Module #2 Risk Assessment, Hazard Identification, Residue Limits

Transcription

1 Module #2 Risk Assessment, Hazard Identification, Residue Limits Hazard Categories: Chemical, Microbiological, Equipment Design and Procedural Hazards (SOPs) History and Analysis of Acceptance Limits Applying Health Based Exposure Limits (PDE, ADE) with case studies New Toxicity Score CASE STUDY Equipment and Process Evaluation

2 ASTM E Cleaning Risk Assessment 6.5 Risk Identification Process residue hazards -Microbiological -Chemical Equipment design hazards Procedural hazards.

3 ICH Q9 Quality Risk Management (June 2006) C. Risk Assessment (4.3) Quality risk assessments begin with a well-defined problem description or risk question. What types and levels of batch-to-batch residue are required to keep cross contamination below health based exposure limits AND below levels that would impact other quality attributes AND be visually clean? Risk identification is a systematic use of information to identify hazards referring to the risk question or problem description. Risk analysis is the estimation of the risk associated with the identified hazards. It is the qualitative or quantitative process of linking the likelihood of occurrence and severity of harms. In some risk management tools, the ability to detect the harm (detectability) also factors in the estimation of risk.

4 ICH Q9 Quality Risk Management (June 2006) Definitions: Harm: Damage to health, including the damage that can occur from loss of product quality or availability. Hazard: The potential source of harm (ISO/IEC Guide 51). Detectability: The ability to discover or determine the existence, presence, or fact of a hazard.

5 Risk? What harm or effect? To End-User: Risk of harm from using product or device Loss of Efficacy or benefit potency, stability, functionality, bioavailability Loss of safety (Adverse effect) Infection; Toxicity- acute, chronic; irritation; Biocompatibility To Product: Risk of defect to design or quality attribute that causes harm or reduces benefit In Production Process: Risk of deviation that leads to defect What is the source of the harm (=hazard)? Residues from prior batch Product related- API, ingredients, degradants, water Process related- micro, detergents, process aids, facility dirt, water

6 Methods, Tools & Equipment Bioactive Residue A Surface (μg/cm2); Rinse (mg/l); Input Starting Materials Drug Substance, Excipients; Quality, Composition (Container/closure, packaging) Media, agents, consumables System Y Conditions, Parameters Power, pressure, Temp, flow, rpm, concentration, timing, position Mfg. Process X Proceduresequence, duration, interval, control Output Product B Quality Attributes Quality, strength, Composition Bioactive Residue A levels (μg/g) Product Realization Product B Profile, Properties -Route of administration; -API Pharmacology, Pharmacokinetics; -API Toxicity -Dose Physicochem stability, convenience, esthetics ADE to Any Impurity Toxicity or Bioactivity

7 Risk = f (Severity of a Hazard, Level of Exposure to That Hazard) If the hazard is intrinsic to a residue (ingredient, detergent, API)) then this general equation can be further refined to: Risk = f (Toxicity Res, Level of Exposure) Exposure to prior batch residue A depends on the use pattern of product B Risk = f (Toxicity ResA, Level of Exposure to B ) How do we calculate/estimate toxicity of residue (adverse effect)? A Process Capability-Derived Scale For Assessing The Risk Of Compound Carryover In Shared Facilities; Cleaning Validation for the 21 st Century series; Pharmaceutical Online; August 9, 2017

8 Cleaning Validation Design Space, Two product system Facility, Systems, Tools, Equipment DHT, Starting Conditions Quality, Composition Media, agents, consumables Methods, Conditions, Parameters (CPPs) Pressure, Temp, flow, rpm, concentration, timing, position Cleaning Process X System Y Output CQAs, Attributes Surface Quality, Proceduresequence, duration, interval, control residues, bacteria Bioactive Residue A, B Surface (μg/cm2); Rinse (mg/l);

9 Bioburden Cleaning Prerinse Wash Rinse Storage Min Process B Max Min Max Cfu/g Start Start B Cfu/cm2

10 Equipment/Residue Evaluation and Risk Matrix For a given operation, identify and evaluate the starting materials, products, processing materials, degradants (residue matrix)? Physical properties; Chemical properties Pharmacology, toxicity, Biological activity- ADI/ADE Composition, purity, formulation Batch size What equipment is used for each product, what process steps, what interconnections or points of contact between product batches? (equipment/residue matrix) How many cleaning processes for each piece of equipment? For a given product? For a product changeover?

11 Compile Process Residue Hazard Data Residue ADE μg/day Wt % Residue Daily Exposure Drug,Biological API A API B, API C Starting Materials Degradants Excipients/Inerts Process Aids Cleaning agents Microbiological/Endotoxin

12 History of Industry Practices and Misconceptions Residue Risk = MAC (or MACO) = 1/1000 dose, or 10 ppm Process Development = First SOP that works Cleaning Validation = passing swab samples

13 Limits Approach for two product system Maximum Allowable level in next product a. 10 mg A/kg B (10 ppm) b. (1/1000)LDD A /MDD B)= μg A/ daily dosage rate B 2. Total amount of residue allowed in equipment ( Maximum Allowable Carryover or MAC ) a. (μg A/day)/( daily dosage rate B) X batch size B total daily dose units= mg A b. 10 mg A/kg B X smallest batch size B kg 3. ARL-Acceptable Residue Level = MAC/shared surface area= μg/cm2.001 dose(μg) A g/(dose B-day) A batch B A A A

14 Lilly Case: 1993 Fourman & Mullen Article Pharmaceutical Technology, 17(4),54-60 (1993) Limits for Multiple Oral Solids in shared equipment train surface area in common Limits based on multiple criteria Dose Criteria (1/1000 dose A> dose Purity criteria (10ppm A>B) Visual (100 mcg/4 sq.in.) PharmaceuticalTechnology, 17(4),54-60 (1993)

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17 Lilly Case: Dose A>B: (0.001)I/J x K/L x M 10 ppm A>B: 10 x S/L x M ADE mcg/day A B C D E J= 1 J= 6 J= 3 J= 4 J= 8 K= K= K= K= K= S= 16 kg S= 13 kg S= 36 kg S= 15 kg S= 26 kg A mg/day B C D E I = dose strength A; J= doses/day B K=Batch size B (dose units); S= kg /batch B L= common surface area (in2); M= sample area (in2/swab)

18 Lilly Case: Multiple Products?Multiple Equipment? Residue/Equipment Matrix Screen Mill Blender Press Coater 2000 in in in in 2 in 2 A X X X B X X X C X X X X D X X E X X X

19 1992 Quantitative Basis for Limits Patient/Consumer Health Risk: Stated in terms of Dosage, Exposure, Toxicity, Potency, Irritant; Allergenic ADI=Acceptable Daily Intake =NOEL(or other data)(mg/kg-day) x BW (kg)x SF x MF NOEL= No Observable Effect Level NOAEL= No Observable Adverse Effect Level LOAEL= Lowest Observable Adverse Effect Level SF = Safety Factor, MF= Modifying Factor, BW= Body weight Amount of drug residue in mg/day a person can be exposed to as a contaminant in another product without causing adverse health effects or pharmacological effects.

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22 Health Basis for Limits (1992) ADI= SF X Dose (based on dosage) X BW X MF 1/100-1/1000 Lowest Toxic Dose (TDL 0 ) or standard therapeutic dose (STD), or lowest daily dose (LDD) ADI=SF X NOEL,NOAEL,LOEL, LOAEL X BW X MF 1/100 No Observed Effect/Adverse Effect Level 1/100 Lowest Observed Effect/Adverse Effect Level ADI=LD50 x SF x BWX MF(modifying factor) LD50 = residue dose in mg/kg body weight of test animal that is lethal to 50% of the test subjects 1/10-1/100 Lowest Toxic Dose (TDL 0 ) X MF (1-1/10) 1/100=1/1000 LD50 or Lowest Lethal Dose (LDL 0 ) X MF (1-1/10)

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24 What if there is no significant health risk from Batch 1(Drug A) into Batch 2 (drug B)?? No-Risk level of Drug A in next product B? Example: ADI=NOEL Drug A/100 X 50 kg =1 mg per day Use of Drug B? Maximum daily dose =10 mg API B/day Allowable concentration of A in B? 1mg A/day 10 mg API B/day= 10% A>B(100,000 ppm!) ADI Drug A dose B, 10 mg API/day 1 mg per day

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26 Residue Carryover Risk Batch 1 into Batch 2 Harm to consumer of Batch 2 (Health Based) Risk of defect in Batch 2 (Quality Based) Purity, dilution, specifications, GMP Functionality- dissolution, solubility, hardness Aesthetics- color, fragrance Quality/Purity Criteria- The amount of API A or formula A or residue from Batch A that would cause quality defect in Batch B

27 PIC-S, 2007

28 Approach- Decision Tree: a. Calculate Health Based Limit of A> B using (1/1000) LDD as estimate of ADI Max. Daily dose B as estimate of daily exposure Low dose products have lower ADI Limit depends on dosage per day of next product Low dose followed by high daily uptake drives down allowable level of A in B b. Calculate quality based limit A>B as 10 mg A/kg B (10 ppm) c. Use lower of ADI based a. or 10 ppm base b. as max level of A in B d. Using batch size of B, and limit of A, calculate the total amount of A that can be left in the equipment (MAC) e. Using common surface area of the equipment used for A and B, determine the allowable surface concentration of A (ARL) f. Compare ARL to visible residue levels and use lower level as surface criteria

29 Experience? Determining Criteria? Typical ARL 1/1000 LDD criteria 5-10% >50 μg/cm2 10 ppm criteria 10-15% 5-50 μg/cm2 Visually clean criteria 75-80% >1-10μg/cm2

30 2010 ISPE-Risk MaPP Risk Based Manufacturing of Pharmaceutical Products (ICH Q9) MAC approach, 1/1000 dose, 10 ppm criteria are arbitrary, should be dropped Cross Contamination Risk- health based ADE- Acceptable Daily Exposure STV-Safety Threshold value 2014 EMA Guideline on Health Based Exposure Limits Cross Contamination Risk- health based PDE- Permissible Daily Exposure Use ADE or PDE?

31 EU EMA- permitted daily exposure (PDE) PDE represents a substance-specific dose that is unlikely to cause an adverse effect if an individual is exposed at or below this dose every day for a lifetime. Determination of a PDE involves (i) hazard identification by reviewing all relevant data, (ii) identification of critical effects, (iii) determination of the no-observed-adverse-effect level (NOAEL) of the findings that are considered to be critical effects (iv) use of several adjustment factors to account for various uncertainties.

32 EU EMA- permitted daily exposure (PDE) Appendices 3 of the ICH Q3C and VICH GL 18 guidelines present the equation for the derivation of the PDE: following F1: A factor (values between 2 and 12) to account for extrapolation between species F2: A factor of 10 to account for variability between individuals F3: A factor 10 to account for repeat-dose toxicity studies of short duration, i.e., less than 4-weeks F4: A factor (1-10) that may be applied in cases of severe toxicity, e.g. nongenotoxic carcinogenicity, neurotoxicity or teratogenicity F5: A variable factor that may be applied if the no-effect level was not established. When only an LOEL is available, a factor of up to 10 could be used depending on the severity of the toxicity.

33 Risk = f (Toxicity ResA, Level of Exposure to B ) ADE Hazard severity relates to the toxicity of Residue A Exposure relates to the use pattern of Product B

34 Limits Approach for two product system MAC MSC-Maximum Safe Carryover in next product =(1/1000 LDD mcg A/day)/max daily dosage rate B =(ADE μg A/day)/max daily dosage rate B ADE μg A =mcga/g B=ppm 2. MAC Total amount of residue allowed in equipment (MSC Equipment) prior to the next batch (μg A/ daily dose g B X batch size B)=mg A ARL MSSR Maximum Safe Surface Residue Equipment surface limit = MAC MSC/equipment surface area = mcg/cm2 A A mg/dose B-day A batch B A

35 Terminology for the same thing?: Acceptable Daily Intake (ADI) Acceptable Daily Exposure (ADE) Permitted Daily Exposure (PDE) Health Based Exposure Level (HBEL) μg A/day Maximum Allowable Carryover (MAC, MACO) Maximum Safe Carryover (MSC) Acceptable Residue Level (ARL); Maximum Safe Surface Residue (MSSR) μg A/day mg B/day) μg A/mg B x kg B μg A/cm2

36 Approach- Decision Tree: a. Calculate Health Based Limit of A> B using ADE (1/1000) LDD as estimate of ADI Max. Daily dose B as estimate of daily exposure Low ADE dose followed by high daily uptake drives down MSC allowable level of A in B b. Calculate quality based limit A>B as 10 mg A/kg B (10 ppm) c. Use lower of ADI based a. or 10 ppm base b. as max level of A in B d. Using batch size of B, and MSC limit of A, calculate the total amount of A that can be left in the equipment (Equipment MAC MSC) e. Using common surface area of the equipment used for A and B, determine the allowable surface concentration of A (ARL MSSR) f. Compare ARL MSSR to visible residue levels and use lower level as surface criteria

37 Experience? Lowest Determining Criteria? HBEL/ADE Criteria 5-10% Arbitrary 1/1000 LDD criteria >90% Visually clean criteria 75-80% (1-10μg/cm2)

38 Comparison of Permitted Daily Exposure with Minimal Daily Dose for Cleaning Validation In this study, the authors investigated the relationship between the MinDD and the PDE values for 140 drug substances as an attempt to identify high-risk groups of products for patient safety. May 02, 2017Pharmaceutical Technology; Volume 41, Issue 5, pg 42 53

39 An ADE-Derived Scale For Assessing Product Cross-Contamination Risk In Shared; Cleaning Validation for the 21st Century series; Pharmaceutical Online May 22, 2017; By Andrew Walsh; Ester Lovsin Barle, Ph.D.; Michel Crevoisier, Ph.D.; David G. Dolan, Ph.D.; Andreas Flueckiger, MD; Mohammad Ovais; Osamu Shirokizawa; and Kelly Waldron Dioxin, ADE 35 pg/day (tox score 10.5). arsenic trioxide, ADE 13 µg/day (tox score 4.9) aspirin, ADE 5 mg/day (tox score = 2.3) sodium chloride, ADE 26 mg/day (tox score = 1.6)

40 A Large-Scale Study Demonstrating The Toxicity Scale Concept In our previous article 3, the ADEs of 304 APIs were compared to their dose-based limits as a demonstration of how inaccurate and overly conservative the dose-based approach is in estimating safe levels for exposure in patients, which could lead to impractical and unachievable limits. >10μg/day <10μg/day An ADE-Derived Scale For Assessing Product Cross-Contamination Risk In Shared; Cleaning Validation for the 21st Century series; Pharmaceutical Online May 22, 2017;

41 An ADE-Derived Scale For Assessing Product Cross-Contamination Risk In Shared; Cleaning Validation for the 21st Century series; Pharmaceutical Online May 22, 2017;

42 ASTM E Risk Identification Process residue hazards Equipment design hazards? Potential hazards presented by equipment design should also be considered, such as the possibility of product buildup. Equipment should be designed to facilitate cleaning, inspection, and monitoring Procedural hazards?. Before use, cleaning procedures should be subjected to risk assessments, for example, cleaning FMEA or other risk management tools, to minimize risk of failure (for example, to ensure that product buildup is avoided), improve the cleaning procedures, and make the cleaning procedures more reliable and robust.

43 Equipment/Residue Process Evaluation and Matrix For a given operation, identify and evaluate the starting materials, products, processing materials, degradants (residue matrix)? Physical properties; Chemical properties Pharmacology, toxicity, Biological activity- ADI/ADE Composition, purity, formulation Batch size What equipment is used for each product, what process steps, what interconnections or points of contact between product batches? (equipment/residue matrix) How many cleaning processes for each piece of equipment? For a given product? For a product changeover?

44 Contamination Sources Microbial, Particulate and Chemical INDIRECT Workers Air Environmental surfaces Process Equipment DIRECT Workers Air Container/Closure Product contact surfaces Product

45 Identify the Nature of the Process and Equipment: Simple Process Size? Scale? Complex use? (90 APIs!)

46 Contamination Control and Process Strategies- Risk Management Disposables/ single use surfaces Multi-use surfaces Dedicated vs. multi-product A1>A2>A3>.A n A>B>C>D vs. B>D>A>C vs. C>A>D>B, etc. Campaign vs. changeover A1>A2>A3>.A n >> B1>B2>B3 >.B n

47 Complex Process Simple use? SA= 8,000 cm2 SA= 14,000 cm2 SA= 6000 cm2 SA= 4,000 cm2

48 PRODUCT Surface Area OIL PHASE WATER PHASE MIX TANK RECEIVER TANK FILLER API 1 CREAM O API X X API 2 CREAM O API X X X API 3 OINTMENT X X X API 4 OINTMENT O API X X X API 4 GEL API X X X API 5 GEL O X X X API 6 OINTMENT X X X API 7CREAM API X X API 8 OINTMENT X X X API 9 GEL O API X X X

49 Residue Carryover Risk Batch 1 into Batch 2 All surfaces are not the same! Knowledge of Equipment Design & Nature of Process Concentration or dispersion of contamination Hot spots -hard-to-clean Transfer of contamination -Common surface area in direct contact Critical sites, concentration points-filling Inspection, sampling and detection reliability

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52 Case: 1993 Fourman & Mullen Article Pharmaceutical Technology, 17(4),54-60 (1993) Limits for Multiple Oral Solids in shared equipment train surface area in common Limits based on multiple criteria Dose Criteria (1/1000 dose A> dose Purity criteria (10ppm A>B) Visual (100 mcg/4 sq.in.) PharmaceuticalTechnology, 17(4),54-60 (1993)

53 Lilly Case: Multiple Products?Multiple Equipment? Residue/Equipment Matrix Screen Mill Blender Press Coater 2000 in in in in 2 in 2 A X X X B X X X C X X X X D X X E X X X

54 Cleaning Process Strategies Blender- Five Products How many cleaning procedures? How many OQ/coverage studies? How many PQ studies? How many analytical methods?

55 SOPs Challenge Products Cleaning Methods OQ PQ Analytical Methods

56 Cleaning Process Evaluation and Strategies One Universal SOP/cycle fits all Multiple, unique SOPs multiple methods, agents, cycles Grouped SOPs one method, time / sequence variations one method, cleaning agent variations Grouping is simply a common Process and common acceptance criteria for designated products in a piece of equipment (avoid the solubility trap )

57 Cleaning Validation Purpose? To provide documented evidence that cleaning process X consistently cleans Product A, (then B, C, D, E) from equipment Y to predetermined acceptance criteria for Product A, (then B, C, D, E)

58 ASTM E Grouping Strategies A group is a collection of products or equipment that share a common cleaning design space and a common cleaning procedure to minimize cleaning process performance studies and reduce the number of runs and samples required. Such a group may must also share a common cleaning control strategy. Any groupings should be scientifically justified based on a risk assessment and from knowledge gained from cleaning development studies. Groupings may also be used as the basis for factors in a DoE Group Design Space? The same CQAs(A/C), CPPs, SOPs

59 Cleaning Validation PPQ Purpose To provide documented evidence that cleaning process X consistently cleans equipment Y to a common predetermined acceptance criteria, that applies to any and all residues within a defined range of cleanability.

60 Validation and Analytical Strategies Process NOT Product focus! Scientifically justified choice of challenge residue Analytical and sampling methods that fit where you are in the risk/development/qualification continuum Use process simulations to reduce assumptions, defend limits justify and correlate methods reduce swabbing!!