Critical GMP Validations for Drugs / BiologicsⅡ Chung Keel Lee, Ph.D. Special Advisor to the Minister, MFDS Advisor, WHO Adjunct / Invited Professor, KU / EWU President, ISPE Korea July 23, 2013

Parametric Release Release or approval of a process step, such as a sterilization cycle, by physical parameters measured during the process without confirmation by laboratory testing. Parametric release can only be used if the processing step and measurement of physical parameters have been validated.

Current Good Manufacturing Practice(CGMP) Validation Aseptic Filling/Closing Activities T. HEPA T. HEPA Freeze -Dryer Laminar Flow Hood with HEPA Machine Room Aseptic Filling Room Vial/Stopper Preparation Room Air-lock

Validation Filling validation via simulated media-fill Growth promotion test of the medium Positive control Environmental monitoring Fill volume measurement Rocking the filled vials before incubation Vial/Stopper washing, sterilization and depyrogenation Personnel involvement in filling validation

Validation Water for Injection system & its operation After all the equipment & piping has been verified as installed correctly & working as specified, Initial phase Develop operation parameters, cleaning / sanitization procedures & frequencies Sampling / Testing: Daily for 2-4 weeks At each step in purification process At each point of use Develop SOPs for WFI operation

Validation Water for Injection system & its operation Second phase Sampling / Testing Same as in Initial phase For additional 2-4 weeks Prove consistent water quality in compliance with SOPs

Validation Water for Injection system & its operation Third phase Sampling/Testing Routine frequencies WFI: daily for a minimum of one point of use tested weekly for all points of use tested Over a long period of time : full year Check seasonal variation Validation of WFI is completed when a full year’s data are obtained. Final validation report signed by operation & QA persons Prove that seasonal variation in feed water does not adversely affect water quality. Acceptance criteria

Validation Cleaning processes : General Validation protocol Sampling procedures Analytical methods Sensitivity of methods Acceptance criteria Revalidation Responsible persons for validation study Responsible persons for approving study Validation report SOP’s detailing the cleaning processes

Validation Cleaning processes : Evaluation Cleaning processes between batches of the same product Validation not required “Visibly Clean” Equipment design In the large equipment with CIP system sanitary type piping without ball valves should be used. The length of time between the end of processing and each cleaning step The drying of residues affects cleaning efficiency. Equipment should be dried before storage.

Validation Cleaning processes : Evaluation Analytical methods Sampling Determine the specificity & sensitivity. Sampling Direct surface sampling (swab method) Indirect sampling (rinsing) Efficiency of recovery Acceptable limit of residues Ensure the limit is scientifically justifiable.

Validation Cleaning processes : Establishment of limits NMT 10ppm of any product will appear in another product. NMT 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product. No quantity of detergent residue should be visible on the equipment after cleaning.

Validation Cleaning processes : Establishment of limits For certain allergenic ingredients, penicillins, cephalosporins, potent steroids & cytotoxics the limit should be below the limit of detection by best available analytical methods. In practice dedicated plants are used.

Validation A process is considered validated if : Validated support system Justified sampling plan for the product The process & product meeting specifications No deviations indicating a lack of process or product control Consistency of the process : meeting predetermined specifications

Sequence of Validation Support systems/processes HVAC, WFI/PW, Steam, Compressed air, Dust collection ∙∙∙∙ Cleaning, Sterilization, Depyrogenation, Decontamination ∙∙∙∙ Manufacturing Processes Critical production processes impacting on : Product quality Reproducibility of the process Parameters Range of variability Sampling Testing via validated methods Consistency : 3 consecutive batches (full production scale)

Laminar Flow Hoods (LFH) Laminar flow vs. Turbulent flow Laminar flow hoods Clean bench (booth) Biological safety cabinet Class Ⅰ Class Ⅱ type A1 Class Ⅱ type B1 Class Ⅱ type B2 Class Ⅱ type A2 Class Ⅲ

Note : O = protected , X = not protected Protection Product O X Personnel X O Environment X O Clean Bench BSC Class Ⅰ BSC Class Ⅱ type A1 Do. type B1 Do. type B2 Do. type A2 BSC Class Ⅲ Note : O = protected , X = not protected

Biological Safety Cabinet Class I BSC A = front opening B = work surface C = window D = exhaust plenum E = HEPA filter

Biological Safety Cabinet The Class II BSC (Type A1) A = blower B = rear plenum C = supply HEPA filter D = exhaust E = sash F = work surface

Biological Safety Cabinet The Class II BSC (Type B1) A = blowers B = supply HEPA filters C = sliding sash D = positive pressure plenums E = additional supply HEPA filter or back pressure plate F = exhaust HEPA filter G = negative pressure exhaust plenum H = work surface

Biological Safety Cabinet The Class II BSC (Type B2) A = storage cabinet B = work surface C = sliding sash D = lights E = supply HEPA filter F = exhaust HEPA filter G = supply blower H = control panel I = filter screen J = negative pressure plenum

Biological Safety Cabinet The Class II BSC (Type A2) A = front opening B = sliding sash C = light D = supply HEPA filter E = positive pressure plenum F = exhaust HEPA filter G = control panel H = negative pressure plenum I = work surface

Biological Safety Cabinet The Class III BSC A = stand B = glove ports C = O-ring for attaching arm-length gloves to cabinet D = sash E = supply HEPA filter F = exhaust HEPA filter (note: the second exhaust HEPA filter required for Class III cabinets is not shown in this diagram) G = double-ended autoclave or pass- through box (note: a chemical dunk tank may be installed which would be located beneath the work surface with access from above.)

LFH(HEPA filter) Testing Testing and certification HEPA-filtered air velocity measurement Leak test using DOP or PAO (Emery 3004) Particle count Air flow pattern Testing frequency 1×/ 6 months

LFH(HEPA filter) Testing Supply airflow velocity measurement At 6-12inches from the filter face At work level : 0.45±20% m/sec m2 → minimum 4 measuring points At least 1point/each filter outlet

LFH(HEPA filter) Testing Filter leak test (DOP or PAO) DOP challenge : 20-80μg/l Polydispersed aerosol of 0.1~3.0μ(m) (mean: 0.3~1.0μ) Acceptable criteria : ≤ 0.01% leak Repair (IEST) Area(filter) : ≤ 3% Dimension : ≤ 1.5 inches Filter scanning At 1-2 inches from the filter face With the speed of ≤ 1-2 inches/sec Sampling rate : ≥ 1 ft3/min