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All You Never Wanted to Know About All You Never Wanted to Know About GLP and GMP GLP and GMP

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Page 1: Fremland GLP GMP

All You Never Wanted to Know AboutAll You Never Wanted to Know AboutGLP and GMPGLP and GMP

Page 2: Fremland GLP GMP

ResearchResearch

By FDA standards . . .By FDA standards . . .

A VERY uncontrolled, undisciplined activity!!!A VERY uncontrolled, undisciplined activity!!!

Note: Innovation is the key.Note: Innovation is the key.

Page 3: Fremland GLP GMP

DevelopmentDevelopment

By comparison . . .By comparison . . .

Much more disciplined.Much more disciplined. GLP and cGMP become considerations.GLP and cGMP become considerations.

Page 4: Fremland GLP GMP

ManufacturingManufacturing

Must be even more disciplined . . .Must be even more disciplined . . .

cGMP takes prioritycGMP takes priority QC becomes an important driver!QC becomes an important driver!

Page 5: Fremland GLP GMP

What is the intent of regulations?What is the intent of regulations?

Provide assurance of identity, quality, and strength of Provide assurance of identity, quality, and strength of pharmaceuticals.pharmaceuticals.

Assure that correct procedures have been followed.Assure that correct procedures have been followed.

Provide documentation, traceability.Provide documentation, traceability.

Overall IntentOverall Intent::

To assure To assure QualityQuality is “built in” to the approach. is “built in” to the approach.

Page 6: Fremland GLP GMP

What is Quality?What is Quality?

The ability to The ability to consistentlyconsistently produce the produce the samesame product to meet the product to meet the samesame specifications time specifications time after time!after time!

Stronger, purer, higher assay, or higher yield . . . Stronger, purer, higher assay, or higher yield . . . is is notnot better! better!

Page 7: Fremland GLP GMP

GLP and GMPGLP and GMP

GMP: GMP: Protect the integrity and quality of Protect the integrity and quality of manufacturedmanufactured productproduct

intended for intended for humanhuman useuse..

GLP:GLP: Protect the integrity and quality of Protect the integrity and quality of laboratorylaboratory datadata used to used to

support a product application.support a product application.

Page 8: Fremland GLP GMP

Current Good Manufacturing Practices (GMP or cGMP)

Current Good Manufacturing Practices (GMP or cGMP)

Must be Must be bothboth currentcurrent andand good!good!

Apply to all aspects of preparation when a drug Apply to all aspects of preparation when a drug entity is intended for use in humans (or target entity is intended for use in humans (or target animal for animal drug). animal for animal drug).

Do not apply when drug is in Pre-Clinical Trials Do not apply when drug is in Pre-Clinical Trials (animal testing).(animal testing).

Page 9: Fremland GLP GMP

Good Laboratory Practices (GLP)

Apply when a non-clinical laboratory study Apply when a non-clinical laboratory study (e.g. Pre-Clinical animal testing) is intended to (e.g. Pre-Clinical animal testing) is intended to support an application for an FDA-regulated support an application for an FDA-regulated product.product.

Page 10: Fremland GLP GMP

Good Laboratory PracticesGood Laboratory Practices

Title 21 CFR:Title 21 CFR:

Part 58: “ . . . For Non-Clinical Laboratory Studies”Part 58: “ . . . For Non-Clinical Laboratory Studies”

Page 11: Fremland GLP GMP

Part 58: Non-Clinical Laboratory StudiesPart 58: Non-Clinical Laboratory StudiesPart 58: Non-Clinical Laboratory StudiesPart 58: Non-Clinical Laboratory Studies

Subpart A: General ProvisionsSubpart A: General Provisions

Subpart B: Organization and PersonnelSubpart B: Organization and Personnel

Subpart C: FacilitiesSubpart C: Facilities

Subpart D: EquipmentSubpart D: Equipment

Subpart E: Testing Facilities OperationSubpart E: Testing Facilities Operation

Subpart F: Test and Control ArticlesSubpart F: Test and Control Articles

Subpart G: Protocol for and Conduct of a Non-Clinical Subpart G: Protocol for and Conduct of a Non-Clinical Laboratory StudyLaboratory Study

Subpart H: [Reserved]Subpart H: [Reserved]

Subpart I: [Reserved]Subpart I: [Reserved]

Subpart J: Records and ReportsSubpart J: Records and Reports

Subpart K: Disqualification of Testing FacilitiesSubpart K: Disqualification of Testing Facilities

Page 12: Fremland GLP GMP

Organization and PersonnelOrganization and Personnel

58.29 Personnel58.29 Personnel

(a)“Each individual engaged in the conduct of or responsible for the (a)“Each individual engaged in the conduct of or responsible for the supervision of a nonclinical laboratory study shall have supervision of a nonclinical laboratory study shall have educationeducation, , trainingtraining, and , and experienceexperience, or combination thereof, to enable that , or combination thereof, to enable that individual to perform the assigned functions.”individual to perform the assigned functions.”

(b)“Each testing facility shall (b)“Each testing facility shall maintainmaintain a current a current summarysummary of of trainingtraining and and experience and job description for each individual engaged in or experience and job description for each individual engaged in or supervising the conduct of a nonclinical laboratory study.”supervising the conduct of a nonclinical laboratory study.”

Page 13: Fremland GLP GMP

Organization and PersonnelOrganization and Personnel

Three Key Responsibilities:Three Key Responsibilities:

Testing Facility ManagementTesting Facility Management

Study DirectorStudy Director

Quality Assurance UnitQuality Assurance Unit

Page 14: Fremland GLP GMP

Organization and PersonnelOrganization and Personnel

58.33 Study Director58.33 Study Director

““For each nonclinical laboratory study, a For each nonclinical laboratory study, a scientistscientist or or otherother professionalprofessional of appropriate education, training, and experience, or of appropriate education, training, and experience, or combination thereof, shall be identified as the combination thereof, shall be identified as the studystudy directordirector. The . The study director has study director has overalloverall responsibilityresponsibility for the technical conduct of for the technical conduct of the study, as well as for the interpretation, analysis, documentation, the study, as well as for the interpretation, analysis, documentation, and reporting of results, and represents the and reporting of results, and represents the singlesingle pointpoint ofof studystudy controlcontrol.”.”

Page 15: Fremland GLP GMP

Organization and PersonnelOrganization and Personnel

58.35 Quality Assurance Unit58.35 Quality Assurance Unit

““A testing facility shall have a A testing facility shall have a qualityquality assuranceassurance unitunit which shall be which shall be responsible for responsible for monitoringmonitoring each study to assure management that each study to assure management that the facilities, equipment, personnel, methods, practices, records, the facilities, equipment, personnel, methods, practices, records, and controls are in and controls are in conformanceconformance withwith thethe regulationsregulations in this part. For in this part. For any given study, the quality assurance unit shall be entirely separate any given study, the quality assurance unit shall be entirely separate from and independent of the personnel engaged in the direction and from and independent of the personnel engaged in the direction and conduct of that study.”conduct of that study.”

Page 16: Fremland GLP GMP

FacilitiesFacilities

58.41 General58.41 General

““Each testing facility shall be of suitable size and construction to Each testing facility shall be of suitable size and construction to facilitate the proper conduct of nonclinical laboratory studies. It shall facilitate the proper conduct of nonclinical laboratory studies. It shall be designed so that there is a degree of separation that will prevent be designed so that there is a degree of separation that will prevent any function or activity from having an adverse effect on the study.”any function or activity from having an adverse effect on the study.”

Animal care facilitiesAnimal care facilities Animal supply facilitiesAnimal supply facilities Facilities for handling test and control articlesFacilities for handling test and control articles Laboratory operation areasLaboratory operation areas Specimen and data storage facilitiesSpecimen and data storage facilities

Page 17: Fremland GLP GMP

EquipmentEquipment

58.61 Equipment Design58.61 Equipment Design

““Equipment used in ... shall be of appropriate design and adequate Equipment used in ... shall be of appropriate design and adequate capacity ...”capacity ...”

58.63 Maintenance and Calibration58.63 Maintenance and Calibration

(b) “The written standard operating procedures ...”(b) “The written standard operating procedures ...”

(c) “Written records shall be maintained ...”(c) “Written records shall be maintained ...”

Page 18: Fremland GLP GMP

Testing Facilities Operation

58.81 Standard Operating Procedures58.81 Standard Operating Procedures(a) “A testing facility shall have standard operating procedures (a) “A testing facility shall have standard operating procedures inin

writingwriting setting forth nonclinical laboratory study methods ... to setting forth nonclinical laboratory study methods ... to insure the quality and integrity of the data generated ...”insure the quality and integrity of the data generated ...”

58.90 Animal Care58.90 Animal Care(e) “Animals of different species shall be housed in separate (e) “Animals of different species shall be housed in separate

rooms when necessary. Animals of the same species, but rooms when necessary. Animals of the same species, but used in different studies, should not ordinarily be housed in used in different studies, should not ordinarily be housed in the same room when inadvertent exposure to control or test the same room when inadvertent exposure to control or test articles or animal mix-up could affect the outcome of either articles or animal mix-up could affect the outcome of either study. If such mixed housing is necessary, study. If such mixed housing is necessary, adequateadequate differentiationdifferentiation by space and by space and identificationidentification shall be made.” shall be made.”

Page 19: Fremland GLP GMP

Test and Control Articles

58.105 Test and Control Article Characterization58.105 Test and Control Article Characterization

(a) “The identity, strength, purity, and composition which (a) “The identity, strength, purity, and composition which appropriately define the test or control article shall be appropriately define the test or control article shall be determined for each batch and shall be documented.”determined for each batch and shall be documented.”

(b) “The stability of each test or control article shall be (b) “The stability of each test or control article shall be determined ...”determined ...”

Page 20: Fremland GLP GMP

Protocol for Conduct of a Nonclinical Laboratory Study

58.120 Protocol58.120 Protocol

(a) “Each study shall have an approved written protocol (a) “Each study shall have an approved written protocol that clearly indicates the objectives and all methods that clearly indicates the objectives and all methods for the conduct of the study.”for the conduct of the study.”

58.130 Conduct of a Non-clinical Laboratory Study58.130 Conduct of a Non-clinical Laboratory Study

(a) “The nonclinical laboratory study shall be conducted (a) “The nonclinical laboratory study shall be conducted in accordance with the protocol”in accordance with the protocol”

Page 21: Fremland GLP GMP

Records and ReportsRecords and Reports

58.185 Reporting of Non-clinical Laboratory Study Results58.185 Reporting of Non-clinical Laboratory Study Results

(a) “A final report shall be prepared for each nonclinical (a) “A final report shall be prepared for each nonclinical laboratory study ...”laboratory study ...”

58.190 Storage and Retrieval of Records and Data58.190 Storage and Retrieval of Records and Data

(a) “All raw data, documentation, protocols, final reports, and (a) “All raw data, documentation, protocols, final reports, and specimens ... shall be retained.”specimens ... shall be retained.”

Page 22: Fremland GLP GMP

Current Good Manufacturing PracticesCurrent Good Manufacturing Practices

Title 21 CFR:Title 21 CFR:

Part 210: “ . . . In Manufacturing, Processing, Part 210: “ . . . In Manufacturing, Processing, Packing, or Holding of Drugs; General”Packing, or Holding of Drugs; General”

Part 211: “ for Finished Pharmaceuticals”Part 211: “ for Finished Pharmaceuticals”

Part 600: BiologicsPart 600: Biologics Part 820: Medical DevicesPart 820: Medical Devices

Page 23: Fremland GLP GMP

Part 210: General ProvisionsPart 210: General Provisions

210.1 (a)210.1 (a)

“The regulations set forth in this part and in parts 211 “The regulations set forth in this part and in parts 211 through 226 of this chapter contain the through 226 of this chapter contain the minimumminimum currentcurrent goodgood manufacturingmanufacturing practicepractice for methods to be used in, for methods to be used in, and the facilities or controls to be used for, the and the facilities or controls to be used for, the manufacture, processing, packing, or holding of a drug to manufacture, processing, packing, or holding of a drug to assure that such drug meets the requirements of the act as assure that such drug meets the requirements of the act as to to safetysafety, and has the , and has the identityidentity and and strengthstrength and meets the and meets the qualityquality and and puritypurity characteristics that it purports or is characteristics that it purports or is represented to possess.”represented to possess.”

Page 24: Fremland GLP GMP

Part 210: General ProvisionsPart 210: General Provisions

210.1 (b) 210.1 (b)

“The “The failurefailure toto complycomply with any regulation set forth ... in the with any regulation set forth ... in the manufacture, processing, packing, or holding of a drug shall manufacture, processing, packing, or holding of a drug shall render such drug to be render such drug to be adulteratedadulterated under section 501(a)(2)(B) under section 501(a)(2)(B) of the act and such drug, as well as the person who is of the act and such drug, as well as the person who is responsible for the failure to comply, shall be subject to responsible for the failure to comply, shall be subject to regulatory action.”regulatory action.”

Page 25: Fremland GLP GMP

Part 211: Finished PharmaceuticalsPart 211: Finished PharmaceuticalsPart 211: Finished PharmaceuticalsPart 211: Finished Pharmaceuticals

Subpart A: General ProvisionsSubpart A: General Provisions

Subpart B: Organization and Personnel*Subpart B: Organization and Personnel*

Subpart C: Buildings and Facilities*Subpart C: Buildings and Facilities*

Subpart D: Equipment*Subpart D: Equipment*

Subpart E: Control of Components and Drug Product Subpart E: Control of Components and Drug Product Containers and Closures*Containers and Closures*

Subpart F: Production and Process Controls*Subpart F: Production and Process Controls*

Subpart G: Packaging and Labeling ControlSubpart G: Packaging and Labeling Control

Subpart H: Holding and DistributionSubpart H: Holding and Distribution

Subpart I: Laboratory Controls*Subpart I: Laboratory Controls*

Subpart J: Records and Reports*Subpart J: Records and Reports*

Subpart K: Returned and Salvaged Drug ProductsSubpart K: Returned and Salvaged Drug Products

Page 26: Fremland GLP GMP

Organization and PersonnelOrganization and Personnel

211.22 (a) Responsibilities of the Quality Control Unit211.22 (a) Responsibilities of the Quality Control Unit“There shall be a “There shall be a qualityquality controlcontrol unitunit that shall have the responsibility that shall have the responsibility to approve or reject all ...”to approve or reject all ...”

211.25 (a) Personnel Qualifications211.25 (a) Personnel Qualifications“Each person engaged in the manufacture, processing, packing, or “Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have holding of a drug product shall have educationeducation, , trainingtraining, and , and experienceexperience, or any combination thereof, to enable that person to , or any combination thereof, to enable that person to perform the assigned functions. Training shall be ...”perform the assigned functions. Training shall be ...”

211.28 Personnel responsibilities211.28 Personnel responsibilities

211.34 Consultants211.34 Consultants

Page 27: Fremland GLP GMP

Buildings and FacilitiesBuildings and Facilities

211.42 Design and Construction Features211.42 Design and Construction Features

(a) “Any building or buildings used in the manufacture, (a) “Any building or buildings used in the manufacture, processing, packing, or holding of a drug product shall be of processing, packing, or holding of a drug product shall be of suitablesuitable size, construction, and location to facilitate size, construction, and location to facilitate cleaningcleaning, , maintenancemaintenance, and , and properproper operationoperation.”.”

211.46 Ventilation, Air Filtration, Air Heating and Cooling211.46 Ventilation, Air Filtration, Air Heating and Cooling

(b) “Equipment for adequate control over air pressure, micro-(b) “Equipment for adequate control over air pressure, micro-organisms, dust, humidity, and temperature shall be provided organisms, dust, humidity, and temperature shall be provided when appropriate for the manufacture, processing, packing, or when appropriate for the manufacture, processing, packing, or holding of a drug product.”holding of a drug product.”

Page 28: Fremland GLP GMP

Buildings and FacilitiesBuildings and Facilities

211.46 (continued)211.46 (continued)

(d) “Air-handling systems for ... penicillin shall be (d) “Air-handling systems for ... penicillin shall be completelycompletely separateseparate from those for other drug products for human use.” from those for other drug products for human use.”

Other IssuesOther Issues:: 211.44 Lighting211.44 Lighting 211.48 Plumbing211.48 Plumbing 211.50 Sewage and refuse211.50 Sewage and refuse 211.52 Washing and toilet facilities211.52 Washing and toilet facilities 211.56 Sanitation211.56 Sanitation 211.58 Maintenance211.58 Maintenance

Page 29: Fremland GLP GMP

EquipmentEquipment

211.63 Equipment Design, Size, and Location211.63 Equipment Design, Size, and Location“Equipment used in the manufacture, processing, packing, or holding of a drug product “Equipment used in the manufacture, processing, packing, or holding of a drug product shall be of appropriate design, adequate size, and suitably located to facilitate shall be of appropriate design, adequate size, and suitably located to facilitate operations for its operations for its intendedintended useuse and for its and for its cleaningcleaning and and maintenancemaintenance.”.”

211.65 Equipment Construction211.65 Equipment Construction

211.67 Equipment Cleaning and Maintenance211.67 Equipment Cleaning and Maintenance(a) “Equipment and utensils shall be (a) “Equipment and utensils shall be cleanedcleaned, , maintainedmaintained, and , and sanitizedsanitized at appropriate at appropriate intervals ...”intervals ...”(b) “(b) “WrittenWritten proceduresprocedures shall be established and followed...” shall be established and followed...”(c) “(c) “RecordsRecords shall be kept ...” shall be kept ...”

Page 30: Fremland GLP GMP

EquipmentEquipment

211.68 Automatic, Mechanical, and Electronic Equipment211.68 Automatic, Mechanical, and Electronic Equipment (a) (a) “... including computers ... may be used. If such equipment “... including computers ... may be used. If such equipment is used, it shall be routinely is used, it shall be routinely calibratedcalibrated, , inspectedinspected, or , or checkedchecked according to a according to a writtenwritten programprogram designed to assure proper designed to assure proper performance. Written records of those calibration checks and performance. Written records of those calibration checks and inspections shall be maintained.”inspections shall be maintained.”

(b) “Appropriate controls shall be exercised over computer or (b) “Appropriate controls shall be exercised over computer or related systems to assure that changes ... are instituted only by related systems to assure that changes ... are instituted only by authorized personnel.”authorized personnel.”

211.72 Filters211.72 Filters

Page 31: Fremland GLP GMP

Control of Components and Drug Product Containers and ClosuresControl of Components and Drug Product Containers and Closures211.80 General Requirements211.80 General Requirements

(a) “There shall be written procedures describing in sufficient (a) “There shall be written procedures describing in sufficient detail the detail the receiptreceipt, , identificationidentification, , storagestorage, , handlinghandling, , samplingsampling, , testingtesting, and , and approvalapproval or or rejectionrejection of components and drug of components and drug product containers and closures; such written procedures shall product containers and closures; such written procedures shall be followed.”be followed.”

211.82 Receipt and Storage211.82 Receipt and Storage::(a) “Upon receipt ... shall be examined visually ...” (a) “Upon receipt ... shall be examined visually ...” (b) “... shall be stored under (b) “... shall be stored under quarantinequarantine until they have been until they have been tested or examined, as appropriate, and released.”tested or examined, as appropriate, and released.”

Page 32: Fremland GLP GMP

Control of Components and Drug Product Containers and ClosuresControl of Components and Drug Product Containers and Closures

211.84 Testing and Approval or Rejection211.84 Testing and Approval or Rejection(a) “Each lot ... shall be withheld from use until the lot has been (a) “Each lot ... shall be withheld from use until the lot has been sampledsampled, , testedtested or examined, as appropriate, and or examined, as appropriate, and releasedreleased forfor useuse by the by the qualityquality controlcontrol unitunit.”.”(b) “Representative samples ... of each lot shall be collected ...”(b) “Representative samples ... of each lot shall be collected ...”(d) “Samples shall be examined and tested as follows ...”(d) “Samples shall be examined and tested as follows ...” ““At least one test ... to verify identity.”At least one test ... to verify identity.” ““... for conformity with all appropriate written specifications ... for conformity with all appropriate written specifications

for purity, strength, and quality”for purity, strength, and quality”

(e) “Any lot ... that (e) “Any lot ... that meetsmeets ... ... specificationsspecifications [by testing according [by testing according to paragraph (d)] may be to paragraph (d)] may be approvedapproved and and releasedreleased forfor useuse.”.”

Page 33: Fremland GLP GMP

Control of Components and Drug Product Containers and ClosuresControl of Components and Drug Product Containers and Closures211.86 Use of Approved [Stock]211.86 Use of Approved [Stock]

“ “... the ... the oldestoldest approved stock is used approved stock is used firstfirst.”.”

211.87 Retesting of approved [stock]211.87 Retesting of approved [stock]

211.89 Rejected [Stock]211.89 Rejected [Stock]“Rejected [stock] shall be ... “Rejected [stock] shall be ... controlledcontrolled ... to ... to preventprevent their use ...” their use ...”

211.94 Drug Product Containers and Closures211.94 Drug Product Containers and Closures::(a) “... shall not be (a) “... shall not be reactivereactive, , additiveadditive, or , or absorptiveabsorptive ...” ...”(b) “... shall (b) “... shall provideprovide adequateadequate protectionprotection ...” ...”(c) “... shall be clean (c) “... shall be clean andand ...” ...”

Page 34: Fremland GLP GMP

Production and Process ControlsProduction and Process Controls

211.100 Written Procedures; Deviations211.100 Written Procedures; Deviations(a) “There shall be (a) “There shall be writtenwritten proceduresprocedures for production and for production and process control ...”process control ...”(b) “Written production and process control procedures shall be (b) “Written production and process control procedures shall be followed ...”followed ...”

211.101 Charge-in of Components211.101 Charge-in of ComponentsNote important detail!Note important detail!(d) “Each component shall be (d) “Each component shall be addedadded toto thethe batchbatch by one person by one person and and verifiedverified by a second person.” by a second person.”

211.103 Calculation of Yield211.103 Calculation of Yield

Page 35: Fremland GLP GMP

Production and Process ControlsProduction and Process Controls

211.105 Equipment Identification211.105 Equipment Identification(a) “[Equipment] shall be properly identified at all times to (a) “[Equipment] shall be properly identified at all times to indicate their contents and, when necessary, the phase of indicate their contents and, when necessary, the phase of processing of the batch.”processing of the batch.”(b) “[Equipment] shall be identified by a (b) “[Equipment] shall be identified by a distinctivedistinctive identificationidentification numbernumber or code ...” or code ...”

211.110 Sampling and Testing of In-Process Materials and 211.110 Sampling and Testing of In-Process Materials and Drug ProductsDrug Products

211.111 Time Limitations on Production211.111 Time Limitations on Production

Page 36: Fremland GLP GMP

Production and Process ControlsProduction and Process Controls

211.113 Control of Microbiological Contamination211.113 Control of Microbiological Contamination(a) for non-sterile drugs(a) for non-sterile drugs(b) for sterile drugs(b) for sterile drugs

211.115 Reprocessing211.115 Reprocessing(a) “(a) “WrittenWritten proceduresprocedures shall be established and followed ...” shall be established and followed ...”(b) “... review and approval of the (b) “... review and approval of the qualityquality controlcontrol unitunit.”.”

Page 37: Fremland GLP GMP

Packaging and Labeling ControlPackaging and Labeling Control

211.122 Materials Examination and Usage Criteria211.122 Materials Examination and Usage Criteria(a) “There shall be (a) “There shall be writtenwritten proceduresprocedures ...” ...”(c) “(c) “RecordsRecords shall be kept ...” shall be kept ...”(d) “Labels and other labeling materials for each different drug (d) “Labels and other labeling materials for each different drug product, strength, dosage form, or quantity of contents ...”product, strength, dosage form, or quantity of contents ...”

211.125 Labeling Issuance211.125 Labeling Issuance(a) “(a) “StrictStrict controlcontrol shall be exercised over labeling issued for use shall be exercised over labeling issued for use in drug product labeling operations.”in drug product labeling operations.”(c) “Procedures shall be used to (c) “Procedures shall be used to reconcilereconcile thethe quantitiesquantities of of labeling issued, used, and returned ...”labeling issued, used, and returned ...”

Page 38: Fremland GLP GMP

Packaging and Labeling ControlPackaging and Labeling Control

211.130 Packaging and Labeling Operations211.130 Packaging and Labeling Operations“There shall be “There shall be writtenwritten proceduresprocedures designed to assure that designed to assure that correct labels, labeling, and packaging materials are used for correct labels, labeling, and packaging materials are used for drug products; such written procedures shall be followed.”drug products; such written procedures shall be followed.”

211.137 Expiration Dating211.137 Expiration Dating“To assure that a drug product meets applicable standards of “To assure that a drug product meets applicable standards of identity, strength, quality, and purity at the time of use, it shall identity, strength, quality, and purity at the time of use, it shall bear an expiration date determined by appropriate stability bear an expiration date determined by appropriate stability testing ...”testing ...”

Page 39: Fremland GLP GMP

Holding and DistributionHolding and Distribution

211.142 Warehousing Procedures211.142 Warehousing Procedures““WrittenWritten proceduresprocedures ... shall be established and followed. They ... shall be established and followed. They shall include:shall include:(a) (a) QuarantineQuarantine of drug products before release by the quality of drug products before release by the quality control unit.control unit.(b) Storage of drug products (b) Storage of drug products underunder appropriateappropriate conditionsconditions ...” ...”

211.150 Distribution Procedures211.150 Distribution Procedures““WrittenWritten proceduresprocedures shall be established and followed. They shall be established and followed. They shall include: shall include: (a) ... the (a) ... the oldestoldest approved stock ... is distributed approved stock ... is distributed firstfirst..(b) ... the distribution of each lot of drug product can be readily (b) ... the distribution of each lot of drug product can be readily determined to determined to facilitatefacilitate itsits recallrecall if necessary.” if necessary.”

Page 40: Fremland GLP GMP

Laboratory ControlsLaboratory Controls

211.160 General Requirements211.160 General Requirements

(a) “The establishment of any specifications, standards, sampling (a) “The establishment of any specifications, standards, sampling plans, test procedures, or other laboratory control mechanisms plans, test procedures, or other laboratory control mechanisms required by this subpart, including any change in such ..., shall required by this subpart, including any change in such ..., shall be drafted by the appropriate organizational unit and be drafted by the appropriate organizational unit and reviewedreviewed and and approvedapproved by the by the qualityquality controlcontrol unitunit. The requirements in . The requirements in this subpart shall be followed and shall be this subpart shall be followed and shall be documenteddocumented atat thethe timetime ofof performanceperformance. Any . Any deviationdeviation ... shall be ... shall be recordedrecorded and and justifiedjustified.”.”

Page 41: Fremland GLP GMP

Laboratory ControlsLaboratory Controls

211.160 (continued)211.160 (continued)

(b) “Laboratory controls shall include the establishment of (b) “Laboratory controls shall include the establishment of scientificallyscientifically soundsound and and appropriateappropriate specifications, standards, specifications, standards, sampling plans, and test procedures designed to assure that sampling plans, and test procedures designed to assure that componentscomponents, , drugdrug productproduct containerscontainers, , closuresclosures, , in-processin-process materialsmaterials, , labelinglabeling, and , and drugdrug productsproducts conform to appropriate conform to appropriate standards of standards of identityidentity, , strengthstrength, , qualityquality, and , and puritypurity.”.”

Note subpart (4): “The Note subpart (4): “The calibrationcalibration of instruments, apparatus, of instruments, apparatus, gauges, and recording devices at suitable intervals in gauges, and recording devices at suitable intervals in accordance with an accordance with an establishedestablished writtenwritten programprogram ...” ...”

Page 42: Fremland GLP GMP

Laboratory ControlsLaboratory Controls

211.165 Testing and Release for Distribution211.165 Testing and Release for Distribution(a) “For each drug product, there shall be appropriate laboratory (a) “For each drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications determination of satisfactory conformance to final specifications for the drug product ...”for the drug product ...”

(e) “The accuracy, sensitivity, specificity, and reproducibility of (e) “The accuracy, sensitivity, specificity, and reproducibility of testtest methodsmethods employed by the firm shall be established and employed by the firm shall be established and documented [documented [validatedvalidated].”].”

Page 43: Fremland GLP GMP

Laboratory ControlsLaboratory Controls

211.166 Stability Testing211.166 Stability Testing“There shall be a “There shall be a writtenwritten testingtesting programprogram designed to assess the designed to assess the stabilitystability characteristics of drug products. The results of such characteristics of drug products. The results of such stability testing shall be used in determining appropriate stability testing shall be used in determining appropriate storagestorage conditionsconditions and and expirationexpiration datesdates.”.”

211.167 Special Testing Requirements211.167 Special Testing Requirements

(a) sterile and/or pyrogen-free products(a) sterile and/or pyrogen-free products

(b) ophthalmic products(b) ophthalmic products

(c) controlled release products(c) controlled release products

211.168 Reserve Samples211.168 Reserve Samples

Page 44: Fremland GLP GMP

Laboratory ControlsLaboratory Controls

211.176 Penicillin Contamination211.176 Penicillin Contamination“If a “If a reasonablereasonable possibilitypossibility exists that a non-penicillin drug exists that a non-penicillin drug product has been exposed to cross-contamination with product has been exposed to cross-contamination with penicillin, the non-penicillin drug product shall be penicillin, the non-penicillin drug product shall be testedtested forfor thethe presencepresence of of penicillinpenicillin. Such drug product shall not be marketed . Such drug product shall not be marketed if if detectabledetectable levelslevels are found when tested according to are found when tested according to procedures specified ...”procedures specified ...”

Page 45: Fremland GLP GMP

Records and ReportsRecords and Reports

211.180 General Requirements211.180 General Requirements(a) and (b)(a) and (b) Any written records “shall be retained for at least 1 Any written records “shall be retained for at least 1 year after the expiration date ... or 3 years after distribution ...”year after the expiration date ... or 3 years after distribution ...”

(c) “... shall be readily available for authorized inspection during (c) “... shall be readily available for authorized inspection during the retention period at the establishment where the activities ... the retention period at the establishment where the activities ... occurred.”occurred.”

(e) “... shall be maintained so that (e) “... shall be maintained so that datadata therein can be used for therein can be used for evaluatingevaluating, , atat leastleast annuallyannually, the , the qualityquality standardsstandards of each drug of each drug product to determine the need for changes in ... specifications or product to determine the need for changes in ... specifications or manufacturing or control procedures. Written procedures shall manufacturing or control procedures. Written procedures shall be established and followed for such evaluations ...”be established and followed for such evaluations ...”

Page 46: Fremland GLP GMP

Records and ReportsRecords and Reports

211.182 Equipment Cleaning and Use Log211.182 Equipment Cleaning and Use Log“A written record of major equipment “A written record of major equipment cleaningcleaning, , maintenancemaintenance, , and and useuse ...” ...”

211.184 Component, Drug Product Container, Closure, and 211.184 Component, Drug Product Container, Closure, and Labeling RecordsLabeling Records(a) “The identity and quantity of each shipment of each lot ...”(a) “The identity and quantity of each shipment of each lot ...”(b) “The results of any test or evaluation performed ...”(b) “The results of any test or evaluation performed ...”(c) “An individual inventory record ... and ... a reconciliation of (c) “An individual inventory record ... and ... a reconciliation of the use ...”the use ...”(d) “Documentation of the examination and review of labels ...”(d) “Documentation of the examination and review of labels ...”(e) “The disposition of rejected ...”(e) “The disposition of rejected ...”

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Records and ReportsRecords and Reports

211.186 Master Production and Control Records211.186 Master Production and Control Records“To “To assureassure the the uniformityuniformity from batch to batch, master production from batch to batch, master production and control records for each drug product, including ...and control records for each drug product, including ...The preparation of master production and control records shall The preparation of master production and control records shall be be describeddescribed in a in a writtenwritten procedureprocedure and such written procedure and such written procedure shall be followed.”shall be followed.”

211.188 Batch Production and Control Records211.188 Batch Production and Control Records“Batch production and control records shall be prepared for “Batch production and control records shall be prepared for each batch of drug product produced and shall include complete each batch of drug product produced and shall include complete information relating to the production and control of each batch.”information relating to the production and control of each batch.”

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Records and ReportsRecords and Reports

211.192 Production Record Review211.192 Production Record Review“All drug product production and control records, including those “All drug product production and control records, including those for packaging and labeling, shall be for packaging and labeling, shall be reviewedreviewed and and approvedapproved by by the the qualityquality controlcontrol unitunit to determine compliance with all to determine compliance with all established, approved written procedures before a batch is established, approved written procedures before a batch is released or distributed. released or distributed.

Any unexplained discrepancy ... or the failure of a batch or any Any unexplained discrepancy ... or the failure of a batch or any of its components to meet any of its specifications shall be of its components to meet any of its specifications shall be thoroughlythoroughly investigatedinvestigated. The investigation shall extend to other . The investigation shall extend to other batches ... that may have been associated with the specific batches ... that may have been associated with the specific failure or discrepancy. A failure or discrepancy. A writtenwritten recordrecord ofof thethe investigationinvestigation shall shall be made and shall include the conclusions and follow-up.”be made and shall include the conclusions and follow-up.”

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Records and ReportsRecords and Reports

211.194 Laboratory Records211.194 Laboratory Records(a) “complete data derived from all tests …(a) “complete data derived from all tests …

(b) “any modification of an established method [including] the (b) “any modification of an established method [including] the reason for the modification and data to verify that ... results are reason for the modification and data to verify that ... results are at least as accurate and reliable ... as the established method.at least as accurate and reliable ... as the established method.

(c) “any testing and standardization of laboratory reference (c) “any testing and standardization of laboratory reference standards, reagents, and standard solutions.standards, reagents, and standard solutions.

(d) “... periodic calibration of laboratory instruments [etc.].(d) “... periodic calibration of laboratory instruments [etc.].

(e) “... stability testing.”(e) “... stability testing.”

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Records and ReportsRecords and Reports

211.196 Distribution Records211.196 Distribution Records“... shall contain the name and strength of the product and “... shall contain the name and strength of the product and description of the dosage form, name and address of the description of the dosage form, name and address of the consignee, date and quantity shipped, and lot or control number consignee, date and quantity shipped, and lot or control number of the drug product.”of the drug product.”

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Records and ReportsRecords and Reports

211.198 Complaint Files211.198 Complaint Files(a) “(a) “WrittenWritten proceduresprocedures describing the handling of all written and describing the handling of all written and oral complaints regarding a drug product shall be established and oral complaints regarding a drug product shall be established and followed. Such procedures shall include provisions for followed. Such procedures shall include provisions for reviewreview by by the the qualityquality controlcontrol unit of any complaint involving the unit of any complaint involving the possiblepossible failurefailure of a drug product to meet any of its specifications and ... a of a drug product to meet any of its specifications and ... a determination as to the need for an determination as to the need for an investigationinvestigation. Such . Such procedures shall include provisions for procedures shall include provisions for reviewreview to determine to determine whether the compliant represents a serious and unexpected whether the compliant represents a serious and unexpected adverseadverse drugdrug experienceexperience which is required to be reported to the which is required to be reported to the FDA.”FDA.”

(b) “A written record of each complaint shall be maintained in a file (b) “A written record of each complaint shall be maintained in a file ...”...”

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Returned and Salvaged Drug ProductsReturned and Salvaged Drug Products

211.204 Returned Drug Products211.204 Returned Drug Products“... shall be “... shall be identifiedidentified as such and held. If the conditions ... as such and held. If the conditions ... castcast doubtdoubt on the ... drug product, [it] shall be destroyed on the ... drug product, [it] shall be destroyed unlessunless examination, testing, or other investigations examination, testing, or other investigations proveprove [it] meets [it] meets appropriate standards ... appropriate standards ... RecordsRecords of returned drug products of returned drug products shall be maintained and shall include ... the shall be maintained and shall include ... the reasonreason for the return for the return ...”...”

211.208 Drug Product Salvaging211.208 Drug Product Salvaging“Drug products that have been subjected to “Drug products that have been subjected to improperimproper storagestorage conditionsconditions ... ... shallshall notnot be salvaged and returned to the be salvaged and returned to the marketplace. Whenever there is a question ... salvaging marketplace. Whenever there is a question ... salvaging operations may be conducted only if there is operations may be conducted only if there is evidenceevidence ...” ...”

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What Does It All Mean What Does It All Mean

Documentation System:Documentation System: Written procedures (SOPs) must be available for all operations and activities from receipt of Written procedures (SOPs) must be available for all operations and activities from receipt of

raw materials to shipment and distribution of finished goods.raw materials to shipment and distribution of finished goods. SOPs must be followed.SOPs must be followed. Records must be kept (of everything!)Records must be kept (of everything!)

Also:Also: Facilities must be appropriate and provide an acceptable environment to protect product Facilities must be appropriate and provide an acceptable environment to protect product

from contamination.from contamination. Equipment must be kept clean and well maintained.Equipment must be kept clean and well maintained.

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Important Documents

Standard Operating Procedure (SOP): Standard Operating Procedure (SOP): A document that A document that describes a routine procedure of general use which is not describes a routine procedure of general use which is not specific to one product.specific to one product.

Master Production and Control Record (MPCR): Master Production and Control Record (MPCR): A A document that describes the procedure for the preparation of a document that describes the procedure for the preparation of a specific product.specific product.

Batch Production and Control Record (BPCR): Batch Production and Control Record (BPCR): An exact An exact copy of the copy of the approvedapproved MPCR issued for each production batch MPCR issued for each production batch to record the data for that particular batch.to record the data for that particular batch.

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Bottom Line Bottom Line

Document, Document, Document!!!Document, Document, Document!!!

In FDA-speak:In FDA-speak:

““If it is not documented . . .If it is not documented . . .

it did not happen!”it did not happen!”

or, it’s a rumor!”or, it’s a rumor!”