

[][]Follow same procedure as Batch Packing Area with the following exception
[][]Specify Physicians sample at the header of the BPR
[][]Do not keep any batch reconciliation and material transfer record in the BPR.

Annexure:

Annexure – I: Format of Batch Manufacturing Record (BMR)
Annexure – II: Format of Batch Packing Record (Primary Packaging)
Annexure – III: Format of Batch Packaging Record (Secondary Packaging)
Annexure-IV: Format of Batch Packaging Record (Physicians Sample)

BMR and BPR Preparation Standard Procedure Read More »

Waste Disposal Procedure For Product Development Area.

SOPs

Waste Disposal, Purpose:

Waste Disposal, To describe the general waste disposal procedure in product development area.

Waste Disposal, Scope:

This SOP is applicable for general waste disposal procedure for product development area of XX Pharmaceuticals Limited.

Definition of Terms:

None

Responsibilities:

The roles and responsibility are as follows:

Executive/ Sr. Executive Product Development

[][]Disposal of waste according to the SOP
[][]Preparation and timely review of the SOP.

Senior Executive, Quality Compliance

[][]Checking the disposal procedure at the time of operation

Head of Plant Operation

[][]Review the waste disposal procedure.

Head of Quality Assurance

[][]Approve the disposal activities.
[][]Implementation of the SOP.

Precaution(s):

[][]All concerned persons have to follow the SOP.
[][]Wear dust mask, safety goggles and rubber gloves during handling waste materials.
[][]Ensure that all containers are closed before sending for salvage.
[][]Keep a record in the log book for different wastes before destroying.
[][]Any deviation from the stated procedure should be documented and reported to the supervisor for corrective measure.

Waste Disposal, Procedure:

Waste originated during product development activities can be classified into five categories such as:
[][]Chemical Waste
[][]Plastic Waste
[][]Paper Waste
[][]Cotton Waste
[][]Broken/ fractured glass bottle

The rejected products shall be accumulated and stored separately in restricted areas with the label “To be destroyed”.

Chemical Waste (Solid, Blister and Liquids)

Solid waste:

[][]Solid waste consists of chemicals spread during different manufacturing stages such as: dispensing, charging, addition, de-dusting etc. These are also produced during Lab batches as the excess granules or tablet/capsule after keeping required quantities of the products for stability studies. These are disposed off as follows:
[][]Sweep off chemicals from the floor with the help of a vacuum cleaner or a brush and handy shovel and keep it in waste bin.
[][]Collect chemical dust from the collector of vacuum cleaner.
[][]Weigh and record it in a register. Fill the Annexure – I of the SOP and take approval for disposal from Manager, Quality Assurance.
[][] In presence of a Quality Compliance Officer dissolve the waste chemicals in water and pass through drain to ETP.
[][]After keeping required quantities of the products for stability studies, weigh the remaining quantities and record the quantity in a register.
[][]Fill the Annexure – I of the SOP and take approval for disposal from Manager, Quality Assurance.
[][]In presence of a Quality Compliance Officer dissolve the remaining granules and tablet/ capsule in water and pass through drain to ETP.

Blister waste:

Blisters containing tablets or capsules become waste after completion of stability studies at different conditions and storage periods and also after expiry date. These are disposed off as follows:
[][]Collect the waste blisters of different products and deblister them manually.
[][]Weigh the waste tablets /capsule and waste blisters.
[][]Record it in a register and Fill the Annexure – I of the SOP and take approval for disposal from Manager, Quality Assurance.

[][]In presence of a Quality Compliance Officer Dissolve the waste tablets /Capsule in water and pass through drain to ETP.
[][]Weigh and record the waste blisters in register book and then send to salvage yard.

Liquid waste:

[][]Liquid waste comprises mainly washings generated during cleaning of different equipment and trace of chemicals spilled during dispensing. All these are disposed off as follows:
[][]Dispose off the liquid waste through floor drain.
[][]Wipe the spillage with a wet cotton brush and dispose off the washings through floor drain. These washings will go through floor drain to Effluent Treatment Plant (ETP).

Plastic Waste

Returnable:

Returnable plastic waste comprises empty PVC drum/ cane of chemicals. All these are returned to store after destruction of labels.

Others:

[][]Other plastic waste comprises empty polyethylene bag, PVC tube, reject strip, broken plastic etc. All these are disposed off as follows
[][]Make it unusable by cutting. Keep them in waste bin.
[][]Weight the waste and record in a register.
[][]Fill the Annexure – I of the SOP and take approval for disposal from Manager, Quality Assurance.
[][]In presence of a Quality Compliance Officer send the waste to the salvage yard.

Paper Waste

[][]Expired documents/confidential company documents:
[][]Make it unusable by cutting Weight the waste and record in a register
[][]Fill the Annexure – I of the SOP and take approval for disposal from Manager, Quality Assurance.
[][]In presence of a Quality Compliance Officer send the waste to salvage yard.

Others:

[][]Paper waste comprises empty paper bag of raw materials, paper drums, rejected labels, leaflet, inner cartoons, shipper cartoons etc. All these are disposed off as follows:
[][]Make the waste unusable (except drum) by cutting and keep it in waste bin.
[][]Weigh and record it in a register. Fill the Annexure – I of the SOP and take approval for disposal from Manager, Quality Assurance.
[][]In presence of a Quality Compliance Officer send the waste for salvage.
[][]In case of drum, tear or destroy label. Weigh and record in the register book, then send to store
[][]Destroy paper bags, rejected labels, leaflets and inner cartoons by cutting.

Cotton waste

[][]Cotton waste consists of cotton bag of raw materials, unusable cotton duster etc. These are disposed off as follows
[][]Make the cotton waste unusable by cutting weight the waste and record in a register. Keep them in waste bin.
[][]Fill the Annexure – I of the SOP and take approval for disposal from Manager, Quality Assurance.
[][]In presence of a Quality Compliance Officer send the waste for salvage.

Broken/fractured glass bottle

[][]Break the unusable bottle by hammer with proper precaution, such as use mask, safety goggles, safety shoes, hand gloves and protective dress.
[][]Weigh and record in the register book.
[][]Weigh and record in the register book.
[][]Fill the Annexure – I of the SOP and take approval for disposal from Manager, Quality Assurance.
[][]In presence of a Quality Compliance Officer send the waste for salvage.
[][]All the waste disposal record forms must be stored in product development department and at the end of the year a total disposal summary will be provided to Manager, Quality Assurance.

Annexure: Waste Disposal

Annexure – I: Waste disposal request form.

Waste Disposal Procedure For Product Development Area. Read More »

Stability Study standard operating procedure

Product Development, SOPs

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.

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.

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correspondence with regulatory affairs

Product Development, SOPs

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.

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New Product Development Procedure

Product Development, SOPs

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.

New Product Development Procedure Read More »

Certification of Analyst

Quality Control, SOPs

Certification of Analyst, Purpose :

Certification of Analyst, The purpose of this SOP is to determine the capability of the newly recruited analyst to perform analysis accurately within the specified parameters and to demonstrate the analyst’s ability to perform in quality control laboratory at XX Pharmaceuticals Ltd.

Certification of Analyst, Scope :

This SOP applies to assure that the analysts are familiar with all test parameters, analytical procedures, instruments operation and documentation in quality control laboratory of XX Pharmaceuticals Ltd.

Definitions/Abbreviation:

Standard Operating Procedure (SOP): Standard Operating Procedure.

Responsibilities:

The roles and responsibility is as follows:

Officer/Executive/ Sr. Executive, Quality Control

[][]To follow the instructions of this procedure correctly.
[][]To maintain the records properly as per SOP.

Manager, Quality Control

[][]Responsible for the certification of analyst and verification of results and comparison with acceptance criteria.
[][]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.

Head of Quality Assurance

[][]Approval of SOP
[][]To ensure the overall implementation of the SOP.

Procedure:

General Precaution(s):

[][]Training should be conducted until the analyst is competent enough to carry out the analysis independently.
[][]Make sure that new employee know about the laboratory safety procedure.
[][]Adequate knowledge on handling of spillages and management of chemicals & reagents in the laboratory.
[][]Hands on waste management in the laboratory.
[][]Understanding the operation, cleaning and calibration procedure of instruments used in the laboratory.

Operation:

[][]Recently approved two specific samples of raw material or finished product or packaging material shall be given to the analyst to perform test for analyst certification.
[][]The samples are to be coded as (A) or (B).
[][]These samples packed in a manner which can prevent exposure to moisture, light and heat.
[][]In-Charge, QC should ensure that the analyst is performing the specified tests following respective method of analysis and specification.
[][]The analytical findings shall be recorded in the respective worksheet and the summary of results shall be entered in the prescribed format (Annexure-I).
[][]In-Charge, QC shall review the results in comparison with the known values for the test carried out and forward to Head of QA for approval.
[][]The analyst shall be considered qualified if the results obtained by him/her within the specification limit and within acceptable limit for certification of analyst.
[][]The details like calculations, chromatograms and spectrums along with comments of Head of QA shall be filed in training file of analyst.
[][]No repeat of the test will be allowed to the analyst.
[][]The result are provided by analyst will be crosscheck to the previous result and check the similarity.
[][]Head of QA will decide for the selection of analyst for routine analysis after review of analysis report. If the analyst is failed to qualify the test analyst will undergo further training.
[][]The certification of analyst shall be applicable to him/her only for carrying out these activities for which he/she is certified.
[][]Re-certification of the analyst shall be carried out once in every three years.
[][]The acceptance criteria for the analytical results shall depend upon the nature of tests carried out and the range provided in the specifications.
[][]Following acceptance criteria may be used for evaluation comparing with approved analyst.
[][]Assay by Spectrophotometer +/- 1% of previous value
[][]Assay by HPLC +/-0.5% of previous value
[][]IR spectra should match with standard and previous spectra
[][]Water content by KF +/-1% of previous value

Annexure:

Annexure-I: Analyst Certification Report.

Certification of Analyst Read More »

Dissolution Tester Calibration with Operation and Cleaning

SOPs

Dissolution Tester Calibration, Purpose :

Dissolution Tester Calibration, The purpose of this SOP is to describe the operation, calibration and cleaning of Dissolution Tester (Model: Electrolab, EDT 14Lx).

Dissolution Tester Calibration, Scope :

This procedure is applicable for Dissolution Tester (Model: Electrolab, EDT 14Lx), installed in the quality control laboratory at XX Pharmaceuticals Limited.

Definitions/Abbreviation:

[][]SOP: Standard Operating Procedure
[][]QC: Quality Control
[][]Dissolution test: Dissolution test is a means to monitor the rate of release of a drug substance from a dosage form to ensure consistency of manufacture and compliance with release specifications.
[][]RPM: Rotations per minute
[][]LED: Light emitting diode
[][]Concentricity: The quality of having the same center (as circles inside one another).
[][]Wobble: Move sideways or in an unsteady way.
[][]NMT: Not more than.

Responsibilities:

The roles and responsibility is as follows:

Officer/Executive/ Sr. Executive, Quality Control

[][]To ensure that the instructions of this procedure are correctly followed.
[][]To ensure cleaning of dissolution tester maintaining safety rules.

Manager, Quality Control

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

Procedure:

General precautions or operational safety:

[][]Do not start the heater if there is no water in the tank.
[][]Always maintain the liquid level within the tank above the minimum level mark using purified water only.
[][]Disconnect the power supply before moving, emptying or cleaning of bath.
[][]Spillage must be cleaned up immediately after use.
[][]Do not use any aggressive material or strong solvent to clean the jar and water bath.
[][]Locate the system on a level bench without movement or distortion.
[][]Do not hold the stirrer while in operation.
[][]For lifting up the stirrer, make sure the paddles are stop.
[][]Do not disturb the sensor tube while cleaning the tank.
[][]External probe should be handled with care.
[][]Use sinkers if the dosage form unit floats. Close the vessels with the cover during Operation.

System Operation:

[][]After the System is set up, switch on the power.
[][]After Power On, the Instrument will initialize itself; the logo screen will flash for 3 seconds and then idle screen will be displayed.
[][]The idle screen displays the current status of the instrument indicating the Date, Time, RPM, Bath Temperature, External probe and loaded protocol number.
[][]Press F3 Key to login.
[][]Username and Password needs to be added.
[][]Press F1 key to enter the username & password or F3 Key to go back to the previous screen.
[][]The idle screen will be displayed.
[][]If security is disabled then the adjacent idle screen will be displayed.

ELECTROLAB
EDT 14Lx
DISSOLUTION
TEST APPARATUS

[][]Press F1 or F2 Key from front panel to enter MENU or PREPARE
[][]Menu Press F1 Key from front Panel to enter menu screen.
[][]Menu <Configure>
[][]Press 1 from alphanumeric keypad to enter configuration menu.
[][]If F3 key is pressed the previous screen will be displayed.
[][]Menu <Configure> l sampling l
[][]Press 1 from alphanumeric keypad to enter sampling menu.
[][]Menu <Configure>l sampling l [ Manual] [][]Press 1 to select manual sampling though syringe manifold or 2 to select manual sampling though pipette.
[][]Menu <Configure>l Individual Probe l
[][]Press 2 to enter individual probe screen. Press 1 from alphanumeric keypad to select the individual probes. The number of probes can be selected either to 6/8/12/14 using up or Down arrow key, press enter to save the No. of probes and return back to configure screen.
[][]Press 2 to select option number.
[][]Press F3 key to return back to the Configure screen.
[][]Menu <Configure>l Temp Gradient l
[][]Press 3 to enter temp gradient.
[][]Set Temp gradient up to 1.5° C using increment & decrement key.
[][]Temperature Controller set.

F1 key: To ‘ON’ the temp Controller.
F2 key: To ‘OFF’ the temp Controller.
F3 key: To ‘SAVE’ & to return back to the Configure screen.

[][]Menu <Configure>l communication l
[][]Press 4 from front panel to enter Communication.
[][]Select RS232 for printer/PC and ETHERNET for LAN connection using 1 or 2 numeric keys.
[][]Press F3 key to go back to configure screen.
[][]Menu <Configure>l Stirrer l
[][]Press 5 in configure screen.
[][]Press 1 to ON the Stirrer and press 2 to OFF the stirrer.
[][]Menu <Configure>l Auto Disp. l
[][]Press 7 to enter auto dispenser screen.
[][]Press 1 or 2 numeric keypad to activate auto dispenser.
[][]Menu <Configure>l Instur. No. l
[][]Press 8 to enter instrument number.10 alphanumeric character serial numbers can be entered.
[][]Press F1 keys to save the entered serial number and F3 to go back to previous screen.
[][]Menu <Protocol>
[][]Press 2 to enter protocol menu.
[][]Menu< Protocol >l Load Protocol l
[][]Press 1 to enter Load Protocol.
[][]20 Programmable protocols can be loaded
[][]Protocol No- Can be loaded using UP/Down key & to register the No. Enter key needs to be pressed.
[][]Press F1 to load next protocol and Press F2 to load previous protocol.
[][]Press F3 to go back to the protocol screen.
[][]Menu< Protocol >l Edit Protocol l
[][]Press 2 to enter Edit Protocol.

[][]Select the protocol which needs to be editing using Up/down arrow and press ‘enter’ key.
[][]The respective protocol details such as Drug name, Media name, pH value, Temperature, Media volume , Power fail, Apparatus, Time Table, Sampling Info, details need to be entered.
[][]The protocol details can be edited using alphanumeric keypad.
[][]The next parameters can be selected for editing before saving the previous parameter by pressing F3 key from front panel.
[][]To select different apparatus press enter key and select the desired apparatus using numeric keys.
[][]To edit time table parameters press Enter key. The sampling time interval, action and total number of samples (1 to 24) can be set as per user requirement using shift & alphanumeric keys.
[][]For the single time point, action table will have only one sampling option. Infinity (min) can be selected after last sample.
[][]For the multiple time point, action table will have only two sampling options media change and sample. Infinity (min) can be selected after last sample.
[][]Press F3 to save & go back to main menu screen.
[][]Menu <Settings >
[][]Press 3 to enter settings
[][]Menu <Settings > l Clock l
[][]Press 1 alphanumeric keypad to enter Clock setting screen
[][]Set Date and Time using ▲▼◄► arrow keys
[][]Press F1 from front panel to save the entered date and time, the idle screen will be displayed
[][]Press F1 from front panel to go back to the setting screen.

[][]Menu <Settings > l Wake Up l
[][]In this parameter the sleep mode time and date are set. The instrument will start automatically at the set time and date for attaining the bath temperature.
[][]Press 2 from setting screen to enter the wakeup setting screen.
[][]Wake up time and date needs to be added using Up/Down and Side arrow keys.
[][]Press F1 key to turn ON the wake up parameter, the LCD display light will be turn OFF automatically and idle screen will be displayed. Or press the F2 key to OFF the wakeup alarm.
[][]Menu <Jar Tamp >
[][]Press 6 from main menu screen to observe the jar tamp attained by individual jar.

To set RPM

[][]Press RPM key from front panel.
[][]Press numeric key to register the RPM range from 20 to 300 RPM.
[][]Press F1 key to Turn-on the motor & F2 key to Turn off.
[][]If RPM is out of range an error screen will be displayed.
[][]To Set Temperature
[][]Press Temperature key from front panel.
[][]Press numeric key to register the temperature range from 200 C to 400 C.
[][]Press F1 to turn On & F3 to turn off heater.
[][]If temperature is out of range an error screen will flash for 3 seconds.
[][]To prepare the test
[][]Load the appropriate protocol no. & press F2 key to start preparing the test.
[][]Batch No. & A.R. No. will be displayed. Using down arrow and enter key, add the batch No. & A.R No. (Lab. Control No.) up to ten digits. Press enter key to register the number.

[][]It will display checking connection where the instrument establishes link with the syringe/peristaltic pump and sample/fraction collector.
[][]After the connection between the instruments is done, sample collector will initialize & ‘Lift Not Park’ Indication will be display (If lift is not parked).
[][]‘Wait for the temperature’ indication will be display till the set temperature is achieved. User can also access MENU to cheek jar temperature.
[][]Ready indication will glow on front panel when jar temperature reach to set point & start indication will be displayed.
[][]Press START key form front panel to start the test.
[][]‘Drop the tablet and press START’ message will be displayed immediately if paddle or 45 was selected and if basket or paddle over disk was selected then ‘Press lift up, Load Apparatus’ will be displayed on screen.
[][]Press Enter to start the test, run screen will be displayed. Current status of the test and sample timing are displayed throughout the test.
[][]After completion of work, switch ‘OFF’ the instrument.
[][]Switch ‘OFF’ the mains when not required.
[][]Fill up the operation log book for Dissolution tester as per Annexure-III.

Physical Calibration

[][]Frequency: Perform mechanical calibration of the dissolution tester once in every six months or if the system has been moved, serviced or a malfunction is suspected.

Temperature Calibration:

[][]Switch on the mains.
[][]Set the temperature to 37°C by following the temperature setting procedure given in operation.

[][]Ensure that the jars are filled with water.
[][]Allow the instrument to stabilize.
[][]Measure the temperature of the water bath and of each jar with a calibrated thermometer and compare the result against the digital display on the apparatus.
[][]Record the observation as per Annexure-I.
[][]Acceptance Criteria: 37°C ± 0.5°C.

RPM Calibration:

[][]Switch on the mains.
[][]Set the RPM to 50 as per procedure given in the operation.
[][]Start the stirrer and measure the RPM by using calibrated tachometer.
[][]Record the observation as per Annexure-I.
[][]Similarly check the RPM 75, 100, and 150 and record the observations.
[][]Acceptable criteria: ± 4% of set value.

Time Calibration:

[][]Switch on the mains.
[][]Set the desired time (30 and 45 minutes) by following the temperature setting procedure given in operation.
[][]Check the time using a calibrated stop watch and record the observations as per Annexure-I.
[][]Acceptable criteria: ± 2% of set value.

Chemical Calibration (Performance Verification Testing)

[][]Frequency: Perform chemical calibration of the dissolution tester once in a year or if the system has been moved, serviced or a malfunction is suspected.
[][]For USP Dissolution Apparatus 1 (basket) and Apparatus 2 (paddle):
[][]If the instrument is outside calibration, a label of “Out of calibration” is placed.
[][]Apparatus must be calibrated with the following :
[][]Disintegrating Type – USP Prednisone Tablets 10 mg at 50 rpm
[][]Non-disintegrating Type – USP Salicylic Acid Tablets 300 mg at 100 rpm
[][]Checking Standards in the on line-USP and printing Lot-Specific Standard Certificates. Verifies Standard Lots are current within expiry.

Disintegrating Type – USP Prednisone tablets 10 mg at 50 rpm:

[][]Follow the directions for storage and use on the label of the reference standard.
[][]If drying instructions are included on the label, only dry sufficient quantity required for the test (use a clean, dry vessel when drying and not the original container).
[][]Standard solutions must be prepared on the day of use.

Prednisone standard preparation:

[][]Accurately weigh 20 mg Prednisone standard into a 100 ml volumetric flask containing 5 ml methanol.
[][]Sonicate to dissolve and dilute to volume with distilled or purified water and mix well.
[][]Further dilute 5.0 ml of this solution to 100 ml with distilled or purified water and mix well.
[][]Dissolution medium preparation and de-aeration:
[][]Filter the dissolution medium (Distilled or purified water 500 ml) with the aid of a vacuum through a 0.45 µm-porosity membrane filter into a suitable filtering flask.

Test procedure:

[][]Using a volumetric flask, measure 500 ml distilled or purified water into each of the six vessels.
[][]Allow medium to equilibrate for approximately 30 minutes before test is commenced.
[][]When dissolution bath has equilibrated, check the temperature of each vessel is 37.0°C ± 0.5°C.

[][]Carefully weigh 6 de-dusted USP Prednisone Tablets 10 mg.
[][]Drop one previously de-dusted tablet into each of the vessels via the sample holes in the lids, raising the stirrer shaft fully before dropping the tablet into the vessel, and pushing the shaft fully down when the tablet has reached the bottom.
[][]Operate the apparatus at 50 rpm for 30 minutes.
[][]After 30 minutes withdraw approximately 50 ml midway between the surface of the dissolution medium and the top of the blade, not less than 1cm from the vessel wall.
[][]Filter through a Whatman Number 1 filter paper, discarding the first few ml of filtrate.
[][]Scan the standard from 300-200 nm to obtain the maximum absorbance at the optimum wavelength (approximately 242 nm).
[][]Determine the absorbance of the six samples at that wavelength in fixed mode.
Calculate the percentage prednisone dissolved for all 12 stations using the following calculations:

% Dissolved =
Absorbance of Sample x Standard Concentration (mg/l) x Standard Potency x 100 DIVIDED BY
Absorbance of Standard x Sample Concentration if 100% dissolved (C100)

Acceptance Criteria:

[][]Check the percentage released limit of USP dissolution calibration tablets (Disintegration type: Prednisone tablets) from the respective batch certificate provided by USP.
[][]If any one station is outside of specification, place an “Instrument out of calibration, DO NOT USE” label on the instrument.
[][]Inform In-charge, QC; if the results do not meet the criteria.

Test interpretation:

The apparatus shall be suitable if the individual calculated values at each indicated speed are within the range specified in the tablet obtained with the each lot of tablets.

Note: An amount of alcohol not to exceed 5% of the total volume of the standard solution may be used to bring the prednisone standard into solution prior to dilution with dissolution medium.

Recording of Results:

[][]All relevant information on the calibration must be completed on Annexure-II.
[][]When all the results have been checked affix a Calibration label to the instrument.

Cleaning procedure

[][]Lift the stirrer unit by using “lift UP” key.
[][]Immerse the replenishment tubes in a vessel of the instrument or a beaker outside of the instrument containing purified water.
[][]Press F1 Key [Menu] from front panel.
[][]Press 5 from alphanumeric keypad to enter Run.
[][]Again press 2 for cleaning cycle.
[][]Iterations of cleaning cycle will be displayed, press F3 to save the command.
[][]Batch No.:, A. R. No.:, User Name: will be displayed. Press Enter 3 times.
[][]Display will be showed Press UP to edit/Press Enter to proceed, again press Enter.
[][]It will display checking connection where the instrument establishes link with the syringe/peristaltic pump and sample/fraction collector. At that time wait for few seconds.
[][]Press START
[][]ABORT STOP will be displayed on the LED screen.
[][]To start the cleaning cycle, press Start.
[][]After completion of cleaning cycle display will show checking connection Press START
[][]ABORT STOP
[][]Press F3 to stop the cleaning cycle and start the empty tube cleaning.
[][]Before start the empty tube cleaning, the replenishment tube should be placed in the open air from vessel or beaker.

[][]Remove the test vessels from their place and discard the medium.
[][]Wash each vessel with purified water and then set them inside the dissolution bath number wise.
[][]Remove basket/ paddle apparatus from the dissolution tester. Wash them with purified water and dry with tissue paper and keep at dedicated place.
[][]Clean and replace the water from dissolution bath fortnightly (once in every two weeks) or if necessary.
[][]Remove all vessels from the dissolution bath.
[][]Remove the basket/ paddle apparatus from the stirrer unit.
[][]Remove the circulating pipe which is provided at the right rare side of the dissolution bath.
[][]Start the circulation pump from the option menu and drain the dirty water in a waste water bucket.
[][]Insert the circulating pump in its proper place.
[][]Wash the dissolution bath with raw water, detergent solution and then again with raw water sequentially until no foam of detergent remains in the bath.
[][]Wash the bath finally with purified water and fill the bath with the same up to the level mark.
[][]De-dust the outer surface of the instrument with a clean dry cloth every day.

Annexure: Dissolution Tester Calibration

Annexure-I: Physical Calibration Information Sheet for Dissolution Tester
Annexure-II: Chemical Calibration Information Sheet for Dissolution Tester
Annexure-III: Operation Log book for Dissolution Tester

Dissolution Tester Calibration with Operation and Cleaning Read More »

Water Sampling and Analysis in QC Laboratory

Quality Control, SOPs

Water Sampling, Purpose :

Water Sampling, The purpose of this SOP is to describe the procedure for sampling and analysis of water in quality control laboratory.

Water Sampling, Scope :

This procedure is applicable for sampling and analysis in Quality Control Laboratory for purified water, water for injection, purified steam condensate, potable water, drinking water and effluent treatment plant water from different user points used in XX Pharmaceuticals Ltd.

Definitions / Abbreviation:

[][]QC: Quality Control
[][]QA: Quality Assurance
[][]QCom: Quality Compliance
[][]COA: Certificate of Analysis
[][]WFI : Water for Injection
[][]PW: Purified water
[][]ETP: Effluent treatment plant

Responsibilities:

The roles and responsibility is as follows:

Lab Attendant, QC

[][]To collect water sample from different sampling points.

Officer / Executive, QC Officer / Executive, QC

[][]To prepare schedule sampling of water.
[][]To organize the sampling of water.
[][]Analysis of water and preparation of respective test report.
[][]Trend analysis of water.
[][]To ensure that this procedure is followed.
[][]To maintain the records properly as per SOP.

Sr. Executive, QC

[][]Reviewing of test report.

Manager, Quality Control

[][]Approval of test report.
[][]To ensure implementation of the SOP after training.

Head of Quality Assurance

[][]To ensure the overall implementation of the SOP.
[][]Approval of the SOP.

Procedure:

Precaution(s):

[][]Use gloves, mask & cap during sampling.
[][]Collect sample carefully to avoid contamination.
[][]Carefully collect water sample with high temperature and close the cap of container freely.

Sample Collection :

[][]Take required number of 500 ml to 1 Liter clean glass containers with cap for sampling.
[][]Open sampling points such as tap fixtures / hosepipe and allow water to run for not less than 1 minute.
[][]Rinse the container with respective water.
[][]Collect approximately 500 ml of water and immediately recap the sample containers after collecting samples. Keep the cap slightly loose when water temperature is above 30°C.
[][]Label the sample container providing information such as name of water, sample point no. / location, time, initial of sampler and date of sampling.
[][]Transfer the sample immediately to laboratory and analyze the sample within 24 hours of sampling. Preserve the sample in refrigerator (2°C to 8°C), if required.
[][]Entry information of sampling in sampling register after sampling.

Test Schedule :

Perform the test as per the following schedule :

Source of Water /Test frequency

Potable Water/ Once in a month
Purified Water/ Once in 14 days
ETP Water /Once in a week
Water for Injection/ Once in a week

Chemical Analysis :

[][]Perform analysis of water as per respective specification and method.
[][]Compile the raw data and prepare the certificate of analysis as per respective annexure with the test results & take approval of the COA.
[][]Share the water test reports with Engineering department and or Production department.
[][]Water test results are to be evaluated on a continuous basis and should be summarized in trend analysis report six monthly in order to identify significant trends.
[][]Inform respective department i.e. Engineering, Production and Quality Assurance Department whenever atypical data found beyond alert limit.
[][]Inform respective department i.e. Engineering, Production and Quality Assurance Department for taking actions whenever data found beyond action limit.

Annexure:

Annexure-I : Format for Certificate of Analysis for Potable water/Drinking water
Annexure-II : Format for Certificate of Analysis for Purified water/Water for injection/Purified Steam Condensate
Annexure-III : Format for Certificate of Analysis for Effluent Water
Annexure-IV : Format for Water Sampling Register
Annexure-V : Water sampling points

Water Sampling and Analysis in QC Laboratory Read More »

Calibration of Semi-micro Osmometer with operation & cleaning

Quality Control, SOPs

Calibration of Semi-micro Osmometer, Purpose:

Calibration of Semi-micro Osmometer, The purpose of this SOP is to describe the operation, calibration and cleaning of Semi-micro Osmometer (Brand: KNAUER; Model: K-7400) used in the quality control laboratory of XX Pharmaceuticals Limited.

Calibration of Semi-micro Osmometer,Scope:

This procedure is applicable for Semi-micro Osmometer, installed in the quality control laboratory general block of Labaid Pharmaceuticals Limited.

Definitions / Abbreviation:

Standard Operating Procedure (SOP): Standard Operating Procedure.
QC: Quality Control.

Responsibilities:

The roles and responsibility is as follows:

Sr. Executive/Executive, QC

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

Manager, Quality Control

Head of Quality Assurance

Approval of the SOP.
To ensure the overall implementation of the SOP.

Procedure:

Precaution(s):

[][]Prior to use, user must ensure that equipment is calibrated.
[][]To ensure a fixed sample volume, always introduce the solutions with a clean and dry pipette into the measuring vessel.
[][]Handle the thermistor always very carefully. All abrasive materials should be kept away from it.
[][]Solutions containing proteins, such as sera, can only be measured once. Freezing causes denaturisation of the protein so that repetition of the measurement with the same sample would result in increased values. Thus, in the case of sera, only one measurement is possible for one sample.
[][]Only real osmolalities can be measured. It is not possible to prepare other standard solutions by dilution of a calibration solution since the activity coefficient of the solution changes with dilution.
[][]In this case Store the water which is used for the zero point calibration in glass bottles.
[][]If the same salt solution is measured several times, it must be mixed after thawing (stir briefly). During the thawing process ice floats to the top of the solution. As ice does not contain salt, the top layer of the solution is diluted while thawing.
[][]Calibration solutions can become more concentrated if the bottle is opened frequently. So, use KNAUER calibration solutions in glass ampoules.
[][]Prior to the measuring, a little bit water condensed in the cooling compartment should be removed with a dry cloth.

Operation:

[][]Preparing the Osmometer K-7400
[][]Switch ON the instrument at least 5 minutes before use.
[][]Press the vibrator key to check the stirrer. It will run for a second.
[][]Optionally a thermo printer can be connected to the RS232 socket. The result of each measurement will be printed automatically.
[][]After a calibration, an outprint of Calibration will be found automatically.
[][]In case of interrupted runs (caused by any error), the screen displays the corresponding error message.

Preparing a Measurement

[][]Place 0.15 ml sample or calibration solution into a clean, dry measurement vial.
[][]Put the vial all the way into the adapter. The meniscus of the liquid must be horizontal.
[][]Place the measuring head on the instrument in such a way that the vial extends into the cooling cavity.
[][]Thus the instrument is ready for calibrating or measuring.

Calibration:

[][]Prepare the instrument for a measurement of deionised water.
[][]Set the first field in the second row of the CALIBRATE screen to „0000“.
[][]Press the start key.
[][]After finishing the run on the screen is displayed 0000 mOsmol > -0.81°C<.
[][]To accept this value, press the START key again.
[][]Wait for the warming up to the stand-by temperature.
[][]Prepare the instrument for a measurement of a 300 mOsm/kg calibration solution.
[][]Activate the second calibration field and select “0300” and repeat steps
[][]For a 4 point calibration, repeat the procedure for calibration fields

Measuring Samples:

[][]Prepare the instrument for a measurement of a sample solution.
[][]Press the START key to start the measurement run.
[][]The instrument detects the freezing point depression and if the crystallisation occurred properly displays the corresponding osmolality on the main screen.
[][]The printer output is given automatically.
[][]If no crystallisation (temperature increase) takes place after the automatically start of the vibrator the measurement will be stopped with the error message “> ERROR < NO FREEZE”.
[][]If the crystallisation (temperature increase) takes place before the start of the vibrator the measurement also will be stopped with an error message> ERROR < FREEZE.
[][]Do not remove the measurement vessel from the adapter before the sample is molten. Otherwise the danger of damaging the measuring head is given. The sample melting can be accelerated by warming up with the fingers.

Cleaning procedure:

[][]Measuring vessel and thermistor should be cleaned occasionally with KNAUER cleaning solution supplied with the instrument. (Dilution: 1: 10 solution in purified water of 40±5°C)
[][]Clean and dry the measuring vessels with alcohol or acetone because remaining solvent vapours could cause false results.

Annexure:

Annexure-I: Operation Logbook for Semi-micro Osmometer.

Calibration of Semi-micro Osmometer with operation & cleaning Read More »

Calibration of HPLC System With Operation & Cleaning

SOPs

Calibration of HPLC, Purpose:

Calibration of HPLC, The purpose of this SOP is to describe the operation, calibration and cleaning of High Performance Liquid Chromatography system with DAD & RID (Brand: Agilent; Model: 1260 Infinity) used in the quality control laboratory at XX Pharmaceuticals Limited.

Calibration of HPLC, Scope:

This procedure is applicable for Agilent PC based Quaternary Gradient Automated High Performance Liquid Chromatography System, installed in the quality control laboratory of XX Pharmaceuticals Limited.

Definitions / Abbreviation:

[][]SOP : Standard Operating Procedure.
[][]QC : Quality Control.
[][]HPLC : High performance liquid chromatography
[][]DAD : Diode Array Detector
[][]RID : Refractive Index Detector

Responsibilities:

The roles and responsibility is as follows:

Sr. Executive/Executive, QC

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

Manager, Quality Control

Procedure:

General Precaution(s):

[][]Prior to use, user must ensure that instrument is calibrated.
[][]Be sure that the drain valve is open before purging and tightly closed after purging.
[][]Before shutting down the system ensure that column is thoroughly washed and kept in appropriate solvent.
[][]Mobile phase, Diluting solvents and other solutions, which are used in HPLC, should be freshly prepared.
[][]Degas the mobile phase before using.
[][]Rinse the flow lines after completion of analysis as per solvent used in the system.
[][]Make sure that the solvent filter/diffuser is completely immersed in solvent.
[][]Update the solvent bottle before run.
[][]During set up the flow rate at priming, do not press Run/Stop to start the pump.
[][]Purge the pump with fresh diluent (filtered and degassed).
[][]Clean the solvent diffuser/filter once in a week.
[][]Fill up & attach Labels of the solvent reservoirs properly.

Operation of DAD:

[][]Switch ‘ON’ the power of Quaternary Pump, Autosampler, Thermostatic Column Compartment, Detector, CPU, Monitor if already not switched on.
[][]Wait until all the modules are initialized and are ready for next operation.
[][]Set specified column in the column compartment.
[][]Computer and Software Log in
[][]Double click on the icon of HPLC_DAD (online) from Desktop.
[][]Click Download to instrument/Upload from instrument/New method from instrument.

Purging Lines

[][]Insert the solvent tubing into the appropriate reservoirs.
[][]Gently shake the filters in the reservoirs to remove any bubbles that may be trapped.
[][]Open the purge valve of pump by half (1/2) turning anticlockwise.

[][]Go to the Agilent modular controller screen.
[][]Click Switch On to switch on all the modules.
[][]Right Click on the mouse over Quat. Pump module.
[][]Click Method.
[][]Enter flow rate 5.00 ml/min.
[][]Enter the % of composition of the desired purging line.
[][]Press OK/Apply.

Update the Solvent Bottle

[][]Right Click on the mouse over Quat. Pump module.
[][]Click Bottle Fillings.
[][]Enter the Solvent Volume of respective Bottles and enter the Total volume of the Bottle.
[][]Click OK.

[][]Create a new Method
[][]Click Method from menu.
[][]Click New Method.
[][]Click Method from menu.
[][]Click Entire Method…
[][]Click OK > OK >OK.
[][]Select Quart. Pump.
[][]Enter Flow rate, % of solvent ratio, stop time and maximum pressure Limit (Max. 400).
[][]For Gradient flow enter the time program.
[][]Select Sampler.

[][]Click OK.
[][]Click desire method.
[][]Click Add Method.
[][]Click OK>OK> OK>OK> OK.
[][]Click Method from menu.
[][]Click Save Method As…
[][]Select location and enter Method Name.
[][]Click OK.

Create a new Sequence

[][]Click Sequence from menu.
[][]Click New Sequence Template.
[][]Click Sequence from menu.
[][]Click Sequence Table…
[][]Enter Sample Location, Sample Name, Method Name and Data File.
[][]Click OK.
[][]Click Sequence from menu.

[][]Click Sequence Parameters…
[][]Locate the Data File Path.
[][]Click Post-Sequence Command/macro.
[][]Select STANDBY from dropdown list.
[][]Click OK.
[][]Click Sequence from menu.
[][]Click Save Sequence Template As…
[][]Select location and enter Sequence Name.
[][]Click OK

Run Samples

[][]Select the created Method.
[][]Select the created Sequence.
[][]Insert the solvent tubing into the appropriate reservoirs.
[][]Click Switch On to switch on all the modules.
[][]Wait for Base line stable.
[][]After getting the Baseline stability click RunControl from menu.
[][]Click Run Sequence.
[][]Instrument will be run as per selected Method and Sequence; and data will save as per selected location.

Data Processing

[][]Double click on the icon of HPLC DAD (offline) from Desktop.
[][]Select desire Sequence file from Data Analysis window.
[][]Double click a file of Navigation Table.
[][]Click Graphics form Menu.
[][]Click Signal Options.
[][]Click Compound Names.
[][]Click OK.
[][]Click Edit or Set Integration Events Table.
[][]Remove the unexpected peak either using Area or Height rejection or using time integration event program.
[][]Click OK.
[][]Click Calibration from Menu.
[][]Click Calibration Settings
[][]Enter Amount Units.
[][]Click OK.
[][]Click Calibration from Menu.
[][]Click New Calibration Table…
[][]Enter Default Amount (Standard wt. in mg).
[][]Click OK.
[][]Enter Compound Name in Calibration Table.
[][]Click OK.
[][]Click Method from Menu.
[][]Click Save Method As Save As New Master Method.
[][]Select location and enter Method Name.
[][]Click OK.
[][]Click Sequence from menu.
[][]Click Sequence Table
[][]Select the desire processing Method and Fill down.
[][]Select Sample Type as Calibration using drop down list for standard injections.
[][]For first Standard select Replace both for Update RF & Update RT using drop down list.
[][]Enter Multiplier.
[][]Click Reprocess.
[][]Click OK.
[][]Sequence will be processed as per selected processing method.

Report Print

[][]Select Data/Set of Data.
[][]Select Review.
[][]Click File from Menu.
[][]Clock Load Template.
[][]Select Template.
[][]Click Open.
[][]Click Print Report from Menu.

Operation of RID:

[][]Switch ‘ON’ the power of Quaternary Pump, Autosampler, Thermostatic Column Compartment, Detectors, CPU, Monitor if already not switched on.
[][]Wait until all the modules are initialized and are ready for next operation.
[][]Set specified column in the column compartment.
[][]Computer and Software Log in
[][]Double click on the icon of HPLC_RID (online) from Desktop.
[][]Click Download to instrument/Upload from instrument/New method from instrument.

Purging Lines

[][]Flow the operation steps
[][]Update the Solvent Bottle
[][]Flow the operation steps

Stabilization of RID detector

[][]Insert the solvent tubing into the appropriate reservoirs. Be sure that the detector waste lines and the sample loop waste line drain into the appropriate container.
[][]Right Click on RID window.
[][]Click Open Purge Valve.
[][]Right Click on RID window.
[][]Click Switch Recycling On.
[][]Wait for baseline stability.
[][]After baseline stability right Click on RID window.
[][]Click Close Purge Valve.
[][]Right Click on RID window.
[][]Click Switch Recycling Off.

Create a new Method

[][]Flow the operation steps
[][]Select DAD.
[][]Deselect Signals and UV Lamp if they are not previously deselected.
[][]Click OK.
[][]Click RID.
[][]Enter the Optical Input Temperature.
[][]Click OK.
[][]Select RID1 A, Refractive Index Signal.
[][]Click Add Method.
[][]Flow the operation steps

Create a new Sequence

[][]Flow the operation steps
[][]Run Samples
[][]Flow the operation steps
[][]Data Processing
[][]Double click on the icon of HPLC_RID (offline) from Desktop.
[][]Flow the operation steps
[][]Click File from menu.
[][]Click Load Signals…
[][]Select a standard file.
[][]Select RID1 A, Refractive Index Signal.
[][]Click OK.
[][]Flow the operation steps

Report Print

Flow the operation steps

Shut Down

[][]Click “Off” icon to stop Instrument.
[][]Carryout system suitability test every day before analysis.
[][]Fill up the column information logbook after analysis.
[][]Wash the column following as per HPLC Column Washing Procedure
[][]Exit from the “OpenLab Chemstation’’ software.
[][]Put off the power of equipment and computer.
[][]Record in the Logbook for operation of HPLC (as per Annexure-IV).

Operation of Queue Planner:

[][]When two or more sequence to be run with the same column and same mobile phase/mobile phase composition; Queue Planner is required.
[][]Save individual method and sequence for individual operation.
[][]Click RunControl from menu.
[][]Click Queue Planner.
[][]Insert/Append sequence when required. Use Up/Down button to rearrange the sequence.
[][]Click Save As.

[][]Select location and enter file name.
[][]Click Add to back of queue.
[][]During using of Queue Planner keep wash method and STANDBY at the last sequence only.

Calibration of HPLC:

Calibrate the HPLC at every 6 month’s frequency either by following procedure or as per supplier’s protocol:
[][]Quaternary Pump : 1260 Qart Pump VL
[][]Check the LED is on.
[][]Turn on the power.
[][]Set Flow Rate at 0.500 ml/min and 5.000 ml/min.
[][]Check flow rate, average value, STD, accuracy and precision.
[][]Record the value in Calibration Information Sheet for Pump Flow and Accuracy of Quaternary Pump VL (Annexure-I).
Set the following parameters:
Injection Volume : 0.0 µl
Flow Rate : 2.0 ml/min
Wavelength : 265 nm
Run Time : 26.0 min
Column Temperature : 40.0 °C
Evaluated Compound : Acetone
[][]Set the following Gradient Program and record the data:
Gradient Pump A/ Pump B
Initial 00% /100%
Step 1 20% /80%
Step 2 40% /60%
Step 3 60% /40%
Step 4 80%/ 20%
[][]Check the height, noise, drift and composition for various compositions.
[][]Record the Height, Noise, Drift and Composition in Calibration Information Sheet for Gradient Composition (Annexure-I).
[][]Thermostatic Column Compartment: 1260 TCC
[][]Check the LED is on.
[][]Turn on the power.
[][]Set Flow Rate 1.0 ml/min.
[][]Set column temperatures at 80.0°C and 40.0°C.
[][]Check the Column Temperature Accuracy and Column Temperature Stability from Column Compartment Display in 4 munities interval.
[][]Record the value in Calibration Information Sheet for Thermostatic Column Compartment (Annexure-II).

[][]Variable Wavelength Detector: 1260 DAD VL
[][]Check the LED is on.
[][]Turn on the power.

Set the following parameters:
Pump Flow Rate : 1.0 ml/min
Run Time : 2.0 min
Injection volume : 15 µl
Column Temperature : 40.0°C
Sample : Caffeine Std
Evaluated Compound : Caffeine
[][]Evaluating Standard Concentration : 25.0 µl/ml (form Certificate of Analysis)
[][]Set wavelengths at 205 nm, 245 nm and 273 nm.
[][]Check the area of the chromatograms for respective wavelengths.
[][]Record the value in Calibration Information Sheet for Variable Wavelength Detector (Annexure-III).
[][]Set the following parameters:
Flow Rate : 1.0 ml/min
Run Time : 24.0 min
Noise Evaluation Start Time : 3.0 min
Noise Evaluation Duration : 20.0 min
Injection Volume : 0.0 µl
Column Temperature : 40.0°C
[][]Check the Noise and Drift.
[][]Record the Noise and Drift in Calibration Information Sheet for Noise and Drift of Variable Wavelength Detector (Annexure-III).
Set the following parameters:
Flow Rate : 1.0 ml/min
Column Temperature : 40.0°C
Run Time : 7.0 min
Injection Volume : 10.0 µl
Noise Evaluation Start Time/Duration : 3.00 min/3.00 min
Evaluation Standard Concentration : 25 µg/ml (Certificate of Analysis)
Sample : Caffeine Std
Evaluation Compound : Caffeine
Detector Path Length : 10 mm
Wavelength : 273 nm
[][]Check the signal to noise ratio.
[][]Record the Signal to Noise in Calibration Information Sheet for Signal to Noise of Variable Wavelength Detector (Annexure-III).
Set the following parameters:
Flow Rate : 1.0 ml/min
Column Temperature : 40.0°C
Run Time : 2.0 min
Injection Volume : 20.0 µl

Sample : Caffeine Std
Wavelength : 273 nm
Evaluation Compound : Caffeine
[][]Check the area and height and find the R/F, R/F average, R/F STD and Coefficient of Determination.
[][]Record the linearity in Calibration Information Sheet for Response Linearity of Variable Wavelength Detector (Annexure-III).
[][]Refractive Index Detector: 1260 RID
[][]Check the LED is on.
[][]Turn on the power.
Set the following parameters:
Flow Rate : 1.0 ml/min
Run Time : 24.0 min
Noise Evaluation Start Time : 3.0 min
Noise Evaluation Duration : 20.0 min
Injection Volume : 0.0 µl
Column Temperature : 40.0°C
[][]Check the Noise and Drift.
[][]Record the Noise and Drift in Calibration Information Sheet for Noise and Drift of Refractive Index Detector (Annexure-IV).
Set the following parameters:
Flow Rate : 1.0 ml/min
Column Temperature : 40.0°C
Run Time : 7.0 min
Injection Volume : 10.0 µl
Noise Evaluation Start Time/Duration : 3.00 min/3.00 min
Evaluation Standard Concentration : 25 µg/ml (Certificate of Analysis)
Sample : RID Std kit
Evaluation Compound : Glycerin
Detector Path Length : 10 mm

[][]Check the signal to noise ratio.
[][]Record the Signal to Noise in Calibration Information Sheet for Signal to Noise of Refractive Index Detector (Annexure-IV).
Set the following parameters:
Flow Rate : 1.0 ml/min
Column Temperature : 40.0°C
Run Time : 2.0 min
Injection Volume : 20.0 µl
Sample : RID Std kit
Evaluation Compound : Glycerin
[][]Check the area and height and find the R/F, R/F average, R/F STD and Coefficient of Determination.
[][]Record the linearity in Calibration Information Sheet for Response Linearity of Variable Wavelength Detector (Annexure-IV).
[][]High Performance Autosampler: 1260 ALS
[][]Check the LED is on.
[][]Turn on the power.
Set the following parameters:
Injection Volume : 20 µl
Run Time : 2.0 min
Flow Rate : 1.0 ml/min
Column Temperature : 40.0°C
Wavelength : 273 nm
Sample : Caffeine Std
Evaluated Compound : Caffeine
Standard Concentration : 25 µg/ml (from Certificate of Analysis)
[][]Check the Area and Height of six chromatograms and calculate average value, standard deviation and %RSD.
[][]Record the value in Calibration Information Sheet for High Performance Autosampler (Annexure-V).
Set the following parameter:
Injection Volume : 20 µl
Run Time : 2.0 min
Flow Rate : 1.0 ml/min
Column Temperature : 40.0 °C
Wavelength : 273 nm
Sample : Caffeine Std
Evaluated Compound : Caffeine
Standard Concentration : 25 µg/ml (from Certificate of Analysis)
[][]Check the Carry Over of Injection.
[][]Record the Carry Over in Calibration Information Sheet for Injection Carry Over of High Performance Autosampler (Annexure-V).
[][]Cleaning procedure
[][]Clean the instrument daily as follows
[][]Switch ‘OFF’ the instrument and switch ‘OFF’ the mains.
[][]Clean the outer surface of the instrument with dry clean cloth.
[][]Clean the surrounding areas of instrument with a cloth dampen in water then wipe with a dry cotton cloth.
[][]Remove any dirt or spot with isopropyl alcohol and then dry with tissue paper.
[][]After completion of each analysis, clean the HPLC as follows
[][]Transfer the used glassware for washing.
[][]Clean the plunger seal by injecting distilled water three to four times with syringe.
[][]Remove the column and replace with joints for the cleaning of tubings & flush with 6N nitric acid, distilled water and then with methanol.
[][]Remove the air in suction pipe by purging the line and flushing with distilled water for some time.
[][]Clean the suction filter by sonicating it into nitric acid for 10 to 15 minutes and then wash it with water, when required.
[][]Replace the joints with column and wash the column first with distilled water and then with methanol.
[][]Switch “OFF” the pump, detector(s), injector and column compartment.
[][]Finally enter fill-up the Logbook for Operation of HPLC (Annexure-VI).

Annexure: Calibration of HPLC

Annexure-I: Calibration Information Sheet for Quaternary Pump VL
Annexure-II: Calibration Information Sheet for Thermostatic Column Compartment
Annexure-III: Calibration Information Sheet for Variable Wavelength Detector
Annexure-IV: Calibration Information Sheet for Refractive Index Detector
Annexure-V: Calibration Information Sheet for High Performance Autosampler
Annexure-VI: Logbook for Operation of HPLC

Calibration of HPLC System With Operation & Cleaning Read More »