BATCH NUMBERING PROCEDURE

1.0              OBJECTIVE:

1.1               The objective of this SOP is:

2.1.1.        To describe a procedure for allocation of batch no. for products manufactured at____.

2.0              RESPONSIBILITY:

2.1               The Executive - Quality Assurance shall be:

2.1.2.        Responsible for giving batch Number.  

                   

2.2               The Chemist  shall be:

2.1.3.        Responsible for ensuring the following of Batch Numbering System.  

3.0              ACCOUNTABILITY:

Head – Quality Manager

                   

4.0              PROCEDURE:

4.1              BATCH NUMBERING SYSTEM FOR PRODUCTS FOR DOMESTIC MARKET:

Ø      For each product R & D gives a prefix, which is unique & product specific with respect to product name & strength, which is stated in master formula record.

Ø      While allocating Batch No. to a product, this prefix shall be used which shall be followed  by 5 alphanumeric characters.

Ø      The first character in the Batch No. is  a numeric figure, which stands for the year in which the batch is manufactured. For e.g. all the batches manufactured in the year 2005 have first character 5, for 2010 it shall be 10, like wise for subsequent years.

Ø      The next three characters are numeric values, which stands for the serial no. Of the batch for a particular product manufactured in the year.

Ø      For e.g. for first batch of a particular product it shall be 001, for second batch 002 and likewise for the further batches.

Ø      The next character in the Batch No. shall be “N”, which stands for the Kachigam..

Ø      The complete batch no shall be like CLTM-5001N

Whereas,

§         “CLTM” stands for the product batch or prefix, which may be either 3 or 4 alphabetic characters.

§         “5” stands for the year in which the batch is manufactured i.e. 2005

§         “001” stands for the 1^st batch of particular product of the year.

§         “N” stands for product manufactured at Kachigam Daman.

4.2              BATCH NUMBERING SYSTEM FOR PRODUCTS FOR EXPORT

The product batch numbering system for export shall be differed from as defined in the stage 4.1 (Batch numbering system for products for domestic market) in respect that suffix “N” used for domestic market shall be replaced by ‘EN’ until the customer (contract giver) specifies the batch no.

SOP for Internal Audit

1.0  Purpose    :   This document describes the conduct of the Management review of the quality system for GMP Conformance Certification, including the conduct of an internal audit to assure the system meets the requirements of ISO Guide and is effectively implemented..

2.0 Objective   :  To Provide Documented Procedure for review of the quality system for GMP Conformance Certification, including the conduct of an internal audit to assure the system meets the requirements.

3.0   Scope        :  To define role/responsibility of various functions responsible for Internal audit

4.0     Responsibility    :

o       Board of Internal Audit and Management Review Committee:  Arranges for the internal audit and gathers all information for the Management Review.

o       QA Management Committee:  Provides all information as required by the Board of Internal Audit and Management Review Committee and is responsible for follow-up corrective and preventive actions.

o       QA Internal Auditor(s):   Conduct the internal audit according to GMP.

5.0      Procedure   :

Ø      The QA Management Committee, by consensus, selects three qualified individuals for the Board of Internal Audit and Management Review Committee. Members to the Committee serve until they are replaced.

Ø      The Board of Internal Audit and Management Review Committee arranges for the annual internal audit to be conducted.

R     The date for the audit is established by mutual agreement between the Board of Internal Audit and Management Review Committee and the General Manager Production and Asst. Manager Production (AMP).

Ø      The audit is conducted by any member of the board or Internal auditor qualified to participate on the Certification Board so long as the auditor is not a member of the QA Management Committee, is qualified and knowledgeable in certification, auditing.

Ø      The audit must be conducted at least every 12 months.

Ø      During the audit, personnel responsible for the area audited are immediately notified of the outcome of the audit of their area.

R     During an audit, it is possible that a difference of opinion can arise as to the severity of an observation. It is important not to spend too much time debating the merits of the observation. If it does not appear that the difference of opinion can be resolved, then the auditee should be informed that the audit report is subject to review by the Board of Internal Audit and Management Review Committee and the QA Management

Ø      The draft report is issued to the Board of Internal Audit and Management Review Committee within 14 calendar days. The Committee members review and comment on the report and a final report is issued.

Ø      The final internal audit report is submitted to the QA Management Committee.

Ø      The QA Management committee drafts a response to the audit report that is finalized after review:

R     Findings, nonconformities, trends, and other opportunities for improvement are identified; investigated to determine the causes; and corrective/preventive actions are developed. These actions are implemented as soon as possible and recorded. 

Ø      The response to the internal audit report is submitted to the Board of Internal Audit and Management Review Committee for their concurrence.

Ø      Upon agreement on the response to the internal audit, the Board of Internal Audit and Management Review Committee prepares a complete Certification Program Management Review Report that includes, as appropriate,:

R     Results of internal and external audits

R     Feedback from clients and interested parties related to the fulfillment of the Certification Process

R     Feedback concerning impartiality

R     Follow-up actions from previous Certification Program Management Review Reports

R     The status of corrective or preventive actions

R     The fulfillment of objectives

R     Changes that could effect the management system

R     Appeals and complaints

Ø      The Board of Internal Audit and Management Review Committee submits their Certification Program Management Review Report to the QA Management Committee.

Ø      The Certification Program Management Review Report with the response to the internal audit is discussed at the next meeting of the full Board. The expected outputs of the review includes decisions and actions related to:

R     Improvement of the effectiveness of the management system and its processes.

R     Resource needs.

Ø      Decisions and actions of the Board are documented in the Board Minutes and all open Corrective/Preventive Actions are reviewed and their status documented at all subsequent quarterly Board Meetings.  

Ø      Effectiveness of completed actions is reviewed at the next Program Management Review.

Analytical Method Validation

.0     Purpose     :   To lay down a procedure for Analytical Method Validation.

2.0     Objective   :  To provide documented procedure for Analytical Method Validation.

3.0     Scope        :   To define role/responsibility of various persons responsible for Analytical Method Validation.

4.0     Responsibility    :

·        Primary        :         Officer QA/ QC

·        Secondary    :         Manager QA/ QC

5.0      Procedure   :

·        General Concepts

Ø      Validation is the act of demonstrating and documenting a procedure that operates effectively.

Ø      The discussion of the validation of analytical procedures is directed to the four most common types of analytical procedure:

R           Identification tests

R           Quantitative tests for impurities content

R           Limit tests for the control of impurities

R           Quantitative tests of the active moiety in samples of drug substance or drug product or other selected components in the drug product.

Ø      Typical validation characteristics which should be considered are:

R           Accuracy

R           Precision

R           Specificity

R           Quantitation Limit

R           Linearity and Range

R           Robustness

·        Method Validation Parameter for the assay of ---:

Ø      Linearity: ----- to be analyzed as per proposed method. The results obtain is used to statistically evaluate for coefficient of determination (r²), standard error of estimate and y intercept.

Ø      Precision: Precision of the chemical method is ascertained by carrying out the analysis as per the procedure and as per normal weight taken for analysis. Repeat the analysis five times. Calculate the % assay, mean assay, % Deviation and % relative standard deviation and %RSD.

Ø      Accuracy: Accuracy of the method is ascertained by standard addition method at 3 levels. Standard quantity equivalent to 80%, 100% and 120% is to be added in sample.

·        Method Validation Parameter for residual solvent by GC for ---:

Ø      Specificity: Resolution of the analyte peak from the nearest peak: Solution of each of the analyte was injected separately and their retention time is noted. The standard working solution containing a mixture of the component being analyze is also injected and each of analyte peaks is check for its resolution from the nearest.

Ø      Precision:

R     Repeatability: Six replicate injections of standard solution for system precision should analyze as per the proposed method and from the chromatograms obtained the percentage % RSD is calculated.

R     Intermediate precision: The purpose of this test is to demonstrate the intermediate precision of the method when method is executed by a different analyst and on different day. Results obtained will be compared.

Ø      Linearity and Range: Solution of analyte solvent, having different concentration should make separate from L.O.Q. concentration, which is 50% to 150%. The result obtained is statistically evaluated for coefficient of determination (r²), standard error of estimate and y intercept.

Ø      LOD & LOQ:

R     The limit of Detection (L.O.D.) was calculated as per below equation:

                    

                      LOD          =              3.3     X       SD

                                                                  Slope 

R     The limit of Quantification (L.O.Q.) was calculated as per below equation:

                                   

                                                LOQ         =              10      X     SD

                                                                                         Slope

Ø      Accuracy / % Recovery (By Standard Addition Method): Accuracy of the method was ascertained by standard addition method at 3 levels.

R     Standard solution quantity equivalent to 50%, 100% and 150% are added in sample.

R     The solutions amount is analyzed by the proposed method and chromatogram obtained.

R     The amount recover by the method is compared to the amount added. Percent deviation is calculated at each levels and a grand average across all the levels are also calculated.

Methanol standard concentration ––  3000 ppm

Acetic acid standard concentration –– 5000 ppm

DMF standard concentration ––          880  ppm

Ø      Robustness:

R     The evaluation of robustness should be considered during the development phase and depends on the type of procedure under study. It should show the reliability of an analysis with respect to deliberate variations in method parameters.

R     If measurements are susceptible to variation in analytical conditions, the analytical condition should be suitably controlled or a precautionary statement should be included in the procedure.

R     One consequence of the robustness should be that a series of system suitability parameters (e.g. resolution test) is established to ensure that the validity of the analytical procedure is maintained whenever used.

Process Validation

1.0     Purpose     :   To lay down a procedure for process validation.

2.0     Objective   :  To provide documented procedure for process validation.

3.0    Scope       : To define role/responsibility of various functions responsible for process validation.

4.0     Responsibility    :

·        Primary        :         Officer QA/ QC/ Production

·        Secondary    :         Manager QA/ QC/ Production

5.0      Procedure   :

Validation is the act of demonstrating and documenting a procedure which operates effectively. Process validation is the means of ensuring and providing documentary evidence that processes (within their specified design parameters) are capable of consistently producing a finished product of the required quality.

·        Types of Process Validation:

Ø      Prospective Validation: Validation carried out during the development stage on the basis of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis of past experience to determine whether they may lead to critical situation.

Ø      Concurrent Validation: Validation carried out during routine production of products intended for sale.

Ø      Retrospective Validation: Involves the evaluation of past experience of production on the condition that composition, procedures and equipment remain unchanged. The source of data for this validation may include batch document, process control chart, maintenance logbook, records of personnel change process capability studies, FP data and stability results.

·        The proposed validation is designed as per the concurrent validation GMP guidelines because of the following reasons:

Ø      All the stages are already commercialized and a large number of batches of each stage are carried out on a large scale.

Ø      All critical quality attributes are established.

Ø      In process checks at each stage for acceptance are established as ‘In-process checks specification’.

Ø      Standard output in terms of quality and quantity is defined and established.

Ø      No failure of process or product at each stage is observed for a large number of batches.

Ø      The process now will be repeated by the standard SOPs for manufacturing, testing, and cleaning at each stage and monitored thoroughly to get output of consistent quality and quantity to create a validation report to comply with concurrent validation provisions.

·        General Concept:

Ø      Three consecutive validations will be performed to prove that the method is validated.

Ø      Whenever a new product is introduced, equipment usage and nature of potential contaminant will be studied to assess whether it poses a challenging study for process validation

·        Description of Process:

Ø      The  manufacturing process comprises of 5 chemical steps, packing and report writing on each step being common for all stages, starting from --. All the stages are taken under purview of the protocol.

R           Stage I:

R           Stage II:

R           Stage III:

R           Stage IV:

R           Stage V l

Ø      Before starting the process equipment should be cleaned and ECR report should be there and all raw materials should be analyzed and attached AR No. report should be attached with process validation report.

Ø      The unit operations with critical process parameter and operating range with in process check is well established as this product is prepared on actual commercial scale. All the three batches that to be taken for process validation is provided in the tabular form.

Ø      Process is well optimized with respect to molar proportion of ingredients, time, temperatures etc.; no parameter needs to be verified in the existing commercial process. Reaction time is the only parameter, which is variable and hence critical. Therefore only time will be monitored as per the frequency given above to establish the consistency of quantity and quality for all V Stages.

Ø      Check that all the stages follow acceptance criteria according to protocol