Current Good Manufacturing Practices (cGMP) Training ICH-Q7- Dr. A. Amsavel.pdf
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Oct 30, 2025
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About This Presentation
Objective of GMP
Quality is not testing of product. Quality, Safety, and Effectiveness must be designed and built into the product. GMP Guidelines. Consequences of Violating GMP. USFDA Inspectional Observations. Data Integrity
Quality Management
Personnel
Buildings And Facilities
Process Equipme...
Slide Content
Change of Regulations
1937:Around 140 children died in US due to diluents used in the
formulation of a syrup (Elixir Sulphanilamide using DEG)
1960: Tragedy of Thalidomide in Europe.
Laws, regulation & Guidelines become stringent in late 1960s
for Pharmaceutical product registration,
One of the regulations is Good Manufacturing Practice,
it is applicable of Drugs, Cosmetic & Food.
1937:Around 140 children died in US due to diluents used in the
formulation of a syrup (Elixir Sulphanilamide using DEG)
1960: Tragedy of Thalidomide in Europe.
Laws, regulation & Guidelines become stringent in late 1960s
for Pharmaceutical product registration,
One of the regulations is Good Manufacturing Practice,
it is applicable of Drugs, Cosmetic & Food.
Objective of GMP
What is tested is not sold
What is sold is not tested
Quality is not testing of product.
Quality, Safety, and Effectiveness
must be designed and built into the product.
Each step in a manufacturing process must be controlled to maximize
the probability that the finished product will meet all its quality and
design specifications and ensure the Safety of Users.
What is tested is not sold
What is sold is not tested
Quality is not testing of product.
Quality, Safety, and Effectiveness
must be designed and built into the product.
Each step in a manufacturing process must be controlled to maximize
the probability that the finished product will meet all its quality and
design specifications and ensure the Safety of Users.
What are called as manufacturing activities ?
Who are all responsible for GMP implementation
and compliance?
Who are all responsible for GMP implementation
and compliance?
Manufacturing activities….
Process Development QbD
Analytical Methods Development & Validation
Scale-up / Process validation
Materials Management-vendor qualification…
Equipment qualification, maintenance, cleaning …..
Production and in-Process control
Utility generation and usage
QC-testing and approvals
QA -Documents, QMS, Batch release etc…….
Process Development QbD
Analytical Methods Development & Validation
Scale-up / Process validation
Materials Management-vendor qualification…
Equipment qualification, maintenance, cleaning …..
Production and in-Process control
Utility generation and usage
QC-testing and approvals
QA -Documents, QMS, Batch release etc…….
GMP Guidelines
oICH Q7: Good Manufacturing Practice Guide For APIs
oUS (FDA): CFR 21-Part 11, 210 and 211 Current Good Manufacturing
Practice
oEU: EudraLex-Volume 4 Good Manufacturing Practice Medicinal Products
for Human and Veterinary Use : Part II: Basic Requirements for Active
Substances used as Starting Materials
oTRS-957 Annex-2 :WHO good manufacturing practices for APIs
oCDSCO: Revised Schedule M-Good Manufacturing Practice.
oANVISA: RDC 69/14 : GMP Guide for APIs
oPIC/S, GMP guide for API
oCEFIC and EFPIA , GMP for Active Ingredients
oICH Q7: Good Manufacturing Practice Guide For APIs
oUS (FDA): CFR 21-Part 11, 210 and 211 Current Good Manufacturing
Practice
oEU: EudraLex-Volume 4 Good Manufacturing Practice Medicinal Products
for Human and Veterinary Use : Part II: Basic Requirements for Active
Substances used as Starting Materials
oTRS-957 Annex-2 :WHO good manufacturing practices for APIs
oCDSCO: Revised Schedule M-Good Manufacturing Practice.
oANVISA: RDC 69/14 : GMP Guide for APIs
oPIC/S, GMP guide for API
oCEFIC and EFPIA , GMP for Active Ingredients
Consequences of Violating GMP?
•Observation (483) : Deviation / Violation of GMP
•Warning Letter and or Import Alert
•Non-Compliance Report -EDQM
•Recall
•Seizure
•Injunction
•Debarment.
•Fine / Imprisonment etc
•Observation (483) : Deviation / Violation of GMP
•Warning Letter and or Import Alert
•Non-Compliance Report -EDQM
•Recall
•Seizure
•Injunction
•Debarment.
•Fine / Imprisonment etc
Top USFDA Inspectional Observations
Jan 2022 to Sept 2024 ; No of Observations-1071
Reference
Number
Short
Description
Long Description Nos
21 CFR
211.22(d)
Procedures not
in writing, fully
followed
The responsibilities and procedures applicable to the
quality control unit are not [in writing] [fully followed].
Specifically, ***
353
21 CFR
211.192
Investigations of
discrepancies,
failures
There is a failure to thoroughly review [any unexplained
discrepancy] [the failure of a batch or any of its
components to meet any of its specifications] whether or
not the batch has been already distributed. Specifically,
***
248
21 CFR
211.100(a)
Absence of
Written
Procedures
Your firm failed to establish [adequate] written procedures
for production and process controls designed to assure that
the drug products have the identity, strength, purity, and
quality that they are purported or represented to possess.
Specifically, ***
212
Jan 2022 to Sept 2024 ; No of Observations-1071
Reference
Number
Short
Description
Long Description Nos
21 CFR
211.22(d)
Procedures not
in writing, fully
followed
The responsibilities and procedures applicable to the
quality control unit are not [in writing] [fully followed].
Specifically, ***
353
21 CFR
211.192
Investigations of
discrepancies,
failures
There is a failure to thoroughly review [any unexplained
discrepancy] [the failure of a batch or any of its
components to meet any of its specifications] whether or
not the batch has been already distributed. Specifically,
***
248
21 CFR
211.100(a)
Absence of
Written
Procedures
Your firm failed to establish [adequate] written procedures
for production and process controls designed to assure that
the drug products have the identity, strength, purity, and
quality that they are purported or represented to possess.
Specifically, ***
212
Top USFDA Inspectional Observations
Jan 2022 to Sept 2024 ; No of Observations-1071
Reference
Number
Short
Description
Long Description Nos
21 CFR
211.160(b)
Scientifically
sound laboratory
controls
Laboratory controls do not include the establishment of
scientifically sound and appropriate [specifications] [standards]
[sampling plans] [test procedures] designed to assure that
[components] [drug product containers] [closures] [in-process
materials] [labeling] [drug products] conform to appropriate
standards of identity, strength, quality and purity. Specifically, ***
203
21 CFR
211.63
Equipment
Design, Size and
Location
Equipment used in the manufacture, processing, packing or
holding of drug products is not [of appropriate design] [of
adequate size] [suitably located] to facilitate operations for its
[intended use] [cleaning and maintenance]. Specifically, ***
159
21 CFR
211.67(a)
Cleaning /
Sanitizing /
Maintenance
Equipment and utensils are not [cleaned] [maintained] [sanitized]
at appropriate intervals to prevent [malfunctions] [contamination]
that would alter the safety, identity, strength, quality or purity of
the drug product. Specifically, ***
144
Jan 2022 to Sept 2024 ; No of Observations-1071
Reference
Number
Short
Description
Long Description Nos
21 CFR
211.160(b)
Scientifically
sound laboratory
controls
Laboratory controls do not include the establishment of
scientifically sound and appropriate [specifications] [standards]
[sampling plans] [test procedures] designed to assure that
[components] [drug product containers] [closures] [in-process
materials] [labeling] [drug products] conform to appropriate
standards of identity, strength, quality and purity. Specifically, ***
203
21 CFR
211.63
Equipment
Design, Size and
Location
Equipment used in the manufacture, processing, packing or
holding of drug products is not [of appropriate design] [of
adequate size] [suitably located] to facilitate operations for its
[intended use] [cleaning and maintenance]. Specifically, ***
159
21 CFR
211.67(a)
Cleaning /
Sanitizing /
Maintenance
Equipment and utensils are not [cleaned] [maintained] [sanitized]
at appropriate intervals to prevent [malfunctions] [contamination]
that would alter the safety, identity, strength, quality or purity of
the drug product. Specifically, ***
144
Top USFDA Inspectional Observations
Jan 2022 to Sept 2024 ; No of Observations-1071
Reference
Number
Short
Description
Long Description Nos
21 CFR
211.113(b)
Procedures for
sterile drug
products
Procedures designed to prevent microbiological
contamination of drug products purporting to be sterile are
not [established] [written] [followed]. Specifically, ***
131
21 CFR
211.68(b)
Computer control
of master formula
records
Appropriate controls are not exercised over computers or
related systems to assure that changes in master production
and control records or other records are instituted only by authorized personnel. Specifically, ***
121
21 CFR 211.67(b)
Written procedures not established/
followed
Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils,
used in the manufacture, processing, packing or holding of a
drug product. Specifically, ***
95
Jan 2022 to Sept 2024 ; No of Observations-1071
Reference
Number
Short
Description
Long Description Nos
21 CFR
211.113(b)
Procedures for
sterile drug
products
Procedures designed to prevent microbiological
contamination of drug products purporting to be sterile are
not [established] [written] [followed]. Specifically, ***
131
21 CFR
211.68(b)
Computer control
of master formula
records
Appropriate controls are not exercised over computers or
related systems to assure that changes in master production
and control records or other records are instituted only by authorized personnel. Specifically, ***
121
21 CFR 211.67(b)
Written procedures not established/
followed
Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils,
used in the manufacture, processing, packing or holding of a
drug product. Specifically, ***
95
Warning Letters content
•During the FDA walk through the inspectors found five original and rewritten
records, which were falsified.
•Inspectors found rough notebooks in the scrap yard as well as the
engineering and QA offices.
•Documents were signed and dated by individuals who were not present at
the site.
•Reprocessing was performed without review and approval of the quality
unit.
•Batch records were not reviewed by production and QA personnel before
release.
•Firm did not identify, report, or investigate the out-of-specification (OOS)
results.
•Access control is not implemented in GC, FTIR and HPLC to prevent
unauthorized access and control
•During the FDA walk through the inspectors found five original and rewritten
records, which were falsified.
•Inspectors found rough notebooks in the scrap yard as well as the
engineering and QA offices.
•Documents were signed and dated by individuals who were not present at
the site.
•Reprocessing was performed without review and approval of the quality
unit.
•Batch records were not reviewed by production and QA personnel before
release.
•Firm did not identify, report, or investigate the out-of-specification (OOS)
results.
•Access control is not implemented in GC, FTIR and HPLC to prevent
unauthorized access and control
Warning Letters & content
•Firm did not retain any raw data related to sample weights and sample
solution preparations for the HPLC assays….2012.
•Firm deleted /disregarded OOS data without investigations, and selectively
reported only passing results.
•The documentation is first done on loose sheets of paper and recorded in
batch record.
•The FDA found an operator performing in process weight checks
memorizing two " weights" , going to the next room where the batch
records are kept and documenting
•
INTRAGATION: During inspection, QC Chemist admitted that, under the
direction of a senior colleague, he had recorded false data in the logbooks for reserve samples
•Firm did not retain any raw data related to sample weights and sample
solution preparations for the HPLC assays….2012.
•Firm deleted /disregarded OOS data without investigations, and selectively
reported only passing results.
•The documentation is first done on loose sheets of paper and recorded in
batch record.
•The FDA found an operator performing in process weight checks
memorizing two " weights" , going to the next room where the batch
records are kept and documenting
•
INTRAGATION: During inspection, QC Chemist admitted that, under the
direction of a senior colleague, he had recorded false data in the logbooks for reserve samples
Consequences of WL?
The cost of remediation, investigation, CAPA will be huge,
It will destroy the image of the company
loose the credibility from customers,
demoralize the employees,
reduces time to gain the market
Affects the future plan of the company……
Spending Time & money for prevention is
better than spending in millions for remediation
Consent degreeHence, follow GMP to prevention of 483 or WL.
The cost of remediation, investigation, CAPA will be huge,
It will destroy the image of the company
loose the credibility from customers,
demoralize the employees,
reduces time to gain the market
Affects the future plan of the company……
Spending Time & money for prevention is
better than spending in millions for remediation
Consent degreeHence, follow GMP to prevention of 483 or WL.
How to achieve the cGMP Compliance ?
Instructing, Training,Educating,
Involvement
&
Commitment
Involvement
&
Commitment
Top Priority is…..
Data Integrity
Data Integrity
Iceberg ofIgnorance
4% Problem known to Top Executives
9% Problem known to Managers
74% Problem known to Shift in- charges
100% Problem known to staffs
Gap : Known by mgt(Unknown
96%)
Gap is
91%
4% Problem known to Top Executives
9% Problem known to Managers
74% Problem known to Shift in- charges
100% Problem known to staffs
Gap : Known by mgt(Unknown
96%)
Gap is
91%
ALCOA Description
ALCOA Description/Explanation Comments
A
AttributableWho performed an action and when?
If a record is changed, who did it and why?
Link to the source data.
Who did it?
Source data
L
Legible Data must be recorded permanently in a
durable medium and be readable .
Can you read it?
Is it permanent
record
C
Contem-
poraneous
The data should be recorded at the time
the work is performed and date/time
stamps should follow in order.
Was it done in
“Real Time”?
O
Original Is the information the original record or a
certified true copy?
Is it original or
true copy?
A
Accurate No errors or editing performed without
documented amendments.
Is it accurate?
ALCOA Description/Explanation Comments
A
AttributableWho performed an action and when?
If a record is changed, who did it and why?
Link to the source data.
Who did it?
Source data
L
Legible Data must be recorded permanently in a
durable medium and be readable .
Can you read it?
Is it permanent
record
C
Contem-
poraneous
The data should be recorded at the time
the work is performed and date/time
stamps should follow in order.
Was it done in
“Real Time”?
O
Original Is the information the original record or a
certified true copy?
Is it original or
true copy?
A
Accurate No errors or editing performed without
documented amendments.
Is it accurate?
ALCOA + (2 CEA)
ALCOA + Description/ExplanationComments
+1Complete The data must be whole; a complete set
All data including repeat or reanalysis performed
21 CFR 211.194
+2ConsistentThe data must be self-consistent
Consistent application of date & time stamps …
Date time
stamps
+3Enduring & durable; lasting throughout the data
lifecycle
Recorded on controlled worksheets, laboratory
notebooks, or electronic media.
Medium -to
record data
+4Available Readily available for review or
inspection purposes
Available/accessible for review/audit for the
lifetime of the record.
For the lifetime
of the record
ALCOA + Description/ExplanationComments
+1Complete The data must be whole; a complete set
All data including repeat or reanalysis performed
21 CFR 211.194
+2ConsistentThe data must be self-consistent
Consistent application of date & time stamps …
Date time
stamps
+3Enduring & durable; lasting throughout the data
lifecycle
Recorded on controlled worksheets, laboratory
notebooks, or electronic media.
Medium -to
record data
+4Available Readily available for review or
inspection purposes
Available/accessible for review/audit for the
lifetime of the record.
For the lifetime
of the record
1.Introduction
2.Quality Management
3.Personnel
4.Buildings And Facilities
5.Process Equipment
6.Documentation And Records
7.Materials Management
8.Production And In- process
Controls
9.Packaging And Identification
Labeling Of APIs
10.Storage And Distribution
11.Laboratory Controls
12.Validation
13.Change Control
14.Rejection And Re-use Of Materials
15.Complaints And Recalls
16.Contract Manufacturers (Including Laboratories)
17.Agents, Brokers, Traders, Distributors, Repackers, And Relabellers
18.Specific Guidance For Apis Manufactured
By Cellculture/Fermentation
19.APIs For Use In Clinical Trials
20.Glossary
ICH Q7: Index
2.Quality Management
3.Personnel
4.Buildings And Facilities
5.Process Equipment
6.Documentation And Records
7.Materials Management
8.Production And In- process
Controls
9.Packaging And Identification
Labeling Of APIs
10.Storage And Distribution
11.Laboratory Controls
12.Validation
13.Change Control
14.Rejection And Re-use Of Materials
15.Complaints And Recalls
16.Contract Manufacturers (Including Laboratories)
17.Agents, Brokers, Traders, Distributors, Repackers, And Relabellers
18.Specific Guidance For Apis Manufactured
By Cellculture/Fermentation
19.APIs For Use In Clinical Trials
20.Glossary
ICH Q7: Index
2.0 QUALITY MANAGEMENT
1.0 Introduction
1.1 Objective
ICH Q7 is Guidance for Good Manufacturing Practice (GMP) for the manufacturing of
APIs
It defines receipt of materials, production , packaging, repackaging, labelling,
relabelling, quality control, release, storage and distribution of APIs
1.2 Regulatory Applicability
API should be manufactured according to this Guide .
1.3 Scope
This Guide applies to the manufacture of APIs for use in human drug ( medicinal)
products.
The sterilization and aseptic processing of sterile APIs are not covered, but follow
appropriate guidance .
Appropriate GMP should be applied to intermediate and/or API manufacturing steps.
1.0 Introduction
1.1 Objective
ICH Q7 is Guidance for Good Manufacturing Practice (GMP) for the manufacturing of
APIs
It defines receipt of materials, production , packaging, repackaging, labelling,
relabelling, quality control, release, storage and distribution of APIs
1.2 Regulatory Applicability
API should be manufactured according to this Guide .
1.3 Scope
This Guide applies to the manufacture of APIs for use in human drug ( medicinal)
products.
The sterilization and aseptic processing of sterile APIs are not covered, but follow
appropriate guidance .
Appropriate GMP should be applied to intermediate and/or API manufacturing steps.
2.0 QUALITY MANAGEMENT
2.1Principles
Qualityshouldbetheresponsibilityofallpersonsinvolvedinmfg.
1.Establish,document,andimplementaneffectivesystemfor
managingqualitythatinvolvestheactiveparticipation.
2.Thesystemformanagingqualityshouldencompassthe
organizationalstructure,procedures,processesandresources,as
wellasactivities.Allquality-relatedactivitiesshouldbedefined
anddocumented.
3.
AllQUALITY-RELATEDACTIVITIESSHOULDBERECORDEDATTHETIME
PERFORMED.
4.Anydeviationfromestablishedproceduresshouldbedocumented
andexplained.Criticaldeviationsshouldbeinvestigated,and
documented.
5.Nomaterialsshouldbereleasedorusedbeforecomplete
evaluationbythequalityunit(s).
2.1Principles
Qualityshouldbetheresponsibilityofallpersonsinvolvedinmfg.
1.Establish,document,andimplementaneffectivesystemfor
managingqualitythatinvolvestheactiveparticipation.
2.Thesystemformanagingqualityshouldencompassthe
organizationalstructure,procedures,processesandresources,as
wellasactivities.Allquality-relatedactivitiesshouldbedefined
anddocumented.
3.
AllQUALITY-RELATEDACTIVITIESSHOULDBERECORDEDATTHETIME
PERFORMED.
4.Anydeviationfromestablishedproceduresshouldbedocumented
andexplained.Criticaldeviationsshouldbeinvestigated,and
documented.
5.Nomaterialsshouldbereleasedorusedbeforecomplete
evaluationbythequalityunit(s).
2.0 QUALITY MANAGEMENT
2.2 Responsibilities of the Quality Unit(s)
TheQualityUnitshouldbeindependentofProduction.
DefineQAwillbeentrustedasAuthorisedPerson
Thequalityunit(s)should
1.involvedinallquality-relatedmatters.
2.reviewandapproveallappropriatequality-relateddocuments.
3.Themainresponsibilitiesshouldnotbedelegated. Responsibilities
shouldbedescribedinwritingandshouldinclude,butnotnecessarily
belimitedto:
4.Approvingallproceduresaffectingthequalityofintermediatesor
APIs.
5.Makingsurethatinternalaudits(self-inspections)areperformed ,
2.2 Responsibilities of the Quality Unit(s)
TheQualityUnitshouldbeindependentofProduction.
DefineQAwillbeentrustedasAuthorisedPerson
Thequalityunit(s)should
1.involvedinallquality-relatedmatters.
2.reviewandapproveallappropriatequality-relateddocuments.
3.Themainresponsibilitiesshouldnotbedelegated. Responsibilities
shouldbedescribedinwritingandshouldinclude,butnotnecessarily
belimitedto:
4.Approvingallproceduresaffectingthequalityofintermediatesor
APIs.
5.Makingsurethatinternalaudits(self-inspections)areperformed ,
5.ApprovingintermediateandAPIcontractmanufacturers,
6.ApprovingchangesthatpotentiallyaffectintermediateorAPIquality,
7.Reviewingandapprovingvalidationprotocolsandreports,
8.Makingsurethatquality-relatedcomplaintsareinvestigatedandresolved,
9.Makingsurethateffectivesystemsareusedformaintainingandcalibrating
criticalequipment,
10.Makingsurethatmaterialsareappropriatelytestedandtheresultsare
reported,
11.Makingsurethatthereisstabilitydatatosupportretestorexpirydates
andstorageconditionsonAPIsand/orintermediates,whereappropriate,
12.Performingproductqualityreviews(asdefinedinSection2.5)
2.0 QUALITY MANAGEMENT
2.2. Responsibilities of the Quality Unit(s)
6.ApprovingchangesthatpotentiallyaffectintermediateorAPIquality,
7.Reviewingandapprovingvalidationprotocolsandreports,
8.Makingsurethatquality-relatedcomplaintsareinvestigatedandresolved,
9.Makingsurethateffectivesystemsareusedformaintainingandcalibrating
criticalequipment,
10.Makingsurethatmaterialsareappropriatelytestedandtheresultsare
reported,
11.Makingsurethatthereisstabilitydatatosupportretestorexpirydates
andstorageconditionsonAPIsand/orintermediates,whereappropriate,
12.Performingproductqualityreviews(asdefinedinSection2.5)
2.0 QUALITY MANAGEMENT
2.2. Responsibilities of the Quality Unit(s)
2.0 : QUALITY MANAGEMENT
2.3 Responsibility for Production Activities
Theresponsibilityforproductionactivitiesshouldinclude,butnotnecessarily
belimitedto:
1.Preparing,reviewing,approving,anddistributingtheinstructionsforthe
2.productionofintermediatesorAPIsaccordingtowrittenprocedures.
3.
ProducingAPIsand,intermediatesaccordingtopre-approvedInstructions.
4.Reviewingallproductionbatchrecordsandensuringthattheseare
completedandsigned.
5.Makingsurethatallproductiondeviationsarereportedandevaluatedand
thatcriticaldeviationsareinvestigatedandtheconclusionsarerecorded.
6.Makingsurethatproductionfacilitiesarecleananddisinfected.
7.Calibrationsareperformedandrecordskept.
8.Premisesandequipmentaremaintainedandrecordskept.
9.Validationprotocolsandreportsarereviewedandapproved.
10.Evaluatingproposedchangesinproduct,processorequipment.
2.3 Responsibility for Production Activities
Theresponsibilityforproductionactivitiesshouldinclude,butnotnecessarily
belimitedto:
1.Preparing,reviewing,approving,anddistributingtheinstructionsforthe
2.productionofintermediatesorAPIsaccordingtowrittenprocedures.
3.
ProducingAPIsand,intermediatesaccordingtopre-approvedInstructions.
4.Reviewingallproductionbatchrecordsandensuringthattheseare
completedandsigned.
5.Makingsurethatallproductiondeviationsarereportedandevaluatedand
thatcriticaldeviationsareinvestigatedandtheconclusionsarerecorded.
6.Makingsurethatproductionfacilitiesarecleananddisinfected.
7.Calibrationsareperformedandrecordskept.
8.Premisesandequipmentaremaintainedandrecordskept.
9.Validationprotocolsandreportsarereviewedandapproved.
10.Evaluatingproposedchangesinproduct,processorequipment.
2.0 : QUALITY MANAGEMENT
2.4 Internal Audits (Self Inspection)
Theresponsibilityforproductionactivitiesshouldinclude,butnotnecessarily
belimitedto:
1.ToverifycompliancewiththeprinciplesofGMPforAPIs,regularinternal
auditsshouldbeperformedinaccordancewithanapprovedschedule.
2.
Auditfindingsandcorrectiveactionsshouldbedocumentedandbrought
totheattentionofresponsiblemanagementofthefirm.
3.Agreedcorrectiveactionsshouldbecompletedinatimelyandeffective
manner.
2.4 Internal Audits (Self Inspection)
Theresponsibilityforproductionactivitiesshouldinclude,butnotnecessarily
belimitedto:
1.ToverifycompliancewiththeprinciplesofGMPforAPIs,regularinternal
auditsshouldbeperformedinaccordancewithanapprovedschedule.
2.
Auditfindingsandcorrectiveactionsshouldbedocumentedandbrought
totheattentionofresponsiblemanagementofthefirm.
3.Agreedcorrectiveactionsshouldbecompletedinatimelyandeffective
manner.
2.0 : QUALITY MANAGEMENT
2.5 Product Quality Review
1.Regular quality-reviews of APIs should be conducted with the objective of
verifying the consistency of the process.
2.Such reviews should normally be conducted and documented annually and
should include at least:
2.5 Product Quality Review
1.Regular quality-reviews of APIs should be conducted with the objective of
verifying the consistency of the process.
2.Such reviews should normally be conducted and documented annually and
should include at least:
3.0 PERSONNEL
3.1 Personnel Qualifications
1.Thereshouldbeanadequatenumberofpersonnelqualifiedby
appropriateeducation,training,and/orexperiencetoperformand
supervisethemanufactureofintermediate
2.Theresponsibilitiesofallpersonnelengagedinthemanufactureof
intermediatesandAPIsshouldbespecifiedinwriting.
3.a)TrainingshouldberegularlyconductedbyqualifiedindividualsforGMP
andrelatestoJob/activity
b)Recordsoftrainingshouldbemaintained.
c)Trainingshouldbeperiodicallyassessed.
3.1 Personnel Qualifications
1.Thereshouldbeanadequatenumberofpersonnelqualifiedby
appropriateeducation,training,and/orexperiencetoperformand
supervisethemanufactureofintermediate
2.Theresponsibilitiesofallpersonnelengagedinthemanufactureof
intermediatesandAPIsshouldbespecifiedinwriting.
3.a)TrainingshouldberegularlyconductedbyqualifiedindividualsforGMP
andrelatestoJob/activity
b)Recordsoftrainingshouldbemaintained.
c)Trainingshouldbeperiodicallyassessed.
3.0 PERSONNEL
3.1 Personnel Qualifications
1.Personnel should practice good sanitation and health habits.
2.Personnel should wear suitable clean clothing.Additional protective apparel, such
as head, face, hand, and arm coverings, should be worn, when necessary, to
protect intermediates and APIs from contamination.
3.Personnel should avoid direct contact with intermediates or APIs.
4.Smoking, eating, drinking, chewing and the storage of food should be restrictedto
certain designated areas separate from the manufacturing areas.
5.
Personnel suffering from an infectious disease or having open lesionson the
exposed surface of the body should not engage in activities that could result in
compromising the quality of APIs.
6.Do not engage affected person until the condition is corrected or qualified medical
personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs.
3.1 Personnel Qualifications
1.Personnel should practice good sanitation and health habits.
2.Personnel should wear suitable clean clothing.Additional protective apparel, such
as head, face, hand, and arm coverings, should be worn, when necessary, to
protect intermediates and APIs from contamination.
3.Personnel should avoid direct contact with intermediates or APIs.
4.Smoking, eating, drinking, chewing and the storage of food should be restrictedto
certain designated areas separate from the manufacturing areas.
5.
Personnel suffering from an infectious disease or having open lesionson the
exposed surface of the body should not engage in activities that could result in
compromising the quality of APIs.
6.Do not engage affected person until the condition is corrected or qualified medical
personnel determine that the person's inclusion would not jeopardize the safety or quality of the APIs.
3.0 PERSONNEL
3.1 . Consultants
1.Consultants advisingon the manufacture and control of intermediates or
APIs should have sufficient education, training, and experience, or any
combination thereof, to advise on the subject for which they are retained
2.Records should be maintained stating the name, address, qualifications , and
type of service providedby these consultants.
3.1 . Consultants
1.Consultants advisingon the manufacture and control of intermediates or
APIs should have sufficient education, training, and experience, or any
combination thereof, to advise on the subject for which they are retained
2.Records should be maintained stating the name, address, qualifications , and
type of service providedby these consultants.
4.0 BUILDINGS AND FACILITIES
4.1 Design and Construction
1.Buildings and facilities should be located, designed, and constructed to facilitate
cleaning, maintenance,
2.Facilities should also be designed to minimize potential contamination.
3.Where required facilities should also be designed to limit exposure to objectionable
microbiological contaminants,.
4.Buildings and facilities should have adequate space for the orderly placement of
equipment and materials to prevent mix-ups and contamination.
5.Where the equipment itself (e.g., closed or contained systems) provides adequate
protection of the material, such equipment can be located outdoors .
6.The flow of materials and personnel through the building or facilities should be
designed to prevent mix-ups or contamination.
4.1 Design and Construction
1.Buildings and facilities should be located, designed, and constructed to facilitate
cleaning, maintenance,
2.Facilities should also be designed to minimize potential contamination.
3.Where required facilities should also be designed to limit exposure to objectionable
microbiological contaminants,.
4.Buildings and facilities should have adequate space for the orderly placement of
equipment and materials to prevent mix-ups and contamination.
5.Where the equipment itself (e.g., closed or contained systems) provides adequate
protection of the material, such equipment can be located outdoors .
6.The flow of materials and personnel through the building or facilities should be
designed to prevent mix-ups or contamination.
4.0 BUILDINGS AND FACILITIES
4.1 Design and Construction
7.There should be defined areasor other control systemsfor the following
activities:
Receipt, identification, sampling, and quarantine of incoming materials,
pending release or rejection;
Quarantine before release or rejection of intermediates and APIs
Sampling of intermediates and APIs
8.Adequateandcleanwashingandtoiletfacilitiesshouldbeprovidedfor
personnel.
9.Thewashingandtoiletfacilitiesshouldbeseparatefrom,buteasilyaccessible
to,manufacturingareas.
10.Laboratoryareas/operationsshouldnormallybeseparatedfromproduction
areas.
11.laboratoryanditsoperationsdonotadverselyaffecttheproductionprocess,
intermediate,orAPI.
4.1 Design and Construction
7.There should be defined areasor other control systemsfor the following
activities:
Receipt, identification, sampling, and quarantine of incoming materials,
pending release or rejection;
Quarantine before release or rejection of intermediates and APIs
Sampling of intermediates and APIs
8.Adequateandcleanwashingandtoiletfacilitiesshouldbeprovidedfor
personnel.
9.Thewashingandtoiletfacilitiesshouldbeseparatefrom,buteasilyaccessible
to,manufacturingareas.
10.Laboratoryareas/operationsshouldnormallybeseparatedfromproduction
areas.
11.laboratoryanditsoperationsdonotadverselyaffecttheproductionprocess,
intermediate,orAPI.
4.0 BUILDINGS AND FACILITIES
4.2 Utilities
1.Allutilitiesthatcouldaffectproductquality(e.g.,steam,gas,
compressedair,heating,ventilation,andairconditioning)shouldbe
qualifiedandappropriatelymonitoredandactionshouldbetakenwhen
limitsareexceeded.
2.Adequateventilation,airfiltrationandexhaustsystemsshouldbe
appropriate.
airpressure,microorganisms(ifappropriate),dust,humidity,and
temperature,
3.Permanentlyinstalledpipe-workshouldbeappropriatelyidentified.
Drainsshouldbeofadequatesizeandshouldbeprovidedwithanair
breakorasuitabledevicetopreventback-siphonage,whenappropriate.
4.2 Utilities
1.Allutilitiesthatcouldaffectproductquality(e.g.,steam,gas,
compressedair,heating,ventilation,andairconditioning)shouldbe
qualifiedandappropriatelymonitoredandactionshouldbetakenwhen
limitsareexceeded.
2.Adequateventilation,airfiltrationandexhaustsystemsshouldbe
appropriate.
airpressure,microorganisms(ifappropriate),dust,humidity,and
temperature,
3.Permanentlyinstalledpipe-workshouldbeappropriatelyidentified.
Drainsshouldbeofadequatesizeandshouldbeprovidedwithanair
breakorasuitabledevicetopreventback-siphonage,whenappropriate.
4.0 BUILDINGS AND FACILITIES
4.3 Water
1.Water should be ensured as suitable for its intended use.
2.Unless otherwise justified, process water should, at a minimum, meet
World Health Organization (WHO) guidelines for drinking (potable) water
quality.
3.
If drinking (potable) water is insufficient to ensure API qualityand tighter
specifications for physical/chemical attributes, total microbial counts,
objectionable organisms, and/or endotoxins should be established.
4.Thetreatment process should be validated and monitoredwith
appropriate action limits.
5.Where the manufacturer of a non-sterile API water used in the final
isolationand purification steps should be monitored and controlled for
total microbial counts, objectionable organisms, and endotoxins.
4.3 Water
1.Water should be ensured as suitable for its intended use.
2.Unless otherwise justified, process water should, at a minimum, meet
World Health Organization (WHO) guidelines for drinking (potable) water
quality.
3.
If drinking (potable) water is insufficient to ensure API qualityand tighter
specifications for physical/chemical attributes, total microbial counts,
objectionable organisms, and/or endotoxins should be established.
4.Thetreatment process should be validated and monitoredwith
appropriate action limits.
5.Where the manufacturer of a non-sterile API water used in the final
isolationand purification steps should be monitored and controlled for
total microbial counts, objectionable organisms, and endotoxins.
4.0 BUILDINGS AND FACILITIES
4.4 Containment
1.Dedicatedproductionareas-facilities, airhandlingequipmentand/or
processequipment,shouldbeusedfortheproductionofhighlysensitizing
materials,suchaspenicillinsorcephalosporins,
Infectiousnatureorhighpharmacologicalactivityortoxicity(e.g.,
certainsteroidsorcytotoxicanti-canceragents)products,usededicated
facilityorensuretovalidateinactivationand/orcleaningprocedures
2.Establishandimplementtopreventcross-contaminationfrompersonnel
andmaterialsmovingfromonededicatedareatoanother.
3.Handlingandstorageofthesehighlytoxicnon-pharmaceuticalmaterials
shouldbeseparatefromAPIs.
4.4 Containment
1.Dedicatedproductionareas-facilities, airhandlingequipmentand/or
processequipment,shouldbeusedfortheproductionofhighlysensitizing
materials,suchaspenicillinsorcephalosporins,
Infectiousnatureorhighpharmacologicalactivityortoxicity(e.g.,
certainsteroidsorcytotoxicanti-canceragents)products,usededicated
facilityorensuretovalidateinactivationand/orcleaningprocedures
2.Establishandimplementtopreventcross-contaminationfrompersonnel
andmaterialsmovingfromonededicatedareatoanother.
3.Handlingandstorageofthesehighlytoxicnon-pharmaceuticalmaterials
shouldbeseparatefromAPIs.
4.0 BUILDINGS AND FACILITIES
4.5 Lighting, 4.6 Sewage & Refuse; 4.7 Sanitation and Maintenance
1.Adequatelightingshouldbeprovidedinalltheareastofacilitate
cleaning,maintenance,andproperoperations.
2.Sewage,refuse,andotherwasteshouldbedisposedofinasafe,timely,
andsanitarymanner.
3.Buildings used in the manufacture of intermediates and APIs should be
properly maintained and repaired and kept in a clean condition.
4.Written procedures for sanitation and describing the cleaning schedules,
methods, equipment, and materials to be used in cleaning buildings and
facilities.
5.When necessary, written proceduresshould also be established for the use
of suitable rodenticides, insecticides, fungicides, fumigating agents, and
cleaning and sanitizing agents at facility and equipment to prevent the
contamination
4.5 Lighting, 4.6 Sewage & Refuse; 4.7 Sanitation and Maintenance
1.Adequatelightingshouldbeprovidedinalltheareastofacilitate
cleaning,maintenance,andproperoperations.
2.Sewage,refuse,andotherwasteshouldbedisposedofinasafe,timely,
andsanitarymanner.
3.Buildings used in the manufacture of intermediates and APIs should be
properly maintained and repaired and kept in a clean condition.
4.Written procedures for sanitation and describing the cleaning schedules,
methods, equipment, and materials to be used in cleaning buildings and
facilities.
5.When necessary, written proceduresshould also be established for the use
of suitable rodenticides, insecticides, fungicides, fumigating agents, and
cleaning and sanitizing agents at facility and equipment to prevent the
contamination
5.0 PROCESS EQUIPMENT
5.1 Design and Construction
1.Equipmentusedshouldbeofappropriatedesignandadequatesize,and
suitablylocatedforitsintendeduse,cleaning,sanitation(where
appropriate),andmaintenance.
2.EnsurethesurfacesdonotalterthequalityoftheintermediatesandAPIs
3.Tobeusedwithinitsqualifiedatoperatingrange.
4.Majorequipmentusedshouldbeappropriatelyidentified.
5.Anysubstancesassociatedwiththeoperationofequipment,suchas
lubricants,heatingfluidsorcoolants,shouldnotcontactwithmaterial
6.UseClosedcondition,Whereopenequipmentisusedtakeprecautionsto
minimizetheriskofcontamination.
5.1 Design and Construction
1.Equipmentusedshouldbeofappropriatedesignandadequatesize,and
suitablylocatedforitsintendeduse,cleaning,sanitation(where
appropriate),andmaintenance.
2.EnsurethesurfacesdonotalterthequalityoftheintermediatesandAPIs
3.Tobeusedwithinitsqualifiedatoperatingrange.
4.Majorequipmentusedshouldbeappropriatelyidentified.
5.Anysubstancesassociatedwiththeoperationofequipment,suchas
lubricants,heatingfluidsorcoolants,shouldnotcontactwithmaterial
6.UseClosedcondition,Whereopenequipmentisusedtakeprecautionsto
minimizetheriskofcontamination.
5.0 PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
1.EstablishSchedulesandproceduresforpreventativemaintenanceof
equipment.
2.Writtenproceduresshouldbeestablishedforcleaningequipment
3.Cleaningproceduresshouldcontainsufficientdetailstoenableoperators
tocleaneachtypeofequipmentinareproducibleandeffectivemanner.
•Cleaning/sanitizingschedules,
•Acompletedescriptionofthemethodsandcleaningagentsusedto
cleanequipment;
•Instructionsfortheremovalorobliterationofpreviousbatch
identification;
•Instructionsfordisassemblingandreassemblingofparts/equipment
•Inspectionofequipmentforcleanliness
5.2 Equipment Maintenance and Cleaning
1.EstablishSchedulesandproceduresforpreventativemaintenanceof
equipment.
2.Writtenproceduresshouldbeestablishedforcleaningequipment
3.Cleaningproceduresshouldcontainsufficientdetailstoenableoperators
tocleaneachtypeofequipmentinareproducibleandeffectivemanner.
•Cleaning/sanitizingschedules,
•Acompletedescriptionofthemethodsandcleaningagentsusedto
cleanequipment;
•Instructionsfortheremovalorobliterationofpreviousbatch
identification;
•Instructionsfordisassemblingandreassemblingofparts/equipment
•Inspectionofequipmentforcleanliness
5.0 PROCESS EQUIPMENT
5.2 Equipment Maintenance and Cleaning
1.Whereequipmentisassignedtocontinuousproductionorcampaign
production,equipmentshouldbecleanedatappropriateintervalsto
preventbuild-upandcarry-overofcontaminants
2.Non-dedicatedequipmentshouldbecleanedbetweenproductionof
different
3.Acceptancecriteriaforresiduesdefinedandjustified.
4.Identifythecleanlinessstatus
5.2 Equipment Maintenance and Cleaning
1.Whereequipmentisassignedtocontinuousproductionorcampaign
production,equipmentshouldbecleanedatappropriateintervalsto
preventbuild-upandcarry-overofcontaminants
2.Non-dedicatedequipmentshouldbecleanedbetweenproductionof
different
3.Acceptancecriteriaforresiduesdefinedandjustified.
4.Identifythecleanlinessstatus
5.0 PROCESS EQUIPMENT
5.3 Calibration
1.Control, weighing, measuring, monitoring, and testing equipment should
be calibrated
2.Establish procedures and schedule.
3.Equipment calibrations should be performed using standards traceable to
certified standards,if they exist.
4.Records of these calibrations should be maintained.
5.3 Calibration
1.Control, weighing, measuring, monitoring, and testing equipment should
be calibrated
2.Establish procedures and schedule.
3.Equipment calibrations should be performed using standards traceable to
certified standards,if they exist.
4.Records of these calibrations should be maintained.
5.0 PROCESS EQUIPMENT
5.4 Computerized Systems
1.GMP-relatedcomputerizedsystemsshouldbevalidated.
2.Ensuresufficientcontrolstopreventunauthorizedaccessorchangesto
data.
3.
Controlstopreventomissionsindata
4.Recordanydatachangemade,whoandwhen
5.Changestocomputerizedsystemsshouldbeformallyauthorized,
documented,andtested.
6.Aback-upsystemshouldbeprovidedtopreventpermanentlossof
records-systembreakdownsorfailures
5.4 Computerized Systems
1.GMP-relatedcomputerizedsystemsshouldbevalidated.
2.Ensuresufficientcontrolstopreventunauthorizedaccessorchangesto
data.
3.
Controlstopreventomissionsindata
4.Recordanydatachangemade,whoandwhen
5.Changestocomputerizedsystemsshouldbeformallyauthorized,
documented,andtested.
6.Aback-upsystemshouldbeprovidedtopreventpermanentlossof
records-systembreakdownsorfailures
6.0 DOCUMENTATION AND RECORDS
6.1 . Documentation System and Specifications
1.All documents should be prepared, reviewed, approved, and distributed
according to written procedures. (paper or electronic).
2.The issuance, revision, superseding, and withdrawalof all documents
should be controlled by maintaining revision histories.
3.A procedure should be established for the documents retention & periods
4.
Follow ALCOA and GDP
5.Corrections to entries should be dated and signed and leave the original
entry still legible.
6.1 . Documentation System and Specifications
1.All documents should be prepared, reviewed, approved, and distributed
according to written procedures. (paper or electronic).
2.The issuance, revision, superseding, and withdrawalof all documents
should be controlled by maintaining revision histories.
3.A procedure should be established for the documents retention & periods
4.
Follow ALCOA and GDP
5.Corrections to entries should be dated and signed and leave the original
entry still legible.
6.0 DOCUMENTATION AND RECORDS
6.1 . Documentation System and Specifications
6.Duringtheretentionperiod,originalsorcopiesofrecordsshouldbe
readilyavailable
7.Specificationsshouldbeestablishedanddocumentedforrawmaterials,
intermediates,APIs,andlabelingandpackagingmaterials.
8.Acceptancecriteriashouldbeestablishedanddocumentedforin-process
controls.
9.Ifelectronicsignaturesareusedondocuments,theyshouldbe
authenticated
6.1 . Documentation System and Specifications
6.Duringtheretentionperiod,originalsorcopiesofrecordsshouldbe
readilyavailable
7.Specificationsshouldbeestablishedanddocumentedforrawmaterials,
intermediates,APIs,andlabelingandpackagingmaterials.
8.Acceptancecriteriashouldbeestablishedanddocumentedforin-process
controls.
9.Ifelectronicsignaturesareusedondocuments,theyshouldbe
authenticated
6.0 DOCUMENTATION AND RECORDS
6.2 . Equipment Cleaning and Use Record
1.Recordsofmajorequipmentuse,cleaning,sanitation,and/orsterilization
andmaintenanceshouldshowthedate,timeproduct,andbatchnumber
2.Incaseswherededicatedequipmentisemployed,therecordsofcleaning,
maintenance,andusecanbepartofthebatchrecordormaintained
separately.
6.2 . Equipment Cleaning and Use Record
1.Recordsofmajorequipmentuse,cleaning,sanitation,and/orsterilization
andmaintenanceshouldshowthedate,timeproduct,andbatchnumber
2.Incaseswherededicatedequipmentisemployed,therecordsofcleaning,
maintenance,andusecanbepartofthebatchrecordormaintained
separately.
6.0 DOCUMENTATION AND RECORDS
6.3 . Records of Raw Materials, Intermediates,
API Labeling and Packaging Materials
Records should be maintained including:
1.The name of the manufacturer, identity, and quantity of each shipment of
each batch of raw materials, intermediates, or labeling and packaging
materials for API's should be traceable & recored
2.Testperformed and record shall be available.
The final decisionregarding rejected raw materials, intermediates, or
API labeling and packaging materials
3.
Master (approved) labelsshould be maintained for comparison to issued
labels.
6.3 . Records of Raw Materials, Intermediates,
API Labeling and Packaging Materials
Records should be maintained including:
1.The name of the manufacturer, identity, and quantity of each shipment of
each batch of raw materials, intermediates, or labeling and packaging
materials for API's should be traceable & recored
2.Testperformed and record shall be available.
The final decisionregarding rejected raw materials, intermediates, or
API labeling and packaging materials
3.
Master (approved) labelsshould be maintained for comparison to issued
labels.
6.0 DOCUMENTATION AND RECORDS
6.4 Master Production Record/Instructions
Master Production Instructions ( Master Production and Control Records)
1.To ensure uniformity from batch to batch, master production instructions
for each intermediate and API should be prepared, dated, and signed by
one person and independently checked, dated, and signed by a person in
the quality unit(s).
2.Master production instructions should include:
1.The name of the intermediate or API with reference code, if applicable;
2.Raw materials and intermediates name or codes
3.Quantity or ratio of each raw material or intermediate to be used, including
the unit of measure.
6.4 Master Production Record/Instructions
Master Production Instructions ( Master Production and Control Records)
1.To ensure uniformity from batch to batch, master production instructions
for each intermediate and API should be prepared, dated, and signed by
one person and independently checked, dated, and signed by a person in
the quality unit(s).
2.Master production instructions should include:
1.The name of the intermediate or API with reference code, if applicable;
2.Raw materials and intermediates name or codes
3.Quantity or ratio of each raw material or intermediate to be used, including
the unit of measure.
6.0 DOCUMENTATION AND RECORDS
6.4 Master Production Record/Instructions
Master Production Instruction / Master production control Records
3.The production locationand majorproduction equipmentto be used;
4.Detailed production instructions, include where appropriate:
sequences to be followed,
ranges of process parameters to be used,
sampling instructions and in-process controls with their acceptance criteria,
time limits for completionof individual processing steps and/or the total
process,
expected yield rangesat appropriate phases of processing or time,
special notations and precautionsto be followed,
The instructions for storage of the intermediate or API to ensure its
suitability for use, including the labelling and packaging materialsand
special storage conditions with time limits,
6.4 Master Production Record/Instructions
Master Production Instruction / Master production control Records
3.The production locationand majorproduction equipmentto be used;
4.Detailed production instructions, include where appropriate:
sequences to be followed,
ranges of process parameters to be used,
sampling instructions and in-process controls with their acceptance criteria,
time limits for completionof individual processing steps and/or the total
process,
expected yield rangesat appropriate phases of processing or time,
special notations and precautionsto be followed,
The instructions for storage of the intermediate or API to ensure its
suitability for use, including the labelling and packaging materialsand
special storage conditions with time limits,
6.0 DOCUMENTATION AND RECORDS
6.5 Batch Production Records
6.5 Batch Production Records (Batch Production & Control Records)
Batch production records should be numbered with a unique batch or
identification number, dated and signed when issued.
Documentation of completion of each significant stepin the batch
production records (batch production and control records) should include:
Dates and, when appropriate, times;
Identity of major equipment (e.g., reactors, driers, mills, etc.) used;
Specific identification of each batch, including weights, measures,
and batch numbers of raw materials, intermediates, or any
reprocessed materials used during manufacturing;
6.5 Batch Production Records
6.5 Batch Production Records (Batch Production & Control Records)
Batch production records should be numbered with a unique batch or
identification number, dated and signed when issued.
Documentation of completion of each significant stepin the batch
production records (batch production and control records) should include:
Dates and, when appropriate, times;
Identity of major equipment (e.g., reactors, driers, mills, etc.) used;
Specific identification of each batch, including weights, measures,
and batch numbers of raw materials, intermediates, or any
reprocessed materials used during manufacturing;
6.0 DOCUMENTATION AND RECORDS
6.5 Batch Production Records
Batch Production Records (Batch Production and Control Records)
1.Actual results recorded for critical process parameters,
2.Any sampling performed,
3.Signatures of the persons performing and directly supervising or checking
each critical step in the operation,
4.In-process and laboratory test results,
5.Actual yield at appropriate phases or times,
6.Description of packaging and label for intermediate or API,
6.5 Batch Production Records
Batch Production Records (Batch Production and Control Records)
1.Actual results recorded for critical process parameters,
2.Any sampling performed,
3.Signatures of the persons performing and directly supervising or checking
each critical step in the operation,
4.In-process and laboratory test results,
5.Actual yield at appropriate phases or times,
6.Description of packaging and label for intermediate or API,
6.0 DOCUMENTATION AND RECORDS
6.5 Batch Production Records
Batch Production Records (Batch Production and Control Records)
7.Representative label of API or intermediate if made commercially
available,
8.Any deviation noted, its evaluation, investigation conducted (if
appropriate) or reference to that investigation if stored separately,
9.Results of release testing,
10.Written procedures should be established and followed for investigating
critical deviations or the failure of a batch of intermediate or API to
meet specifications. The investigation should extend to other batches
that may have been associated with the specific failure or deviation.
6.5 Batch Production Records
Batch Production Records (Batch Production and Control Records)
7.Representative label of API or intermediate if made commercially
available,
8.Any deviation noted, its evaluation, investigation conducted (if
appropriate) or reference to that investigation if stored separately,
9.Results of release testing,
10.Written procedures should be established and followed for investigating
critical deviations or the failure of a batch of intermediate or API to
meet specifications. The investigation should extend to other batches
that may have been associated with the specific failure or deviation.
6.0 DOCUMENTATION AND RECORDS
6.6 Laboratory Control Records
Laboratory control records should include complete data derived from all tests
conducted to ensure compliance with established specifications
1.
Adescriptionofsamplesreceivedfortesting,includingthematerialnameor
source,batchnumberorotherdistinctivecode,datesamplewastaken,and,
whereappropriate,thequantityanddatethesample
2.Astatementoforreferencetoeachtestmethodused;
3.Astatementoftheweightormeasureofsampleusedforeachtestas
describedbythemethod;dataonorcross-referencetothepreparationand
testingofreferencestandards,reagentsandstandardsolutions;
4.Acompleterecordofallrawdatageneratedduringeachtest,inadditionto
graphs,chartsandspectrafromlaboratoryinstrumentation, properly
identifiedtoshowthespecificmaterialandbatchtested;
6.6 Laboratory Control Records
Laboratory control records should include complete data derived from all tests
conducted to ensure compliance with established specifications
1.
Adescriptionofsamplesreceivedfortesting,includingthematerialnameor
source,batchnumberorotherdistinctivecode,datesamplewastaken,and,
whereappropriate,thequantityanddatethesample
2.Astatementoforreferencetoeachtestmethodused;
3.Astatementoftheweightormeasureofsampleusedforeachtestas
describedbythemethod;dataonorcross-referencetothepreparationand
testingofreferencestandards,reagentsandstandardsolutions;
4.Acompleterecordofallrawdatageneratedduringeachtest,inadditionto
graphs,chartsandspectrafromlaboratoryinstrumentation, properly
identifiedtoshowthespecificmaterialandbatchtested;
6.0 DOCUMENTATION AND RECORDS
6.6 Laboratory Control Records (con’d)
5.Arecordofallcalculationsperformedinconnectionwiththetest,
including,forexample,unitsofmeasure,conversionfactors,and
equivalencyfactors;
6.Astatementofthetestresultsandhowtheycomparewithestablished
acceptancecriteria;
7.
Thesignatureofthepersonwhoperformedeachtestandthedate(s)the
testswereperformed;
8.Thedateandsignatureofasecondpersonshowingthattheoriginal
recordshavebeenreviewedforaccuracy,completeness,andcompliance
withestablishedstandards.
6.6 Laboratory Control Records (con’d)
5.Arecordofallcalculationsperformedinconnectionwiththetest,
including,forexample,unitsofmeasure,conversionfactors,and
equivalencyfactors;
6.Astatementofthetestresultsandhowtheycomparewithestablished
acceptancecriteria;
7.
Thesignatureofthepersonwhoperformedeachtestandthedate(s)the
testswereperformed;
8.Thedateandsignatureofasecondpersonshowingthattheoriginal
recordshavebeenreviewedforaccuracy,completeness,andcompliance
withestablishedstandards.
6.0 DOCUMENTATION AND RECORDS
6.6 Laboratory Control Records (con’d)
Laboratory Control Records
Completerecordsshouldalsobemaintainedfor:
1.Anymodificationstoanestablishedanalyticalmethod;
2.Periodiccalibrationoflaboratoryinstruments,apparatus,gauges,and
recordingdevices;
3.AllstabilitytestingperformedonAPIs;
4.Out-of-specification(OOS)investigations.
6.6 Laboratory Control Records (con’d)
Laboratory Control Records
Completerecordsshouldalsobemaintainedfor:
1.Anymodificationstoanestablishedanalyticalmethod;
2.Periodiccalibrationoflaboratoryinstruments,apparatus,gauges,and
recordingdevices;
3.AllstabilitytestingperformedonAPIs;
4.Out-of-specification(OOS)investigations.
6.0 DOCUMENTATION AND RECORDS
6.7 Batch Production Record Review
1.Written proceduresshould be established and followed for the reviewand
approval of batch production and laboratory control records of the
intermediate or APIs.
2.Batch production and laboratory control records of critical process steps
should be reviewed and approved by the quality unit(s) before an API
batch is released or distributed.
3.non-critical process steps can be reviewed by qualified production
personnelor other units following procedures approved by the quality
unit(s).
4.
All deviation, investigation, and OOS reports should be reviewed as part of
the batch record review before the batch is released.
6.7 Batch Production Record Review
1.Written proceduresshould be established and followed for the reviewand
approval of batch production and laboratory control records of the
intermediate or APIs.
2.Batch production and laboratory control records of critical process steps
should be reviewed and approved by the quality unit(s) before an API
batch is released or distributed.
3.non-critical process steps can be reviewed by qualified production
personnelor other units following procedures approved by the quality
unit(s).
4.
All deviation, investigation, and OOS reports should be reviewed as part of
the batch record review before the batch is released.
7.0 MATERIALS MANAGEMENT
7.1 General
1.There should be written procedures describing the receipt, identification,
quarantine, storage, handling, sampling, testing, and approval or
rejection of materials.
2.Manufacturers of intermediates and/or APIs should have a system for
evaluating the suppliers of critical materials.
3.Purchase the Materials against an agreed specification, from a supplier,
4.If the supplier of a critical material is not the manufacturerof that
material, the name and address of that manufacturer should be known.
5.Changing the source of supply of critical raw materials should be treated
according to Section 13, Change Control.
7.1 General
1.There should be written procedures describing the receipt, identification,
quarantine, storage, handling, sampling, testing, and approval or
rejection of materials.
2.Manufacturers of intermediates and/or APIs should have a system for
evaluating the suppliers of critical materials.
3.Purchase the Materials against an agreed specification, from a supplier,
4.If the supplier of a critical material is not the manufacturerof that
material, the name and address of that manufacturer should be known.
5.Changing the source of supply of critical raw materials should be treated
according to Section 13, Change Control.
7.0 MATERIALS MANAGEMENT
7.2 Receipt and Quarantine
1.Upon receipt and before acceptance, each container or grouping of containers of
materials should be examined
1.visually for correct labeling,
2.container damage, broken seals and evidence of tampering or contamination.
2.Materials should be held under quarantine until they have been sampled,
examined, or tested, as appropriate, and released for use.
3.Before incoming materials are mixedwith existing stocks (e.g., solvents or stocks in
silos), they should be identified as correct, tested, if appropriate, and released.
4.
If bulk deliveries are made in non-dedicated tankers, there should be assurance of
no cross- contamination from the tanker. Egcertificate of cleaning, • testing for
trace impurities, • audit of the supplier.
5.A system shouldbe in place to identify the status of each batch.
7.2 Receipt and Quarantine
1.Upon receipt and before acceptance, each container or grouping of containers of
materials should be examined
1.visually for correct labeling,
2.container damage, broken seals and evidence of tampering or contamination.
2.Materials should be held under quarantine until they have been sampled,
examined, or tested, as appropriate, and released for use.
3.Before incoming materials are mixedwith existing stocks (e.g., solvents or stocks in
silos), they should be identified as correct, tested, if appropriate, and released.
4.
If bulk deliveries are made in non-dedicated tankers, there should be assurance of
no cross- contamination from the tanker. Egcertificate of cleaning, • testing for
trace impurities, • audit of the supplier.
5.A system shouldbe in place to identify the status of each batch.
7.0 MATERIALS MANAGEMENT
7.3 Sampling and Testing of Incoming Production Materials .
1.Atleastonetesttoverifytheidentityofeachbatchofmaterialshouldbe
conducted,withtheexceptionofthematerialsdescribedbelow.
2.Supplierapprovalshouldincludeanevaluationthatprovidesadequate
evidencethatthemanufacturercanconsistentlyprovidematerialmeeting
specifications.
3.Completeanalysesshouldbeconductedonatleastthreebatchesbefore
reducingin-housetesting.
4.However,asaminimum,acompleteanalysisshouldbeperformedat
appropriateintervalsandcomparedwiththecertificatesofanalysis.
Reliabilityofcertificatesofanalysisshouldbecheckedatregularintervals.
7.3 Sampling and Testing of Incoming Production Materials .
1.Atleastonetesttoverifytheidentityofeachbatchofmaterialshouldbe
conducted,withtheexceptionofthematerialsdescribedbelow.
2.Supplierapprovalshouldincludeanevaluationthatprovidesadequate
evidencethatthemanufacturercanconsistentlyprovidematerialmeeting
specifications.
3.Completeanalysesshouldbeconductedonatleastthreebatchesbefore
reducingin-housetesting.
4.However,asaminimum,acompleteanalysisshouldbeperformedat
appropriateintervalsandcomparedwiththecertificatesofanalysis.
Reliabilityofcertificatesofanalysisshouldbecheckedatregularintervals.
7.0 MATERIALS MANAGEMENT
7.3 Sampling and Testing of Incoming Production Materials
5.Processingaids,hazardousorhighlytoxicrawmaterials,otherspecial
materials,ormaterialstransferredtoanotherunitwithinthecompany’s,
canbeapprovedonCOA
Visualexaminationofcontainers,labels,andrecordingofbatchnumbers
Samplingmethodsshouldspecifythenumberofcontainers/where/and
amountofmaterialtobetaken
6.Sampleindesignedareatopreventcontamination
7.SampledContainersshouldbeopenedcarefullyandsubsequentlyre-
closed.
8.Theyshouldbemarkedtoindicatethatissampled
7.3 Sampling and Testing of Incoming Production Materials
5.Processingaids,hazardousorhighlytoxicrawmaterials,otherspecial
materials,ormaterialstransferredtoanotherunitwithinthecompany’s,
canbeapprovedonCOA
Visualexaminationofcontainers,labels,andrecordingofbatchnumbers
Samplingmethodsshouldspecifythenumberofcontainers/where/and
amountofmaterialtobetaken
6.Sampleindesignedareatopreventcontamination
7.SampledContainersshouldbeopenedcarefullyandsubsequentlyre-
closed.
8.Theyshouldbemarkedtoindicatethatissampled
7.0 MATERIALS MANAGEMENT
7.4 Storage & 7.5 Reevaluation
1.Materialsshouldbehandledandstoredinamannertopreventdegradation,
contamination,andcross- contamination.
2.Materialsstoredinfiberdrums,bags,orboxesshouldbestoredoffthefloor
3.Materialsshouldbestoredtopreventfromadverseeffectontheirquality,and
controlledtouseoldeststockfirst.
4.Whenmaterialsarestoredoutdoorsensurethatcontainersaresuitable,labels
remainlegibleandcontainersarecleanedbeforeopeninganduse.
5.Rejectedmaterialsshouldbeidentifiedandcontrolledunderaquarantinesystem
designedtopreventtheirunauthorizeduseinmanufacturing.
6.Materialsshouldbere-evaluated,asappropriate,todeterminetheirsuitabilityfor
use(e.g.,re-testingafterprolongedstorageorexposuretoheatorhumidity).
7.4 Storage & 7.5 Reevaluation
1.Materialsshouldbehandledandstoredinamannertopreventdegradation,
contamination,andcross- contamination.
2.Materialsstoredinfiberdrums,bags,orboxesshouldbestoredoffthefloor
3.Materialsshouldbestoredtopreventfromadverseeffectontheirquality,and
controlledtouseoldeststockfirst.
4.Whenmaterialsarestoredoutdoorsensurethatcontainersaresuitable,labels
remainlegibleandcontainersarecleanedbeforeopeninganduse.
5.Rejectedmaterialsshouldbeidentifiedandcontrolledunderaquarantinesystem
designedtopreventtheirunauthorizeduseinmanufacturing.
6.Materialsshouldbere-evaluated,asappropriate,todeterminetheirsuitabilityfor
use(e.g.,re-testingafterprolongedstorageorexposuretoheatorhumidity).
8.0 PRODUCTION AND IN- PROCESS CONTROLS
8.1 Production Operations
1.Raw materials for intermediate and API manufacturing should be weighed or
measured under appropriate conditions that do not affect their suitability for use.
2.Weighing and measuring devices should be of suitable accuracy
3.If a material should be identified
Material name and/or item code
Receiving or control number
Weight or measure of material in the new container
Re-evaluation or retest date if appropriate
4.Critical weighing, measuring, or subdividing operations should be witnessed or
subjected to an equivalent control.
5.Other critical activities should be witnessed or subjected to an equivalent control.
8.1 Production Operations
1.Raw materials for intermediate and API manufacturing should be weighed or
measured under appropriate conditions that do not affect their suitability for use.
2.Weighing and measuring devices should be of suitable accuracy
3.If a material should be identified
Material name and/or item code
Receiving or control number
Weight or measure of material in the new container
Re-evaluation or retest date if appropriate
4.Critical weighing, measuring, or subdividing operations should be witnessed or
subjected to an equivalent control.
5.Other critical activities should be witnessed or subjected to an equivalent control.
8.0 PRODUCTION AND IN-PROCESS CONTROLS
8.1 Production Operations
6.Actualyieldsshouldbecomparedwithexpectedyieldsatdesignatedsteps
intheproductionprocess.
7.Deviationsinyieldassociatedwithcriticalprocessstepsshouldbe
investigatedtodeterminetheirimpact
8.Anydeviationshouldbedocumentedandexplained.Anycriticaldeviation
shouldbeinvestigated.
9.Materialstobereprocessedorreworkedshouldbeappropriately
controlledtopreventunauthorizeduse.
8.1 Production Operations
6.Actualyieldsshouldbecomparedwithexpectedyieldsatdesignatedsteps
intheproductionprocess.
7.Deviationsinyieldassociatedwithcriticalprocessstepsshouldbe
investigatedtodeterminetheirimpact
8.Anydeviationshouldbedocumentedandexplained.Anycriticaldeviation
shouldbeinvestigated.
9.Materialstobereprocessedorreworkedshouldbeappropriately
controlledtopreventunauthorizeduse.
8.0 PRODUCTION AND IN-PROCESS CONTROLS
8.2 Time Limits
1.If time limitsare specified in the master production instruction (see 6.40),
these time limits should be met to ensure the quality of intermediates and
APIs.
2.Deviationsshould be documented and evaluated.
3.Time limits may be inappropriatewhen processing to a target value (e.g.,
pH adjustment, hydrogenation, drying to predetermined specification)
because completion of reactions or processing steps are determined by in-
process sampling and testing.
4.Intermediates held for further processingshould be stored under
appropriate conditionsto ensure their suitability for use.
8.2 Time Limits
1.If time limitsare specified in the master production instruction (see 6.40),
these time limits should be met to ensure the quality of intermediates and
APIs.
2.Deviationsshould be documented and evaluated.
3.Time limits may be inappropriatewhen processing to a target value (e.g.,
pH adjustment, hydrogenation, drying to predetermined specification)
because completion of reactions or processing steps are determined by in-
process sampling and testing.
4.Intermediates held for further processingshould be stored under
appropriate conditionsto ensure their suitability for use.
8.0 PRODUCTION AND IN- PROCESS CONTROLS
8.3 In-process Sampling and Controls
1.Written procedures should be establishedto monitor the progress and control
2.In-process controls and their acceptance criteriashould be defined based on the
information gained during the developmental stage or from historical data.
3.In-process controls can be performed by qualified production department personnel
4.All tests and resultsshould be fully documented as part of the batch record .
5.Written proceduresshould describe the sampling methods for in-process materials,
intermediates, and APIs.
6.Sampling plans and proceduresshould be based on scientifically sound sampling
practices.
7.Out-of-specification (OOS) investigationsare not normally needed for in-process
tests that are performed for the purpose of monitoring and/or adjusting the
process.
8.3 In-process Sampling and Controls
1.Written procedures should be establishedto monitor the progress and control
2.In-process controls and their acceptance criteriashould be defined based on the
information gained during the developmental stage or from historical data.
3.In-process controls can be performed by qualified production department personnel
4.All tests and resultsshould be fully documented as part of the batch record .
5.Written proceduresshould describe the sampling methods for in-process materials,
intermediates, and APIs.
6.Sampling plans and proceduresshould be based on scientifically sound sampling
practices.
7.Out-of-specification (OOS) investigationsare not normally needed for in-process
tests that are performed for the purpose of monitoring and/or adjusting the
process.
8.0 PRODUCTION AND IN- PROCESS CONTROLS
8.4 Blending Batches of APIs
1.Forthepurposeofthisdocument,blendingisdefinedastheprocessofcombining
materialswithinthesamespecificationtoproduceahomogeneousintermediateor
API.
2.In-processmixingoffractionsfromsinglebatches(e.g.,collectingseveral
centrifugeloadsfromasinglecrystallizationbatch)orcombiningfractionsfrom
severalbatchesforfurtherprocessingisconsideredtobepartoftheproduction
processandisnotconsideredasblending.
3.Out-of-specificationbatchesshouldnotbeblendedwithotherbatchesforthe
purposeofmeetingspecifications.
4.Acceptableblendingoperationsinclude,butarenotlimitedto:
Blendingofsmallbatchestoincreasebatchsize;
Blendingoftailings(i.e.,relativelysmallquantitiesofisolatedmaterial)from
batchesofthesameintermediateorAPItoformasinglebatch;
8.4 Blending Batches of APIs
1.Forthepurposeofthisdocument,blendingisdefinedastheprocessofcombining
materialswithinthesamespecificationtoproduceahomogeneousintermediateor
API.
2.In-processmixingoffractionsfromsinglebatches(e.g.,collectingseveral
centrifugeloadsfromasinglecrystallizationbatch)orcombiningfractionsfrom
severalbatchesforfurtherprocessingisconsideredtobepartoftheproduction
processandisnotconsideredasblending.
3.Out-of-specificationbatchesshouldnotbeblendedwithotherbatchesforthe
purposeofmeetingspecifications.
4.Acceptableblendingoperationsinclude,butarenotlimitedto:
Blendingofsmallbatchestoincreasebatchsize;
Blendingoftailings(i.e.,relativelysmallquantitiesofisolatedmaterial)from
batchesofthesameintermediateorAPItoformasinglebatch;
8.0 PRODUCTION AND IN-PROCESS CONTROLS
8.3 Blending Batches of APIs
6.Blendingprocessesshouldbecontrolledanddocumented,andtheblendedbatch
shouldbetestedandconformedthequality.
7.Thebatchrecordoftheblendingprocessshouldallowtraceabilitybacktothe
individualbatchesthatmakeuptheblend.
8.Validationshouldincludetestingofcriticalattributes(e.g.,particlesize
distribution,bulkdensity,andtapdensity)thatmaybeaffectedbytheblending
process.
9.Theexpiryorretestdateoftheblendedbatchshouldbebasedonthe
manufacturingdateoftheoldesttailingsorbatchintheblend.
8.3 Blending Batches of APIs
6.Blendingprocessesshouldbecontrolledanddocumented,andtheblendedbatch
shouldbetestedandconformedthequality.
7.Thebatchrecordoftheblendingprocessshouldallowtraceabilitybacktothe
individualbatchesthatmakeuptheblend.
8.Validationshouldincludetestingofcriticalattributes(e.g.,particlesize
distribution,bulkdensity,andtapdensity)thatmaybeaffectedbytheblending
process.
9.Theexpiryorretestdateoftheblendedbatchshouldbebasedonthe
manufacturingdateoftheoldesttailingsorbatchintheblend.
8.0 PRODUCTION AND IN-PROCESS CONTROLS
8.5 Contamination Control
1.Residual materialscan be carried over into successive batchesof the same
intermediate or API.
2.Such carryover should not result in the carryover of degradantsor
microbial contamination that may adversely alter the impurity profile.
3.Production operationsshould be conducted in a manner that prevents
contaminationof intermediates or APIs by other materials.
4.Precautions to avoid contaminationshould be taken when APIs are handled
after purification.
8.5 Contamination Control
1.Residual materialscan be carried over into successive batchesof the same
intermediate or API.
2.Such carryover should not result in the carryover of degradantsor
microbial contamination that may adversely alter the impurity profile.
3.Production operationsshould be conducted in a manner that prevents
contaminationof intermediates or APIs by other materials.
4.Precautions to avoid contaminationshould be taken when APIs are handled
after purification.
9.0 PACKAGING AND IDENTIFICATION LABELING
9.1 General
1.There should be written procedures describing the receipt,
identification, quarantine, sampling, examination, and/or
testing, release, and handling of packaging and labeling
materials.
2.Packaging and labeling materials should conform to established
specifications.
9.1 General
1.There should be written procedures describing the receipt,
identification, quarantine, sampling, examination, and/or
testing, release, and handling of packaging and labeling
materials.
2.Packaging and labeling materials should conform to established
specifications.
9.0 PACKAGING AND IDENTIFICATION LABELING
9.2 Packaging Materials
1.Containers should provide adequate protection against deterioration or
contaminationof the intermediate or API while transportation and
storage.
2.Containers should be cleanand, where indicated by the nature of the
intermediate or API, sanitizedto ensure the suitability of intended use.
3.Should not use the reactive, additive, or absorptive containers, to prevent
alter the quality of product beyond the specified period.
4.If containers are reused,they should be cleaned adequately and all
previous labels should be removed or defaced.
9.2 Packaging Materials
1.Containers should provide adequate protection against deterioration or
contaminationof the intermediate or API while transportation and
storage.
2.Containers should be cleanand, where indicated by the nature of the
intermediate or API, sanitizedto ensure the suitability of intended use.
3.Should not use the reactive, additive, or absorptive containers, to prevent
alter the quality of product beyond the specified period.
4.If containers are reused,they should be cleaned adequately and all
previous labels should be removed or defaced.
9.0 PACKAGING AND IDENTIFICATION LABELING
9.3 Label Issuance and Control
1.Accesstothelabelstorageareasshouldbelimitedtoauthorized
personnel.
2.Proceduresshouldbeestablishedtoreconcilethequantitiesoflabels
issued,used,andreturnedandtoevaluatediscrepanciesfoundbetween
thenumberofcontainerslabeledandthenumberoflabelsissued.
3.Suchdiscrepanciesshouldbeinvestigated,andtheinvestigationshouldbe
approvedbythequalityunit(s).
4.Allexcesslabelsbearingbatchnumbersorotherbatch-relatedprinting
shouldbedestroyed.
9.3 Label Issuance and Control
1.Accesstothelabelstorageareasshouldbelimitedtoauthorized
personnel.
2.Proceduresshouldbeestablishedtoreconcilethequantitiesoflabels
issued,used,andreturnedandtoevaluatediscrepanciesfoundbetween
thenumberofcontainerslabeledandthenumberoflabelsissued.
3.Suchdiscrepanciesshouldbeinvestigated,andtheinvestigationshouldbe
approvedbythequalityunit(s).
4.Allexcesslabelsbearingbatchnumbersorotherbatch-relatedprinting
shouldbedestroyed.
9.0 PACKAGING AND IDENTIFICATION LABELING
9.3 Label Issuance and Control
6.Returnedlabelsshouldbemaintainedandstoredinamannerthat
preventsmix-upsandprovidesproperidentification.
7.Printingdevicesusedtoprintlabelsforpackagingoperationsshouldbe
controlledtoensurethatallimprintingconformstotheprintspecifiedin
thebatchproductionrecord.
8.Printedlabelsissuedforabatchshouldbecarefullyexaminedforproper
identityandconformitytospecificationsinthemasterproductionrecord.
Theresultsofthisexaminationshouldbedocumented
9.Aprintedlabelrepresentativeofthoseusedshouldbeincludedinthe
batchproductionrecord.
9.3 Label Issuance and Control
6.Returnedlabelsshouldbemaintainedandstoredinamannerthat
preventsmix-upsandprovidesproperidentification.
7.Printingdevicesusedtoprintlabelsforpackagingoperationsshouldbe
controlledtoensurethatallimprintingconformstotheprintspecifiedin
thebatchproductionrecord.
8.Printedlabelsissuedforabatchshouldbecarefullyexaminedforproper
identityandconformitytospecificationsinthemasterproductionrecord.
Theresultsofthisexaminationshouldbedocumented
9.Aprintedlabelrepresentativeofthoseusedshouldbeincludedinthe
batchproductionrecord.
9.0 PACKAGING AND IDENTIFICATION LABELING
9.4 Packaging and Labeling Operations
1.Thereshouldbedocumentedproceduresdesignedtoensurethatcorrectpackaging
materialsandlabelsareused.
2.Labelingoperationsshouldbedesignedtopreventmix-ups.Thereshouldbe
physicalorspatialseparationfromoperationsinvolvingotherintermediatesorAPIs.
3.Labelsusedoncontainersofshouldindicatethenameoridentifyingcode,batch
number,andstorageconditionsofintermediateorAPI.
4.IftheintermediateorAPIisintendedtobetransferredoutsidethecontrolofthe
manufacturer’smaterialmanagementsystem,thenameandaddressofthe
manufacturer,quantityofcontents,specialtransportconditions,andanyspecial
legalrequirementsshouldalsobeincludedonthelabel.
5.ForintermediatesorAPIswitharetestdate,theretestdateshouldbeindicated
onthelabeland/orcertificateofanalysis.
9.4 Packaging and Labeling Operations
1.Thereshouldbedocumentedproceduresdesignedtoensurethatcorrectpackaging
materialsandlabelsareused.
2.Labelingoperationsshouldbedesignedtopreventmix-ups.Thereshouldbe
physicalorspatialseparationfromoperationsinvolvingotherintermediatesorAPIs.
3.Labelsusedoncontainersofshouldindicatethenameoridentifyingcode,batch
number,andstorageconditionsofintermediateorAPI.
4.IftheintermediateorAPIisintendedtobetransferredoutsidethecontrolofthe
manufacturer’smaterialmanagementsystem,thenameandaddressofthe
manufacturer,quantityofcontents,specialtransportconditions,andanyspecial
legalrequirementsshouldalsobeincludedonthelabel.
5.ForintermediatesorAPIswitharetestdate,theretestdateshouldbeindicated
onthelabeland/orcertificateofanalysis.
9.0 PACKAGING AND IDENTIFICATION LABELING
9.4 Packaging and Labeling Operations
5.Packagingandlabelingfacilitiesshouldbeinspectedimmediatelybefore
usetoensurethatallmaterialsnotneededforthenextpackaging
operationhavebeenremovedandrecorded.
6.Ensurethatcontainersandpackageshavethecorrectlabelanditshould
bepartofthepackagingoperationandrecordedinBPR.
7.IntermediateorAPIcontainersthataretransportedoutsideofthe
manufacturer'scontrolshouldbesealedinamannersuchthat,iftheseal
isbreachedormissing,therecipientwillbealertedtothepossibilitythat
thecontentsmayhavebeenaltered.
9.4 Packaging and Labeling Operations
5.Packagingandlabelingfacilitiesshouldbeinspectedimmediatelybefore
usetoensurethatallmaterialsnotneededforthenextpackaging
operationhavebeenremovedandrecorded.
6.Ensurethatcontainersandpackageshavethecorrectlabelanditshould
bepartofthepackagingoperationandrecordedinBPR.
7.IntermediateorAPIcontainersthataretransportedoutsideofthe
manufacturer'scontrolshouldbesealedinamannersuchthat,iftheseal
isbreachedormissing,therecipientwillbealertedtothepossibilitythat
thecontentsmayhavebeenaltered.
10.0 STORAGE AND DISTRIBUTION
10.1 Warehousing Procedures
1.Facilitiesshouldbeavailableforthestorageofallmaterialsunder
appropriateconditions(e.g.,controlledtemperatureandhumiditywhen
necessary).
2.Recordsshouldbemaintainedoftheseconditionsiftheyarecriticalfor
themaintenanceofmaterialcharacteristics.
3.Unlessthereisanalternativesystemtopreventtheunintentionalor
unauthorizeduseofquarantined,rejected,returned,orrecalled
materials,separatestorageareasshouldbeassignedfortheirtemporary
storageuntilthedecisionastotheirfutureusehasbeenmade.
10.1 Warehousing Procedures
1.Facilitiesshouldbeavailableforthestorageofallmaterialsunder
appropriateconditions(e.g.,controlledtemperatureandhumiditywhen
necessary).
2.Recordsshouldbemaintainedoftheseconditionsiftheyarecriticalfor
themaintenanceofmaterialcharacteristics.
3.Unlessthereisanalternativesystemtopreventtheunintentionalor
unauthorizeduseofquarantined,rejected,returned,orrecalled
materials,separatestorageareasshouldbeassignedfortheirtemporary
storageuntilthedecisionastotheirfutureusehasbeenmade.
10.0 STORAGE AND DISTRIBUTION
10.2 Distribution Procedures
1.APIs and intermediates should only be released for distributionto third parties
after they have been released by the quality unit(s).
2.APIs and intermediates can be transferred under quarantine to another unit under
the company’s control when authorized by the quality unit(s) and if appropriate
controls and documentation are in place.
3.APIs and intermediates should be transported in a mannerthat does not adversely
affect their quality. Special transport or storage conditionsfor an API or
intermediate should be stated on the label.
4.The manufacturer should ensure transportation of the API or intermediate
followed the appropriate transport and storage conditions.
5.A system should be in placeby which the distribution of each batchcan be readily
determined to permit its recall.
10.2 Distribution Procedures
1.APIs and intermediates should only be released for distributionto third parties
after they have been released by the quality unit(s).
2.APIs and intermediates can be transferred under quarantine to another unit under
the company’s control when authorized by the quality unit(s) and if appropriate
controls and documentation are in place.
3.APIs and intermediates should be transported in a mannerthat does not adversely
affect their quality. Special transport or storage conditionsfor an API or
intermediate should be stated on the label.
4.The manufacturer should ensure transportation of the API or intermediate
followed the appropriate transport and storage conditions.
5.A system should be in placeby which the distribution of each batchcan be readily
determined to permit its recall.
11.0 LABORATORY CONTROLS
11.1 General Controls
1.Theindependentqualityunit(s)shouldhaveatitsdisposaladequatelaboratory
facilities.
2.Thereshouldbedocumentedproceduresdescribingsampling,testing,approval,or
rejectionofmaterialsandrecordingandstorageoflaboratorydata.
3.Allspecifications,samplingplans,andtestproceduresshouldbescientifically
soundandappropriatetoensurethatrawmaterials,intermediates,APIs,andlabels
andpackagingmaterialsconformtoestablishedstandardsofqualityand/orpurity.
4.Specificationsandtestproceduresshouldbeconsistenttoregistration/filing.
Specifications, samplingplans,andtestprocedures,includingchangestothem,
shouldbedraftedbytheappropriateorganizationalunitandreviewedand
approvedbythequalityunit(s).
11.1 General Controls
1.Theindependentqualityunit(s)shouldhaveatitsdisposaladequatelaboratory
facilities.
2.Thereshouldbedocumentedproceduresdescribingsampling,testing,approval,or
rejectionofmaterialsandrecordingandstorageoflaboratorydata.
3.Allspecifications,samplingplans,andtestproceduresshouldbescientifically
soundandappropriatetoensurethatrawmaterials,intermediates,APIs,andlabels
andpackagingmaterialsconformtoestablishedstandardsofqualityand/orpurity.
4.Specificationsandtestproceduresshouldbeconsistenttoregistration/filing.
Specifications, samplingplans,andtestprocedures,includingchangestothem,
shouldbedraftedbytheappropriateorganizationalunitandreviewedand
approvedbythequalityunit(s).
11.0 LABORATORY CONTROLS
11.1 General Controls (Con..d)
5.AppropriatespecificationsshouldbeestablishedforAPIs.
6.Thespecificationsshouldincludecontrolofimpurities(e.g.,organicimpurities,
inorganicimpurities,andresidualsolvents).IftheAPIhasaspecificationfor
microbiologicalpurity,appropriateactionlimitsfortotalmicrobialcountsand
objectionableorganismsshouldbeestablishedandmet.Establishlimitandmetthe
EndotoxinsforAPIasappropriate.
7.Laboratorycontrolsshouldbefollowedanddocumentedatthetimeof
performance.Anydeparturesfromtheabove-describedproceduresshouldbe
documentedandexplained.
8.Anyout-of-specificationresultobtainedshouldbeinvestigatedanddocumented
accordingtoaprocedure.
9.Reagentsandstandardsolutionsshouldbepreparedandlabeledfollowingwritten
procedures.Usebydatesshouldbeapplied,foranalyticalreagentsorstandard
solutions
.
11.1 General Controls (Con..d)
5.AppropriatespecificationsshouldbeestablishedforAPIs.
6.Thespecificationsshouldincludecontrolofimpurities(e.g.,organicimpurities,
inorganicimpurities,andresidualsolvents).IftheAPIhasaspecificationfor
microbiologicalpurity,appropriateactionlimitsfortotalmicrobialcountsand
objectionableorganismsshouldbeestablishedandmet.Establishlimitandmetthe
EndotoxinsforAPIasappropriate.
7.Laboratorycontrolsshouldbefollowedanddocumentedatthetimeof
performance.Anydeparturesfromtheabove-describedproceduresshouldbe
documentedandexplained.
8.Anyout-of-specificationresultobtainedshouldbeinvestigatedanddocumented
accordingtoaprocedure.
9.Reagentsandstandardsolutionsshouldbepreparedandlabeledfollowingwritten
procedures.Usebydatesshouldbeapplied,foranalyticalreagentsorstandard
solutions
.
11.0 LABORATORY CONTROLS
11.1 General Controls (Con..d)
10.Primaryreferencestandardsobtainedfromanofficiallyrecognizedsourceare
normallyusedwithouttestingifstoredunderrecommendedconditions.
11.Whereaprimaryreferencestandardisnotavailable,anin-houseprimarystandard
shouldbeestablished.Appropriatetestingshouldbeperformedtoestablishfully
theidentityandpurityoftheprimaryreferencestandardandmaintaindocument.
12.Secondaryreferencestandardsshouldbeappropriatelyprepared,identified,
tested,approved,andstored.
Thesuitabilityofeachbatchofsecondaryreference
standardshouldbedeterminedpriortofirstusebycomparingagainstaprimaryreference
standard.
13.Eachbatchofsecondaryreferencestandardshouldbeperiodicallyre-qualifiedin
accordancewithawrittenprotocol.
11.1 General Controls (Con..d)
10.Primaryreferencestandardsobtainedfromanofficiallyrecognizedsourceare
normallyusedwithouttestingifstoredunderrecommendedconditions.
11.Whereaprimaryreferencestandardisnotavailable,anin-houseprimarystandard
shouldbeestablished.Appropriatetestingshouldbeperformedtoestablishfully
theidentityandpurityoftheprimaryreferencestandardandmaintaindocument.
12.Secondaryreferencestandardsshouldbeappropriatelyprepared,identified,
tested,approved,andstored.
Thesuitabilityofeachbatchofsecondaryreference
standardshouldbedeterminedpriortofirstusebycomparingagainstaprimaryreference
standard.
13.Eachbatchofsecondaryreferencestandardshouldbeperiodicallyre-qualifiedin
accordancewithawrittenprotocol.
11.0 LABORATORY CONTROLS
11.2 Testing of Intermediates and APIs
1.All batches of intermediate and API, appropriately tested to determine
conformance to specifications.
2.An impurity profile ieidentified and unidentified impurities should be
established and controlled for each API,
1.Identity or some qualitative analytical designation (e.g. retention
time), the range of each impurity observed, and type of impurity (e.g .
inorganic, organic, solvent). The impurity profile , which are
dependent upon the production process and origin of the API.
3.The impurity profile should be compared at appropriate intervals against
the impurity profile in the regulatory submission or trended to detect
changes to the API due modifications in raw materials, equipment
operating parameters, or the production process.
4.Appropriate microbiological tests should be conducted on each batch of
intermediate and API where microbial quality is specified.
11.2 Testing of Intermediates and APIs
1.All batches of intermediate and API, appropriately tested to determine
conformance to specifications.
2.An impurity profile ieidentified and unidentified impurities should be
established and controlled for each API,
1.Identity or some qualitative analytical designation (e.g. retention
time), the range of each impurity observed, and type of impurity (e.g .
inorganic, organic, solvent). The impurity profile , which are
dependent upon the production process and origin of the API.
3.The impurity profile should be compared at appropriate intervals against
the impurity profile in the regulatory submission or trended to detect
changes to the API due modifications in raw materials, equipment
operating parameters, or the production process.
4.Appropriate microbiological tests should be conducted on each batch of
intermediate and API where microbial quality is specified.
11.0 LABORATORY CONTROLS
11.4 Certificates of Analysis
1.Certificates of Analysis should be issued for each batch of intermediate or API on
request.
2.It should have the following;
name of product and its grade, the batch number, and the date of release,
manufacturing & expiry / Retest date,
Each test performed as per compendialor customer requirements with
acceptance limits, and the numerical results obtained (if test results are
numerical).
should be dated and signed by authorised personnel of the quality unit(s) and
should show the name, address and telephone number of the original
manufacturer. should show the name, address and telephone number of the
repacker/reprocessorand a reference to the name of the original manufacturer.
11.4 Certificates of Analysis
1.Certificates of Analysis should be issued for each batch of intermediate or API on
request.
2.It should have the following;
name of product and its grade, the batch number, and the date of release,
manufacturing & expiry / Retest date,
Each test performed as per compendialor customer requirements with
acceptance limits, and the numerical results obtained (if test results are
numerical).
should be dated and signed by authorised personnel of the quality unit(s) and
should show the name, address and telephone number of the original
manufacturer. should show the name, address and telephone number of the
repacker/reprocessorand a reference to the name of the original manufacturer.
11.0 LABORATORY CONTROLS
11.5 Stability Monitoring of APIs
1.Stability Testing program should be designed and followed for APIs, to
confirm appropriate storage conditions and retest or expiry dates.
2.The test procedures used in stability testing should be validated and be
stability indicating.
3.Stability samples should be stored in containers that simulate the market
container. samples can be packaged in bags of the same material and in
smaller material composition to the market drums.
4.First three commercial production batches should be placed on the
5.stability monitoring program to confirm the retest or expiry date.
6.Then, at least one batch per year of API added if manufactured
7.Stability storage conditions should be consistent with the ICH guidelines
on stability.
11.5 Stability Monitoring of APIs
1.Stability Testing program should be designed and followed for APIs, to
confirm appropriate storage conditions and retest or expiry dates.
2.The test procedures used in stability testing should be validated and be
stability indicating.
3.Stability samples should be stored in containers that simulate the market
container. samples can be packaged in bags of the same material and in
smaller material composition to the market drums.
4.First three commercial production batches should be placed on the
5.stability monitoring program to confirm the retest or expiry date.
6.Then, at least one batch per year of API added if manufactured
7.Stability storage conditions should be consistent with the ICH guidelines
on stability.
11.0 LABORATORY CONTROLS
11.6 Expiry and Retest Dating
1.When an intermediate is intended to be transferred outside the control of the
manufacturer’s supporting stability information should be available .
2.An API expiry or retest date should be based on an evaluation of data derived
from stability studies. Common practice is to use a retest date, not an
expiration date.
3.Preliminary API expiry or retest dates can be based on pilot scale batches,
If the pilot batches of similar to manufacturing process and procedure that
simulates the commercial manufacturing scale; and the quality of the API
represents the material to be made on a commercial scale
.
4.A representative sample should be taken for the purpose of performing a
retest.
11.6 Expiry and Retest Dating
1.When an intermediate is intended to be transferred outside the control of the
manufacturer’s supporting stability information should be available .
2.An API expiry or retest date should be based on an evaluation of data derived
from stability studies. Common practice is to use a retest date, not an
expiration date.
3.Preliminary API expiry or retest dates can be based on pilot scale batches,
If the pilot batches of similar to manufacturing process and procedure that
simulates the commercial manufacturing scale; and the quality of the API
represents the material to be made on a commercial scale
.
4.A representative sample should be taken for the purpose of performing a
retest.
11.0 LABORATORY CONTROLS
11.7 Reserve/Retention Samples
1.The packaging and holding of reserve samples is to future evaluation of
the quality of batches of API and not for future stability testing
purposes.
2.Reserve samples should be retained for one year after the expiry date
or retest date of the, or for three years after distribution of the batch,
whichever is the longer.
3.The reserve sample should be stored in the same packaging system in
which the API is stored or in one that is equivalent to or more
protective than the marketed packaging system.
4.Sample should be retained to conduct at least two full compendial
analyses / two full specification analyses.
11.7 Reserve/Retention Samples
1.The packaging and holding of reserve samples is to future evaluation of
the quality of batches of API and not for future stability testing
purposes.
2.Reserve samples should be retained for one year after the expiry date
or retest date of the, or for three years after distribution of the batch,
whichever is the longer.
3.The reserve sample should be stored in the same packaging system in
which the API is stored or in one that is equivalent to or more
protective than the marketed packaging system.
4.Sample should be retained to conduct at least two full compendial
analyses / two full specification analyses.
12.0 VALIDATION
2.1. Validation Policy
1.Thecompany'soverallpolicy,intentions,andapproachtovalidation,
includingthevalidationofproductionprocesses,cleaningprocedures,
analyticalmethods,in-processcontroltestprocedures,computerized
systems,andpersonsresponsiblefordesign,review,approval,and
documentationofeachvalidationphase,shouldbedocumented.
2.Thecriticalparameters/attributesshouldnormallybeidentifiedduring
thedevelopmentstageorfromhistoricaldata,andthenecessaryranges
forthereproducibleoperationshouldbedefined.
3.Validationshouldextendtothoseoperationsdeterminedtobecriticalto
thequalityandpurityoftheAPI.
2.1. Validation Policy
1.Thecompany'soverallpolicy,intentions,andapproachtovalidation,
includingthevalidationofproductionprocesses,cleaningprocedures,
analyticalmethods,in-processcontroltestprocedures,computerized
systems,andpersonsresponsiblefordesign,review,approval,and
documentationofeachvalidationphase,shouldbedocumented.
2.Thecriticalparameters/attributesshouldnormallybeidentifiedduring
thedevelopmentstageorfromhistoricaldata,andthenecessaryranges
forthereproducibleoperationshouldbedefined.
3.Validationshouldextendtothoseoperationsdeterminedtobecriticalto
thequalityandpurityoftheAPI.
12.0 VALIDATION
2.2. Approaches to Process Validation
Process Validation (PV) is the documented evidence that the process,
operated within established parameters, can perform effectively and
reproducibly to produce an intermediate or API meeting its predetermined
specifications and quality attributes.
There are three approaches to validation. Prospective validation is the
preferred approach,
1.Prospective validation should normally be performed for all API processes
2.Prospective validation of an API process should be completed before the
commercial distribution of the final drug product manufactured from that
API.
2.2. Approaches to Process Validation
Process Validation (PV) is the documented evidence that the process,
operated within established parameters, can perform effectively and
reproducibly to produce an intermediate or API meeting its predetermined
specifications and quality attributes.
There are three approaches to validation. Prospective validation is the
preferred approach,
1.Prospective validation should normally be performed for all API processes
2.Prospective validation of an API process should be completed before the
commercial distribution of the final drug product manufactured from that
API.
12.0 VALIDATION
12.2. Approaches to Process Validation
Concurrent validation can be conducted when data from replicate
production runs are unavailable because only a limited number of API
batches have been produced, API batches are produced infrequently, or
API batches are produced by a validated process that has been modified.
Prior to the completion of concurrent validation, batches can be released
and used in final drug product for commercial distribution based on
thorough monitoring and testing of the API batches.
12.2. Approaches to Process Validation
Concurrent validation can be conducted when data from replicate
production runs are unavailable because only a limited number of API
batches have been produced, API batches are produced infrequently, or
API batches are produced by a validated process that has been modified.
Prior to the completion of concurrent validation, batches can be released
and used in final drug product for commercial distribution based on
thorough monitoring and testing of the API batches.
12.0 VALIDATION
12.3 Qualification
Qualification of critical equipment and ancillary systems should be completed.
Qualification is carried out as below;
Design Qualification (DQ): documented verification of proposed design of the
facilities, equipment, or systems is suitable for the intended purpose.
Installation Qualification (IQ): documented verification of the equipment or
systems, as installed or modified, comply with the approved design, the
manufacturer’s recommendations and/or user requirements.
Operational Qualification (OQ): documented verification that the equipment or
systems, as installed or modified, perform as intended throughout the anticipated
operating ranges.
Performance Qualification (PQ): documented verification that the equipment and
ancillary systems, as connected together, can perform effectively and reproducibly
based on the approved process method and specifications.
12.3 Qualification
Qualification of critical equipment and ancillary systems should be completed.
Qualification is carried out as below;
Design Qualification (DQ): documented verification of proposed design of the
facilities, equipment, or systems is suitable for the intended purpose.
Installation Qualification (IQ): documented verification of the equipment or
systems, as installed or modified, comply with the approved design, the
manufacturer’s recommendations and/or user requirements.
Operational Qualification (OQ): documented verification that the equipment or
systems, as installed or modified, perform as intended throughout the anticipated
operating ranges.
Performance Qualification (PQ): documented verification that the equipment and
ancillary systems, as connected together, can perform effectively and reproducibly
based on the approved process method and specifications.
12.0 VALIDATION
12.5 Process Validation Program
1.The number of process runs for validation base don the process or the magnitude
of the process change.
For prospective and concurrent validation, three consecutive batches should be
used.
For retrospective validation, generally data from ten to thirty consecutive
batches should be examined
2.Critical process parameters should be controlled and monitored. Process
parameters unrelated to quality are not required.
3.Process validation should confirm that the impurity profile for each API is within
the limits specified.
4.The impurity profile should be comparable to or better than historical data. Profile
should be comparable during development or for batches used for pivotal clinical
and toxicological studies.
12.5 Process Validation Program
1.The number of process runs for validation base don the process or the magnitude
of the process change.
For prospective and concurrent validation, three consecutive batches should be
used.
For retrospective validation, generally data from ten to thirty consecutive
batches should be examined
2.Critical process parameters should be controlled and monitored. Process
parameters unrelated to quality are not required.
3.Process validation should confirm that the impurity profile for each API is within
the limits specified.
4.The impurity profile should be comparable to or better than historical data. Profile
should be comparable during development or for batches used for pivotal clinical
and toxicological studies.
12.0 PROCESS VALIDATION
12.6
Periodic Review of Validated Systems
1.Systemsandprocessesshouldbeperiodicallyevaluatedtoverifythat
theyarestilloperatinginavalidmanner.
2.Wherenosignificantchangeshavebeenmadetothesystemorprocess,
andaqualityreviewconfirmsthatthesystemorprocessisconsistently
producingmaterialmeetingitsspecifications,thereisnormallynoneed
forrevalidation.
12.6
Periodic Review of Validated Systems
1.Systemsandprocessesshouldbeperiodicallyevaluatedtoverifythat
theyarestilloperatinginavalidmanner.
2.Wherenosignificantchangeshavebeenmadetothesystemorprocess,
andaqualityreviewconfirmsthatthesystemorprocessisconsistently
producingmaterialmeetingitsspecifications,thereisnormallynoneed
forrevalidation.
12.0 PROCESS VALIDATION
12.7 Cleaning Validation
1.Cleaningproceduresshouldnormallybevalidated.Ingeneral,cleaning
validationshouldbedirectedtosituationsorprocessstepswhere
contaminationorcarryoverofmaterialsposesthegreatestrisktoAPI
quality.
Forexample,inearlyproductionitmaybeunnecessarytovalidateequipment
cleaningprocedureswhereresiduesareremovedbysubsequentpurificationsteps.
2.2.Validationofcleaningproceduresshouldreflectactualequipment
usagepatterns.IfvariousAPIsorintermediatesaremanufacturedinthe
sameequipmentandtheequipmentiscleanedbythesameprocess,a
representativeintermediateorAPIcanbeselectedforcleaning
validation.
12.7 Cleaning Validation
1.Cleaningproceduresshouldnormallybevalidated.Ingeneral,cleaning
validationshouldbedirectedtosituationsorprocessstepswhere
contaminationorcarryoverofmaterialsposesthegreatestrisktoAPI
quality.
Forexample,inearlyproductionitmaybeunnecessarytovalidateequipment
cleaningprocedureswhereresiduesareremovedbysubsequentpurificationsteps.
2.2.Validationofcleaningproceduresshouldreflectactualequipment
usagepatterns.IfvariousAPIsorintermediatesaremanufacturedinthe
sameequipmentandtheequipmentiscleanedbythesameprocess,a
representativeintermediateorAPIcanbeselectedforcleaning
validation.
13.0 CHANGE CONTROL
1.Aformalchangecontrolsystemshouldbeestablishedtoevaluateallchangesthat
couldaffecttheproductionandcontroloftheintermediateorAPI.
2.Writtenproceduresshouldprovidefortheidentification,documentation,
appropriatereview,andapprovalofchangesinrawmaterials,specifications,
analyticalmethods,facilities, supportsystems,equipment(includingcomputer
hardware),processingsteps,labelingandpackagingmaterials,andcomputer
software.
3.AnyproposalsforGMPrelevantchangesshouldbedrafted,reviewed,andapproved
bytheappropriateorganizationalunitsandreviewedandapprovedbythequality
unit(s).
4.Thepotentialimpactoftheproposedchangeonthequalityoftheintermediateor
APIshouldbeevaluated.
5.Aclassificationhelpstodeterminetheleveloftesting,validation,and
documentationneededtojustifychangestoavalidatedprocess.
Changescanbe
classified(e.g.,asminorormajor) dependingonthenatureandextentofthechanges,andthe
effectsthesechangesmayimpartontheprocess.
1.Aformalchangecontrolsystemshouldbeestablishedtoevaluateallchangesthat
couldaffecttheproductionandcontroloftheintermediateorAPI.
2.Writtenproceduresshouldprovidefortheidentification,documentation,
appropriatereview,andapprovalofchangesinrawmaterials,specifications,
analyticalmethods,facilities, supportsystems,equipment(includingcomputer
hardware),processingsteps,labelingandpackagingmaterials,andcomputer
software.
3.AnyproposalsforGMPrelevantchangesshouldbedrafted,reviewed,andapproved
bytheappropriateorganizationalunitsandreviewedandapprovedbythequality
unit(s).
4.Thepotentialimpactoftheproposedchangeonthequalityoftheintermediateor
APIshouldbeevaluated.
5.Aclassificationhelpstodeterminetheleveloftesting,validation,and
documentationneededtojustifychangestoavalidatedprocess.
Changescanbe
classified(e.g.,asminorormajor) dependingonthenatureandextentofthechanges,andthe
effectsthesechangesmayimpartontheprocess.
13.0 CHANGE CONTROL
6.Scientificjudgmentshoulddeterminewhatadditionaltestingandvalidation
studiesareappropriatetojustifyachangeinavalidatedprocess.
7.Whenimplementingapprovedchanges,measuresshouldbetakentoensure
thatalldocumentsaffectedbythechangesarerevised.
8.Afterthechangehasbeenimplemented,thereshouldbeanevaluationof
thefirstbatchesproducedortestedunderthechange.
9.Thepotentialforcriticalchangestoaffectestablishedretestorexpiry
datesshouldbeevaluated.
Ifnecessary,samplesoftheintermediateorAPI
producedbythemodifiedprocesscanbeplacedonanacceleratedstabilityprogram
and/orcanbeaddedtothestabilitymonitoringprogram.
10.Currentdosageformmanufacturersshouldbenotifiedofchangesfrom
establishedproductionandprocesscontrolproceduresthatcanaffectthe
qualityoftheAPI.
6.Scientificjudgmentshoulddeterminewhatadditionaltestingandvalidation
studiesareappropriatetojustifyachangeinavalidatedprocess.
7.Whenimplementingapprovedchanges,measuresshouldbetakentoensure
thatalldocumentsaffectedbythechangesarerevised.
8.Afterthechangehasbeenimplemented,thereshouldbeanevaluationof
thefirstbatchesproducedortestedunderthechange.
9.Thepotentialforcriticalchangestoaffectestablishedretestorexpiry
datesshouldbeevaluated.
Ifnecessary,samplesoftheintermediateorAPI
producedbythemodifiedprocesscanbeplacedonanacceleratedstabilityprogram
and/orcanbeaddedtothestabilitymonitoringprogram.
10.Currentdosageformmanufacturersshouldbenotifiedofchangesfrom
establishedproductionandprocesscontrolproceduresthatcanaffectthe
qualityoftheAPI.
14.0 REJECTION AND REUSE OF MATERIALS
14.1 Rejection
1.IntermediatesandAPIsfailingtomeetestablishedspecificationsshouldbe
identifiedassuchandquarantined.
2.TheseintermediatesorAPIscanbereprocessedorreworkedasdescribed
below.
3.Thefinaldispositionofrejectedmaterialsshouldberecorded.
14.1 Rejection
1.IntermediatesandAPIsfailingtomeetestablishedspecificationsshouldbe
identifiedassuchandquarantined.
2.TheseintermediatesorAPIscanbereprocessedorreworkedasdescribed
below.
3.Thefinaldispositionofrejectedmaterialsshouldberecorded.
14.0 REJECTION AND REUSE OF MATERIALS
14.1 Reprocessing
1.IntroducinganintermediateorAPI,includingonethatdoesnotconformto
standardsorspecifications,backintotheprocessandreprocessingbyrepeatinga
crystallizationsteporotherappropriatechemicalorphysicalmanipulationsteps
(e.g.,distillation,filtration,chromatography,milling)thatarepartofthe
establishedmanufacturingprocessisgenerallyconsideredacceptable.
2.However,ifsuchreprocessingisusedforamajorityofbatches, suchreprocessing
shouldbeincludedaspartofthestandardmanufacturingprocess.
3.Continuationofaprocessstepafteranin-processcontroltesthasshownthatthe
stepisincompleteisconsideredtobepartofthenormalprocess. Thisisnot
consideredtobereprocessing.
4.Introducingun-reactedmaterialbackintoaprocessandrepeatingachemical
reactionisconsideredtobereprocessingunlessitispartoftheestablished
process. EnsurethatthequalityoftheintermediateorAPIisnotadverselyaffected
duetothepotentialformationofby-productsandover-reactedmaterials.
14.1 Reprocessing
1.IntroducinganintermediateorAPI,includingonethatdoesnotconformto
standardsorspecifications,backintotheprocessandreprocessingbyrepeatinga
crystallizationsteporotherappropriatechemicalorphysicalmanipulationsteps
(e.g.,distillation,filtration,chromatography,milling)thatarepartofthe
establishedmanufacturingprocessisgenerallyconsideredacceptable.
2.However,ifsuchreprocessingisusedforamajorityofbatches, suchreprocessing
shouldbeincludedaspartofthestandardmanufacturingprocess.
3.Continuationofaprocessstepafteranin-processcontroltesthasshownthatthe
stepisincompleteisconsideredtobepartofthenormalprocess. Thisisnot
consideredtobereprocessing.
4.Introducingun-reactedmaterialbackintoaprocessandrepeatingachemical
reactionisconsideredtobereprocessingunlessitispartoftheestablished
process. EnsurethatthequalityoftheintermediateorAPIisnotadverselyaffected
duetothepotentialformationofby-productsandover-reactedmaterials.
14.0 REJECTION AND REUSE OF MATERIALS
14.2 Re-working
1.IntroducinganintermediateorAPI,includingonethatdoesnotconformto
standardsorspecifications,backintotheprocessandreprocessingbyrepeatinga
crystallizationsteporotherappropriatechemicalorphysicalmanipulationsteps
(e.g.,distillation,filtration,chromatography,milling)thatarepartofthe
establishedmanufacturingprocessisgenerallyconsideredacceptable.
2.However,ifsuchreprocessingisusedforamajorityofbatches, suchreprocessing
shouldbeincludedaspartofthestandardmanufacturingprocess.
3.Continuationofaprocessstepafteranin-processcontroltesthasshownthatthe
stepisincompleteisconsideredtobepartofthenormalprocess. Thisisnot
consideredtobereprocessing.
4.Introducingun-reactedmaterialbackintoaprocessandrepeatingachemical
reactionisconsideredtobereprocessingunlessitispartoftheestablished
process. EvaluatethequalityoftheintermediateorAPIisnotadverselyaffected
duetothepotentialformationofby-productsandover-reactedmaterials.
14.2 Re-working
1.IntroducinganintermediateorAPI,includingonethatdoesnotconformto
standardsorspecifications,backintotheprocessandreprocessingbyrepeatinga
crystallizationsteporotherappropriatechemicalorphysicalmanipulationsteps
(e.g.,distillation,filtration,chromatography,milling)thatarepartofthe
establishedmanufacturingprocessisgenerallyconsideredacceptable.
2.However,ifsuchreprocessingisusedforamajorityofbatches, suchreprocessing
shouldbeincludedaspartofthestandardmanufacturingprocess.
3.Continuationofaprocessstepafteranin-processcontroltesthasshownthatthe
stepisincompleteisconsideredtobepartofthenormalprocess. Thisisnot
consideredtobereprocessing.
4.Introducingun-reactedmaterialbackintoaprocessandrepeatingachemical
reactionisconsideredtobereprocessingunlessitispartoftheestablished
process. EvaluatethequalityoftheintermediateorAPIisnotadverselyaffected
duetothepotentialformationofby-productsandover-reactedmaterials.
14.0 REJECTION AND REUSE OF MATERIALS
14.1 Recovery of Materials and Solvents
1.Recovery(e.g.,frommotherliquororfiltrates)ofreactants,intermediates,or
theAPIisconsideredacceptable,providedthatapprovedproceduresexistfor
therecoveryandtherecoveredmaterialsmeetspecificationssuitablefortheir
intendeduse.
2.Solventscanberecoveredandreusedinthesameprocessesorindifferent
processes,providedthattherecoveryproceduresarecontrolledand
monitoredtoensurethatsolventsmeetappropriatestandardsbeforereuseor
comminglingwithotherapprovedmaterials.
3.Freshandrecoveredsolventsandreagentscanbecombinedifadequate
testinghasshowntheirsuitabilityforallmanufacturingprocessesinwhich
theymaybeused.
4.Theuseofrecoveredsolvents,motherliquors,andotherrecoveredmaterials
shouldbeadequatelydocumented.
14.1 Recovery of Materials and Solvents
1.Recovery(e.g.,frommotherliquororfiltrates)ofreactants,intermediates,or
theAPIisconsideredacceptable,providedthatapprovedproceduresexistfor
therecoveryandtherecoveredmaterialsmeetspecificationssuitablefortheir
intendeduse.
2.Solventscanberecoveredandreusedinthesameprocessesorindifferent
processes,providedthattherecoveryproceduresarecontrolledand
monitoredtoensurethatsolventsmeetappropriatestandardsbeforereuseor
comminglingwithotherapprovedmaterials.
3.Freshandrecoveredsolventsandreagentscanbecombinedifadequate
testinghasshowntheirsuitabilityforallmanufacturingprocessesinwhich
theymaybeused.
4.Theuseofrecoveredsolvents,motherliquors,andotherrecoveredmaterials
shouldbeadequatelydocumented.
15.0 COMPLAINTS AND RECALLS
1.Allquality-relatedcomplaints,whetherreceivedorallyorinwriting,
shouldberecordedandinvestigatedaccordingtoawrittenprocedure.
2.Complaintrecordsshouldinclude:
Nameandaddressofcomplainant;
Name(and,whereappropriate,title)andphonenumberofpersonsubmitting
thecomplaint;
Complaint nature (including name and batch number of the API);
Date complaint is received;
Action initially taken (including dates and identity of person taking the action);
Any follow-up action taken;
Response provided to the originator of complaint (including date response sent);
Final decision on intermediate or API batch or lot;
3.Recordsofcomplaintsshouldberetainedtoevaluatetrends,product-
relatedfrequencies,andseveritywithaviewtotakingadditional,andif
appropriate,immediatecorrectiveaction.
1.Allquality-relatedcomplaints,whetherreceivedorallyorinwriting,
shouldberecordedandinvestigatedaccordingtoawrittenprocedure.
2.Complaintrecordsshouldinclude:
Nameandaddressofcomplainant;
Name(and,whereappropriate,title)andphonenumberofpersonsubmitting
thecomplaint;
Complaint nature (including name and batch number of the API);
Date complaint is received;
Action initially taken (including dates and identity of person taking the action);
Any follow-up action taken;
Response provided to the originator of complaint (including date response sent);
Final decision on intermediate or API batch or lot;
3.Recordsofcomplaintsshouldberetainedtoevaluatetrends,product-
relatedfrequencies,andseveritywithaviewtotakingadditional,andif
appropriate,immediatecorrectiveaction.
15.0 COMPLAINTS AND RECALLS
4.Recordsofcomplaintsshouldberetainedtoevaluatetrends,product-
relatedfrequencies,andseveritywithaviewtotakingadditional,andif
appropriate,immediatecorrectiveaction.
5.Thereshouldbeawrittenprocedurethatdefinesthecircumstances
underwhicharecallofanintermediateorAPIshouldbeconsidered.
6.Therecallprocedureshoulddesignatewhoshouldbeinvolvedin
evaluatingtheinformation,howarecallshouldbeinitiated,whoshould
beinformedabouttherecall,andhowtherecalledmaterialshouldbe
treated.
7.Intheeventofaseriousorpotentiallylife-threateningsituation,local,
national,and/orinternationalauthoritiesshouldbeinformedandtheir
advicesought.
4.Recordsofcomplaintsshouldberetainedtoevaluatetrends,product-
relatedfrequencies,andseveritywithaviewtotakingadditional,andif
appropriate,immediatecorrectiveaction.
5.Thereshouldbeawrittenprocedurethatdefinesthecircumstances
underwhicharecallofanintermediateorAPIshouldbeconsidered.
6.Therecallprocedureshoulddesignatewhoshouldbeinvolvedin
evaluatingtheinformation,howarecallshouldbeinitiated,whoshould
beinformedabouttherecall,andhowtherecalledmaterialshouldbe
treated.
7.Intheeventofaseriousorpotentiallylife-threateningsituation,local,
national,and/orinternationalauthoritiesshouldbeinformedandtheir
advicesought.
16.0 CONTRACT MANUFACTURERS
(INCLUDING LABORATORIES)
1.All contract manufacturers (including laboratories) should comply with the
GMP. Ensure the prevention of cross-contamination and to maintaining
traceability.
2.Contract manufacturers (including laboratories) should be evaluated by
the contract giver to ensure GMP compliance of the operations at site.
3.Approved contract or formal agreement (TQA) between the contract giver
and the contract acceptor that defines in detail the GMP responsibilities,
including the quality measures, of each party.
4.TQA should permit the contract giver to audit the facilities for compliance
with GMP.
(INCLUDING LABORATORIES)
1.All contract manufacturers (including laboratories) should comply with the
GMP. Ensure the prevention of cross-contamination and to maintaining
traceability.
2.Contract manufacturers (including laboratories) should be evaluated by
the contract giver to ensure GMP compliance of the operations at site.
3.Approved contract or formal agreement (TQA) between the contract giver
and the contract acceptor that defines in detail the GMP responsibilities,
including the quality measures, of each party.
4.TQA should permit the contract giver to audit the facilities for compliance
with GMP.
16.0 CONTRACT MANUFACTURERS
(INCLUDING LABORATORIES)
5.The contract acceptor should not pass to a third party any of the work
entrusted to him under the contract without the contract giver's prior
evaluation and approval.
6.Manufacturing and laboratory records should be kept at the site where the
activity occurs and be readily available.
7.Changes in the process, equipment, test methods, specifications, or other
contractual requirements should not be made unless the contract giver is
informed and approves the changes.
(INCLUDING LABORATORIES)
5.The contract acceptor should not pass to a third party any of the work
entrusted to him under the contract without the contract giver's prior
evaluation and approval.
6.Manufacturing and laboratory records should be kept at the site where the
activity occurs and be readily available.
7.Changes in the process, equipment, test methods, specifications, or other
contractual requirements should not be made unless the contract giver is
informed and approves the changes.
Q&A
Thank you
Dr. A. Amsavel
Thank you
Dr. A. Amsavel
Tags
objective of gmp
gmp guidelines
usfda inspectional observation
data integrity
quality management
documentation and records
materials management
process equipment
production and in-process cont
buildings and facilities
storage and distribution
laboratory controls
validation
change control
complaints and recalls
rejection of material
contract manufacturers
regulations
personnal
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