PMTC Knowledge Day 2017 August 31 st Cleaning validation hot topics. THOMAS ALTMANN. Global Technical Manager ECOLAB LIFE SCIENCES RD&E.

Transcription

1 PMTC Knowledge Day 2017 August 31 st 2017 Cleaning validation hot topics THOMAS ALTMANN. Global Technical Manager ECOLAB LIFE SCIENCES RD&E.

2 Cleaning validation hot topics. Overview Limit setting PDE approach for detergents? Visually clean Cleanability

3 Limit setting. Overview Limit discussion is ongoing since 1984 Practical / Achievable / Verifiable (FDA; PIC/S) Visually clean?

4 Limit setting. FDA recommendation 10 PPM htm PIC/S recommendation < 10 ppm of any product will appear in another product 1/1000 of the normal therapeutic dose < 0.1% of the normal therapeutic dose No residue No quantity of residue should be Remark: cleaning validation limits are set at 1/1000th of the minimum therapeutic dose

5 Limit setting. Limits we find today for APIs. Fixed values (e. g. 10 ppm) Threshold of toxicological concern (TTC) Dose based limits based on: therapeutic dose toxicological dose Analytical possibilities Visually clean? The objective is to scientifically justify why you set particular residual limits. (GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES published in

6 Limit setting. Limits for active ingredients Risk based approach to validation is recommended Guidelines on Good Manufacturing Practices: Validation, Appendix 7: Non-sterile Process Validation. WHO Technical Report Series, No. 992, 2015, Annex 3 (2015; 12 pages) Health-based risk assessment approach (Risk-MaPP, based on ICH Q9) Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities

7 Limit setting. ANNEX 15 ANNEX 15

8 Limit setting. Limits for active ingredients - risk-based approach

9 Limit setting. Acute toxcicity LD 50 Single exposure Lethal dose ; 50% of test organisims die Unit declared as mg/kg (bodyweight) Effect should occur within 14 days Lethal animal testing discussion OECD 401 (obsolete) Repeated exposure NOAEL Daily exposure for time period / lifetime No physical effect evident or occurring Units declared as mg/kg (bodyweight) /day Upto date and more applicable study

10 Limit setting. Limits calculated by conventional method and risk-based approach LD 50 and NOAEL values Substance LD 50 Wert [mg/kg] NOAEL [mg/kg(day)] Surfactant 2 > (rat, 90 d, gavage) Henkel 1990/91 Surfactant (HPV SIDS FND Amines Category) Soap component (rat, 90d, oral feed) HPV dossier Soap component 2 >2000 * > 3000 (rat, 2-16w, oral feed) BIBRA, Analogy to caprylic acid NaOH 500 gastric conversion to NaCl uptake negligible compared to food Phosphonate > (rat, 90d, oral feed) OECD SIDS, Analogy to acid Substance LD 50 Wert [mg/kg] NOAEL [mg/kg(day)] Organic Acid (rat, lifetime, drinking water) HPV dossier, analogy to calcium formate Organic Acid (rat, 90d, oral feed) OECD SIDS Phosphoric Acid (rat, 90w, oral feed) JECFA

11 Limit setting. Limits for active ingredients - risk-based approach

12 12 Toxicological Factors.

13 13 Toxicological Factors. ne/2009/10/wc pdf

14 Limit setting. Limits calculated by conventional method and risk-based approach COSA product LD 50 dose [mg/kg bodyweight] DNEL mix [mg/kg bodyweight] DNEL worst case substance [mg/kg bodyweight] COSA CIP COSA CIP COSA CIP COSA CIP COSA CIP COSA CIP COSA DES COSA PUR COSA PUR COSA PUR COSA PUR COSA PUR COSA FOAM COSA FLUX

15 Limit setting. Limits calculated based on acute toxicity (LD 50 ) - conventional method LD 50 -value for mixtures Schweizer formula LD %Substance 1 %Substance 2 %Substance 3... Substance Substance 2 50Substance 3 LD LD LD %Substance(X) = mass content of the component in the preparation [%] Literature: CLP Guideline (EG) No. 1272/2008

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17 Calculation example.

18 Limit setting. Summary There are different possibilities to calculate limits for cleaning agents Calculated no effect levels based on LD 50 values are very conservative! Fixed / pre-defined levels like 10 ppm or TTC are in the same range as values calculated based on LD 50 values

19 Cleaning validation hot topics Overview Limit setting PDE approach for detergents? Visually clean? Cleanability

20 Coupon 1 Coupon 2 Coupon 3 Coupon 4 Visually clean. VISUAL INSPECTION Station 1 Different material Basic information of construction have a different apperance when visually clean. Operators have to be trained to be Question aware as to.. "What does visually Coupon clean visual look clean? like?" Please evaluate if the coupons (made of different materials) are visually clean. Use your own opinion and experience to judge if a coupon is visually clean or not! Remark: Always wear gloves by handling the coupons! Do not remove coupons out of the tray

21 Visually clean API powder materials Clean Clean Clean Clean Clean Clean Clean Clean Clean Clean Clean Clean ~ 400 µg/100cm² (~4µg/cm²) Frank Buscalferria, Dr. Sabine Lorenzenb, Dr. Michael Schmidt, Dr. Hans-Martin Schwarmd, Dr. Ehrhard Anhalte, Dr. Reinhard Herzoga und Prof. Ronald Zieglera Bestimmung der Sichtbarkeitsgrenzen von pharmazeutischen Feststoffen auf Edelstahloberflächen [Pharm. Ind. 62 Nr. 6 (2007)]

22 1µg/cm² 10µg/cm² Different detergents applied to stainless steel surfaces. Demin water Acid detergent 1 Acid detergent 2 Alkaline + Surfactants Alkaline detergent

23 Visually clean Visibility of detergents. For different COSA product concentrates we can state An amount of 1 µg/cm² can be detected visually Concentrations of 1µg/cm² show spots on surface Concentrations of 10µg/cm² show different appearances (depending on the product applied)

24 Cleaning validation hot topics. Overview Limit setting PDE approach for detergents? Visual clean Cleanability

25 Cleanability.

26 Cleanability studies- examples. Support to decide on which is the right cleaning procedure for specific processes and products. The two most common procedures for the evaluation are: Solubility test Mostly used for tablets and solids or for pre-testing Dipping test Mostly used for ointments or liquids

27 Cleanability studies- examples. Solubility test Is a detergent solution able to dissolve the residue? Physical aspects e.g. is the solution getting more viscous with addition of chemistry Chemical aspects e.g. Is there reaction with the residues and the detergent?

28 Cleanability studies examples. 28 Cleaning recommendation Cleaning evaluation All cleaning recommendation are proposals and based on solubility of residues in the correct chemistries/detergents. Cleaning optimisation in terms of time, temp, mechanical action & final chemical concentration will need to be determined & validated on site.

29 29 Cleanability studies examples. Temperature Concentration

30 Cleaning validation hot topics Thank you for your attention. Any Questions? Please find ECOLAB out in the foyer area.

31 List of abbreviations ADI Acceptable Daily Intake ADE BW DNEL NOAEL NOEL MACO PDE SF TTC UF Acceptable Daily Exposure Body Weight Derived No Effect Level No Observed Adverse Effect Level No Observed Effect Level Maximum Allowable Carry-Over Permitted Daily Exposure (=DNEL*weight adjustment) Safety Factor Threshold of Toxicological Concern Uncertainty Factor