1 / 35

Cleaning 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.

ankti
Download Presentation

Cleaning Validation

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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.

More Related