Production and Process Controls

1 Quality Production Laboratory Materials Facilities and Equipment Packaging and LabelingRegulatory Educationfor Industry (REdI):Focus on CGMPs & FDA InspectionsSheraton | Silver Spring, MD | July 15-16, 2015 Production and Process Controls :Overview of CGMP Regulations and Regulatory ExpectationsPresenters:VibhakarShah, , Consumer Safety OfficerOffice of Policy for Pharmaceutical Quality, OPQ, CDERV inayakPawar, , Senior Review MicrobiologistOffice of Process and Facility Assessment, OPQ, CDERQ uality Production Laboratory Materials Facilities and Equipment Packaging and LabelingThe Six Components Quality Production Laboratory Materials Facilities & Equipment Packaging & Labeling2 Quality Production Laboratory Materials Facilities and Equipment Packaging and LabelingOverview Public Health and product Quality Expectations Pharmaceutical Manufacturing Operation Production Relevant CGMP Regulations Regulatory Tools for Compliance Regulatory Expectations Summary QuestionsQuality Production Laboratory Materials Facilities and Equipment Packaging and LabelingPublic Health -ExpectationsPublic Health Care System -Stakeholders Patients/Consumers Expects reliable access to safe, efficacious.

2 Stable and affordable high quality pharmaceuticals Manufacturers Manage reliable and secure supply chain Maintain risk mitigated, reliable, and efficient manufacturing operations Provide safe, efficacious, and defect-free high quality drug products Regulators Stand in for the consumer (patient) to ensure quality Exercise risk-commensurate regulatory oversightQuality Production Laboratory Materials Facilities and Equipment Packaging and LabelingDrug Regulation FrameworkLegalRegulatory Framework5 Quality Production Laboratory Materials Facilities and Equipment Packaging and LabelingDrug Regulation FrameworkStatuteFD&C Act Section 501(a)(2)(B) A drug shall be deemed to be adulteratedif the methodsused in, or the facilitiesor controlsused for, its manufacture, processing, packing, or holdingdo not conform to or are not operated or administeredin conformity with current good manufacturing practiceto assure that such drug meets the requirements of this Act as to safetyand has the identityand strength, and meets the qualityand puritycharacteristics, which it purports or is represented to possess.

3 6 Quality Production Laboratory Materials Facilities and Equipment Packaging and LabelingCurrent Good Manufacturing Practice(CGMP) Legal Basis FD&C Act Sec. 501(a)(2)(B) requires conformity with Current Good Manufacturing Practice(CGMP) for manufacture of drugs No distinctionbetween API, excipients and finished pharmaceuticals CGMP regulations-Agency s interpretation of the statute for compliance Production Laboratory Materials Facilities and Equipment Packaging and Labeling8 CGMP Regulations : Law of the (b)(21) (b)(20)Acceptance (b)(15)Quality control (b)(12) (b)(2)Batch (b)(10) (b)(9)In- Process (b)(8)Inactive (b)(7)Active (b)(4)Drug (b)(3)ComponentCGMPs21 CFR 210 DefinitionsCGMPs21 CFR 210 DefinitionsCGMPs21 CFR 211 SubpartsFD&C Act Section 501(a)(2)(B) A drug shall be deemed to themethodsused in, or the facilitiesor controlsused for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformitywithcurrent good manufacturing to assurethat such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.

4 Quality Production Laboratory Materials Facilities and Equipment Packaging and Labeling9 CGMP Regulations : Law of the LandSUBPARTKR eturned & SalvagedDrug .SUBPARTJR ecords and ..SUBPARTIL aboratory ..SUBPARTHH olding & .SUBPART GPackaging & Labeling ..SUBPART FProduction & Process ..SUBPART EComponents & ..SUBPART ..SUBPARTCB uildings & ..SUBPARTBO rganizations & ..SUBPARTAG eneral , CFR 211FD&C Act Section 501(a)(2)(B) A drug shall be deemed to themethodsused in, or the facilitiesor controlsused for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity withcurrent good manufacturing to assurethat such drug meets the requirements of this Act as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess.

5 CGMPs21 CFR 210 DefinitionsCGMPs21 CFR 211 SubpartsQuality Production Laboratory Materials Facilities and Equipment Packaging and Labeling10 CGMP Regulations: Production System 21 CFR 211 Subpart FProduction and Process Controls Applies to Finished drug products Prescription drug products (Rx) NDA, ANDA, BLAs Over-The-Counter drug products (OTC) Unapproved drugs Compounded drugs (under Sec. 503B of the Act) Any type of Method of Manufacture Batch, Semi-continuous, Continuous Aseptic, Sterile, BiotechnologyQuality Production Laboratory Materials Facilities and Equipment Packaging and LabelingProduction System Production System includes measures and activities to control the manufacture of in- Process materials and drug products including batch compounding dosage form Production in- Process sampling and testing and Process validation establishing, following, and documenting performance of approvedmanufacturing procedures See 21 CFR 211 Subparts B, F, I, and J11 Quality Production Laboratory Materials Facilities and Equipment Packaging and Labeling12 Typical Pharmaceutical Manufacturing OperationsBlendingDosage Form Formation Compression, FillingCoating.

6 PolishingPackagingDispensingMixingFiltra tion*CCS Filling**PackagingDispensingMixingDevice FillingDevice AssemblyPackagingDispensingLiquids/Suspe nsionsSolid Orals: Tablets, capletsDrug-Device Nasal Sprays, MDI. DPIQ uality Production Laboratory Materials Facilities and Equipment Packaging and Labeling21 CFR 211 Subpart FProduction and Process Controls procedures; deviations of components of yield identification and testing of in- Process materials and drug products limitations on Production . of microbiological contamination I -Laboratory Controls : (b)(2)(3)-Sampling procedures for in- Process materials and finished drug productsSubpart J -Records and Reports: (e)(2)(3) -Annual product Review Production Record Review, Deviation and investigation13 Quality Production Laboratory Materials Facilities and Equipment Packaging and Labeling 21 CFR procedures; deviations Key points(a)Requires written procedures for Production and Process control designedto assurethat the drug products have the identity, strength, quality, and puritythey purport or represent to possess.

7 Shall include all requirements in this Subpart F Responsibility of the appropriate organizational units todraft the procedures including any changes, review, and approve Responsibility of the quality control unit to review and approve(b)The written PPC procedures shall be followed in the execution of the various Production and Process control (PPC) functions documented at the time of performance any deviationfrom the written procedures shall be recorded and justified14 Quality Production Laboratory Materials Facilities and Equipment Packaging and Labeling 21 CFR of components Key pointsWritten PPC procedures shall include the following:(a) The batch shall be formulatedwith the intentto provide not less than 100 percentof the labeled or established amount of active ingredient(b) Components for drug product manufacturing shall be weighed, measured, or subdividedas appropriate.

8 If a component is removed from the original container to another, the new container shall be identified with the following information:(1) Component name or item code;(2) Receiving or control number;(3) Weight or measure in new container;(4) Batch for which component was dispensed, including its product name, strength, and lot Production Laboratory Materials Facilities and Equipment Packaging and Labeling 21 CFR of Components Key pointsWritten PPC procedures shall include the following:(c) Weighing, measuring, or subdividing & dispensing of componentsManual operation: Requires adequate supervisionby a second Second person must examineand assure(1) release of the components to Mfg. by the quality control unit (QCU)(2) the weight/measure matches the Batch Production Records (BPRs)(3) proper identification of the containersAutomated equipment Operation ( ): Requires only one person to verify theses operations and assure (c)(1)-(3)(d)Component addition: ( , order of addition) Manual Operation: Require one person to add and a second to verify Automated equipment Addition( ): Require one person to verify16 Quality Production Laboratory Materials Facilities and Equipment Packaging and Labeling 21 CFR of yield Key points Requires determination of actual yields and % theoretical yield at the conclusion of each appropriatephase of manufacturing, processing, packaging, or holding of the drug product .

9 Yield calculations performed by one person independently verified by a second person Yield calculations by automated equipment ( ) independently verified by one person17 Quality Production Laboratory Materials Facilities and Equipment Packaging and Labeling21 CFR Equipment identification Key points(a)Requires proper identification(ID) of all equipment at all times during Production compounding and storage containers processing lines major equipment to indicate their contents to indicate the phase of processing of the batch when necessary(b) Requires identificationand recordingof a major equipment by a distinctive ID number or code in the batch Production record to show the use of a specific equipment for manufacture of each DP batch ID by equipment name allowed in lieu of a distinctive ID number or code if only one of a particular type of equipment exists in a facility18 Quality Production Laboratory Materials Facilities and Equipment Packaging and Labeling 21 CFR & testing of in- Process materials & drug products Key points(a)

10 Requires establishing and following written procedures To assurebatch uniformity and integrityof drug products That describethe in- Process Controls , and tests, or examinationsto be conducted on appropriate samples of in- Process materials of each batch To monitorthe outputand validatethe performanceof those manufacturing processes responsible for causing variability in the characteristics of in- Process material and the drug product19 Quality Production Laboratory Materials Facilities and Equipment Packaging and Labeling 21 CFR & testing of in- Process materials & drug products -Key points(a)Requires establishing and following written procedures Such control procedures shall include, but are not limited to, the following (characteristics), where appropriate:(1) Tablet or capsule weight variation(2) Disintegration time(3) Adequacy of mixing to assure uniformity and homogeneity(4) Dissolution time and rate(5) Clarity, completeness, or pH of solutions(6) Bioburden testing20 Quality Production Laboratory Materials Facilities and Equipment Packaging and Labeling 21 CFR & testing of in- Process materials & drug products -Key points(b) Requires establishing validin- Process specifications for such characteristics shall be consistent with drug product final specifications shall be derived from previous acceptable Process average and Process variability estimates where possible determined by the application of suitable statistical procedures where appropriate.