Validation Download

8/8/2019 Validation Download

1/47

FDA cGMP Inspections

www.pharmasri.com


2/47

FDA Inspectionsy Periodic (biennial) comprehensive cGMPy Pre-Approval Inspection(PAI)y For cause

y Inspection may involve more than oneassignment and will verify corrections to

previous inspections.

y All inspections cover GMPs

www.pharmasri.com


3/47

Foreign Inspections by Country in FY 2004India14%

Germany14%

Italy10%

China7%

United Kingdom7%

Canada7%

France5%

Japan5%

Switzerland4%

Spain4%

Ireland4%

Others19%

www.pharmasri.com


4/47

Type

API51%

Dosage27%

In erme d ates10%

Co ntrol Lab2%

Bot h API a nd Dosage9% Micro nizer

1%

www.pharmasri.com


5/47

FDA cGMPs for 21 st Century Initiative

Announced 8/2002; objectives include:y E ncourage adoption of new technologiesy Promote industry use of modern quality system

approachesy E ncourage risk-based approaches which focus

on critical elementsy E nsure FDA review, compliance and inspection

policies based on state-of-art pharmaceuticalscience

www.pharmasri.com


6/47

FDA cGMPs for 21st

Century Initiativey S ystems Based Inspectionsy Risk-Based Approach to Manufacturing and Regulationy Pharmaceutical Inspectoratey PAT Guidance document/ PAT Teamy Quality S ystems Guidance documenty Process Validation (Compliance Policy Guide revised;

Guidance being revised)y 21 CFR Part 11 E lectronic Records Guidance (risk-based;geared toward GMP documents)

www.pharmasri.com


7/47

Pharmaceutical Inspectoratey Cadre of most experienced investigators who are dedicated

to drug inspectionsy Intensively trained along with quality reviewers and

compliance staff in FDA headquarters (HQ)y Overall goal is to have PI work closely with HQ personnel

more efficiently integrate review and inspection functions

www.pharmasri.com


8/47

Pharmaceutical InspectorateFDA Review staff, Compliance Officers and PI candidatesattended training modules which focused on:

y Current Regulatory Programsy

Advanced Quality Systemsy PAT and Modern Pharmaceutical Technologyy Risk Management

www.pharmasri.com


9/47

Pharmaceutical InspectorateField Investigators (18) from across U.S. make up the

Pharmaceutical Inspectoratey Screening process with certification boardy

Completed training with HQ personnely One month detail working with HQ staff y Level III certification (highest level)y Conduct PAIs, complex drug inspections

www.pharmasri.com


10/47

Process Analytical TechnologyPAT is a system for designing, analyzing and controllingmanufacturing through real time measurements of criticalquality attributes of raw and in-process materials andprocesses, with the goal of ensuring final product quality.

y See FDA Guidance document on PAT

www.pharmasri.com


11/47

Process Analytical TechnologyE xamples of PAT applications:y Continuous real time measurements of content uniformity of

tablets during production (using near Infra-Red)

y Near IR measurement of moisture level during API dryingprocess to determine actual end of operation for each batch

www.pharmasri.com


12/47

Process Analytical TechnologyA process is generally considered well understood when:y All critical sources of variability are identified and

explainedy Variability is managed by the process

Quality cannot be tested into products; it should be built-in orshould be by design.

www.pharmasri.com


13/47

Process ValidationLife Cycle Approach

y Process validation begins with process development and

continues beyond the initial validation batches for aslong as product is manufactured/ marketedy Sources of critical variability identified and controlledy Quality System role in maintaining validated state

(quality built in; not tested into product)

www.pharmasri.com


14/47

Process Validationy FDA Compliance Policy Guide

Process Validation Requirements for Drug Products andActive Pharmaceutical Ingredients CPG 7132c.08; revision

date 12 March 2004

y FDA Industry Guideline on Process Validation currently being revised

www.pharmasri.com


15/47

System Inspectionsy Qualityy Facilities andE quipmenty Materialsy Productiony Packaging/Labelingy Laboratory Controls

www.pharmasri.com


16/47

Most Common GMP Deficiencies by System API/Dosage Inspections for 2004/5

Quality46%

Mat er ial s6%

Faciliti es & Eq uipm e t17%

Pa ck aging and Lab eling1%

Pr du ction11%

Labo r ato r y19%

www.pharmasri.com


17/47

S tate of Controly Detailed inspection of a system so that the findings reflect the

state of control in that system for every product (profile)class

y

If one of the six systems is out of control, the firm isconsidered out of controly A system is considered out of control based on GMP

deficiencies which suggest lack of assurance of quality

www.pharmasri.com


18/47

Quality Systemy Quality must be built into the processy Quality is not tested into the product

y Assurance of Quality comes from- Design of robust process based on thorough knowledge of that process and the sources of variability- E ffective Quality System in place

www.pharmasri.com


19/47

Role of Management in QSManagement is responsible for:

y Organizational structurey All Processesy All Proceduresy Facilities & Resources

In short, everything to insure product quality, customersatisfaction and continuous improvement

www.pharmasri.com


20/47

Quality System Responsibilitiesy Assures overall compliance with cGMPsy Review and approval duties for:1) Product Quality Reviews (at least annually)2) Complaint reviews3) Discrepancy/ failure investigations4) Change Control

5) CAPA (Corrective And Preventive Action)

www.pharmasri.com


21/47

Quality system (continued)

6 ) Reprocess/ Rework7) Validation/ Revalidation8) Rejects

9) Stability Failures/ Out of trend data10) Quarantine products11) Documented GMP & Job Related Training

www.pharmasri.com


22/47

Laboratory Control Systemy Adequate lab facilities under the Quality Unit which is

independent from Productiony Adequately staffed laboratories (supervisory and bench

personnel)y Written specifications for raw materials, intermediates,

APIs, labels & packagingy Written procedures for sampling, testing, approval or

rejection of materials and for the recording and storageof data

y Change control for written proceduresy Method validation/ revalidation

www.pharmasri.com


23/47

Laboratory Control Systemy Reference Standards (primary; secondary)y E quipment Qualificationy Calibration: written procedures, schedule, documentationy

Validation and Security for computerized handling of testresults and related data; system for assuring integrity of alllab data

y Laboratory controls followed and documented

www.pharmasri.com


24/47


25/47

Laboratory Control Recordsy

Description of samplesy Identification of method usedy Raw data for sample/ standard preparation, reagentsy Complete record of all data from testingy Record of all calculationsy Statement of the test results; how compare with established acceptance

criteriay Signature of the person who performed each test; dates tests

performedy Date/ signature of second qualified person who reviewed original test

records for accuracy, completeness and compliance with establishedstandards

www.pharmasri.com


26/47

Production Systemy Training (documented; job-related)y Master production and control recordsy Batch production and control recordsy

Change control procedurey Contemporaneous, accurate and complete batch productiondocumentation

y Implementation and documentation of in-process controls,tests, and examinations

www.pharmasri.com


27/47

Production system (continued)

y Adequate written procedures & practice for charge-in of materials

y Identification of equipment with contents, stage of manufacturing, status

y E quipment cleaning recordsy E stablished time limits for completion of production steps/

stages

www.pharmasri.com


28/47

Production system (continued)

y Deviations investigated and documentedcontemporaneously with investigation

y Process validation based on knowledge of process(scientific basis for identifying critical steps/ criticalprocess parameters/control points)

y Justification and consistency of in-process specificationsand final product specifications

y Data/ information documented and available to QualityUnit for review (trending, investigations etc.)

www.pharmasri.com


29/47

Facilities & Equipment SystemFACILITIE S

y Location, design, construction appropriate to facilitatecleaning, maintenance, operations

y Layout and air handling designed and constructed to preventcross-contamination

y Flow of materials & personnel designed to prevent mix-upsor contamination

www.pharmasri.com


30/47

Facilities & Equipment SystemDefined areas or other control systems to prevent mix-ups orcontamination

y Incoming materials (id, quarantine)y

Sampling area (prevent contamination)y Quarantine (intermediates, APIs)y Released materialsy Rejection

www.pharmasri.com


31/47

Facilities & Equipment SystemE QUIPME NT

y Appropriate design, size, location, non-reactive product contactsurfaces

y Identification clearly markedy Qualification (DQ, IQ,OQ, PQ)y Calibrationy Preventive Maintenance schedule and proceduresy Cleaning procedures and validationy Records of use, cleaning, maintenance

www.pharmasri.com


32/47

Facilities & Equipment Systemy Lubricants, heating fluids or coolants (not contact/alter

product quality)y Closed or contained equipmenty

Inspection prior to use************************************y Separate facilities or containment where needed (penicillins,

highly potent compounds etc.)

www.pharmasri.com


33/47


34/47

Watery Process water at minimum meeting WHO guidelines for

potable watery Justify quality of water used to achieve stated API quality

and establish specificationsy Water treatment facilities validatedy API to be used for incorporation into sterile dosage form

water used in later stages should be monitored and

controlled for total microbial counts, objectionableorganisms and endotoxins

www.pharmasri.com


35/47

Materials Systemy Written procedures for receipt, identification,

quarantine, storage, handling, sampling, testing andapproval or rejection of materials

y

System to evaluate suppliers (critical materials)y Purchased against agreed specificationy Change control process for changing suppliersy Upon receipt check for correct labeling, sealsy Before co-mingling bulk material, id/testy Assurances obtained from non-dedicated tankers

www.pharmasri.com


36/47

Materials Systemy

Identification on large storage containers and associatedmanifolds, filling and discharge linesy Code given to received batches; status identityy At minimum, a specific identity test on incoming batches;

COAy Supplier evaluation should include three fully tested batches;

one fully tested batch/yeary

Written sampling plan with justificationy Prevent contamination of sampled containers

www.pharmasri.com


37/47

Materials Systemy Stored in manner to prevent degradation, contamination,

no adverse effect on qualityy Drums, bags, boxes off the floory First in, first outy Rejected materials identified and controlled under a

quarantine system

y E stablished re-test/ re-evaluation periods

www.pharmasri.com


38/47

Packaging & Labeling Systemy Written procedures for receipt, identification, quarantine,

sampling, examination and/or testing P&Ly P&L should conform to specificationsy Records maintained for each shipment (showing receipt,

examination & result)y Containers protective, clean, not alter product quality; if re-

used, cleaned & labeling defaced

www.pharmasri.com


39/47

Labeling y Access to label storage area limitedy Written procedures for reconciliation; investigation if

discrepancyy All excess labels with batch #, destroyedy Obsolete labels destroyedy Printing devices controlled to insure accuracy of label

(against batch record)y Print labels checked against master and a copy placed into

the batch record

www.pharmasri.com


40/47

Packaging/ Labeling Operationsy

Documented procedures to assure correct packagingmaterials/ labels usedy Operations designed to prevent mix-upsy Labels: API name, batch #, storage conditionsy Shipped API: Name/ address manufacturer; special

transport conditions; expiry/ retest datey Documented clearance before operationsy

Packaged/ labeled intermediates or APIs examined as partof packaging (documented)y Seal employed to assure package integrity

www.pharmasri.com


41/47

APIs are Drug Substancesy FDA Food, Drug and Cosmetic Act definition of

drug includes articles intended for use in thediagnosis, cure, mitigation, treatment orprevention of disease in man or other animals(no distinction between APIs & dosage forms)

y Before ICH Q7A, FDA used dosage drugregulations as guidance for API inspection

y S till true (see next slide) , however, ICH Q7Aprovides guidance on the application of thosecGMPs to APIs)

www.pharmasri.com


42/47


43/47

Current FDA Compliance Guide onProcess validation

From FDA Compliance Policy Guide Process ValidationRequirements for Drug Products and Active PharmaceuticalIngredients CPG 7132c.08; revision date 12 March 2004:

Validation of manufacturing processes is arequirement of the Current GoodManufacturing Practice (cGMP) regulations forfinished pharmaceuticals, and is considered anenforceable element of current goodmanufacturing practice for activepharmaceutical ingredients (APIs) under thebroader statutory cGMP provisions of theFederal Food, Drug, and Cosmetic Act.

www.pharmasri.com


44/47

Differences API/ Dosage Formy APIs involve purification stepsy GMP controls tighter for later API stepsy API impurity profile is critical focus and steps which produce

or remove impurities require greater control and validationy Dosage forms do not involve purification

www.pharmasri.com


45/47

S imilarities APIs/Dosage Formsy Require demonstrated knowledge of process

and application of appropriate GMP controls toassure safety, identity, strength, quality and

purity.y S ystems in control to be in compliancey Life Cycle Approach to Validation (beyond the

initial conformance batches)

www.pharmasri.com


46/47

S imilarities include.y Processes for specific products vary in

complexity (either API or dosage can involvecomplex or simple processes)

y In-Process Controlsy Finished Product Controlsy Critical S teps/ Critical Process Parametersy Process Validationy

Quality Assurance for consumer is based onunderstanding & Control of S ources of Process/Product Variability

www.pharmasri.com


47/47

More S imilarities..y S cience based approach for the establishment of

processesy Knowledge of process based on Process

Development workDesign Of E xperiments (DO E )Quality S ystem (review/ trending)

y Continuous Improvement possible within well

characterized process

www.pharmasri.com

Documents

Validation Download