DOCUMENT CONTROL SOP

1.0 PURPOSE :
To provide a procedure for document control.
2.0 SCOPE :
To ensure a complete control over all the authorised documents.
3.0 RESPONSIBILITY :
QA Personnel
4.0 PROCEDURE :
4.1 All documents should be identified by a unique title and document number.
4.2. Document should be designed, prepared, received, approved, signed and dated by authorised persons and distributed to concerned departments.
4.3. Approved documents should not be corrected manually with a pen / pencil for any reason.

Preparation of Documents
4.4 Master Formula Record -
Master formula record to be prepared by QA in consultation with Formulation development, Production and Quality Control.
Master formula record includes :
4.4.1 Batch Manufacturing record (BMR).
4.4.2 Batch Packing record (BPR).
4.4.3 Intermediate/ Packing Material / Finished product specification.
4.4.4 Specimen of Printed packaging material.
4.5 All documents of “ Master Formula Record” should be stamped as “Master Copy” in Green at the non- text side (back side).
4.6 Batch Manufacturing Records consists of following.
4.6.1 Manufacturing Work Order.
4.6.2 Coating Work Order
4.6.3 Stage wise processing details
4.6.4 In-process checks
4.6.4.1 Compression and coating (Tablets)
4.6.5 Deviation (if any)
4.7 Batch Packing Records consists of following.
4.7.1 Packing work order.
4.7.2 Over printing details
4.7.3 Packing details
4.7.4 In-process checks
4.7.4.1 Over printing
4.7.4.2 Bottle washing and filling (liquid orals)
4.7.4.3 Bottle cleaning and filling (Dry Syrup)
4.7.4.4 Packing
4.7.4.5 Shipper weight profile
4.7.5 Deviation record (if any)
Document Issuing
4.8 During the issue of a document the necessary entries have to be made in the respective document control register with details of Document name, Document number, Issued by, received by, Retrieved document No., (if any) Number of copies retrieved, destroyed by, Date, Checked by details.
4.9 BMR / BPR - photo copies of master copy are issued for regular production. All sheets of photo copies should be signed and dated by QA Personnel.
4.10 Completed batch record should come back to QA for review.
4.11 After review of the records and QC analytical results, QA will release the batch (Product) for sale.
4.12 All the completed batch records should be controlled by QA.
4.13 All batch record should be retained atleast for five year after the shelf life of the product.
4.14 Validation protocol / Report / Summary: All validation protocols to be prepared by QA and issued to respective department.
4.15 After completion of validation, the Protocols, Reports along with the QC results and Summary report to be prepared and filed by Q.A. department in respective validation records.
4.16 Protocols and reports of cleaning validation with the QC analytical reports to be prepared and filed in a Cleaning validation file.
4.17 Equipment Qualification: Equipment Qualification protocols / Reports to be issued by QA to the respective department.
4.18 All completed Equipment Qualification Protocol / Reports should be compiled by QA in respective qualification files.
4.18.1 Design Qualification
4.18.2 Installation qualification
4.18.3 Operational qualification
4.18.4 Performance qualification
4.18.5 Visit reports (if any)
4.19 Specifications :
All specifications of Raw material / Packing material / Intermediate / Finished product specification to be prepared by QC and authorised by QA. Original documents should be filed in respective master files of QA Department with a “MASTER COPY” seal in green colour on the text side (backside) of the page.
4.20 A controlled copy of specification should be issued to the QC department with “CONTROLLED COPY” seal in red colour on top of each page on the printed side.
4.21 Standard Operating Procedure :
SOP to be prepared as per the SOP preparation of SOP.
4.22 Master copies of SOP should be filed in QA department in respective files with “MASTER COPY” seal in green colour on the non text side (backside) of the page.
4.23 Different stamps should be used for circulating SOP to the concerned departments either with a “CONTROLLED COPY” seal in red colour or “DISPLAY COPY" in blue colour on top of each page on the printed side as per the need.
4.24 Third party document :
Separate files to be maintained for each third party.
4.25 Batch records for Third parties to be prepared by QA Department according to their requirement.
4.26 Master copy of the records to be filed in respective files and controlled copies should be issued to concerned parties.
4.27 Batch summary sheet and other related documents to be collected by them, reviewed and filed by QA.
4.28 Art works
All documents related to artwork approval including the specimen samples to be filed and controlled by QC and QA department.
4.29
Stability samples
Details of stability samples to be maintained.
4.30
Log Books : Following Log books should be maintained (Annexure – List of log books with numbers)
4.30.1
Production Department
4.30.1.1
Equipment Operation
4.30.1.2
Equipment Cleaning
4.30.1.3
Planned Preventive Maintenance of Equipment
4.30.1.4
Temperature and Humidity
4.30.1.5
Pressure Differential
4.30.1.6
Balance Calibration
4.30.1.7
General House Keeping
4.30.1.8
PestoFlash
4.30.1.9
Issue and control of stereos
4.30.1.10
Issue and control of Punches and dies
4.30.1.11
Intermediate log
4.30.1.12
Overprinting of Packaging Materials
4.30.1.13
pH meter log
4.30.1.14
Transfer pump and Transfer line log
4.30.2
Utility Department
4.30.2.1
DM Plant Operation
4.30.2.2
DM Plant Regeneration
4.30.2.3
Planned Preventive Maintenance of AHUs
4.30.2.4
Compressed Air
4.30.3
Quality Control Department
4.30.3.1
Instrument Operation and cleaning
4.30.3.2
Volumetric Solutions
4.30.3.3
Reference Standard
4.30.3.4
Working Standards
4.30.3.5
Reserve Sample
4.30.3.6
Control Sample
4.30.3.7
Glass ware calibration
4.30.3.8
Calculation sheet
4.30.3.9
pH meter
4.30.3.10
Distilled water log
4.30.3.11
Autoclave Calibration
4.30.3.12
Sub culturing and destruction of sub culture
4.30.3.13
Media Stock Register
4.30.3.14
De-fumigation checks log
4.30.3.15
Media Preparation
4.30.3.16
Media destruction
4.30.3.17
Growth Promotion test
4.30.3.18
Plate exposure
4.30.3.19
UV lamp log
4.30.3.20
Raw materials analysis
4.31
Training record : The training records of individual personnel, should be retained till the last record which has to be signed by him expires.
Training Records consists of
4.31.1
Annual training Schedule
4.31.2
Training modules
4.31.3
Individual Training records
4.31.4
General Training record
4.31.5
Material/Visual aids/Literature used for Training
4.32
Apart from the above documents, QA Department should also maintain the following records.
4.32.1
Technical Change Procedure
4.32.2
Audit report
4.32.3
Fumigation record
4.32.4
Packing specification
4.32.5
Monthly report
4.32.6
Annual report
4.32.7
Training record- Schedule and individual training files
4.32.8
Medical checkup record
4.32.9
Pest control record
4.32.10
Market complaint
4.32.11
Instrument calibration(External agency)
4.32.12
Batch Record Register
4.32.13
Validation Register (Cleaning, Process and Method)
4.32.14
Change control
4.32.15
Deviation
4.32.16
Out of specification records
4.33
Document Retrieval
A revised document will be issued only after retrieval of the superceded Control copy and Display copy from concerned department. The superceded Master Copy will be retained with the "OBSOLETE COPY" stamp in black colour for future reference and other copies (Controlled and Display copy) will be destroyed.
A record of issue of documents and retrieval and destruction of the superceded documents will be maintained.
Retention of Documents
4.34
All documents should be retained for at least one year after the expiry of finished products.

SOP - CALIBRATION OF BALANCES

1.0
PURPOSE:
To provide a written procedure for the steps to be followed while calibration of balances.
2.0
SCOPE:
Applicable to all balances except analytical balances.
3.0
RESPONSIBILITY:
All Department Heads
4.0
ACCOUNTABILITY :
Assistant Manager Manufacturing / Quality Assurance Manager
5.0
DEFINITIONS:
Calibration: The demonstration that an instrument or a device produces results within specified limits when compared to those produced by a reference standard (or) the standard, which is traceable to a national or International standard, over an appropriate range Of measurements.
6.0
PROCEDURE:
6.1
Check the cleanliness of the area.
6.2
Check that platform and exposed parts of the balance are clean and dry.
6.3
Check the level of the balance with the help of spirit level. Adjust level, if not leveled.
6.4
Switch on the main power supply of the balance.
6.5
Following parameters to be checked while performing calibration.
· Accuracy
· Linearity
· Precision
· Corner Load Test
FREQUENCY: Every 3 months (± 7 days)
Note: If balance is not calibrated within the time period, stop using the balance till
satisfactory calibration is done.
6.6
ACCURACY
6.6.1
Check the accuracy of the balance by using 5 standard stamped weights.
6.6.2
Place standard weight one by one in the ascending order in the center of the platform and record the observations in the balance calibration record.
6.6.3
Acceptance Criteria: Standard Weight ± 2 x Least Count
6.7
LINEARITY
Draw the linearity curve for the above readings and find out the correlation factor. Record the observations in the balance calibration record.(Limit: NLT 0.9999)
6.8
PRECISION
6.8.1
Check the Precision of the balance by using standard weight equivalent to 5 % of
Maximum capacity.
6.8.2
Repeat the procedure for 5 time and record the readings.
6.8.3
Repeat 6.8.1 to 6.8.2 using standard weight equivalent to 50 % of maximum
capacity.
6.8.4
Calculate % RSD for both the standard weights. Record the observations in the
Balance calibration record.
6.8.5
Acceptance Criteria :
% RSD NMT 0.5 %
6.9
CORNER LOAD TEST
6.9.1
Place standard weight equivalent to 30 % of maximum capacity in four corners and center of the balance and note down the readings in record. Calculate % RSD.
Record the observations in the balance calibration record.
6.9.2
Acceptance Criteria:
Deviation: Standard Weight ± 2 x Least Count
% RSD: NMT 0.5 %
6.10
If all the parameters fall with the acceptance criteria limit, affix the calibration tag (no. LBGN:003) on the balance.
6.11
If any of the observation is out of limit, correct and reset the balance.
6.12
After resetting, calibrate again all the parameters as mentioned in point 6.6 to 6.9
6.13
Switch off the balance at the end of day.
Note: No repairs should be made to any balance by anyone other than a qualified validation person from validation team.
7.0
REFERENCES:
Nil
8.0
ENCLOSURE:
8.1
Balance calibration record : XXXXXXX
9.0
ABBREVIATIONS:
9.1
NMT : Not More Than
9.2
RSD : Relative Standard deviation

PROCEDURE FOR CALIBRATION OF AUTOCLAVE -SOP

1.0. PURPOSE:
This SOP provides an authorised procedure to carry out calibration & validation of Autoclave.
2.0. SCOPE:
This SOP provides the relevant methodology for the calibration and validation of Autoclave.
3.0. RESPONSIBILITY :
Q.C. Microbiologist.
4.0. ACCOUNTABILITY:
Manager-Quality Control
5.0. DEFINITIONS:
6.0. FREQUENCY:
6.1 Chemical Indicator - Every load.
6.2 Biological Indicator - Every Month.
7.0 Procedure :
7.1 Calibration:
7.1.1 Calibrate the temperature indicator, pressure gauge and probe once in a year by external agency or whenever any replacement or maintenance done on the apparatus.
7.1.2 Place the Benzoic acid AR grade as a chemical indicator for temperature calibration in regular sterilisation cycle . It melts at 121°C.
7.1.3 Maintain the records, and abort the particular load used for calibration.
7.2 Validation:
7.2.1 Perform the validation of autoclave during installation of Equipment and revalidation.
7.2.2 Heat distribution studies on empty chamber 3 times by using a multi-point data logger.
7.2.3 All probes must reach temperature 121°C to 124°C. Pressure must be with in 15 to 18 lbs maintain the same for 15 minutes cycle.
7.2.4 Heat distribution studies on minimum load of a load pattern one time by using a multi-point data logger.
7.2.5 All probes must reach temperature 121°C to 124°C. Pressure must be with in 15 to 18 lbs maintain for 15 minutes, & find the lag time.
7.2.6 Heat distribution studies on maximum load of a load pattern three time by using a multi-point data logger.
7.2.7 All probes must reach temperature 121°C to 124°C. Pressure must be with in 15 to 18 lbs maintain for 15 minutes, and find the lag time.
7.2.8 Heat penetration studies on minimum load of a load pattern three times by using a multi-point data logger.
7.2.9 All probes must reach temperature 121°C to 124°C. Pressure must be with in 15 to 18 lbs maintain for 15 minutes, and find the lag time.
7.2.10 Heat penetration studies on maximum load of a load pattern three times by using a multi-point data logger.
7.2.11 All probes must reach temperature 121°C to 124°C. Pressure must be with in 15 to 18 lbs maintain for 15 minutes, and find the lag time.
7.2.12 With the above heat penetration study the maximum lag time plus 15 minutes is regular operating cycle of the validated load pattern.
7.2.13 Microbial Challenge Test:
7.2.13.1 Keep spores suspension of Bacillus Stearothermophilus of having population 10 6 at various location of the autoclave along with probes during maximum load heat penetration study.
7.2.13.2 Sterilised spore ampoules incubate at 55° to 60°C for 120 hours.
7.2.13.3 Spore ampoules should not show any colour change at the end of the incubation.
7.2.13.4 Maintain the records.
7.3 Cleaning:
7.3.1 Ensure that the equipment is isolated from the power before starting the cleaning activity.
7.3.2 The outside of the autoclave should be wiped with a wet sponge and allow to dry.
7.3.3 Clean the chamber with 0.1% SLS solution using the sponge.
7.3.4 Wash thoroughly with purified water till get free from the detergent.
7.3.5 Enter the cleaning details in the log book.

PROCEDURE FOR CALIBRATION OF B.O.D. INCUBATOR

1.0 PURPOSE :
This SOP provides an authorized procedure for cleaning, calibration and validation of BOD incubator.
2.0 SCOPE :
This SOP covers the cleaning, calibration and validation method for BOD incubator (QCI – 43).
3.0 RESPONSIBILITY :
Microbiologist.
4.0 ROCEDURE
4.1.0 CALIBRATION :
Calibration of temperature indicator view controller to be carried out once in a year by external agency or whenever any maintenance done on the apparatus.
4.1.1 :Maintain the record of calibration.
4.2.0 VALIDATION
4.2.1 :Perform the validation of B.O.D. Incubator once in a year.
4.2.2 :Follow the operating procedure for operation after altering set temperature perform the temperature mapping inside the chamber.
4.2.3 :Five calibrated thermometers are kept in different places inside the incubator.
4.2.4 :All the thermometers should maintain the temperature of
± 2 °C of set temperature for 8 hours.
4.2.5 :Maintain the records of validation.
4.3.0 CLEANING METHOD
4.3.1 Disconnect the BOD Incubator from main electrical supply.
4.3.2 Clean the outside and inside of incubator with dry non shredding cloth. Wipe with IPA 70% v/v.
4.3.3 Maintain the log book for cleaning.
4.3.4 Frequency : Once in a week.

CLEANING VALIDATION PROTOCOL

1.0 APPROVAL SHEET
Approval Sheet contains particulars about the Names of persons with designations and signature with date and nature of work performed for preparing this document. User of this document should prepare the Table and incorporate in this section.

2.0 Introduction:

Medicinal products can be contaminated by other medicinal products, by cleaning agents, by microorganisms or by other material (e.g. Air borne particles, dust, lubricants, raw materials, intermediates, auxiliaries. In many cases, the same equipment may be used for processing different products. To avoid contamination of medicinal products, adequate and validated cleaning procedures are essential.

3.0 Unit Operation:
Cleaning of Equipment.
4.0 Objective:
To ensure that the Cleaning Procedure as detailed in the SOP is effective and removes all residues up to a predetermined acceptance level, and that there is no possibility of any resultant cross contamination.
5.0 Site of the Study :
Production Department.
6.0 Validation Team:
Representatives from : Production
Quality Assurance
Quality Control
Engineering
Individuals name to be entered in the report.

7.0 Description of the Equipment to be cleaned:

All equipment’s used in the manufacturing of Tablet and Capsule: Details of the machine like
Machine name and Code No. of Equipment/s to be entered in the report.
8.0 Standard Operating Procedure (SOP) for Cleaning of Equipment:
SOP applicable to the cleaning of equipment: SOP No. To be recorded in the report.
9.0 Control:
9.1 Absence of traces of Active Ingredient and cleaning agent in swab/Rinse by validated analytical method.
9.2 Determination of bioburden (Microbiological Contamination)
9.3 Analytical method validation for cleaning validation shall be done. It should include analytical performance parameters like limit of detection and recovery of swab samples.
9.4 SOP for taking swab: SOP No. to be entered in the report.
10.0 Experimental Details:
10.1 Clean the equipment as per the SOP.
10.2 Collect the Swab / Rinse individually various parts as per the sampling plan.
10.3 Collect the final rinse in potable water.
10.4 Collect final rinse in purified water.
10.5 Swab various parts of the equipment for microbiological analysis.
10.6 Estimate the content of active in Swab / Rinse as per the validated analytical method.
10.7 Find the presence of cleaning agent in all rinse.
10.8 Visual inspection of final rinse.
10.9 Visually inspect the equipment and its parts to ensure that it is clean.
0.10 Based on the above analysis, calculate the amount of residue present in each rinse and swab and estimate probable contamination in the next product.
10.11 Calculate the limits for Acceptance criteria as follows:
10.10.1 DOSE CRITERION
FORMULA:

I/J x K/L x M = _________mg of previous product / 4sqinch.

Where,
I = 0.001 of smallest strength of previous product in mg / tablet (or) Capsule.
K = No. of dosage units per batch of final mixture of next product.
J = Maximum number of dosage units of next product taken / day.
L = Surface area of equipment's common for both the products.
M = 4 square inch / swab.
10.10.2 10 PPM CRITERION:

FORMULA:

R x S x U
_______________ =________mg of previous product / 4sqinch
T
Where,
R = 10
S = Kilograms per batch of final product of next product.
T = Surface area of equipment's common for both the products.
U = 4 square inch/swab.
The carry over of previous product residue should not be more than the lowest value
among the dose criterion & 10 ppm criterion.
10.11 Criteria for microbiological contamination:
10.11.1 Total Bacterial Count: Not More Than (NMT) 100 CFU per 4 square inch / swab
10.11.2 Mold and Yeast: NMT 10 CFU 4 square inch / swab
11.0 Acceptance criteria:
11.1 Equipment should be visually clean.
11.2 Residue of previous product or products in the swabs should be less than the minimum
Value determined by dose Criterion and 10 ppm Criterion.
12.0 Type of validation: Concurrent Validation
13.0 Frequency : Three validations exercise per equipment.
Three validations exercise per equipment for change in cleaning procedure.
Three validations exercise per equipment for major change in equipment.
Re – validation every two years.

WATER SAMPLING & ANALYSIS FOR VALIDATION

1.0. PURPOSE :
To validate the water System by providing a procedure for Sampling & analysis of water.
2.0. SCOPE :
Applicable for DM water (Purified Water) and Raw Water.
3.0. RESPONSIBILITY :
Quality Control Chemist / officer.
4.0. PROCEDURE :
4.1 MICROBIAL ANALYSIS:
4.1.1 Microbial Analysis of water is carried out as per table 4.12
4.1.2
Frequency, Method and Limit of Microbial Analysis

4.1.3 Collect about 200ml of sample at the point of supply in a pre sterilised clean glass bottle & proceed for microbial analysis within 30 minutes of sampling.
4.1.4 Incase the sample is found above the alert limit for microbial count the cleaning and sanitation of DM plant, overhead tank as the case may be is carried out. After sanitation the equipment is repeatedly flushed with hot water and revalidated.
4.2 CHEMICAL ANALYSIS:
4.2.1 The chemical Analysis of water is carried out as per the table 4.2.2
4.2.2 Frequency, Method and chemical analysis of water.



4.2.3 Collect the sample at the point of supply in a clean dry stoppered glass/plastic bottle.
4.2.4 Carry out the analysis as per the individual specification of DM water and Raw Water.
4.2.5 Analytical report is prepared which is authorized by QC Manger and report is filed in the respective file.
4.2.6 Incase of any deviation from the prescribed standards, it is immediately informed to Quality Assurance and corrective action is taken and same to be documented.
4.2.7 The result for all the points of sampling is summarized in the format for validation of Raw DM water, which is reviewed by QC manager along the QA.
4.2.3 Collect the sample at the point of supply in a clean dry stoppered glass/plastic bottle.
4.2.4 Carry out the analysis as per the individual specification of DM water and Raw Water.
4.2.5 Analytical report is prepared which is authorized by QC Manger and report is filed in the respective file.
4.2.6 Incase of any deviation from the prescribed standards, it is immediately informed to Quality Assurance and corrective action is taken and same to be documented.
4.2.7 The result for all the points of sampling is summarized in the format for validation of Raw DM water, which is reviewed by QC manager along the QA.

1.0 PURPOSE : To provide a procedure for visual inspections of control samples
2.0 SCOPE : To inspect the control sample by visual means.
3.0 RESPONSIBILITY : QC Chemist and QC Manager.
4.0 PROCEDURE
4.1 : All the control samples, of tablets, powder and liquid products
kept in control sample room shall be checked visually.
4.2 : The sample shall be checked once in 6 months.
4.3 : The sample shall be checked for the following parameters
i) Appearance of the tablets, powder and liquid.
ii) Colour change in any
iii) Solidification or sedimentation in case of liquids.
4.4 : The observations are to be recorded in visual inspection report.
4.5 : Incase of discrepancies the report should be forwarded to QA and production to take further action.

COLLECTION OF SWAB FOR CLEANING VALIDATION - SOP

1.0 PURPOSE:
To provide a written procedure for collection of swab for cleaning validation.
2.0 SCOPE:
Applicable to sample from hard to clean area of cleaned equipments.
3.0 RESPONSIBILITY:
Executive Manufacturing, Executive QA, Assistant Manager QA.
4.0 ACCOUNTABILITY:
Manager Quality Assurance.
5.0 DEFINITIONS:
Nil
6.0 PROCEDURE:
6.1 Check the area / part of the equipment which is hard to clean.
6.2 Select 4 x 4 square inch area of the hard surface to clean.
6.3 Swab the marked area using Readymade Swab in four direction as shown below


6.4 Collect the swab sample as per the sampling plan.
6.5 Collect the swab in clean glass bottle labeled properly.
7.0 REFERENCES:
Nil
8.0 ENCLOSURES:
Nil
9.0 ABBREVIATION:
9.1 QA : Quality Assurance