Elemental Impurities: An Industry Perspective
Elemental Impurities: An Industry Perspective
Ernest Parente, PhD Mallinckrodt Pharmaceuticals May 17, 2016 2016 GPhA CMC Workshop
Overview Risk Assessment The Supplier Interface The Contractor Interface Contract Laboratories Contract Manufacturers The Laboratory Interface Managing the Lab Lab Best Practices
Mohammed Abubakr’s Circular Periodic Table
Notice: Opinions expressed are those of the author not necessarily those of Mallinckrodt Pharmaceuticals.
Quality Risk Management While well-known in other industries, the concepts and methods of Quality Risk Management are only slowly gaining acceptance as a tool in establishing product quality specifications in the pharmaceutical industry1. “Zero Risk Tolerance” culture Lack of understanding of how to identity, quantify and mitigate risk Risk Management Strategy Risk Assessment • Identify risks, probability of harm and severity of harm Risk Control • The purpose of risk control is to reduce the risk to an acceptable level. • Includes decision making to reduce and/or accept risks. • What can be done to reduce or eliminate risks?
1. 3
See International Conference on Harmonization (ICH) Guideline Q9 “Quality Risk Management,” Step 4, 9 Nov 2005 . 5/11/2016
EI Quality Risk Management Basic Concept of Risk Assessment as Related to the Permitted Daily Exposure (PDE) Limit of Elemental Impurities in Drug Products
1. 2. 3. 4.
Risk Concept
Elemental Impurity Risk Assessment
Identify risk Probability of risk Severity of harm Detection of risk
1. 2. 3. 4.
Identify possible elements present Evaluate using PDE Control Threshold1 Defined by the PDE for each element Sensitive Methods (e.g., ICP-MS)
Risk Control The “risk” is that an identified Target Element could potentially exceed the PDE. Think of the Control Threshold as an “action limit” that signals that a remediation or control may be needed to mitigate risk To clarify, Control Threshold is not another compliance limit. Rather, it is a tool to justify a Quality Risk Management decision. 1. 4
The Control Threshold is defined in ICH Q3D, “Guideline for Elemental Impurities” as 30% of the element PDE. 5/11/2016
Risk Assessment & Control Strategy Identify: Conduct an assessment to identify known and potential sources of elemental impurities that may find their way into the product
Evaluate: Compare the observed or predicted levels with the established PDE
Summarize and Document the Risk Assessment: Consider the significance of the observed or predicted level for elements potentially present
Control: Implement a control strategy, if needed, to ensure elemental impurities in the drug product do not exceed the PDE.
5
5/11/2016
Risk Assessment What is needed for Ingredient/Product risk assessment?
IDENTIFY a list of Target Elements 1. 2. 3. 4. 5.
ICH recommended elements (route of administration) Elements used or likely to be present identified on Supplier Questionnaire Elements listed on Certificate of Analysis (CoA) Literature search Other sources of information
EVALUATE results against the element PDE limit for Target Elements. Are elements above or below PDE Limit? Above or below the Control Threshold? • If above, consider reducing risk or establishing a control • If below, no additional action may be needed
If close to the Control Threshold, is variability a factor? • 95% confidence that Control Threshold will not be exceeded?
6
5/11/2016
Risk Assessment If sufficient, “reliable” information isn’t available, testing may be needed. Testing Strategy: (1) Test finished product, (2) Test Ingredients or (3) Both • If significant risks are identified in the packaging or manufacturing assessment, the summation strategy may not be an option. • Liquids will need a finished product method to assess inorganic leachables Determine appropriate Target values (J Values) Recommended – ICP-MS test methods validated to USP standard or validated as “suitable for the intended use.”
CONTROL elements or materials identified during the Evaluation. If the Risk Assessment identifies elements above the Control Threshold, develop a control strategy. • Control “Key” ingredients or test product If below the Control Threshold: • No testing required • Possible periodic testing/re-evaluation performed for Lifecycle Management • Re-evaluate for change control 7
5/11/2016
Drug Product Compliance Strategy Test ingredients, not products, and use summation to demonstrate compliance
8
Pros
Cons
Assured compliance because ingredients are controlled (QbD) No OOS/CAPA or destruct at the batch level Easier to develop methods for single ingredients than finished products Once ingredients are tested, compliance can be calculated for varying products and strengths May be able to get information from suppliers to reduce testing
Initial large workload to develop/validate methods for ingredients (more ingredients than products) On-going incoming raw material testing may be required (routine/periodic testing) Assumes metal impurities from product manufacturing process are controlled by GMPs (wear products)
5/11/2016
Drug Product Compliance Strategy Test Products not ingredients
9
Pros
Cons
Low initial development cost Holistic approach including contributions from ingredients, the manufacturing process and packaging May be able to get information from suppliers to support product lifecycle management
Possible OOS/CAPA or destruct at batch level • Not possible to rework product Complex failure investigations More difficult to develop methods? Added risk for skip testing approach
5/11/2016
So Far – So Good… Or Is It? Situation 1: A man parachutes from a plane three times and lands successfully without harm or incident. Conclusion : There is no risk in skydiving. Situation 2: The man continues to skydive until one day his parachute fails to open and he tragically crashes to his death. New Conclusion: There actually is risk in skydiving. Maybe this risk could have been mitigated if there was: Quality control on the airplane Quality control on the pilot Quality control on the skydiver Quality control on the… parachute! 10
5/11/2016
Risk Assessment – Testing Finished Products Question: If the EI burden for three, full-scale finished product batches is consistently below the 30% PDE Control Threshold, can it be concluded there is no need for any knowledge of what’s in the ingredients? Point 1 to consider: It is not QbD approach. Point 2 to consider: Testing quality into the finished product is not a GMP approach. The Wrong Answer: If you think the answer is “Yes,” you didn’t learn anything from the parachuting story. The Right Answer: If you know what to test for, testing every batch of finished product is a “control strategy” that eliminates the risk of releasing sub-standard product. However, it is hard to justify the process as a “good” risk assessment strategy since it doesn’t assess/control risk factors. Take home message: It important to know what’s in the ingredients even if you test the finished product.
11
5/11/2016
Target Selection Based on route of administration and formulation Target (Concentration Limit) = Permitted Daily Exposure (PDE) / daily dose Assume, Limit of Quantitation (LOQ) = 0.1 x Target (i.e., 0.1J) Comparison of Targets and LOQs for Different Maximum Daily Doses 20 g/day Limit 10 g/day Limit
Element
PDE (Oral) (µg/day)
Cd Pb As Hg
5 5 15 30
5 g/day Limit
Target LOQ Target LOQ Target LOQ (µg/g) (µg/g) (µg/g) (µg/g) (µg/g) (µg/g)
0.25 0.25 0.75 1.5
0.025 0.025 0.075 0.15
0.5 0.5 1.5 3
0.05 0.05 0.15 0.3
1.0 1.0 3.0 6
0.1 0.1 0.3 0.6
If below the LOQ, use the LOQ in the Summation calculation as “worst case” LOQ must be sufficient low to permit assessment of 30% PDE Control Threshold
12
5/11/2016
Evaluation – Summation Approach Selecting J and Doing the Math The LOQ is defined by the lowest validation recovery value. The USP Accuracy Range (0.5J - 1.5J) may need to be expanded to assess the 30% PDE Control Threshold. SUPERTABS, 600 mg Doses per day 10 PDE Limits Oral
tablet
Quantity per Daily Max dose Components (mg/tablet) Dose (mg) API 600.00 6000.00 Excipient 1 100.00 1000.00 Excipient 2 30.00 300.00 Excipient 3 80.00 800.00 Excipient 4 100.00 1000.00 Excipient 5 90.00 900.00 Total 1000.00 10000.00 PDE (µg/day): % of PDE consumed: 13
Assume (1) All values below LOQ (2) 10 g/day Target Pb LOQ = 0.1 J found exposure (µg/g) (µg/day)
Ernest Parente, PhD Mallinckrodt Pharmaceuticals May 17, 2016 2016 GPhA CMC Workshop
Overview Risk Assessment The Supplier Interface The Contractor Interface Contract Laboratories Contract Manufacturers The Laboratory Interface Managing the Lab Lab Best Practices
Mohammed Abubakr’s Circular Periodic Table
Notice: Opinions expressed are those of the author not necessarily those of Mallinckrodt Pharmaceuticals.
Quality Risk Management While well-known in other industries, the concepts and methods of Quality Risk Management are only slowly gaining acceptance as a tool in establishing product quality specifications in the pharmaceutical industry1. “Zero Risk Tolerance” culture Lack of understanding of how to identity, quantify and mitigate risk Risk Management Strategy Risk Assessment • Identify risks, probability of harm and severity of harm Risk Control • The purpose of risk control is to reduce the risk to an acceptable level. • Includes decision making to reduce and/or accept risks. • What can be done to reduce or eliminate risks?
1. 3
See International Conference on Harmonization (ICH) Guideline Q9 “Quality Risk Management,” Step 4, 9 Nov 2005 . 5/11/2016
EI Quality Risk Management Basic Concept of Risk Assessment as Related to the Permitted Daily Exposure (PDE) Limit of Elemental Impurities in Drug Products
1. 2. 3. 4.
Risk Concept
Elemental Impurity Risk Assessment
Identify risk Probability of risk Severity of harm Detection of risk
1. 2. 3. 4.
Identify possible elements present Evaluate using PDE Control Threshold1 Defined by the PDE for each element Sensitive Methods (e.g., ICP-MS)
Risk Control The “risk” is that an identified Target Element could potentially exceed the PDE. Think of the Control Threshold as an “action limit” that signals that a remediation or control may be needed to mitigate risk To clarify, Control Threshold is not another compliance limit. Rather, it is a tool to justify a Quality Risk Management decision. 1. 4
The Control Threshold is defined in ICH Q3D, “Guideline for Elemental Impurities” as 30% of the element PDE. 5/11/2016
Risk Assessment & Control Strategy Identify: Conduct an assessment to identify known and potential sources of elemental impurities that may find their way into the product
Evaluate: Compare the observed or predicted levels with the established PDE
Summarize and Document the Risk Assessment: Consider the significance of the observed or predicted level for elements potentially present
Control: Implement a control strategy, if needed, to ensure elemental impurities in the drug product do not exceed the PDE.
5
5/11/2016
Risk Assessment What is needed for Ingredient/Product risk assessment?
IDENTIFY a list of Target Elements 1. 2. 3. 4. 5.
ICH recommended elements (route of administration) Elements used or likely to be present identified on Supplier Questionnaire Elements listed on Certificate of Analysis (CoA) Literature search Other sources of information
EVALUATE results against the element PDE limit for Target Elements. Are elements above or below PDE Limit? Above or below the Control Threshold? • If above, consider reducing risk or establishing a control • If below, no additional action may be needed
If close to the Control Threshold, is variability a factor? • 95% confidence that Control Threshold will not be exceeded?
6
5/11/2016
Risk Assessment If sufficient, “reliable” information isn’t available, testing may be needed. Testing Strategy: (1) Test finished product, (2) Test Ingredients or (3) Both • If significant risks are identified in the packaging or manufacturing assessment, the summation strategy may not be an option. • Liquids will need a finished product method to assess inorganic leachables Determine appropriate Target values (J Values) Recommended – ICP-MS test methods validated to USP standard or validated as “suitable for the intended use.”
CONTROL elements or materials identified during the Evaluation. If the Risk Assessment identifies elements above the Control Threshold, develop a control strategy. • Control “Key” ingredients or test product If below the Control Threshold: • No testing required • Possible periodic testing/re-evaluation performed for Lifecycle Management • Re-evaluate for change control 7
5/11/2016
Drug Product Compliance Strategy Test ingredients, not products, and use summation to demonstrate compliance
8
Pros
Cons
Assured compliance because ingredients are controlled (QbD) No OOS/CAPA or destruct at the batch level Easier to develop methods for single ingredients than finished products Once ingredients are tested, compliance can be calculated for varying products and strengths May be able to get information from suppliers to reduce testing
Initial large workload to develop/validate methods for ingredients (more ingredients than products) On-going incoming raw material testing may be required (routine/periodic testing) Assumes metal impurities from product manufacturing process are controlled by GMPs (wear products)
5/11/2016
Drug Product Compliance Strategy Test Products not ingredients
9
Pros
Cons
Low initial development cost Holistic approach including contributions from ingredients, the manufacturing process and packaging May be able to get information from suppliers to support product lifecycle management
Possible OOS/CAPA or destruct at batch level • Not possible to rework product Complex failure investigations More difficult to develop methods? Added risk for skip testing approach
5/11/2016
So Far – So Good… Or Is It? Situation 1: A man parachutes from a plane three times and lands successfully without harm or incident. Conclusion : There is no risk in skydiving. Situation 2: The man continues to skydive until one day his parachute fails to open and he tragically crashes to his death. New Conclusion: There actually is risk in skydiving. Maybe this risk could have been mitigated if there was: Quality control on the airplane Quality control on the pilot Quality control on the skydiver Quality control on the… parachute! 10
5/11/2016
Risk Assessment – Testing Finished Products Question: If the EI burden for three, full-scale finished product batches is consistently below the 30% PDE Control Threshold, can it be concluded there is no need for any knowledge of what’s in the ingredients? Point 1 to consider: It is not QbD approach. Point 2 to consider: Testing quality into the finished product is not a GMP approach. The Wrong Answer: If you think the answer is “Yes,” you didn’t learn anything from the parachuting story. The Right Answer: If you know what to test for, testing every batch of finished product is a “control strategy” that eliminates the risk of releasing sub-standard product. However, it is hard to justify the process as a “good” risk assessment strategy since it doesn’t assess/control risk factors. Take home message: It important to know what’s in the ingredients even if you test the finished product.
11
5/11/2016
Target Selection Based on route of administration and formulation Target (Concentration Limit) = Permitted Daily Exposure (PDE) / daily dose Assume, Limit of Quantitation (LOQ) = 0.1 x Target (i.e., 0.1J) Comparison of Targets and LOQs for Different Maximum Daily Doses 20 g/day Limit 10 g/day Limit
Element
PDE (Oral) (µg/day)
Cd Pb As Hg
5 5 15 30
5 g/day Limit
Target LOQ Target LOQ Target LOQ (µg/g) (µg/g) (µg/g) (µg/g) (µg/g) (µg/g)
0.25 0.25 0.75 1.5
0.025 0.025 0.075 0.15
0.5 0.5 1.5 3
0.05 0.05 0.15 0.3
1.0 1.0 3.0 6
0.1 0.1 0.3 0.6
If below the LOQ, use the LOQ in the Summation calculation as “worst case” LOQ must be sufficient low to permit assessment of 30% PDE Control Threshold
12
5/11/2016
Evaluation – Summation Approach Selecting J and Doing the Math The LOQ is defined by the lowest validation recovery value. The USP Accuracy Range (0.5J - 1.5J) may need to be expanded to assess the 30% PDE Control Threshold. SUPERTABS, 600 mg Doses per day 10 PDE Limits Oral
tablet
Quantity per Daily Max dose Components (mg/tablet) Dose (mg) API 600.00 6000.00 Excipient 1 100.00 1000.00 Excipient 2 30.00 300.00 Excipient 3 80.00 800.00 Excipient 4 100.00 1000.00 Excipient 5 90.00 900.00 Total 1000.00 10000.00 PDE (µg/day): % of PDE consumed: 13
Assume (1) All values below LOQ (2) 10 g/day Target Pb LOQ = 0.1 J found exposure (µg/g) (µg/day)
