application of ichq9 risk management principles to assess

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

Teeramanas Tanaekakarapong, a peritoneal dialysis patient

|

Extractable & Leachable Risk Assessment

2

Asia Pacific More than 11,000 employees

Feedback and observations

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

The term risk assessment means something different to each individual

Output of risk assessment doesn’t inform experimental work. Generic experiments conducted regardless

|

FDA Regulatory Requirements and Guidance

3


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? • MDI Mouthpiece vs Valve

(Inhalation)

• PFS stopper vs 316 SS (Injections)

|

EMEA Regulatory Requirements and Guidance

4



2005 EMEA Guidance: Guideline on Plastic Immediate Packaging Materials

|

ICH Regulatory Requirements and Guidance

5


Duration of treatment

< 1 month >1 - 12 months >1 - 10 years >10 years to lifetime

Daily intake [μg/day] 120 20 10 1.5

2014 ICH M7: Genotoxic Impurities

Risk Based Approach Applied to

Substance Toxicity

Knowledge/data Recycling – Animal

Testing Discouraged

Knowledge Driven

|

Leachable Risk Management

6

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

|

Risk Identification

7

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.

|

Risk Analysis

8

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

|

Risk Analysis

9

Informing Severity - Knowledge Hierarchy D

egre

e of

Und

erst

andi

ng

Knowledge Hierarchy to Understand the Hazard(s) associated with Materials used within Pharmaceutical/Medical Applications (i.e. Severity)

|

Risk Analysis

10

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

|

Risk Analysis

11

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

|

Risk Analysis

12

Informing Probability – Knowledge Hierarchy

Aggressive orExhaustiveExtractable

Study

TargetedExtractable

Study

ProbabilityContact Time

ProbabilityFluid

Composition

ProbabilityProductContact

Surface AreaRatio

ProbabilityTemperature

ProbabilityIncompatibility

TargetedLeachable

Study

Simulated orAcceleratedExtractable

Study

LeachableStudy onDifferentProduct

ProjectSpecific

LeachableStudy

Deg

ree

of U

nder

stan

ding

Knowledge Hierarchy to Understand the Probability of Leachables within a Drug Product (i.e. Probability)

|

Risk Evaluation and Control

13

When does a risk become unacceptable?

Severity

Prob

abili

ty 1 4 7 10

4 16 28 40 7 28 49 70 10 40 70 100

Severity

Prob

abili

ty 1 4 7 10

4 16 28 40 7 28 49 70 10 40 70 100

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?

or

Risk Matrix: Process to define when the risk of leachables adversely impacting product safety/quality requires attention

What options do I have to reduce risk? • Gain a greater understanding of actual risk • Change material • Change process

|

Leachable Risk Management

14

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

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

Teeramanas Tanaekakarapong, a peritoneal dialysis patient

|

Case Study 1

16

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

|

Case Study 1

17

Scoring severity

Knowledge acquired to inform severity:

10 4 7 1

Category: Sub Category:Outcome: Describes the conclusions that have been/can be drawn from the knowledge obtained

Extractable Data Aggressive or Exhaustive Extractable Study

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 10993 ISO10993: Complies with the requirements for the materials intended use (i.e category, contact and duration)

USP USP 661 Material Complies

Other Compositional Information Knowledge provided by supplier confirms absence of highly toxic species

Other Food Compliance EU Material Complies

Other Food Compliance FDA Material Complies

Other REACH Material Complies

|

Case Study 1

18

Scoring probability

Knowledge acquired to inform probability:

10 4 7 1

Category Sub CategoryOutcome: Describes the conclusions that have been/can be drawn from the knowledge obtained

Leachable DataLeachable Study: Different Product

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

TheoreticalProbability: 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

TheoreticalProbability: Purging, Removal or Dilution Potential No Potential

|

Case Study 2

19

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

|

Case Study 2

20

Scoring severity


10 4 7 1

Category: Sub Category:Outcome: Describes the conclusions that have been/can be drawn from the knowledge obtained

Biocompatibility ISO 10993 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

|

Case Study 2

21

Scoring probability


10 4 7 1


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°CTheoretical Probability: Incompatibility Very Low: Material is known to be compatible with its intended use

Theoretical Probability: Purging, Removal or Dilution Potential

No Potential

|

Case Study 3

22

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

|

Case Study 3

23

Scoring severity


10 4 7 1

No knowledge available

|

Case Study 3

24

Scoring probability


10 4 7 1

• Bulk formulation of different product is very similar (aq. based with 0.02% PS80)

• Stopper identical


Leachable DataLeachable Study: Different Product

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.

application of ichq9 risk management principles to assess

Documents