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Standard Operating Procedure (SOP) for preparation, review, approval, issuance, maintenance, and archival of controlled Master Batch Record (MBR) throughout the product lifecycle to meet and maintain sustainable compliance to current Good Manufacturing Practices (cGMPs).

SOP for Master Batch Record (MBR)

1.0   PURPOSE:

• • The purpose of this procedure is to establish uniform requirements and guidelines utilizing a risk-based systems approach for

• • • Preparation.

• • • Review.

• • • Approval.

• • • Issuance.

• • • Maintenance and

• • • Archiving of

• • A controlled Master Batch Record (MBR) throughout the product lifecycle to meet and maintain sustainable compliance to current Good Manufacturing Practices (cGMPs).

2.0   SCOPE:

• • This SOP applies to Master Batch Records (MBR) for biological products, drug substances, drug products, bulk products, intermediates, and medical devices manufacturing.

• • This SOP applies to Master Batch Records (MBR) in both paper-based (pMBR) and electronic (eMBR) formats and extends to paper-based Batch Production Records (pBPR), electronic Batch Production Records (eBPR) or hybrid Batch Production Records (hBPR) where a validated computer system utilizing an eMBR file generates then prints an exact match on paper to be used as an executable hBPR.

3.0   REFERENCES:

• • SOP for Document Control

• • SOP for Quality Risk Assessment

• • Good Documentation Practices (GDP) SOP.

• • SOP for Change Control Management

4.0   RESPONSIBILITY:

• • Head Production shall be responsible for-

• • Providing leadership to ensure that ongoing Master Batch Record (MBR)…

• • • Preparation.

• • • Implementation and

• • • Maintenance processes

• • Operate efficiently with goals oriented toward maintaining sustainable compliance.

• • Assuring the provision of adequate resources.

• • Supporting a Cross-Functional Team (CFT) approach by assigning a team leader and qualified personnel from across various functions and departments appropriate to the tasks identified throughout the Master Batch Record preparation process.

• • Maintaining responsibility while delegating authority for

• • • Origination.

• • • Distribution.

• • • Maintenance.

• • • Change control, and

• • Archiving of all GMP documentation and records within a department or unit.

• • Quality Assurance (QA) Head/Designee shall be responsible for-

• • Authorizing and overseeing creation of Master Batch Record (MBR) procedures.

• • Defining the numbering and formatting conventions in procedures for Master Batch Record (MBR)s.

• • Establishing procedures to enable document control personnel to assign a unique identification number to each Master Batch Record (MBR) and to assign sequentially ordered, unique identifying numbers to each BPR.

• • Recording the unique Master Batch Record (MBR) and BPR identifying number into a controlled logbook or electronic tracking system when the record created/issued.

• • Maintaining a GMP compliant document control system for the review, approval, issuance, and maintenance of pMBRs, eMBRs, pBPRs,eBPRs, and hBPRs throughout the product lifecycle.

• • The archival of these documents will follow written procedures as per the SOP of Documents & Records.

• • Establishing a system to prevent inadvertent use of superseded documents to ensure only current versions are accessible to authorized users.

• • Establishing Chain-of-Custody procedures to control the transfer of MBR’s and BPRs between document users, (e.g. Production, Packaging, and Quality, also between other sites and third party manufacturers during technology transfer activities) and to define applicable security controls both within on-site departments and during off-site transfers.

• • Ensuring all paper-based or electronic documents related to the manufacture of intermediates, APIs, Finished Products or devices prepared, executed, reviewed, approved, signed, and dated by appropriately trained, responsible persons and distributed according to written procedures.

• • Serving as a final approver for MBRs, Protocols, and Reports.

• • MBR-cross functional team (CFT) Leader / Relevant Stakeholder / Designee shall be responsible for

• • Serving as the Initiator of Change Control activities and Preparer of the Master Batch Record (MBR) or delegates these duties to qualified team members for specific sections of the MBR.

• • Ensuring assigned MBR team members are representative of all areas associated with the manufacture of a batch of API, bulk formulation, Finished Product or device, and qualified to perform correctly by Confirming objective evidence for all MBR team members demonstrating their qualifications to perform their respective tasks available from Human Resources for review by inspectors.

• • Establishing training records for all MBR team members demonstrating that each member trained on relevant policies, standards, and procedures.

• • These records shall maintain by a site Training Department or relevant department and available for reviewers and inspectors to evaluate the individual’s required credentials.

• • Maintaining all documentation related to specific product/process MBR activities in the Master Batch Record File in accordance with site document control procedures.

• • Assuring documentation, prior to implementation, of any introduction of a new method/process or proposed change to an existing method process using proper risk management assessments (refer to the SOP for Quality Risk Management and SOP for Change Control Management.

5.0   ABBREVIATIONS – Master Batch Record (MBR):

• • API: Active Pharmaceutical Ingredient

• • APR: Annual Product Review

• • BR/BPR: Batch Record/Batch Packing Record

• • CC No: Change Control Number

• • CFT : Cross-Functional Team

• • CMO: Contract Manufacturing Organization

• • CPP: Critical Process Parameter

• • CQ: Corporate Quality

• • CQA: Critical Quality Attributes

• • eBPR: Electronic System Batch Production Record

• • eMBR: Electronic System Master Batch Record (MBR)

• • ERP: Enterprise Resource Planning

• • hBPR: Hybrid Batch Production Record

• • IPC: In process Control

• • MES: Manufacturing Execution Systems

• • NDC: National Drug Code

• • PDF: Portable Document File

• • PQR: Product Quality Review

• • SME: Subject Matter Expert

6.0   DEFINITION – MASTERBATCH RECORD (MBR):

• • Acceptance Quality Limit (AQL):

• • A statistical measurement of the maximum number of defective goods considered acceptable in a particular sample size.

• • If the Acceptance Quality Limit (AQL) is not attained for a particular sampling of goods, manufacturers will review the various parameters in the production process to determine the areas causing the defects.

• • Note: The definition of AQL was changed from Acceptable Quality Level to Acceptance Quality Limit in 1997 by the American Society for Quality (ASQ). Also, see ISO 2859.

• • Active Pharmaceutical Ingredient:

• • An ingredient intended to furnish pharmacologic activity or other direct effects in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body; it does not include intermediates used in the synthesis of such an ingredient.

• • Annual Product Review:

• • An annual review done by the quality unit on each drug manufactured made according to written annual review procedures.

• • The review reports in detail information that demonstrates the manufacturing process is under control.

• • The report should provide a summary of all lots produced to identify any that failed in-process or finished product testing, any other critical factors, and investigations.

• • ANSI/ASQ Z1.4 Standard, Sampling Procedures, and Tables for Inspection by Attributes, American Society for Quality:

• • A collection of sampling plans (used for AQLs) that are used to derive the number of units needed to be inspected to assess the acceptability of the population based on attribute criteria. Refer to 21 CFR 820.250 (b).

• • Batch (or Lot):

• • A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous, to have uniform composition, character, and quality within specified limits, and is produced according to a master manufacturing order.

• • Batch Record (BR) or Batch Production Record (BPR) :

• • All documents associated with the manufacture of a batch of API, bulk product, or finished product.

• • The BR/BPR is a controlled document that provides a historical record of each batch manufactured and all circumstances pertinent to the quality of the batch.

• • It includes the formulation, theoretical yield, manufacturing procedures, equipment and processes used, packaging components, assay and in-process testing requirements and results, date and timesteps that are completed, sampling, and labeling of batches or production lots. (Also refer to Master Batch Record (MBR)).

• • Chain of Custody:

• • The unbroken and documented trail of accountability that ensures the physical security of samples, data, and records in a cGMP Quality System.

• • Clearance (or Line Clearance):

• • A documented visual inspection of the manufacturing or packaging facilities immediately before use to assure that all drug products, drug substances, and intermediates have been removed from previous operations, including the removal of all cleaning agents and supplies, packaging and labeling materials, utensils and portable equipment not suitable for subsequent operations, and that the room and equipment are visually clean.

• • Contract Manufacturing Organization:

• • An organization that supports any part of or completes the process of manufacturing, labeling, packing, testing, and distribution of product on behalf of another organization.

• • Contract manufacturing involves the production of goods by an organization, under the label or brand of another organization.

• • Critical Process Parameter:

• • A process parameter whose variability has an impact on a critical quality attribute and should be monitored or controlled to ensure that the process produces the desired quality.

• • Critical Quality Attributes:

• • Chemical, physical, biological and microbiological attributes that can be defined, measured, and continually monitored to ensure final product outputs remain within acceptable quality limits.

• • Cross-Functional Team:

• • A group of people with different functional expertise working toward a common goal.

• • The team may be responsible for the development, review, and implementation of the Master Batch Record (MBR).

• • Current Good Manufacturing Practices:

• • A set of regulated manufacturing and testing practices, which help to ensure the production of a quality pharmaceutical product.

• • Document Management Group:

• • A generic industry term used to denote the primary decision-makers associated with a particular production process described in a Master Batch Record (MBR) or SOP who are responsible for the attainment of production goals and maintaining sustainable compliance.

• • Group members will vary based on functional areas utilized to control a process or produce a product.

7.0   PROCEDURE – HANDLING OF MASTER BATCH RECORD (MBR):

• Preparation of Master Batch Record (MBR):

• • The Preparer(s) of a Master Batch Record (MBR) shall gather appropriate information for consideration and inclusion in the MBR from the following, but not limited to:

• • • Master Formulae

• • • GMP requirements

• • • Regulatory commitments

• • • Validation/Qualification documents, as applicable

• • • Technical Information/Reports

• • • Pilot Plant Data

• • • Development Protocols and Reports

• • • Product Specifications/Packaging Specifications

• • • Bill of Materials

• • • Change Control documents

• • • Investigation Report commitments, if applicable

• • • Audit commitments, if applicable

• • • Related Subject SOPs

• • • APRs or PQRs

• • • Rework or Reprocess documentation, if applicable

• • • Product-specific equipment or tools used to manufacture.

• • • License documents, License applications, or equivalent documents.

• • Formal, approved drawings showing the movement of materials, personnel, and equipment through all production areas: they should be sufficiently detailed to show travel pathways, storage areas, and movement into and out of process rooms.

• • The Master Batch Record (MBR) Preparer(s) shall:

• • Compile a list of the affected areas and departments related to the product to be produced.

• • Confer with the document management group that will own the Master Batch Record (MBR) to initiate a change control to document the reason itis being created or revised.

• • Confirm the composition of the Master Batch Record (MBR)-CFT includes personnel from the affected functional areas e.g.

• • • Quality Unit.

• • • Business Development.

• • • R&D.

• • • Engineering.

• • • Regulatory affairs,

• • • Production operations.

• • • EHS/safety.

• • • Materials Management,

• • • Purchasing,

• • • Statistics and

• • • Clinical.

• • For the creation of a new Master Batch Record (MBR) or revising the existing, assigned team members from each relevant area/department shall provide a detailed procedure and process flow and ensure:

• • All in-process controls (IPCs), Critical process parameters (CPPs), and Critical Quality Attributes(CQAs) that need to be controlled to assure process performance are identified and included.

• • The availability of information for consideration and inclusion in the Master Batch Record (MBR).

• • Challenge every step for whether it is necessary, value-added, required by regulation, industry-standard, or by the company.

• • Gain consensus from team members to each of, but not limited to, the following detailed challenges for each defined process step:

• • • Individual Process Step Described in detail?

• • • Process Defined?

• • • Procedure in-place? Change Control needs to be followed, as necessary.

• • • Infrastructure Requirements clearly defined?

• • • Roles & Responsibilities -Accountability included for each step?

• • • Trained Employees in place?

• • • Capacity analyses completed?

• • • Follow-up requirements – who, when, how, communicated defined?

• • • Documents required at each step included?

• • • Inputs and outputs for each step clear?

• • • Input from or output to another Quality System noted?

• • • Risks Determined at each step –what can go wrong, consequences, and if it mitigates?

• • • Is QA Role clear?

• • • Metrics in place?

• • • Clear definition of steps in the process?

• • • What are accountabilities and management controls for each step?

• • • Timing Requirements for each step established?

• • • Performance Issues included?

• • • Communicated to Levels that responsible for execution?

• • Once all steps have been determined and a consensus gained from the team members, the Master Batch Record (MBR)-CFT Leader shall appoint team members to draft specific parts of the Master Batch Record (MBR) by describing each step in the process as per Annexure no. 7 & 8 respectively.

• • Master Batch Record (MBR)-CFT shall responsible for the preparation of bill of material and risk assessment report.

• • Unconfirmed Bill of Material shall review by MBR-CFT.

• • If required risk assessment report shall also be reviewed by MBR-CFT.

• REVIEW OF MASTER BATCH RECORD (MBR):

• • The Preparer(s) shall deliver the section of the Master Batch Record (MBR), or the compiled MBR document, to the document management group that will own the Master Batch Record (MBR) who in turn routes the document to the designated reviewers.

• • Follow the Chain of Custody procedure.

• • Master Batch Record (MBR)-Cross Functional Team (CFT) shall responsible for the review.

• • Concern Production Department (Manufacturing/Packing) shall responsible for review draft copy and send to QA for review.

• • Quality Assurance Department (QA) shall review the draft copy MBMR/MBPR against initiated change control, product permission (license copy), master product specification, and or site transfer master batch record and confirmed bill of material.

• • Review designees from the areas affected by specific sections of the Master Batch Record (MBR) shall review that portion of the document and provide comments or corrections to the Preparer(s) to ensure:

• • Documents have unambiguous contents: steps accurately follow the process flow, stated clearly, easily understood, and fully describe the work done in actual practice.

• • Compliance with regulatory commitments.

• • Correct technical information.

• • Compliance with current GMPs.

• • The suitability of proposed equipment.

• • CPPs and IPC checks and limits are correct.

• • RM quantities are correct.

• • The process and batch sizes are correct.

• • All records are accurate and complete.

• APPROVAL OF MASTER BATCH RECORD (MBR):

• • The Preparer and the document management group that owns the Master Batch Record (MBR) shall refer to and follow site SOPs regarding approver responsibilities for confirming Master Batch Record (MBR) accuracy, content, completeness, and compliance.

• • The QA Head/designee shall approve the Master Batch Record (MBR).

• • The Preparer will work with the document management group to route the Master Batch Record (MBR) document to the designated approvers who shall indicate their approval by signing and dating the Master Batch Record (MBR).

• ISSUANCE OF MASTER  BATCH RECORD (MBR):

• • Describe the controls for the preparation, review, approval, and storage of executable manufacturing or packaging batch records in the specific SOP.

• • Issue the executable Batch Production Records (pBPRs or eBPRs) for each batch of production materials or products manufactured, processed, packaged, or labeled.

• • Generate the Electronic Batch Production Records (eBPRs) from the electronic Master Batch Record by an ERP system.

• • Each BPR issued shall be an exact reproduction of its Master Batch Record (MBR) and shall have a unique batch number assigned to it and printed on it.

• • Check all BPR reproductions for completeness, for legibility and compared to the current Master Batch Record (MBR) version to assure accuracy then dated and signed before being issued.

• • Prepare BPRs for each batch of manufactured raw materials and components, intermediates, bulk drug, finished product, or device and should include complete information pertaining to the production and control of each batch.

• • Incorporate Forms as part of the production process into the Master Batch Record (MBR) unless otherwise approved by the QA Head/designee.

• • Batch-specific forms that cannot be incorporated into the Master Batch Record (MBR) shall:

• • • Controlled to ensure that the current version is available.

• • • Issued as part of the pBPR or associated as part of the eBPR with the batch number identifier.

• • • Reconciled after use in accordance with site standard operating procedures.

• • All non-batch-specific forms that cannot be incorporated into the Master Batch Record (MBR) or issued with the BPR shall be:

• • • Marked with the batch number identifier

• • • Initialed and dated

• • • Attached to the BPR at the time of use.

• • • Reconciled once executed before the release into the market.

• • Notes:

• • A batch-specific form is one where the batch number is printed on the form and the form(s) accompany the batch production record at the start of the production process, such as a process control chart used for recording in-process measurements, e.g. tablet weights.

• • A batch-specific form is a standard part of the issued batch record.

• • A non-batch-specific form is one that does not have a batch number printed on it and is obtained by production if required,

• • After production has been initiated, e.g. if forms provided with the batch record are not sufficient to record all the required data.

• • A non-batch-specific form is obtained to record the additional data – in this case, the batch number must be recorded on the form.

• • Quality Assurance Department (QA) shall issue the green color of the Batch Manufacturing Record folder and light green of the Batch Packing Record/Batch Redressing Record folder.

• • The production officer should generate the BMR request in dual copy and send a signed copy to QA.

• • QA designee shall receive BMR request (Annexure 2) and sent one copy to Production and retained one copy with QA and during issuance attach BMR request with the issued BMR.

• • The packing department should generate the BPR request (Annexure 2) in dual copy and send the signed copy to QA.

• • QA designee shall receive a BPR request (Annexure 2) and sent one copy to Packing and retained one copy with QA and during issuance attach BPR request with the issued BPR.

• • After verification QA should take required photocopy from the respective master batch record and ensure that all the pages of master copy and photocopy are available.

• • Confirm the batch number from BMR request, the same shall stamp in green ink on each page of the photocopy and put a green-colored “Quality Assurance” stamp on all pages of BMR.

• • After confirming

• • • The batch number,

• • • Mfg. Date,

• • • Exp. Date and

• • • Batch Size from BPR request,

• • The batch number shall stamp in green ink on each page of the photocopy and manually put

• • • Mfg. Date,

• • • Exp. Date,

• • • Batch size, and

• • • Put a green-colored “Quality Assurance” stamp on all pages of BPR.

• • In case, Batch record issued through PD Fill software, QA shall make a PDF copy of the respective master batch record and scan the required approval pages.

• • After completion of PDF and scan of approval pages, ensure that all the pages of the master are available then archive (PDF or scan) into the respective protected folder.

• • After confirming batch number from BMR request, the same shall put as per Annexure 5 through PDF Editor (Software) in black ink on each page of the PDF copy and from BPR request batch number shall put as per Annexure 5 through PDF Editor (Software) in black ink on each page of the PDF copy.

• • QA Designee manually put the Mfg. Date, Exp. Date and Batch Size in the photocopy.

• • After that, the green-colored “Quality Assurance” stamp shall put on all pages of BMR/BPR/BRR demonstrated below.

• • Assigning BMR Record No.:

• • Looking at the batch number one cannot come to know the number of batches of a particular product manufactured in the past.

• • To overcome this, a serial number is generated, which consists of nine or ten (depend upon the product code) alphanumeric digits.

• • Give the serial number as Master Batch Record (MBR) No. without considering Version No./ 001.

• • QA officer should issue the Batch Manufacturing Record (BMR) after verifying that batch comes under process validation/clinical trial and or monitoring batch.

• • QA officer should issue the Batch Packing Record (BPR) after verifying that batch comes under stability batch/process validation/clinical trial and or monitoring batch.

• • Entry in the BMR/BPR/BRR issuance and closing register (Annexure-1) and take the sign of production officer/trained personnel in BMR/BPR/BRR request as a token of receiving the issued BMR/BPR/BRR.

• • A Non-batch-specific form/Extra Page Issuance Request (Annexure-6) of batch records is issued in case any accidental torn or soiled or insufficient pages for any operations.

• • When Non-batch-specific form/Extra Page Issuance Request (Annexure-6) of the working BMR, BPR, BRR are required, the same shall be requested after approval of Non-batch-specific requests by production head/designee or packing head/designee with proper justification.

• • On receipt of the duly filled Non-batch-specific form/Extra Page Issuance Request (Annexure-6), the IPQA person shall take the print copy of the requested page from the Master Copy.

• • IPQA person shall maintain the Non-batch-specific register/Extra Page Issuance register as per Annexure-3.

• • Quality Assurance Stamp:

• • Return the canceled BMR/BPR/BRR to QA after proper justification and getting approval from Production Head and marked as ‘Cancelled’ in the opening page of the batch record.

• • QA officer received canceled BMR/BPR/BRR and making entry of the same in the issuance come closing register and destroy it.

• • Packing Officer checked the batch record (after completion of the batch) and submitted to QA (Packing)and after verification QA officer submit the batch record-to-record room with the submission of documents forms.

• • QA Officer makes necessary entries in the BMR/BPR and BRR issuance and closing register and batch records are stored in the designated place.

• • Processing trends are prepared for BMR and the finish product report is attached to BMR/BPR/BRR then close the BMR/BPR/BRR.

• • If closed BMR, BPR, and BRR required. Reissued after making the entry in the re-issuance register of closed BMR, BPR, and BRR (Annexure- 4).

• MAINTENANCE AND ARCHIVING OF MBR: 

• • Review the Master Batch Record (MBRs) at intervals prescribed in site standard operating procedures to verify the version in use the current version, that it accurately reflects the Master Formulae, and to assess if any reason for revision exists.

• • The document management group that owns the Master Batch Record (MBR) must initiate a change control when a product is discontinued to document that the Master Batch Record (MBR) is to be retired.

• • The change control must specify the duration of the retention period the Master Batch Record (MBR) will remain in-active status before it is archived or placed in off-site storage according to current regulatory requirements.

• • Quality Assurance Department (QA) shall archive soft copy (Master) in the respective folder with password protected.

• • Quality Assurance Department (QA) shall attache master copy (final status) to master product file and retired the superseded (previous) version, stamped in red ink on all the pages, stating sign and date on the first page and stored as retired copy for history and update the product list.

• REQUIREMENTS:

• • The Master Batch Record (MBR) shall include provision for all required documentation, sequentially paginated and issued with no loose, uncontrolled forms permitted in any operational area.

• • List the steps within the Master Batch Record (MBR) in the order of those to be executed sequentially: steps that may be executed concurrently should be identified and indicated clearly.

• • To assure uniformity from batch to batch, master production and control records for each batch of

• • • Intermediates,

• • • Active pharmaceutical ingredients (API),

• • • Finished products and devices,

• • Including each batch size thereof prepared, dated, and signed (handwritten) by one qualified person and independently checked, dated, and signed by a second qualified person.

• • Master Batch Record (MBR) must include clearly written, specific and complete manufacturing, packaging, and control information required to manufacture batches while consistently meeting current validation requirements.

• • Where validation has not yet been completed, the Master Batch Record (MBR) must include specific production process instructions and clearly identify activities performed to confirm replication and review of the process.

• • Drug Product Master Batch Record (MBR) and control records shall include:

• • • The name,

• • • Strength,

• • • Code number,

• • • NDC number (if applicable),

• • • Site of manufacturing/packaging/labeling,

• • • The unique batch or control number,

• • • Effective date,

• • • Expiry period,

• • • The dosage form and/or package configuration of the product.

• • The name and weight or measure of each active ingredient per dosage unit or per unit of weight or measure of the drug product and a statement of the total weight or measure of any dosage unit.

• • The Master Batch Record (MBR) shall contain a complete list of components designated by codes, names and descriptions, and the unique identification numbers of the actual components used.

• • If an added component does not appear in the product it should still be included in the list of components.

• • An accurate statement of the weight or measure of each raw material or component, using the same weight system (metric, avoirdupois, or apothecary) for each component.

• • Reasonablevariances may be permitted in the weight or measure of components necessary for the preparation in the dosage form, provided they had been documented as being technically justified previously in the Master Batch Record (MBR) and control records.

• • A statement –

• • • Concerning any calculated excess of the component.

• • • Theoretical weight or measure at appropriate phases of processing.

• • • Theoretical yield, including the maximum and minimum percentages of theoretical yield beyond which an investigation is required.

• • A description of the drug product containers, closures, and packaging materials, including a specimen or copy of each label and all other labelings, signed and dated by the person or persons responsible for approval of such labeling.

• • Complete sampling and testing procedures, specifications, special notations, and precautions are to be followed.

• • Ensure Master Batch Record (MBR) has sufficient space for data fields and necessary explanations so the individual(s) performing, checking and verifying the steps in the BPR for completion of their tasks can initial and date in the relevant places on the BPR should handwritten corrections need to be made to a Master Batch Record (MBR) or BPR, they shall be made in accordance with requirements specified in the SOP for Good Documentation Practices (GDP).

• • The three actions denoted by the naming conventions Performed by, Reviewed by and Verified by/Checked by in the Master Batch Record (MBR) are similar in that:

• • • Only qualified individuals can complete these actions, that using their initials to acknowledge completion of an action is cGMP compliant.

• • • All initials signifying completion of a task during the execution of a BPR must be traceable to a controlled log sheet or controlled log book.

• • • Initials and dates are to be applied to the data fields for each completed action.

• • The three actions are different as follows:

• • “Performed by” Signature of the person performing the work being recorded.

• • “Reviewed by” Signature of the person certifying accuracy and completeness of the document.

• • “Verified by/Checked by” The signature of the person responsible for witnessing or conducting an independent check to ensure the operation, test, inspection, calculation or other actions followed required instructions and procedures and for verifying entries in the record made by the person performing the task.

Notes:      1) Full Signatures are required of two people as per 21 CFR 211.186(a) (a)when Master Batch Record (MBR) is approved, (b) when BPRs are prepared and issued and(c) when executed BPRs are reviewed and verified to be complete.

2) All signatures on executable copies of Master Batch Record (MBR) must be traceable to a controlled signature log sheet or controlled logbook and to training records to confirm the identity and current, complete status of training of personnel.

• Production:

• • Where Weighing Sheets are not integral to the Master Batch Record (MBR), procedure and Master Batch Record (MBR) instructions shall require that WeighingSheets or scale printouts be attached and include entry of information indicating:

• • • Date and Time.

• • • Scale Name and a unique identifier of the scale used.

• • • Weights – Tare, Gross and Net

• • • Performed by and Verified by signatures.

• • • Scale calibration status information.

• • The Master Batch Record (MBR) will have data fields for verification of weighing, measuring, or subdividing operations for components.

• • Each container of a component dispensed to manufacturing shall be verified by a second individual to ensure that:

• • • The containers are identified properly.

• • • The component(s) is released and within expiry.

• • • The weight or measure is correct.

• • Only controlled log sheets or controlled logbooks are permitted in any operational area and must meet physical security and Chain of Custody procedural requirements.

• • Arithmetic formulas for any manual calculations to be performed and results of all such calculations must:

• • • Be made using calculators qualified for GMP use according to a written Calculator Qualification procedure.

• • • Have entry “performed by” fields.

• • Operating ranges for equipment and tolerances for instruments need to be provided by the process owner and approved by the QA Head/designee in accordance with validation and Calibration Programs.

• • Full process information contains within the Master Batch Record (MBR), including set points or ranges of operating parameters with data fields to provide for signatures against each significant step, including actual parameters used and on-inequality oversight approvals.

• • Data entry fields for “verified by” signatures must be provided for all critical process steps, including, but not limited to:

• • • Mill settings

• • • Mixing speeds

• • • Temperatures

• • • Filling/packaging line speeds

• • • Press/encapsulation speeds

• • • Humidity

• • • Pressures

• • Time limits/stamps for all significant steps, including:

• • • Completion of-component additions.

• • • Cycle start and stop times

• • • Hold Start and stop times

• • • Sampling activities

• • • Completion of in-process analyses

• • • Material Transfers

• • All In-Process test steps within a Master Batch Record (MBR) must stipulate requirements to ensure unique identifiers of the equipment used shall be documented to assure traceability of specific equipment and state of calibration.

• • All In-Process tests required for continuing production or maintaining product within specifications must have:

• • • Instructions that clearly state when approval is required to proceed.

• • • Data fields for the signature of a person authorized to provide approval.

• • For In-Process tests conducted by production personnel:

• • • Specifications or targets shall be included in the Master Batch Record (MBR).

• • • Sufficient data fields shall be available for documentation of or reference to all data secured in the course of each test or examination.

• • • Including all calculations.

• • • Unique identification numbers of all monitoring devices or testing equipment used and calibration status of the same.

• • A Master Batch Record (MBR) shall include instructions, stipulate reject levels and provide sufficient data fields to document the following as applicable, but not limited to:

• • • Equipment challenges

• • • Equipment checks

• • • Downtime (unplanned or excessive)

• • • Runtime

• • • Acceptance Quality Limit (AQL)

• • Actual yields and percentages of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the biological products, drug substances, drug products, bulk products, intermediates or medical devices:

• • • Such calculations shall be performed either by one person and independently checked by a second person.

• • • If the yield is calculated by automated equipment as mentioned in 21 CFR 211.68,

• • • It will be independently checked by one qualified person and another independent qualified person checks that the equipment properly performed the operation.

• • Acceptable validated hold time limits and storage conditions for all manufactured products should be stipulated in the Master Batch Record (MBR), when available and have entry fields.

• • Written procedures for all aspects of sample collection and handling, forms used, personnel responsible, hand-offs, and sign-offs should be followed.

• • The Master Batch Record (MBR) shall stipulate the location and/or date of sample collections when appropriate, or include a cross-reference to the appropriate procedure.

• • Sampling Plan parameters identified within the Master Batch Record (MBR) must be based on an appropriate statistical sampling plan, i.e., ANSIZ1.4 tables since ANSI Z1.4 is defensible whereas the use of an (√n + 1) sampling plan is not.

• • The steps and instructions within the Master Batch Record (MBR) for the cleaning of production/manufacturing areas and equipment should reflect clearly those verified steps identified in specific CleaningValidation Protocols and written procedures.

• Documentation:

  • The Master Batch Record (MBR) shall be maintained under version control and will include a traceable history of revisions made to the Master Batch Record (MBR) throughout the product lifecycle.

• • The Master Batch Record (MBR) and subsequent BPRs will be controlled by a procedure for issuing that includes security of hand-offs(Chain of Custody), holding, and traceability during use.

• • MBR will include the use of the date format established in good Documentation procedures.

• • All documentation of time and verification of time and datestamps shall be performed using a consistent source, i.e.,

• • • A slave Clock system where all clocks in production, lab, and packaging areas depend on a master clock to assure uniformity of performance.

• • A Master Batch Record (MBR) must indicate that when attaching printouts to a Batch Record, the printout should be signed and dated so it is clear it was added at the time, and on the date, indicated.

Note:       

• If thermal paper printouts are to be used as official records, a xerox copy of the thermal paper record shall be made and attached to the BPR.

• • A Master Batch Record (MBR) should contain sufficient data fields for entry of typical information or infrequent entries, as needed.

• • The Master Batch Record (MBR) must identify clearly within the production and packaging sections where the QA Head/designee has direct oversight/sampling responsibilities and must provide signatures.

• Packaging and Labeling:

  • Packaging and Labeling batch record sections should be within the Master Batch Record (MBR) and issued and controlled by the Document Control Department.

• • • Where a Packaging & Labeling Record is not an integral part of a Master Batch Record (MBR):

• • • The Packaging & Labeling unit should develop detailed cleaning, inspection, and line clearance wrote procedures and forms specific to the lines used and the products produced.

• • • The Master Batch Record (MBR) should have data fields available to document the specific procedures followed and forms used for each batch and product.

• • • Any form used must be a controlled document issued by the Document Control Department then attached to the BPR and maintained in the Master Batch Record (MBR) file to assure traceability.

• • The Master Batch Record (MBR) Packaging & Labeling section shall include:

• • • A complete list of all packaging material designated by codes, names and descriptions, and the unique identification numbers of the actual packaging materials used and data fields to include or reference related processing records.

• • • The weight/measure of each component and/or packaging material, using the same calibrated weight system for each component and/or packaging material.

• • The actual weights and measures of each component and/or packaging materials used in the course of processing.

• • Specification of the approved processing areas and the unique number of the area/line where processing occurred shall be recorded on the BPR.

• • Type and model of equipment to be used and the unique identifier number of the specific equipment used shall be recorded on the BPR.

• • Inspection of packaging and labeling area(s)/line(s) before and after use.

• • Cleaning and set-up steps with data fields for documenting the packaging and labeling area(s)/line(s), and for each piece of equipment used.

• • The QA Head/designee shall perform the verification of the line clearance approval process.

• • The documented system instituted to issue labeling and inserts to packaging lines must eliminate any opportunity for cross-contamination.

• • The QA Head/designee performs a check of the sample print for a lot number and expiry.

• • Label reconciliation shall be included within the Packaging section of the Master Batch Record (MBR) with pre-defined ranges scientifically based on a statistical method.

• • Where there is no label Vision System or when hand-labeling is done, 200% label inspection (2 x 100 %) must be performed and instructions and data fields for these activities must be in the Master Batch Record (MBR).

• • The Packaging section of the Master Batch Record (MBR) shall include instructions and data fields for collecting, signing, dating, and attaching specimens of all labels, Patient Advisory Leaflets or informational inserts, and individually printed unit cartons to the BPR.

• • A validated manual or electronic system and procedures for material/batch disposition must be in place to assure that the disposition of rejected materials is controlled and documented within the system.

• • The issuance of Status of Release Labels, their accountability, and reconciliation should be detailed in a written procedure and have appropriate, controlled documentation in place.

• • Quarantine labels are only to be issued and placed by QA Head/designee personnel with quarantined materials and products stored in controlled access, locked areas.

• Handling of BMR Under Temporary Change :

  • In case of Temporary change where major correction required in BMR, the following procedure is to be followed:-

• • • Additional page/pages to be prepared as an Addendum to the ISSUED BMR, for proposed temporary change mentioning Ref. BMR No. & Temporary Change Control No. along-with the step no of BMR from where the BMR steps are discontinued.

• • • The above Addendum shall be pre-approved.

• • • It shall be prepared by the initiating department, Reviewed by Executive QA or designee, and finally approved by Production In-charge, Plant Head & Quality Head (in line with BMR).

• • • Original copy of the above Addendum is to be attached to the Temporary change control form.

• • • The photocopy of above Addendum to be issued along-with required BMR

• • In the issued copy /photocopy of the master BMR, at the place where temporary change is applicable, QA shall manually put the asterisk sign’*’ and shall mention the reference of the above Addendum in RED color with sign and date.

• • Delete the contents of the BMRs, which are not to be followed, .by means a single strike through the printed matter.

• • None other than QA shall be authorized to make corrections in BMR.

• • QA shall also mention Ref. Temporary Change Control No. on the top right-hand side corner of the issued BMR in RED color with sign and date.

                 Note: Addendum is to be prepared in the following case (s), but not limited to:-

• • • Where the addition or deletion of the step is to be performed.

• • • A need for writing in the additional sheet is required, it is to be mentioned in the addendum.

• • • Wherever additional data is to be captured, to be in line with the proposed change.

  • In case of Temporary change where minor/multiple corrections required in BMR, the following procedure is to be followed:-

  • In the issued copy of the BMR, wherever the proposed change is applicable, QA shall correct the entries by cutting the printed matter at all the applicable places/steps, in RED color with sign and date.

• • QA shall also mention Ref. Temporary Change Control No. on the top right-hand side corner of issued BMR in RED color with sign and date.

• • None other than QA shall be authorized to make corrections in BMR.

Note: Addendum is to be prepared in the following case (s), but not limited to:-

• • Single correction for the change in the equipment no.

• • Single correction due to change in process parameters like temperature, time duration, quantity, etc.

• • Depending upon the temporary proposed change, the changes in the BMR where there is no need for additional sheet/addendum, such changes are to be made as mentioned above.

8.0   DISTRIBUTION OF SOP FOR MASTER BATCH RECORD (BPR):

• • Quality Assurance

• • Quality Control

• • Maintenance

• • Environment, Health, and Safety

• • Personnel and Administration

• • Warehouse

• • Information Technology

• • Production

9.0   ANNEXURES:

• Annexure 1: BMR/BPR Issuance and Closing Register.

• • Prepare the logbook by using the following table contents…

• • Sr. No.

• • Master BMR No.

• • Product Name.

• • Batch No.

• • Batch Size.

• • Mfg. Date.

• • Exp. Date

• • Record No.

• • Issued By/Date.

• • Issued To/Date.

• • Complete BMR/BPR Received By.

• • Status.

• • Remark.

• Annexure 2: BMR, BPR, and BRR Request.

BMR/BPR Requisition

Code	Product Name	Batch No Product Batch Code Lot No. Lot Size Unit	Mfg. Date	Exp. Date	Batch Size	Rate	Work Order type
Work Order No.:_______________ Work order Date: __/__/__   BOM Code: __________

• Annexure 3: Non-batch-specific Register / Extra Page Issuance Register.

Sr. No.	Date	Product Name	Batch No.	Page No.	Issued By	Received By	Reason

• Annexure 4: Re-issuance Register of Closed BMR, BPR, and BRR.

Sr. No.	Product Name	Batch No.	BMR/BPR/ Template	Purpose	Issued By	Taken By	Returned By	Received By	Remark

• Annexure 5: PDF Editor (Software) Working process.

  • Click on the PDF Editor Software

• • Go to the Menu Bar Status

• • Click on Document option from Menu Bar

• • Select Header or Footer option from Document

• • Then it a box display (Header or Footer’s Properties)

• • First click in a box which shows Header or Footer onto a PDF page

• • After then put the required data

• • In Left Header Text or In Center Header Text or In Right Header Text

• • After that Set Font Properties if required

• • After that Set Margin from Edges if required

• • Then go to Close option and close

• • After that go to Menu Bar Status

• • Save the Edited PDF As required or Select Print the Edited PDF File

• Annexure 6: Non-batch-specific Form / Extra Page Issuance Request.

Requested by Department
Product Name
MBR No.
Batch Number
Page Number
Reason

 

Request By Concerned Dept. (Sign / Date)	Approved By Concerned Dept. (Sign / Date)

Received By QA (Sign / Date):                   Issued By QA (Sign / Date):

• Annexure 7: Template for New BMR Format.

BATCH MANUFACTURING RECORD
Generic  Name		Batch No.
Product
MBMR No.		Page No.

 

Supersedes No.		Mfg. Lic. No.
Reference MBMR No.		Schedule (D & C Act)
Reference Location		Shelf Life
Change Control No.		Packing Type
		MBMR Status
Effective Date		Effective B. No.

PRODUCT DETAILS

Label Claim

Product Description

Dosage Form

Market

Precaution

Batch Size Details

Standard B. Size

Standard Weight of Tablet (in mg)

Actual B. Size

Kg.

Tablets

Core

Finish

Kg.

Tablets

Type Of Batch (Tick The Applicable Box)

Regular

Validation

Monitoring

1

2

3

1

2

3

UPDATED BY QA (SIGN & DATE)

Date of Commencement

/

/

Date of Compounding

/

/

Manufacturing Date

/

Expiry Date

/

Date of Completion

/

/

 

APPROVAL OF MASTER BATCH MANUFACTURING RECORD (MBR) :

Particular	Name	Signature/Date
Initiator: Production
Checked by: Quality Assurance
Reviewed by: Production – Manager
Approved By: HOD – Production
Approved By: QA Head

 

BATCH MANUFACTURING ISSUANCE RECORD
BMR Record No.
Issued By QA (Sign/Date)
Reviewed By Manufacturing  (Sign/Date)

 

TABLE OF CONTENTS:

Sr. No.	CONTENT LIST	Page No.

 

PROCEDURE:______________________________________________________

BATCH SUMMARY:__________________________________________________

Deviation (If any):___________________________________________________

Raw Material :
Process :
In-process checks and Results :
Yield :
BMR Reviewed By Production Head/Designee Sign & Date)	BMR Verified By QA Head/Designee (Sign & Date)

 

REVISION HISTORY:

MBMR Version Number	Change Control Number	Details of  Revision