Pharm. Quality Assurance Unit IVB.PHARM 6th SEM

Document maintenance in PharmaceuticalIndustry: Batch Formula record, Master formularecord, SOP, Quality audit, Quality review &Quality documentation, reports & documents ,distribution records

BY DR NISHA SHARMA, ASSOCIATEPROFESSOR, UIP, CSJMU, KANPUR

Document maintenance in PharmaceuticalIndustry: Batch Formula record, Master formularecord, SOP, Quality audit, Quality review &Quality documentation, reports & documents ,distribution records

BY DR NISHA SHARMA, ASSOCIATEPROFESSOR, UIP, CSJMU, KANPUR

Dr. Nisha Sharma

Batch Record• What is Batch ?• “A specific quantity of a drug or other material that is intended to have

uniform character and quality, within specified limits, and is producedaccording to a single manufacturing order during the same cycle ofmanufacture”

• It is a written document of the batch, prepared during pharmaceuticalmanufacturing process. It contains actual data and step by step processfor manufacturing each batch.

• It is a proof that batches were properly made and checked by qualitycontrol personnel

• should be prepared for each intermediate and API/formulation andshould include complete information relating to the production andcontrol of each batch.

• Should have unique batch or identification number and dated and signedwhen issued

• Batch number should be immediately recorded in a logbook or byelectronic data processing system. The record should include date ofallocation, product identity, and size of batch.

• What is Batch ?• “A specific quantity of a drug or other material that is intended to have

uniform character and quality, within specified limits, and is producedaccording to a single manufacturing order during the same cycle ofmanufacture”

• It is a written document of the batch, prepared during pharmaceuticalmanufacturing process. It contains actual data and step by step processfor manufacturing each batch.

• It is a proof that batches were properly made and checked by qualitycontrol personnel

• should be prepared for each intermediate and API/formulation andshould include complete information relating to the production andcontrol of each batch.

• Should have unique batch or identification number and dated and signedwhen issued

• Batch number should be immediately recorded in a logbook or byelectronic data processing system. The record should include date ofallocation, product identity, and size of batch.

Dr. Nisha Sharma

Batch Record• Two type: Batch Processing Records & Batch Packaging Records• Batch Processing Records:• Its maintained for each batch

• It should be based on approved Manufacturing formula & Processinginstructions

• Design of batch processing records should be such that it shouldavoid any transcription errors

• Record must carry batch number of processed lot

• Before any processing begins, there should be recorded checks thatthe equipment and work station are clear of previous products,documents or materials not required for the planned process, and thatequipment is clean and suitable for use.

• Two type: Batch Processing Records & Batch Packaging Records• Batch Processing Records:• Its maintained for each batch

• It should be based on approved Manufacturing formula & Processinginstructions

• Design of batch processing records should be such that it shouldavoid any transcription errors

• Record must carry batch number of processed lot

• Before any processing begins, there should be recorded checks thatthe equipment and work station are clear of previous products,documents or materials not required for the planned process, and thatequipment is clean and suitable for use.

Dr. Nisha Sharma

BATCH PROCESSING RECORD INCLUDESDuring processing, the following information should be recorded at the time each action istaken and, after completion, the record should be dated and signed in agreement by theperson responsible for the processing operations:a) Name of the product

b) Dates and times of commencement, of significant intermediate stages and of completionof production

c) Name of the person responsible for each stage of production

d) Initials of the operator of different significant steps of production and, whereappropriate, of the person who checked each of these operations (e.g. weighing);

e) The batch number and/or analytical control number as well as the quantities of eachstarting material actually weighed (including the batch number and amount of anyrecovered or reprocessed material added);

f) Any relevant processing operation or event and major equipment used;

g) A record of the in-process controls and the initials of the person(s) carrying them out,and the results obtained;

h) The amount of product yield obtained at different and pertinent stages of manufacture;

i) Notes on special problems including details, with signed authorization for any deviationfrom the Manufacturing Formula and Processing Instructions.

During processing, the following information should be recorded at the time each action istaken and, after completion, the record should be dated and signed in agreement by theperson responsible for the processing operations:a) Name of the product

b) Dates and times of commencement, of significant intermediate stages and of completionof production

c) Name of the person responsible for each stage of production

d) Initials of the operator of different significant steps of production and, whereappropriate, of the person who checked each of these operations (e.g. weighing);

e) The batch number and/or analytical control number as well as the quantities of eachstarting material actually weighed (including the batch number and amount of anyrecovered or reprocessed material added);

f) Any relevant processing operation or event and major equipment used;

g) A record of the in-process controls and the initials of the person(s) carrying them out,and the results obtained;

h) The amount of product yield obtained at different and pertinent stages of manufacture;

i) Notes on special problems including details, with signed authorization for any deviationfrom the Manufacturing Formula and Processing Instructions.

Dr. Nisha Sharma

BATCH PACKAGING RECORDSBe kept for each batch or part batch processed.

It should be based on the relevant parts of the PackagingInstructions and the method of preparation of such records shouldbe designed to avoid transcription errors.

The record should carry the batch number and the quantity of bulkproduct to be packed, as well as the batch number and the plannedquantity of finished product that will be obtained.

Before any packaging operation begins, there should be recordedchecks that the equipment and work station are clear of previousproducts, documents or materials not required for the plannedpackaging operations, and that equipment is clean and suitable foruse.

Be kept for each batch or part batch processed.

It should be based on the relevant parts of the PackagingInstructions and the method of preparation of such records shouldbe designed to avoid transcription errors.

The record should carry the batch number and the quantity of bulkproduct to be packed, as well as the batch number and the plannedquantity of finished product that will be obtained.

Before any packaging operation begins, there should be recordedchecks that the equipment and work station are clear of previousproducts, documents or materials not required for the plannedpackaging operations, and that equipment is clean and suitable foruse.

Dr. Nisha Sharma

BATCH PACKAGING RECORDSThe following information should be entered at the time each action istaken and, after completion, the record should be dated and signed inagreement by the person(s) responsible for the packaging operations:a) The name of the product;

b) The date(s) and times of the packaging operations;

c) The name of the responsible person carrying out the packagingoperation;

d) The initials of the operators of the different significant steps;

e) Records of checks for identity and conformity with the PackagingInstructions including the results of in-process controls;

• f) Details of the packaging operations carried out, including referencesto equipment and the packaging lines used;

The following information should be entered at the time each action istaken and, after completion, the record should be dated and signed inagreement by the person(s) responsible for the packaging operations:a) The name of the product;

b) The date(s) and times of the packaging operations;

c) The name of the responsible person carrying out the packagingoperation;

d) The initials of the operators of the different significant steps;

e) Records of checks for identity and conformity with the PackagingInstructions including the results of in-process controls;

• f) Details of the packaging operations carried out, including referencesto equipment and the packaging lines used;

Dr. Nisha Sharma

BATCH PACKAGING RECORDSg) Whenever possible, samples of printed packaging materials used,including specimens of the batch coding, expiry dating and anyadditional overprinting;

• h) Notes on any special problems or unusual events including detailswith signed authorization for any deviation from the ManufacturingFormula and Processing Instructions;

• i) The quantities and reference number or identification of all printedpackaging materials and bulk product issued, used, destroyed orreturned to stock and the quantities of obtained product, in order toprovide for an adequate reconciliation. (M.H.R.A., PIC/S GMP Guide)

g) Whenever possible, samples of printed packaging materials used,including specimens of the batch coding, expiry dating and anyadditional overprinting;

• h) Notes on any special problems or unusual events including detailswith signed authorization for any deviation from the ManufacturingFormula and Processing Instructions;

• i) The quantities and reference number or identification of all printedpackaging materials and bulk product issued, used, destroyed orreturned to stock and the quantities of obtained product, in order toprovide for an adequate reconciliation. (M.H.R.A., PIC/S GMP Guide)

Dr. Nisha Sharma

BATCH MANUFACTURING RECORD• is a product and batch specific document designed to give a

complete and reliable picture of the manufacturing history ofeach batch of every product.

• shall be essentially based on the master formula record and shallbe compiled, checked, approved and authorized by competenttechnical person responsible for production and quality control.

• Name of the product

• Batch number

• Date of commencement & completion of significantintermediate stage

• Name of the person responsible for each stage of production

• Initials of operators who carried out significant processes andinitial of persons who checked, wherever applicable

• is a product and batch specific document designed to give acomplete and reliable picture of the manufacturing history ofeach batch of every product.

• shall be essentially based on the master formula record and shallbe compiled, checked, approved and authorized by competenttechnical person responsible for production and quality control.

• Name of the product

• Batch number

• Date of commencement & completion of significantintermediate stage

• Name of the person responsible for each stage of production

• Initials of operators who carried out significant processes andinitial of persons who checked, wherever applicable

Dr. Nisha Sharma

BATCH MANUFACTURING RECORD• Quantity, batch number, quality control report number of each

ingredient actually weighed and amount of any recovered materialadded

• In-process controls carried out their results and signature of personwho performed

• Theoretical yield & actual yield at appropriate stage of productiontogether with explanation, if variation beyond expectationobserved

• Authorization of any deviation, if made.

Examples of Batch manufacturing records: BMR For Tablets:Mixing, Drying, etc.

• Quantity, batch number, quality control report number of eachingredient actually weighed and amount of any recovered materialadded

• In-process controls carried out their results and signature of personwho performed

• Theoretical yield & actual yield at appropriate stage of productiontogether with explanation, if variation beyond expectationobserved

• Authorization of any deviation, if made.

Examples of Batch manufacturing records: BMR For Tablets:Mixing, Drying, etc.

Dr. Nisha Sharma

Batch Formula record INCLUDES• Dates , times

• Identity of major equipment used (e.g., reactors, driers, mills, etc.)

• Specific identification of each batch :weights, measures, batch numbers of raw materials,intermediates, or any reprocessed materials used during manufacturing

• Actual results recorded for critical process parameters

• Any sampling performed

• Signatures of the persons performing & supervising / checking critical steps of operation

• In-process and laboratory test results

• Actual yield at specific stages

• Description of packaging and label

• Representative label (commercial supply)

• Any deviation noted, its evaluation, & investigation conducted

• Results of release testing

• All analytical records relating to the batch, or a reference that will permit their retrieval

• A decision for the release or rejection of the batch, with the date and signature of theperson responsible for the decision

• The production record review

• Dates , times

• Identity of major equipment used (e.g., reactors, driers, mills, etc.)

• Specific identification of each batch :weights, measures, batch numbers of raw materials,intermediates, or any reprocessed materials used during manufacturing

• Actual results recorded for critical process parameters

• Any sampling performed

• Signatures of the persons performing & supervising / checking critical steps of operation

• In-process and laboratory test results

• Actual yield at specific stages

• Description of packaging and label

• Representative label (commercial supply)

• Any deviation noted, its evaluation, & investigation conducted

• Results of release testing

• All analytical records relating to the batch, or a reference that will permit their retrieval

• A decision for the release or rejection of the batch, with the date and signature of theperson responsible for the decision

• The production record review

Dr. Nisha Sharma

MASTER FORMULA RECORD• Master formula record is a product specific document compiled,

checked, authorized and approved by competent technical personnelfrom different but interlinked functions such as development,production, packaging and QC as necessary and appropriate.

• Master formula record shall be open for review, Changes, if any to beapproved by designated persons of production and QC

• Master formula record shalla. Give patent/proprietary name of the product, and its strength.b. Give pharmacopoeial/generic name of the product, and its strength.c. Give dosage form (e.g. tablet, ampoule) and physical characteristicsof the product.d. Give sufficient, detailed information of product pack and primarypackaging materials.e. Give identity, quality and quantity of every ingredient, includingoverages/assay value based quantities, if any, irrespective of whether,or not, the material. Next →

• Master formula record is a product specific document compiled,checked, authorized and approved by competent technical personnelfrom different but interlinked functions such as development,production, packaging and QC as necessary and appropriate.

• Master formula record shall be open for review, Changes, if any to beapproved by designated persons of production and QC

• Master formula record shalla. Give patent/proprietary name of the product, and its strength.b. Give pharmacopoeial/generic name of the product, and its strength.c. Give dosage form (e.g. tablet, ampoule) and physical characteristicsof the product.d. Give sufficient, detailed information of product pack and primarypackaging materials.e. Give identity, quality and quantity of every ingredient, includingoverages/assay value based quantities, if any, irrespective of whether,or not, the material. Next →

Dr. Nisha Sharma

MASTER FORMULA RECORDi) is an active drug substance in the formulation/product,

ii) is used as a pharmaceutical aid (excipient).

iii) appears, or is detected/tested in the final product.f. Briefly describe all the raw materialsg. Give broad outlines of the process of manufacture (as a flow-chart, for example).h. Give brief description of equipment/ machinery used formanufacturing the product.i. Give step-wise manufacturing process.j. Give theoretical and practical (expected) yields at different stagesof manufacture.

k. Bring out in sufficient details precautions to be taken duringmanufacturing to ensure birth product quality and personnel safety.l. Give all analytical controls, including limits thereof, applicable tothe finished product.

i) is an active drug substance in the formulation/product,

ii) is used as a pharmaceutical aid (excipient).

iii) appears, or is detected/tested in the final product.f. Briefly describe all the raw materialsg. Give broad outlines of the process of manufacture (as a flow-chart, for example).h. Give brief description of equipment/ machinery used formanufacturing the product.i. Give step-wise manufacturing process.j. Give theoretical and practical (expected) yields at different stagesof manufacture.

k. Bring out in sufficient details precautions to be taken duringmanufacturing to ensure birth product quality and personnel safety.l. Give all analytical controls, including limits thereof, applicable tothe finished product.

Dr. Nisha Sharma

MASTER FORMULA RECORDm. Give stability test results covering the assigned shelf life..n. Have a ‘product history’ data giving references inmanufacturing/packaging introduced over the year.o. (Preferably) contain samples of printed packaging components.

Dr. Nisha Sharma

STANDARD OPERATING PROCEDURES SOP• SOP is written document or instruction detailing all steps and

activities of a process or procedure. These should be carried outwithout any deviation or modification to guarantee the expectedoutcome.

• Any modification or deviation from a given SOP should bethoroughly investigated and outcomes of the investigationdocumented according the internal deviation procedure.

• Quality impacting processes and procedures should be as perStandard Operating Procedures (SOPs).

LOOK FOR VARIOUS SOP FORMATS AVAILABLE AT GOOGLE

• SOP is written document or instruction detailing all steps andactivities of a process or procedure. These should be carried outwithout any deviation or modification to guarantee the expectedoutcome.

• Any modification or deviation from a given SOP should bethoroughly investigated and outcomes of the investigationdocumented according the internal deviation procedure.

• Quality impacting processes and procedures should be as perStandard Operating Procedures (SOPs).

LOOK FOR VARIOUS SOP FORMATS AVAILABLE AT GOOGLE

Dr. Nisha Sharma

BENEFITS OF SOP1. To provide people with all the safety, health, environmental and operationalinformation necessary to perform a job properly. Placing value only onproduction while ignoring safety, health and environment is costly in the longrun. It is better to train employees in all aspects of doing a job than to faceaccidents, fines and litigation later.

• 2. To ensure that production operations are performed consistently to maintainquality control of processes and products. Consumers, from individuals tocompanies, want products of consistent quality and specifications. SOPs specifyjob steps that help standardize products and therefore quality.

• 3. To ensure that processes continue uninterrupted and are completed on aprescribed schedule. By following SOPs, you help ensure against process shut-downs caused by equipment failure or other facility damage.

• 4. To ensure that no failures occur in manufacturing and other processes thatwould harm anyone in the surrounding community. Following health andenvironmental steps in SOPs ensures against spills and emissions that threatenplant neighbors and create community outrage.

1. To provide people with all the safety, health, environmental and operationalinformation necessary to perform a job properly. Placing value only onproduction while ignoring safety, health and environment is costly in the longrun. It is better to train employees in all aspects of doing a job than to faceaccidents, fines and litigation later.

• 2. To ensure that production operations are performed consistently to maintainquality control of processes and products. Consumers, from individuals tocompanies, want products of consistent quality and specifications. SOPs specifyjob steps that help standardize products and therefore quality.

• 3. To ensure that processes continue uninterrupted and are completed on aprescribed schedule. By following SOPs, you help ensure against process shut-downs caused by equipment failure or other facility damage.

• 4. To ensure that no failures occur in manufacturing and other processes thatwould harm anyone in the surrounding community. Following health andenvironmental steps in SOPs ensures against spills and emissions that threatenplant neighbors and create community outrage.

Dr. Nisha Sharma

BENEFITS OF SOP5. To ensure that approved procedures are followed in compliance with

company and government regulations. Well-written SOPs help ensurethat government regulations are satisfied. They also demonstrate acompany's good-faith intention to operate properly. Failure to write anduse good SOPs only signals government regulators that your company isnot serious about compliance.

• 6. To serve as a training document for teaching users about the processfor which the SOP was written.Thorough SOPs can be used as the basisfor providing standardized training for employees who are new to aparticular job and for those who need re-training.

• 7. To serve as a checklist for co-workers who observe job performance toreinforce proper performance. The process of actively caring aboutfellow workers involves one worker coaching another in all aspects ofproper job performance. When the proper procedures are outlined in agood SOP, any co-worker can coach another to help improve work skills.

5. To ensure that approved procedures are followed in compliance withcompany and government regulations. Well-written SOPs help ensurethat government regulations are satisfied. They also demonstrate acompany's good-faith intention to operate properly. Failure to write anduse good SOPs only signals government regulators that your company isnot serious about compliance.

• 6. To serve as a training document for teaching users about the processfor which the SOP was written.Thorough SOPs can be used as the basisfor providing standardized training for employees who are new to aparticular job and for those who need re-training.

• 7. To serve as a checklist for co-workers who observe job performance toreinforce proper performance. The process of actively caring aboutfellow workers involves one worker coaching another in all aspects ofproper job performance. When the proper procedures are outlined in agood SOP, any co-worker can coach another to help improve work skills.

Dr. Nisha Sharma

BENEFITS OF SOP• 8. To serve as a checklist for auditors. Auditing job performance is a

process similar to observation mentioned in the previous item only itusually involves record keeping. SOPs should serve as a strong basis whendetailed audit checklists are developed.

• 9. To serve as an historical record of the how, why and when of steps inan existing process so there is a factual basis for revising those stepswhen a process or equipment are changed. As people move from job tojob within and between companies, unwritten knowledge and skillsdisappear from the workplace. Properly maintained written SOPs canchronicle the best knowledge that can serve new workers when older onesmove on.

• 10. To serve as an explanation of steps in a process so they can bereviewed in accident investigations. Although accidents are unfortunate,view them as opportunities to learn how to improve conditions. A goodSOP gives you a basis from which to being investigating accidents.

• 8. To serve as a checklist for auditors. Auditing job performance is aprocess similar to observation mentioned in the previous item only itusually involves record keeping. SOPs should serve as a strong basis whendetailed audit checklists are developed.

• 9. To serve as an historical record of the how, why and when of steps inan existing process so there is a factual basis for revising those stepswhen a process or equipment are changed. As people move from job tojob within and between companies, unwritten knowledge and skillsdisappear from the workplace. Properly maintained written SOPs canchronicle the best knowledge that can serve new workers when older onesmove on.

• 10. To serve as an explanation of steps in a process so they can bereviewed in accident investigations. Although accidents are unfortunate,view them as opportunities to learn how to improve conditions. A goodSOP gives you a basis from which to being investigating accidents.

Dr. Nisha Sharma

Guidelines to prepare SOP• Some guidelines are given below to prepare SOPS.

(i) Give a clear & descriptive title to each SOP.(ii) Provide sufficient details. The SOP should meet the need of anindividual, all the same, it should be general enough for more than one user.(iii) Flexibility should be written in the SOP wherever appropriate but itshould not be made too general for, it may be useless in meeting itsintended purpose(iv) Organize SOPs according to order of sequence of events involved inperforming the operation. Write the text in straight forward and easy tofollow manner.(v) After drafting SOP, use it in performing the operation to ensure that ithas sufficient details to perform the operation in intended manner.(vi) Take into account the instructions from the manufacturer of theequipment which is employed in performing the operation while draftingSOP.(vii) Indicate total number of pages so that user is certain that he isperforming the complete operation.(viii) Indicate the effective date of the SOP.

• Some guidelines are given below to prepare SOPS.(i) Give a clear & descriptive title to each SOP.(ii) Provide sufficient details. The SOP should meet the need of anindividual, all the same, it should be general enough for more than one user.(iii) Flexibility should be written in the SOP wherever appropriate but itshould not be made too general for, it may be useless in meeting itsintended purpose(iv) Organize SOPs according to order of sequence of events involved inperforming the operation. Write the text in straight forward and easy tofollow manner.(v) After drafting SOP, use it in performing the operation to ensure that ithas sufficient details to perform the operation in intended manner.(vi) Take into account the instructions from the manufacturer of theequipment which is employed in performing the operation while draftingSOP.(vii) Indicate total number of pages so that user is certain that he isperforming the complete operation.(viii) Indicate the effective date of the SOP.

Dr. Nisha Sharma

Quality audit• Auditing : Defined as inspection of a process or a system to make

sure that it complies with the requirements of its intended use.

• Quality Audit is key element of ISO quality system i.e. ISO 9001

• pharmaceutical industry: Audits are systematic, independentexamination of a Manufacturer’s quality system performed atdefinite intervals & sufficient frequency.

Aims of Audit:

• To check that quality system activities and results comply withQuality system procedures.

• Effective implementation of procedures

• Whether procedures are suitable to obtain quality system objective

If there are any deviations corrective measures can be taken tobring the activities to normal

• Auditing : Defined as inspection of a process or a system to makesure that it complies with the requirements of its intended use.

• Quality Audit is key element of ISO quality system i.e. ISO 9001

• pharmaceutical industry: Audits are systematic, independentexamination of a Manufacturer’s quality system performed atdefinite intervals & sufficient frequency.

Aims of Audit:

• To check that quality system activities and results comply withQuality system procedures.

• Effective implementation of procedures

• Whether procedures are suitable to obtain quality system objective

If there are any deviations corrective measures can be taken tobring the activities to normal

Dr. Nisha Sharma

Quality auditAims of Audit:

• Assess company’s performance based on facts• Obtain unbiased information on company’s activities• To know facts, whether company is at risk?

• Evaluate Manufacturer complaince with GMP

• Identify deficiencies & faults, improve quality

• Investigate root cause of quality related problems

• Help Mgt. reducing cost

• Educate & train people within organization

• Control external activities like supplies by vendors, & outsorcedactivities

• To make aware the suppliers about any quality related problems

Aims of Audit:

• Assess company’s performance based on facts• Obtain unbiased information on company’s activities• To know facts, whether company is at risk?

• Evaluate Manufacturer complaince with GMP

• Identify deficiencies & faults, improve quality

• Investigate root cause of quality related problems

• Help Mgt. reducing cost

• Educate & train people within organization

• Control external activities like supplies by vendors, & outsorcedactivities

• To make aware the suppliers about any quality related problems

Dr. Nisha Sharma

TYPES Quality audit:• Internal Audit (Self Inspection): Conducted within the premises

to monitor the implementation and respect of GMP. This is alsodone to have prior information about the flaws in the system andtaking necessary corrective and preventive measures.

• Observations of internal team must be well documented

• Written instructions by company for internal audit, questionnaire

1. Personnel 2. Premises including personnel facilities

3. Maintenance of buildings & equipments

4. Storage of starting materials & finished products

5. Equipment 6. Production & in process controls

7. Q.C. 8. Documentation 9. Sanitation & HYGIENE

10. Validation & revalidation programmes 11. Recall procedure

• Internal Audit (Self Inspection): Conducted within the premisesto monitor the implementation and respect of GMP. This is alsodone to have prior information about the flaws in the system andtaking necessary corrective and preventive measures.

• Observations of internal team must be well documented

• Written instructions by company for internal audit, questionnaire

1. Personnel 2. Premises including personnel facilities

3. Maintenance of buildings & equipments

4. Storage of starting materials & finished products

5. Equipment 6. Production & in process controls

7. Q.C. 8. Documentation 9. Sanitation & HYGIENE

10. Validation & revalidation programmes 11. Recall procedure

Dr. Nisha Sharma

INTERNAL Quality audit12. Calibration of instruments 13. Complaints Mgt14. Labeling control15. Results of previous self inspections & corrective measures taken

STEPS OF INTERNAL QUALITY AUDIT1. Constitution of Internal audit team: Team members from outside or inside the company constituted by Mgt. , Expert should beexperienced, familiar of GLP concept2. Frequency of Audit: At least once a year, stated in procedure3. Audit Report: At completion of process, report of results,evaluation, conclusions of inspection along with the correctivemeasures4. Follow up action: Company should evaluate internal audit &recommend corrective measures to be followed timely foreffective results

12. Calibration of instruments 13. Complaints Mgt14. Labeling control15. Results of previous self inspections & corrective measures taken

STEPS OF INTERNAL QUALITY AUDIT1. Constitution of Internal audit team: Team members from outside or inside the company constituted by Mgt. , Expert should beexperienced, familiar of GLP concept2. Frequency of Audit: At least once a year, stated in procedure3. Audit Report: At completion of process, report of results,evaluation, conclusions of inspection along with the correctivemeasures4. Follow up action: Company should evaluate internal audit &recommend corrective measures to be followed timely foreffective results

Dr. Nisha Sharma

EXTERNAL Quality auditExternal Audit: Conducted for the suppliers or any outsourcingoperations carried out by the pharmaceutical industry. The contract giver(Industry) is responsible to access the competence of the Contractacceptor (supplier or any other outsource operations department) as perthe GMP guidelines.Done to evaluate the ability of suppliers (raw material, packagingmaterials etc.) to conform GLP std. Pharmaceutical company mayconduct audits of their suppliers – External auditsSTEPS1. Notification: To alert the company, Date & time of audit. List ofdocuments auditors wants to review can be provided2. Planning: The auditor identify key areas of risk & areas of concern tobe evaluated during audit3. Opening Meeting: Meeting b/w auditors & staff of company underaudit. Process of audit is described. Company under audit – explainsauditors about schedule of employees, areas of concern of audit

External Audit: Conducted for the suppliers or any outsourcingoperations carried out by the pharmaceutical industry. The contract giver(Industry) is responsible to access the competence of the Contractacceptor (supplier or any other outsource operations department) as perthe GMP guidelines.Done to evaluate the ability of suppliers (raw material, packagingmaterials etc.) to conform GLP std. Pharmaceutical company mayconduct audits of their suppliers – External auditsSTEPS1. Notification: To alert the company, Date & time of audit. List ofdocuments auditors wants to review can be provided2. Planning: The auditor identify key areas of risk & areas of concern tobe evaluated during audit3. Opening Meeting: Meeting b/w auditors & staff of company underaudit. Process of audit is described. Company under audit – explainsauditors about schedule of employees, areas of concern of audit

Dr. Nisha Sharma

EXTERNAL Quality auditSTEPS4. Start of Audit procedure: After opening meeting, final audit planis prepared. Company employees are notified of audit sch. &procedure starts

5. Communication: Audit team should be in touch with company’saudit team for clarifications on procedures, for access to companydocs.

6. Draft audit report: After completion of audit, draft report isprepared. It contains outcomes of audit, list of concerns. Thensubmitted to company Mgt. for review & suggestions if any

7. Mgt response: Final audit report is prepared and submitted tocompany Mgt. The Mgt is requested for there agree/ disagree withreport, any corrective measures, problems etc. & expected date ofaddressal of problems or compliance.

STEPS4. Start of Audit procedure: After opening meeting, final audit planis prepared. Company employees are notified of audit sch. &procedure starts

5. Communication: Audit team should be in touch with company’saudit team for clarifications on procedures, for access to companydocs.

6. Draft audit report: After completion of audit, draft report isprepared. It contains outcomes of audit, list of concerns. Thensubmitted to company Mgt. for review & suggestions if any

7. Mgt response: Final audit report is prepared and submitted tocompany Mgt. The Mgt is requested for there agree/ disagree withreport, any corrective measures, problems etc. & expected date ofaddressal of problems or compliance.

Dr. Nisha Sharma

EXTERNAL Quality auditSTEPS8. Final Meeting: Between auditors & company officials/ Mgt. toclose loose ends, discuss Mgt. response & sccope of audit

9. Report distribution: Distribution of final audit report toconcerned officials inside & outside audit area

10. Feedback: Audited company implements recommendedchanges & auditors review, test quality, adherence effects ofimplemented changes.

STEPS8. Final Meeting: Between auditors & company officials/ Mgt. toclose loose ends, discuss Mgt. response & sccope of audit

9. Report distribution: Distribution of final audit report toconcerned officials inside & outside audit area

10. Feedback: Audited company implements recommendedchanges & auditors review, test quality, adherence effects ofimplemented changes.

Dr. Nisha Sharma

Quality audit• It is mandatory that there should be a well written procedure for

conducting an audit whether it is an internal or external audit.

Important points in Quality Audit

• Frequency of Audit: The procedure how frequency of audit mustbe defined and as per that frequency must be set and followedaccordingly.

• Responsibilities: The audit team must be defined that who will beresponsible for conducting and reviewing the audit reports. Thepeople in the audit team must be well equipped with the operationsand procedures that are being audited.

• Documentation: It is important to document each and every auditconducted as it not only helps from regulatory perspective but alsoact as reference document to have a insight of flaws previouslyfaced.

• It is mandatory that there should be a well written procedure forconducting an audit whether it is an internal or external audit.

Important points in Quality Audit

• Frequency of Audit: The procedure how frequency of audit mustbe defined and as per that frequency must be set and followedaccordingly.

• Responsibilities: The audit team must be defined that who will beresponsible for conducting and reviewing the audit reports. Thepeople in the audit team must be well equipped with the operationsand procedures that are being audited.

• Documentation: It is important to document each and every auditconducted as it not only helps from regulatory perspective but alsoact as reference document to have a insight of flaws previouslyfaced.

Dr. Nisha Sharma

Quality auditCONDUCTING AUDIT:

• The audit team must abide rules and regulations specific to theoperations carried out at the premises. Ex: if the audit is conductedin aseptic section it is mandatory to put the safety clothing as percGMP that is must for everyone who so ever enter that portion.

• The audit must be done by communicating by the audit team withthe personnel working and all the findings must be documented.But it is also important to explain the observations that make itmore realistic rather than just noting it down and explaining lateron.

• The audit team must be flexible. The procedure to meet therequirements of cGMP could be different in different industrieshence the auditor must focus on the results and then decide aboutthe observations.

• The conclusions obtained must be prepared, documented andfinally completed as a audit report.

CONDUCTING AUDIT:• The audit team must abide rules and regulations specific to the

operations carried out at the premises. Ex: if the audit is conductedin aseptic section it is mandatory to put the safety clothing as percGMP that is must for everyone who so ever enter that portion.

• The audit must be done by communicating by the audit team withthe personnel working and all the findings must be documented.But it is also important to explain the observations that make itmore realistic rather than just noting it down and explaining lateron.

• The audit team must be flexible. The procedure to meet therequirements of cGMP could be different in different industrieshence the auditor must focus on the results and then decide aboutthe observations.

• The conclusions obtained must be prepared, documented andfinally completed as a audit report.

Dr. Nisha Sharma

Quality review & Quality documentation• Quality Review is the last stage in QC procedure, before the

dispatch of product• It ensures that the finished product released for sale, all the

relevant records (production and control records) are crosschecked i.e. reviewed.

• Thorough investigation of any batch not conforming to standards• Other batches of same product with specific failure needs to be

investigated• Written record of investigation, conclusion of investigation, follow

up (remedial measures) must be keptObjective of Product Quality Review:

To evaluate compliance status of manufacture & identify areas ofimprovementsIt should involve personnel from QC unit, production,engineering, maintenance, Purchase etc.

• Quality Review is the last stage in QC procedure, before thedispatch of product

• It ensures that the finished product released for sale, all therelevant records (production and control records) are crosschecked i.e. reviewed.

• Thorough investigation of any batch not conforming to standards• Other batches of same product with specific failure needs to be

investigated• Written record of investigation, conclusion of investigation, follow

up (remedial measures) must be keptObjective of Product Quality Review:

To evaluate compliance status of manufacture & identify areas ofimprovementsIt should involve personnel from QC unit, production,engineering, maintenance, Purchase etc.

Dr. Nisha Sharma

Quality review & Quality documentation• Review of following should be done periodically & documented:• Starting materials/ packaging material used, sources, supply chain• Critical in process controls & finished product test• Failed batches with results of investigation• Significant deviations, investigations, preventive measures taken• Changes done in process & analytical methods• Sales authorization submitted, granted, rejected for third party

(Exports) dossiers• Stability monitoring results, adverse trends• All quality related returns, complaints, recalls, investigation made• Previous product, process or equipment corrective measures• Post marketing commitments, new marketing authorizations etc• Qualifying status of equipments, utilities used: HVAC

• Review of following should be done periodically & documented:• Starting materials/ packaging material used, sources, supply chain• Critical in process controls & finished product test• Failed batches with results of investigation• Significant deviations, investigations, preventive measures taken• Changes done in process & analytical methods• Sales authorization submitted, granted, rejected for third party

(Exports) dossiers• Stability monitoring results, adverse trends• All quality related returns, complaints, recalls, investigation made• Previous product, process or equipment corrective measures• Post marketing commitments, new marketing authorizations etc• Qualifying status of equipments, utilities used: HVAC

Dr. Nisha Sharma

QUALITY DOCUMENT (GDP Good document practices)• Document is any written statement or proof of any activity in

pharmaceuticals. Documentations are to define the manufacturerssystem of information & control, to minimize the risk ofmisinterpretation & errors inherent in oral or casually writtencommunication, to provide unambiguous procedures to be followed toprovide confirmation of performance, to allow calculations to bechecked & to allow tracing of batch history

• Good documentation is a systematic procedure of preparation,checking, verifying, issuing, storing and reviewing of any documents.

• prevent errors of various activities in pharma• Purpose of Documentations

• Defines specifications and procedures for all materials and methodsof manufacture and control• Ensures all personnel know what to do and when to do it• Ensure that authorized persons have all information necessary forrelease of product• Ensures documented evidence, traceability, provide records andaudit trail for investigation• Ensures availability of data for validation, review and statisticalanalysis.

• Document is any written statement or proof of any activity inpharmaceuticals. Documentations are to define the manufacturerssystem of information & control, to minimize the risk ofmisinterpretation & errors inherent in oral or casually writtencommunication, to provide unambiguous procedures to be followed toprovide confirmation of performance, to allow calculations to bechecked & to allow tracing of batch history

• Good documentation is a systematic procedure of preparation,checking, verifying, issuing, storing and reviewing of any documents.

• prevent errors of various activities in pharma• Purpose of Documentations

• Defines specifications and procedures for all materials and methodsof manufacture and control• Ensures all personnel know what to do and when to do it• Ensure that authorized persons have all information necessary forrelease of product• Ensures documented evidence, traceability, provide records andaudit trail for investigation• Ensures availability of data for validation, review and statisticalanalysis.

Dr. Nisha Sharma

QUALITY DOCUMENT (GDP Good document practices)

• Classification of Documentation• organization & Personnel.• For Buildings & facilities• For Equipments.• For Handling of R.M.& P.M.• For Production & process control.• For Packaging & Labeling control.• For Holding & Distribution• For Laboratory Control.• For Records & Reports.• For Return & Salvaged finished products.

• Classification of Documentation• organization & Personnel.• For Buildings & facilities• For Equipments.• For Handling of R.M.& P.M.• For Production & process control.• For Packaging & Labeling control.• For Holding & Distribution• For Laboratory Control.• For Records & Reports.• For Return & Salvaged finished products.

Dr. Nisha Sharma

QUALITY DOCUMENT (GDP Good document practices)

• Preparation, issues and uses of DocumentsDocuments should be carefully and logically specify to preventwrong uses. All necessary information’s are writtenunambiguously. Each document includes:1. Company name2. Purpose and title of documents3. Identification No and revision No.4. Date of authorization5. Date of review6. Signature of prepared by, checked and authorized by.7. Distribution list8. Page no.9. Reason for revision should be documented.10. Abbreviation and reference

• Preparation, issues and uses of DocumentsDocuments should be carefully and logically specify to preventwrong uses. All necessary information’s are writtenunambiguously. Each document includes:1. Company name2. Purpose and title of documents3. Identification No and revision No.4. Date of authorization5. Date of review6. Signature of prepared by, checked and authorized by.7. Distribution list8. Page no.9. Reason for revision should be documented.10. Abbreviation and reference

Dr. Nisha Sharma

QUALITY DOCUMENT (GDP Good document practices)

• Preparation, issues and uses of DocumentsDocuments should be carefully and logically specify to preventwrong uses. All necessary information’s are writtenunambiguously. Each document includes:1. Company name2. Purpose and title of documents3. Identification No and revision No.4. Date of authorization5. Date of review6. Signature of prepared by, checked and authorized by.7. Distribution list8. Page no.9. Reason for revision should be documented.10. Abbreviation and reference

• Preparation, issues and uses of DocumentsDocuments should be carefully and logically specify to preventwrong uses. All necessary information’s are writtenunambiguously. Each document includes:1. Company name2. Purpose and title of documents3. Identification No and revision No.4. Date of authorization5. Date of review6. Signature of prepared by, checked and authorized by.7. Distribution list8. Page no.9. Reason for revision should be documented.10. Abbreviation and reference

Dr. Nisha Sharma

Quality

Manual

POLICY

PROCEDURE

Outlines company’s Goal, mission, vision

Define the quality objectives

Describes what should be done, bywhom,, how, when, where

HEIRARCHY OF QUALITY DOCUMENTATION SYSTEM

Dr. Nisha Sharma

PROCEDURE

Workinginstruction

Records

Describes what should be done, bywhom,, how, when, where

Description of activities

Quality documentation system

QUALITY MANUAL• It is guiding document, approved by upper management, outlines

companies goals, vision and mission,• Describes the scope of QMS: what to be included in Quality system• Explains each & every requirement of ISO 9001

It should include:• Title & table of contents• Scope of QMS• Exclusions from ISO 9001• Version information & approval• Quality policy & objectives• QMS description• Business process model of organization• Definition of responsibilities for all personnel for all personnels• References to relevant documents• Relevant appendices

• It is guiding document, approved by upper management, outlinescompanies goals, vision and mission,

• Describes the scope of QMS: what to be included in Quality system• Explains each & every requirement of ISO 9001

It should include:• Title & table of contents• Scope of QMS• Exclusions from ISO 9001• Version information & approval• Quality policy & objectives• QMS description• Business process model of organization• Definition of responsibilities for all personnel for all personnels• References to relevant documents• Relevant appendices

Dr. Nisha Sharma

QUALITY MANUAL• Purpose of QUALITY MANUAL:

• Communicate mgt’s expectations for quality to the organization• Organizations conformity with ISO 9001 requirements

• Measure for compliance to Mgt’s expectations for Internal audits:ISO Registrar audits, customer audits

QUALITY POLICY:

• It is declaration by the organization

• It defines the quality objectives to which the organization strives.

• Should provide outline for creating, stating, measuring theperformance of quality objectives

• Ex: To provide products & services meeting the expectations ofcustomers. Actively pursue ever improving quality by variousprograms so to enable the employees to do the wok correctly forthe first time and ever

• Purpose of QUALITY MANUAL:

• Communicate mgt’s expectations for quality to the organization• Organizations conformity with ISO 9001 requirements

• Measure for compliance to Mgt’s expectations for Internal audits:ISO Registrar audits, customer audits

QUALITY POLICY:

• It is declaration by the organization

• It defines the quality objectives to which the organization strives.

• Should provide outline for creating, stating, measuring theperformance of quality objectives

• Ex: To provide products & services meeting the expectations ofcustomers. Actively pursue ever improving quality by variousprograms so to enable the employees to do the wok correctly forthe first time and ever

Dr. Nisha Sharma

QUALITY MANUAL• QUALITY PROCEDURES:

• Can be described by text, tables, flowcharts to make them effective

• Elements of quality procedures:

1. Title: Identifies procedure

2. Purpose: Explain why this procedure

3. Scope: what expects will be covered in procedure & what will not

4. Responsibilities of all persons, functions to be the part

5. Records as a result of activities done as per procedure

6. Document control: Identification of changes, date of review, approval& version of document should be included in procedure

7. Description of activities: This relates all other elements of procedures,describes what to be done, by whom, how, when & where. Its mostimp. Inputs & outputs of activities must be explained

8. Appendices to be included if required

• QUALITY PROCEDURES:

• Can be described by text, tables, flowcharts to make them effective

• Elements of quality procedures:

1. Title: Identifies procedure

2. Purpose: Explain why this procedure

3. Scope: what expects will be covered in procedure & what will not

4. Responsibilities of all persons, functions to be the part

5. Records as a result of activities done as per procedure

6. Document control: Identification of changes, date of review, approval& version of document should be included in procedure

7. Description of activities: This relates all other elements of procedures,describes what to be done, by whom, how, when & where. Its mostimp. Inputs & outputs of activities must be explained

8. Appendices to be included if required

Dr. Nisha Sharma

QUALITY MANUALWork Instructions: covers following

1. Manner in which work will be done

2. Equipment & tools that will be used

3. Environment or location associated with the work

4. Material handling requirements

5. Safety alerts for all employees

6. Cross reference to any other required process or instructions

7. Critical process & Product parameters to be monitored includinginstructions of monitoring

8. Equipment maintenance procedures

9. Methods for verifying that product meets specs

10. Other non product related criteria for the final product

Work Instructions: covers following

1. Manner in which work will be done

2. Equipment & tools that will be used

3. Environment or location associated with the work

4. Material handling requirements

5. Safety alerts for all employees

6. Cross reference to any other required process or instructions

7. Critical process & Product parameters to be monitored includinginstructions of monitoring

8. Equipment maintenance procedures

9. Methods for verifying that product meets specs

10. Other non product related criteria for the final product

Dr. Nisha Sharma

QUALITY MANUALRECORDS:

• It is final tier of Quality Documentation system. All data,information's, records, forms etc are achieved. Quality recordsmanagement shows that quality system has been executed.

• It describes how the quality of end product was verified to meetthe specs, meeting the customers satisfaction and needs.

• SOURCES QUALITY RECORDS

• Non conformance investigations

• CAPA’s (Corrective & preventive action)• AUDIT RESULTS

• SUPPLIER DOCUMENTATION

• CALIBRATION RESULTS

• MAINTENANCE RECORDS

RECORDS:

• It is final tier of Quality Documentation system. All data,information's, records, forms etc are achieved. Quality recordsmanagement shows that quality system has been executed.

• It describes how the quality of end product was verified to meetthe specs, meeting the customers satisfaction and needs.

• SOURCES QUALITY RECORDS

• Non conformance investigations

• CAPA’s (Corrective & preventive action)• AUDIT RESULTS

• SUPPLIER DOCUMENTATION

• CALIBRATION RESULTS

• MAINTENANCE RECORDS

Dr. Nisha Sharma

QUALITY MANUALRECORDS:

• It is final tier of Quality Documentation system. All data,information's, records, forms etc are achieved. Quality recordsmanagement shows that quality system has been executed.

• It describes how the quality of end product was verified to meetthe specs, meeting the customers satisfaction and needs.

• SOURCES QUALITY RECORDS

• Non conformance investigations

• CAPA’s (Corrective & preventive action)• AUDIT RESULTS

• SUPPLIER DOCUMENTATION

• CALIBRATION RESULTS

• MAINTENANCE RECORDS

RECORDS:

• It is final tier of Quality Documentation system. All data,information's, records, forms etc are achieved. Quality recordsmanagement shows that quality system has been executed.

• It describes how the quality of end product was verified to meetthe specs, meeting the customers satisfaction and needs.

• SOURCES QUALITY RECORDS

• Non conformance investigations

• CAPA’s (Corrective & preventive action)• AUDIT RESULTS

• SUPPLIER DOCUMENTATION

• CALIBRATION RESULTS

• MAINTENANCE RECORDS

Dr. Nisha Sharma

Model of document• D- Design, development, dossiers, drug master file for regulated

markets, distribution records• O- Operational procedures, techniques, methods, out of specs. (OOS),

Out of trend (OOT)• C- Cleaning, calibration, controls, complaints, containers, closures,

contamination, change control• U- User requirement specs, utilities likewater systems, HVAC, AHU (air

handling unit) etc• M- Man, materials, machines, methods, maintenance, mfg, mfg

operations & control, monitoring, Master formula, manuals (quality,safety, environment), medical records

• E- Engg. Control & practices, Envion. Control, equipment qualification,documents,

• N- Non routine activities, New products & substances• T- Technology transfer, training, testing, trend analysis, technical

dossiers• S- SOP, safety practices, sanitation, storage, self inspection,

standardization, supplier qualification, specification & standard testprocedures & site master file

• D- Design, development, dossiers, drug master file for regulatedmarkets, distribution records

• O- Operational procedures, techniques, methods, out of specs. (OOS),Out of trend (OOT)

• C- Cleaning, calibration, controls, complaints, containers, closures,contamination, change control

• U- User requirement specs, utilities likewater systems, HVAC, AHU (airhandling unit) etc

• M- Man, materials, machines, methods, maintenance, mfg, mfgoperations & control, monitoring, Master formula, manuals (quality,safety, environment), medical records

• E- Engg. Control & practices, Envion. Control, equipment qualification,documents,

• N- Non routine activities, New products & substances• T- Technology transfer, training, testing, trend analysis, technical

dossiers• S- SOP, safety practices, sanitation, storage, self inspection,

standardization, supplier qualification, specification & standard testprocedures & site master file

Dr. Nisha Sharma

Reports & documents• They are used through out manufacturing process, and in

supporting process (QA/QC). It must meet Good DocumentationProcess. Various records/ reports are (some)

• Batch Record Form * Bill of materials• Specifications * Policies• Protocols * SOP’s• Work instructions * Checklist• Forms/ Log sheets * Certificate of analysis• Technical transfer reports * Technical agreements• Technical reports * Test methods• Training assessments * Worksheets, logbooks, etc• Validation docs * Quality manual• Audit plans * Manufact./ pack. Instructions• Quality system docs * Deviation reports etc

• They are used through out manufacturing process, and insupporting process (QA/QC). It must meet Good DocumentationProcess. Various records/ reports are (some)

• Batch Record Form * Bill of materials• Specifications * Policies• Protocols * SOP’s• Work instructions * Checklist• Forms/ Log sheets * Certificate of analysis• Technical transfer reports * Technical agreements• Technical reports * Test methods• Training assessments * Worksheets, logbooks, etc• Validation docs * Quality manual• Audit plans * Manufact./ pack. Instructions• Quality system docs * Deviation reports etc

Dr. Nisha Sharma

DISTRIBUTION RECORDS• Good distribution practices (GDP) : Proper storage & distribution of

drug products minimizes risk of its quality• These are written data of distribution of drug products from Mfg. to

distributors• Records of distribution retained, accessible to trace history if req.• Helps in recall of product when in need• Distribution Records contain information on wholesalers, direct

costumers• SOP’s of warehousing & distribution of products to be adopted• Periodic audit of warehouse & distribution centers• Before dispatch of a batch, ensure about the testing, approval, & release

by QC,• Random inspection on consignments to ensure correctness of goods

must be done• Maintain Distribution registers having details about distribution: Name,

strength, dosage form description, consignees name & address, date &quantity shipped, lot number of drug product. Maintain inventory cardalso to find the position of stock.

• Good distribution practices (GDP) : Proper storage & distribution ofdrug products minimizes risk of its quality

• These are written data of distribution of drug products from Mfg. todistributors

• Records of distribution retained, accessible to trace history if req.• Helps in recall of product when in need• Distribution Records contain information on wholesalers, direct

costumers• SOP’s of warehousing & distribution of products to be adopted• Periodic audit of warehouse & distribution centers• Before dispatch of a batch, ensure about the testing, approval, & release

by QC,• Random inspection on consignments to ensure correctness of goods

must be done• Maintain Distribution registers having details about distribution: Name,

strength, dosage form description, consignees name & address, date &quantity shipped, lot number of drug product. Maintain inventory cardalso to find the position of stock.

Dr. Nisha Sharma

DISTRIBUTION RECORDSFORMAT OF INVENTORY CARD

M/S Name & address of company

Name of Poduct

Receipt No Date of issue

Transfer No.

Quantity Received

Quantity Issued Invoice No.

Inventory card

Dr. Nisha Sharma

Quantity Issued Invoice No.

Batch No.

Address of distributor

Balance Sign of issuing person

DISTRIBUTION RECORDS• Checklist of distribution records

1. Whether pre dispatch inspections are carried out before releaseY/N

2. Whether periodic audit of distribution centre are carried out toaccess warehousing practices Y/N

3. Whether distribution records are part of batch record. If nothow batch wise distribution record up to retail levels aremaintained Yes/N

4. Whether instruction for warehousing & stocking of productslike Low volume parentrals (LVP’s), heat sensitive etc. areavailable in store Yes/N

5. Whether Good distribution practices followed Y/N

Inventory card

• Checklist of distribution records

1. Whether pre dispatch inspections are carried out before releaseY/N

2. Whether periodic audit of distribution centre are carried out toaccess warehousing practices Y/N

3. Whether distribution records are part of batch record. If nothow batch wise distribution record up to retail levels aremaintained Yes/N

4. Whether instruction for warehousing & stocking of productslike Low volume parentrals (LVP’s), heat sensitive etc. areavailable in store Yes/N

5. Whether Good distribution practices followed Y/N

Dr. Nisha Sharma