Teeramanas Tanaekakarapong, a peritoneal dialysis patient

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1 Teeramanas Tanaekakarapong, a peritoneal dialysis patient Application of ICHQ9 Risk Management Principles to Assess the Risk of Leachables Adversely Impacting the Quality and/or Safety of Complex Biopharmaceuticals Mike Hodgson Rockville, US, March 2017

2 Extractable & Leachable Risk Assessment Feedback and observations The term risk assessment means something different to each individual Companies focus on probability. Severity is rarely defined Any data or knowledge is regarded as good /useful information Risk Assessments are perceived as ways to reduce workload & take shortcuts Asia Pacific More than 11,000 employees Output of risk assessment doesn t inform experimental work. Generic experiments conducted regardless 2

3 FDA Regulatory Requirements and Guidance Aligns to the application of a science led risk based approach 1999 FDA Guidance: Container Closure Systems for Packaging Human Drugs & Biologics Highest Risk from Dose Form and Route of Administration Do the following components present the same risk? Asia Pacific More than 11,000 employees MDI Mouthpiece vs Valve (Inhalation) PFS stopper vs 316 SS (Injections) 3

4 EMEA Regulatory Requirements and Guidance Aligns to the application of a science led risk based approach 2005 EMEA Guidance: Guideline on Plastic Immediate Packaging Materials Asia Pacific More than 11,000 employees 4

5 ICH Regulatory Requirements and Guidance Aligns to the application of a science led risk based approach 2014 ICH M7: Genotoxic Impurities Duration of treatment < 1 month >1-12 months >1-10 years >10 years to lifetime Daily intake [μg/day] Risk Based Approach Applied to Substance Toxicity Knowledge Driven Knowledge/data Recycling Animal Testing Discouraged 5

6 Leachable Risk Management Aligning strategy to ICHQ9 to Leachables? Effective leachable risk management relies on a diverse team of Subject Matter Experts (SMEs) to identify, describe, evaluate and control risks to a level that doesn't adversely impact product quality and/or safety. Any process should have applicability to all dosage forms and pharmaceutical/medical products Definition of risk: Risk = Severity x Probability 6

7 Risk Identification Risk Statements Systematically identify all potential sources of leachables: Manufacturing process Container closure system Packaging system Drug delivery system Identified risks should be described and discussed in the form of risk statements that are structured as follows; the cause, risk event and effect. A risk statement provides the clarity and descriptive information required for a reasoned and defensible assessment of the risk's occurrence probability and areas of impact. A well-written risk statement ensures the risk is clearly articulated, effectively understood by a wide variety of SMEs and managed. 7

8 Risk Analysis Severity Definition and Application to E&L ICHQ9 defines severity as "a measure of the possible consequences of a hazard. In terms of Extractables/Leachables, the hazard is directly related to materials that are used to manufacture, contain and deliver pharmaceutical products, as they are a potential source of substances that can harm patients and/or adversely impact product quality. Materials should be classified in accordance with knowledge that informs the substances and/or toxicity of substances present within the material 8

9 Risk Analysis Informing Severity - Knowledge Hierarchy Knowledge Hierarchy to Understand the Hazard(s) associated with Materials used within Pharmaceutical/Medical Applications (i.e. Severity) Degree of Understanding 9

10 Risk Analysis Material Classification Measure of Severity Class 1: Materials that have been confirmed, via experimental studies, to contain substances that are proven to be, or widely regarded as, highly toxic. Typically, these materials have failed biocompatibility testing (USP<87>, USP<88> and/or ISO10993), failed elemental content (ICHQ3D) or undergone a aggressive/exhaustive extraction study that confirmed the presence of highly toxic species. Score = 10 Class 2: Materials from suppliers that aren't able to demonstrate pharmacopeial/regulatory compliance and/or suitability for pharmaceutical/medical applications. Typically, these materials are manufactured by smaller, specialist or unknown suppliers that the pharmaceutical industry have limited experience with, are commodity grade materials manufactured on a large scale, have complex additive packages and/or are manufactured using a highly reactive process that is challenging to control and is widely regarded to produce numerous by-products (i.e. vulcanisation process for rubber). Score = 7 Class 3: Materials from reputable suppliers that are able to demonstrate pharmacopieal/regulatory compliance and suitability for medical, pharmaceutical or food applications. Typically, these materials contain a variety of chemicals, but none of these are considered highly toxic as demonstrated by the materials biocompatibility and/or extractable profile. Score = 4 Class 4: Materials that are well characterized and understood (i.e. glass, stainless steel), widely regarded as safe and used routinely within the pharmaceutical industry and/or confirmed to contain a limited number of substances that are widely regarded as safe for use within food, medical and pharmaceutical applications. Score = 1 10

11 Risk Analysis Probability Definition and Application to E&L Probability defines the likelihood of the risk event described in the risk statement of occurring to an extent that it would result in an adverse toxicological or product quality event: Very High High Some Potential Very Low In terms of Extractables/Leachables, the probability of substances leaching during the manufacture, storage and/or administration of a pharmaceutical product up to the end of shelf life is complex, and is best understood using leachable data. However, in the absence of leachable data, there are many other theoretical factors and experimental data that can inform probability: Contact Time Fluid Composition Product Contact Surface Area Ratio Temperature Incompatibility Simulated or Accelerated Extractable Studies 11

12 Risk Analysis Informing Probability Knowledge Hierarchy Knowledge Hierarchy to Understand the Probability of Leachables within a Drug Product (i.e. Probability) Degree of Understanding Aggressive or Exhaustive Extractable Study Targeted Extractable Study Probability Contact Time Probability Fluid Composition Probability Product Contact Surface Area Ratio Probability Temperature Probability Incompatibility Targeted Leachable Study Simulated or Accelerated Extractable Study Leachable Study on Different Product Project Specific Leachable Study 12

13 Risk Evaluation and Control When does a risk become unacceptable? Taken for ICQQ9: Achieving a shared understanding of the application of risk management among diverse stakeholders is difficult because each stakeholder might perceive different potential harms, place a different probability on each harm occurring and attribute different severities to each harm. At what point is risk reduction necessary? Risk Matrix: Process to define when the risk of leachables adversely impacting product safety/quality requires attention Severity Severity Probability or Probability What options do I have to reduce risk? Gain a greater understanding of actual risk Change material Change process 13

14 Leachable Risk Management Summary and Key Messages Risk assessments, if applied correctly, provide a systematic process for ensuring a comprehensive understanding of risk Risks should be defined with a high degree of detail, clarity and accuracy Not all data/knowledge is useful, or equivalent, when attempting to understand the actual risk Severity and probability should be clearly defined such that all factors that influence both are considered during the scoring of risks The output from the risk assessment process should direct experimental work and influence leachable risk management strategy The knowledge gained from experimental work should feed back into the risk assessment to further understand and scientifically justify the actual risk 14

15 Teeramanas Tanaekakarapong, a peritoneal dialysis patient Application of ICHQ9 Risk Management Principles to Assess the Risk of Leachables Adversely Impacting the Quality and/or Safety of Complex Biopharmaceuticals Panel Discussion Rockville, US, March 2017

16 Case Study 1 Manufacturing Tubing Risk Statement Risk Statement: Because of the use of a 5cm piece of LDPE tubing between the Water for Injection (WFI) source and a stainless steel vessel There is a risk that during the transfer of WFI at a flow rate of 1.5L/min over a 10 minute period, substances present within the LDPE tubing migrate into the WFI at such a level that they would present a significant toxicological risk to the patient when the aqueous based PFS is intravenously delivered into the patient's bloodstream Resulting in a product that contains unsafe levels of leachables that the patient is exposed to 16

17 Case Study 1 Scoring severity Knowledge acquired to inform severity: Category: Extractable Data Sub Category: Aggressive or Exhaustive Extractable Study Outcome: Describes the conclusions that have been/can be drawn from the knowledge obtained Unknown extractables detected, and quantified using a surrogate standard, to be less than the most conservative reporting threshold (SCT/TTC). Known extractables detected, and quantified using a surrogate standard, to be less than their PDE/ADI. Biocompatibility USP 88 Plastic: Class VI Biocompatibility ISO ISO10993: Complies with the requirements for the materials intended use (i.e category, contact and duration) USP USP 661 Material Complies Other Compositional Information Other Food Compliance EU Material Complies Other Food Compliance FDA Material Complies Other REACH Material Complies Knowledge provided by supplier confirms absence of highly toxic species

18 Case Study 1 Scoring probability Knowledge acquired to inform probability: Category Leachable Data Sub Category Leachable Study: Different Product Outcome: Describes the conclusions that have been/can be drawn from the knowledge obtained Unknown leachables detected, quantified via a surrogate standard and confirmed to be present at levels less than the most conservative reporting threshold (SCT/TTC). Known leachables detected, quantified via a reference standard and confirmed to be present at levels less than 30% of their PDE/ADI. Theoretical Probability: Contact Duration Transitory: Less than 1hr Theoretical Probability: Composition of Fluid Weak: Aqueous based with a ph between 6 and 8. Absence of surfactants or other excipients that might promote migration Theoretical Probability: Contact Surface Area to Volume Ratio Large Theoretical Probability: Temperature Ambient/Room Temperature: 15 C to 30 C Theoretical Probability: Incompatibility Very Low: Material is known to be compatible with its intended use Theoretical Probability: Purging, Removal or Dilution Potential No Potential

19 Case Study 2 Inhaler Mouthpiece Risk Statement Risk Statement: Because of the short term contact between the patients oral mucosal membranes and the polypropylene mouthpiece of a dry powder inhalation device There is a risk that during the time it takes for a patient to use their inhaler to take their medication, substances present within the polypropylene migrate into the oral cavity and mucosal membranes of the patient at such a level that they would present a significant toxicological risk to the patient via the oral route of administration Resulting in patient exposure to leachables that present a risk to a patient's health 19

20 Case Study 2 Scoring severity Knowledge acquired to inform severity: Category: Sub Category: Outcome: Describes the conclusions that have been/can be drawn from the knowledge obtained Biocompatibility ISO ISO10993: Complies with the requirements for the materials intended use (i.e category, contact and duration) Other REACH Material Complies USP USP 661 Material Complies

21 Case Study 2 Scoring probability Knowledge acquired to inform probability: Category Sub Category Outcome: Describes the conclusions that have been/can be drawn from the knowledge obtained Theoretical Probability: Contact Duration Transitory: Less than 1hr Theoretical Probability: Composition of Fluid Weak: Aqueous based with a ph between 6 and 8. Absence of surfactants or other excipients that might promote migration Theoretical Probability: Contact Surface Area to Volume Ratio Moderate Theoretical Probability: Temperature Hot: 30 C - 50 C Theoretical Probability: Incompatibility Very Low: Material is known to be compatible with its intended use Theoretical Probability: Purging, Removal or Dilution Potential No Potential

22 Case Study 3 Pre-Filled Syringe Stopper Change Risk Statement: Because of a supplier notified change to the 13mm stopper within a pre-filled syringe used to contain and store a biopharmaceutical at refrigierated conditions There is a risk that during the shelf life of the biopharmaceutical (2yrs), the long term contact between the alternative bromobutyl stopper and the aqueous based biopharmaceutical drug product that contains 0.05% Polysorbate 80 as a surfactant, substances contained within the stopper migrate into the product at such a level that they would present a significant toxicological risk to the patient via the intravenous route of administration Resulting in a product that contains unsafe levels of leachables that the patient is exposed to 22

23 Case Study 3 Scoring severity Knowledge acquired to inform severity: No knowledge available

24 Case Study 3 Scoring probability Knowledge acquired to inform probability: Category Leachable Data Sub Category Leachable Study: Different Product Outcome: Describes the conclusions that have been/can be drawn from the knowledge obtained Unknown leachables detected, quantified via a surrogate standard and confirmed to be present at levels less than the most conservative reporting threshold (SCT/TTC). Known leachables detected, quantified via a reference standard and confirmed to be present at levels less than 30% of their PDE/ADI. Bulk formulation of different product is very similar (aq. based with 0.02% PS80) Stopper identical