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Cleaning Validation

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  1. Cleaning Validation Eun-Sook Gi April 12, 2004 ㈜ 삼양제넥스 생명공학 연구소

  2. 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

  3. 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

  4. 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

  5. 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

  6. 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)

  7. 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

  8. 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

  9. Sampling Location for Swab

  10. 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

  11. Coupon Study • Coupon: 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 visualinspection

  12. 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

  13. 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

  14. 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, pressureend point • End point 측정: conductivity, pH

  15. 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

  16. Coverage Study (CIP) • Milk powder visual • Rivoflavin UV detection • Pressure • Visual detection • Photo documentation

  17. 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

  18. Instrument Tees • Instrument Tee for CIP: L/D <1.5 D L Bad Good Best Adequate turbulence (Flow rate) for CIP 5 ft/sec ½ ft/sec 5 ft/sec <Cleaning and cleaning validation: A biotechnology perspective, pub PDA, 1996>

  19. Dead Leg Orientation • Branch piping : horizontal Vertical up Bad design Vertical down Good Design horizontal <Cleaning and cleaning validation: A biotechnology perspective, pub PDA, 1996>

  20. 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

  21. 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

  22. 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

  23. 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>

  24. Allowable Contaminant Limit General limit (10ppm carry over) for swab area 10mg/kg x MBS(kg)/equipment surface area x Swab area

  25. 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>

  26. 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>

  27. What is being removed • Active ingredient • Decomposition product of active ingredient • Microbial contamination • Endotoxins • Sanitizing agent • Lubricant • Environmental dust • Residual rinse water

  28. 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

  29. 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

  30. Non-Specific Assays • TOC: Determination of various compound or compound class 연소산화(Pt)/습식산화(uv induced) CO2NDIR측정 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)

  31. Category of Analysis Type of analyte Assays Protein 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

  32. Commonly used anal. Method for biopharm.Contaminants and Impurities J. of Parental Science & Technology, 13-19(45), 1991

  33. 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

  34. 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.

  35. Cleaning Validation Report • Introduction • Summary:method • Results: table • Conclusion • Recommendation • Appendices: analytical raw data, chromatogram, etc.