Regulatory and Requirements
FDA, July 1993
Guide to inspection for validation of cleaning process
Application regulation and requirements: 21CFR 211.65, 21CFR 211.67
Written cleaning procedure,21 CFR 211.182
Reference Cleaning and cleaning validation: A biotechnology
perspective, pub PDA, 1996 www. cleaningvalidation.com Guidance on aspects of cleaning validation in active
pharmaceutical ingredient plants, APIC, 2000
1) Cleaning validation an exclusive publication,
2) J of validation technology: Cleaning validation II pub by Inst. of Validation Technology
Cleaning Validation Overview 목적 : Product: purity, safety, efficacy, quality 유지 Product:cross contamination, previous residual product,
microbial residue, detergent, degradant 잔류 방지
언제 Cleaning validation 실시 ? New equipment/product Changed : 생산 process, cleaning process, 세척제 Changed : major component
Cleaning validation Overview Good system design Master validation plan Preliminary study - Coupon study - Cycle Development study - Continuous data monitoring - Justifiable acceptance criteria Effective cleaning process development Adequate analytical technique
Master Validation Plan
Appropriate cleaning procedure Identification of cleaning agent Description of sampling procedure Acceptance criteria Analytical method A copy of protocol and final report A list of equipment Manufacturing process( a flow diagram)
Master Validation Plan CIP or COP Equipment matrix for CV Description of equipment and its location Surface area of equipment Average batch size of each equipment Training program for production and analytical personnel Reference to the company’s change control program
Sampling Procedure
Sampling SOP Rinse or swab(surface) sampling Rinse sampling: volume, valve define Swab sampling: map of each equipment
the most-difficult-to-clean, easy-to-clean
“Easy-to-clean”: cleaning failure 확인
Sampling Location for Swab
No Description Sampling time 1 1번 Impeller 상
2 2번 Impeller 상
3 2번 Impeller 하
4 Shaft
5 벽면 1
6 벽면 2
7 Sparger 하
8 P01 valve 부위
9 Sparger 상
10 배양액 경계벽면
11 P09 line 옆 벽면
12 발효조 상부
6
P 01
1
2 3
4
5
7 8
9
10
11
12
6
Product/Cleaning Agent 관계 Molecular structure (Bio product or small
molecule) Prod related compound Solubility: in water or in org. solvent? Reactivity Contaminant: Fluid or Solid? Cleaning agent selection
Coupon Study Coupon: Equipment 와 동일 surface type SUS or
Glass (5 x 5 cm, 10 x10 cm) Swab: polyester Characterization of residue Worst case of cleaning condition Selection of cleaner visually clean Cleaning condition 설정 : temp. range, cleaning
agent conc., pressure(agitation, shaking), rinse volume visual inspection
Swab Test / Swab Recovery Swab method: sample, control and blank test
Spiking of known quantity of analyte/residue Swab recovery test (70~130%) recovery
factor CV 실시 시 반영 Estimation of swab sample solution stability Estimation of swab extraction time Residue limit TOC/prod specific
Cycle Development Study Performed prior to process validation Characteristic of residuals Cleaning agent select and concentration Rinse cycle time and volume Cleaning agent temperature CIP-Pressure (Turbulence) Cleaning procedure development Cleaning-SOP change or improve Continuous data monitoring Acceptance limit Operator training 및 training report
Cleaning SOP
Cleaning procedure development (SOP 정량화 )
Pre-rinse: volume, pressure Soaking: alkaline/acid, organic solvent or other
detergent volume, temperature, soaking time Rinse recycle: time, temperature Rinse volume, pressure end point Final rinse volume, pressureend point End point 측정 : conductivity, pH
Equipment ValidationCIP 설비의 validation status 확인
IQ: requirement of safety, utility, installation and documentation, accuracy of P&ID etc.
OQ: Test of flow rate, volume of washes and rinses, temperature(inlet/outlet), turbulence, heating time of cleaning solution, gas flow, purges
Spray ball: coverage study
Coverage Study (CIP)
P 01
Milk powder visual
Rivoflavin UV detection
Pressure
Visual detection
Photo documentation
Equipment System Design
Consideration of CIP system for effective cleaning
Piping size 와 구조 (slope) Potential dead leg Turbulence of CIP solution Nozzle design: locate seal near vessel wall Branch piping
Instrument Tees Instrument Tee for CIP: L/D <1.5
DL
½ ft/sec 5 ft/sec 5 ft/sec
Adequate turbulence (Flow rate) for CIPAdequate turbulence (Flow rate) for CIP
Bad Good Best
<Cleaning and cleaning validation: A biotechnology perspective, pub PDA, 1996>
Dead Leg Orientation
Branch piping : horizontal
Good Design
Vertical up
Vertical down
horizontal
Bad design
<Cleaning and cleaning validation: A biotechnology perspective, pub PDA, 1996>
Recommended Drain Line Size
Drain line: locate vessel drain high enough to slope down to CIP return pump
- 100L tank: 1.0 inch
- 1,000L tank: 1.5 inch
- 10,000L tank: 2.0 inch
Sampling valve: Diaphram valve Design: CIP visually 확인 가능한 설계 Cleaning and cleaning validation: A
Acceptance Criteria Visually clean Cleaning capability Sample test time limit Cleaning time limit: DEHT, CEHT Number of batches: 3consecutive batch Deviation handling Allowed contaminant limit - General limit - Maximum daily dose - Toxicity based carry over
Allowable Contaminant Limit General ppm Limit:toxicological data for intermediate
are not known, API product 에 적용
MACOppm= MAXCONC x MBS
MACOppm: maximum allowable carry over from previous product, calculated from general ppm limit
MAXCONC:general limit for maximum allowed concentration of “previous” substance to next batch
MBS: Minimum batch size for the next product
Allowable Contaminant Limit
General ppm limit MAXCONC is often set to 5~100ppm depending on toxicity and
pharmacological activity
MAXCONC for API : 10ppm is very frequent
계산 예 : MBS of next product: 200kg
MACOppm= 0.00001(mg/mg) x 200 000 000 (mg) = 2000 (mg)
<Ref: APIC 2000: cleaning validation guidance>
Allowable Contaminant Limit
Identity No 계산 단위 EL- 101 EL101 ET- 101
Capacity 350L ~ET101 150L
① 처리량/Batch [kg/B] 350 3.08 150
② 처리 Batch수 [B/Lot] 6 6 6
③ 처리량/Lot ① x ② [ug/Lot] 2.10E+12 1.85E+10 9.00E+11
④ Surface area [cm2] 53128 10977 41716
⑤ Carryover 10x10- 6[ppm] 1.00E- 05 1.00E- 05 1.00E- 05 1.00E- 05
⑥ Coupon area 25[cm2] 25 25 25
⑦ MACO/swab ⑤x(③/④)x⑥ ug/swab 9882 421 5394
⑧ MACO/equip ⑦x④/(25 x1000) [mg] 21000 185 9000
General limit (10ppm carry over) for swab area 10mg/kg x MBS(kg)/equipment surface area x Swab area
Allowable Contaminant Limit
Based on Therpeutic Daily Dose MACO= TDDprev x MBS/SF x TDDnext
- MACO: Maximum allowable carry over - TDDprev: Std therapeutic dose of inv. prod - TDDnext: Std therapeutic daily dose for next prod - MBS: Minimum batch size for next prod - SF: Safety factor (normally 1000 in calculations
based on TDD) <Ref: APIC 2000: cleaning validation guidance>
Allowable Contaminant Limit Based on Toxicological Data NOEL= LD50(g/kg) x 70kg/2000 MACO= NOEL x MBS/SF x TDSnext - NOEL: no observed effect level - 2000: an empirical constant - TDSnext: Largest normal daily dose for next prod - Safety factor : parental: 1000~10000 oral prod: 100~1000 topicals: 10~100
<Ref: APIC 2000: cleaning validation guidance>
What is being removed
Active ingredient Decomposition product of active ingredient Microbial contamination Endotoxins Sanitizing agent Lubricant Environmental dust Residual rinse water
Type of Analytes Proteins: active, inactive but intact, fragmented protein, as
contaminating intra-/extra cellular protein
Organic comp: cellular comp. DNA, RNA, endotoxin, carbohydrate, lipid, other org compound
Inorganic comp: process-/medium component, detergent
Biol contaminat: mycoplasma, viral, bacterial, non viral host bacteria
Specific Assays Cytotoxicity: to verify the detoxification of bacterial
toxin by heat inactivation
Immunoassay: ELISA, specific but poor reproducible
HPLC: protein, peptide, nucleic acid, small molecules accuracy, reproducibility, recovery rate very good, 1~2% SD
PAGE: specificity is limited to protein size
Non-Specific Assays TOC: Determination of various compound or
compound class 연소산화 (Pt)/ 습식산화 (uv induced) CO2NDIR 측정 by 1700cm-1
Colorimetric protein assay: binding to dye(Blue G250), determine spectrophotometrically by 595nm
Coductivity: simple and effective for measurement of residual inorganic material
pH, UV/VIS TDS(Total dissolved solids)
Category of Analysis
Type of analyte AssaysProtein Bioassay, ELISA, HPLC
PAGE, Absorbance, TOC
Org compound TOC, HPLC, UV-Abs., TDS
Inorg compound Conductivity, pH,
o-Phosphate, ICP, TDS
Biol Systems Viable cell analysis
Commonly used anal. Method for biopharm.Contaminants and Impurities
Impurities and Contaminants
TOC HPLC ELISA PAGE Lowry Protein
LAL Ion- Exchange
Media + + - + + - + Metabolites + + - - - - + Endotoxin + - - - - +
DNA/nucleic acid + - + - - - + Carbohydrates + + + - - - +
Lipids + + + - - - + Proteins Native
Denaturated
+ +
+ +
+ -
+ -
+ +
- -
- -
Stabilizers + + - - - - + Cleaning agent
Organic Inorganic
+ +
+ -
- -
- -
- -
- -
+ +
J. of Parental Science & Technology, 13-19(45), 1991
Analytical Method Validation
ICH Q2A/Q2B Accuracy Precision Linearity and Range Specificity (no need to perform by TOC-method) LOD/LOQ Intermediate precision Sample solution stability Allowable acceptance limit > LOQ
Cleaning Validation Protocol Objective Scope Reference inclusive SOP Responsibility Material and method Procedure Acceptance criteria: training, deviation, batch, ….. Work sheet/equipment: cleaning procedure, raw
data record, sampling, analytical procedure, etc.
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