Analytical Method Validation
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Transcript Analytical Method Validation
Cleaning Validation
Eun-Sook Gi
April 12, 2004
㈜ 삼양제넥스 생명공학 연구소
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 failure확인
Sampling Location for Swab
No
1
Description
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
Sampling time
12
11
10
6
6
4
2
3
5
1
9
7
8
P01
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
Equipment와 동일surface 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
Coupon:
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 (SOP정량화)
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 Validation
CIP 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)
Milk powder visual
Rivoflavin UV detection
Pressure
Visual detection
Photo documentation
P01
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
L
D
Bad
Good
Best
Adequate turbulence (Flow rate) for CIP
½ ft/sec
5 ft/sec
5 ft/sec
<Cleaning and cleaning validation: A biotechnology perspective, pub PDA, 1996>
Dead Leg Orientation
Branch
piping : horizontal
Vertical up
Bad design
Vertical down
horizontal
Good 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 product에 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
General limit (10ppm carry over) for swab area
10mg/kg x MBS(kg)/equipment surface area x Swab area
Identity No
계산
단위
Capacity
EL-101
EL101
ET-101
350L
~ET101
150L
① 처리량/Batch
[kg/B]
350
3.08
150
② 처리 Batch수
[B/Lot]
6
6
6
[ug/Lot]
2.10E+12
1.85E+10
9.00E+11
[cm2]
53128
10977
41716
1.00E-05
1.00E-05
1.00E-05
1.00E-05
25[cm2]
25
25
25
③ 처리량/Lot
① x ②
④ Surface area
⑤ Carryover
10x10-6[ppm]
⑥ Coupon area
⑦ MACO/swab
⑤x(③/④)x⑥
ug/swab
9882
421
5394
⑧ MACO/equip
⑦x④/(25 x1000)
[mg]
21000
185
9000
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) CO2NDIR측정 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
Protein
Org compound
Inorg compound
Biol Systems
Assays
Bioassay, ELISA, HPLC
PAGE, Absorbance, TOC
TOC, HPLC, UV-Abs., TDS
Conductivity, pH,
o-Phosphate, ICP, TDS
Viable cell analysis
Commonly used anal. Method for
biopharm.Contaminants and Impurities
Impurities and
Contaminants
TOC
HPLC
ELISA
PAGE
Lowry
Protein
LAL
IonExchange
Media
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Metabolites
Endotoxin
DNA/nucleic acid
Carbohydrates
Lipids
Proteins
Native
Denaturated
Stabilizers
Cleaning agent
Organic
Inorganic
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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.
Cleaning Validation Report
Introduction
Summary:method
Results:
table
Conclusion
Recommendation
Appendices: analytical raw data,
chromatogram, etc.