Elemental Impurities: An Industry Perspective

Transcription

1 Elemental Impurities: An Industry Perspective Ernest Parente, PhD Mallinckrodt Pharmaceuticals May 17, GPhA CMC Workshop

2 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.

3 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 industry 1. 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. See International Conference on Harmonization (ICH) Guideline Q9 Quality Risk Management, Step 4, 9 Nov /11/2016

4 EI Quality Risk Management Basic Concept of Risk Assessment as Related to the Permitted Daily Exposure (PDE) Limit of Elemental Impurities in Drug Products Risk Concept 1. Identify risk 2. Probability of risk 3. Severity of harm 4. Detection of risk Elemental Impurity Risk Assessment 1. Identify possible elements present 2. Evaluate using PDE Control Threshold 1 3. Defined by the PDE for each element 4. 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. The Control Threshold is defined in ICH Q3D, Guideline for Elemental Impurities as 30% of the element PDE. 4 5/11/2016

5 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

6 Risk Assessment What is needed for Ingredient/Product risk assessment? IDENTIFY a list of Target Elements 1. ICH recommended elements (route of administration) 2. Elements used or likely to be present identified on Supplier Questionnaire 3. Elements listed on Certificate of Analysis (CoA) 4. Literature search 5. 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

7 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 <233> 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

8 Drug Product Compliance Strategy Test ingredients, not products, and use summation to demonstrate compliance Pros 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 Cons 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) 8 5/11/2016

9 Drug Product Compliance Strategy Test Products not ingredients Pros 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 Cons 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 9 5/11/2016

10 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

11 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

12 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 5 g/day Limit Element PDE (Oral) (µg/day) Target (µg/g) LOQ (µg/g) Target (µg/g) LOQ (µg/g) Target (µg/g) LOQ (µg/g) Cd Pb As Hg 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

13 Evaluation Summation Approach Selecting J and Doing the Math The LOQ is defined by the lowest validation recovery value. The USP <233> 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 tablet PDE Limits Oral Quantity per dose Daily Max Dose (mg) Pb LOQ = 0.1 J found (µg/g) Assume (1) All values below LOQ (2) 10 g/day Target exposure (µg/day) Pb LOQ = 0.5 J found (µg/g) exposure (µg/day) Components (mg/tablet) API < < Excipient < < Excipient < < Excipient < < Excipient < < Excipient < < Total PDE (µg/day): 5 5 % of PDE consumed: 10.0% 50.0% Highest Contribution Use LOQ >30% PDE 13 5/11/2016

14 Material Supplier Interface : The Mostly Current State Many suppliers currently make a commitment to comply, but few are providing useful, reliable, quantitative data on EI in materials. Kicking the can down the road: Big Pharma Supply is well aware of the full litany of USP, FDA, EMA, ICH etc. etc., regulations. While we are sure our products do not contain any of the elements on the periodic table, we are evaluating our material and assure you we will comply with all of the regulations past, present and future by January 1, While encouraged by the commitment The regulation is for drug products not ingredients. So, while the materials need to be suitable for the intended use, there is nothing per se for them to comply with. It s really about customer service. Finished products need to comply by January 1, There is no implementation date for ingredients. To be useful for product compliance, information on ingredients is needed now.

15 Material Supplier Interface: The Desired State It is important for drug product manufacturers and ingredient suppliers to partner on compliance. Wish Lists of Information from Suppliers: Supplier Questionnaire disclosing the use of catalyst, metal-containing reagents used and other elements potentially present. Quantitative data for three, full-scale batches for target elements of interest. Indication of the method and LOQ for each element tested. Confirmation that appropriate methods were used for testing and that they were validated to the standards appropriate for the intended use (e.g., USP General Chapter <233>). Samples of three batches of the material with CoA for confirmatory testing. How often the supplier will test and how the information will be reported? Typical values Highest acceptable values 15 5/11/2016

16 Laboratory Testing Options Option 1 : Develop ICP-MS testing capability at manufacturing sites Pros : Ready access to testing Cons : Significant capital investment in equipment and facilities requiring specialized technical expertise Option 2: Centralize testing at an in-house Center of Excellence for ICP-MS Technology Pros : Optimize capital investment, technical expertise and economy of scale, in control of test schedule Cons : Logistics issues in shipping samples and managing a multi-site workload Option 3: Use an external contract lab for testing Pros : No capital investment, no technical expertise needed Cons : Cost?, logistic issues in shipping samples, problem resolution may be more complicated, testing priority outside of internal control 16 5/11/2016

17 Contract Lab Interface Important to develop clear expectations on both sides up front on roles and responsibilities and costs. Some initial questions for discussion What capabilities are available (ICP-MS KED capable, ICP-OES, AA, etc.)? Does the lab specifically have experience in USP <232>, <233> and ICH Q3D compliance testing? Have they ever been audited by FDA? Do they have experience in preparing reports for regulatory filings? What are the lab deliverables? Testing results report Method validation report Who will do the risk assessment? SOP available? Decision on Target elements and LOQs Decision on testing product or ingredients Control Strategy Justification Report 17 5/11/2016

18 Contract Manufacturer Interface Important to develop clear expectations on both sides. Define roles and responsibilities in a Quality Agreement, Supply Agreement or Contract up front. Sponsor ultimately responsible for developing an approvable regulatory submission and on-going compliance program Information needed for filing : Supplier Questionnaire and CoA Manufacturing, Packaging and Product/Ingredient Risk Assessments Method Validation Reports (compliant with USP <233>) SOP for Risk Assessment Justification for Control Strategy Test Ingredients and use summation option or Test finished product Test every batch or skip test No testing needed (change control monitoring) 18 5/11/2016

19 Contract Manufacturer Interface Some contractor manufacturers will test in-house, but many indicate they plan to out-source finished product testing (40-50%) to a contract lab. Two levels of contractors to manage Manufacturing contractor and Lab sub-contractor Define responsibilities and costs Who will manage the contract lab? Who is responsible for failures and failure resolution? Cost? If ingredients are not controlled, failures at the batch level can occur. OOS and CAPA procedures If skip testing is used and the product is in distribution, a failure could trigger a field alert (3 day notification) Bottom Line: High level of transparency needed at both levels of contractors. 19 5/11/2016

20 Managing the Lab Workflow Validation Protocol Issue: Each method validation needs to be conducted under an approved protocol Challenge: Hundreds of very similar protocols are involved requiring approval The Approach: Develop an umbrella protocol with a provision for moving parts. Thus, only one, general, pre-approved protocol is needed to cover most situations. The elements and limits are given in the ICH Q3D guideline Validation Acceptance Criteria are specified in the USP <233> The ICP-MS testing conditions are more or less standardized The moving parts are the sample preparation procedures. One procedure generally can cover many test articles. So, there is a limited number of sample preparation procedures. 20 5/11/2016

21 Managing the Lab Workflow Test Methods General Method Since many of the methods are similar, a general test method can be created that references appropriate sample procedures. Validation Reports Calculation Template A large amount of data are generated for each validation report. Consider developing an Excel template that automates all of the report calculations, linearity plots, etc. Training and Method Transfer Skill-based training Include end user (e.g., Quality Control) in the method validation process 21 5/11/2016

22 Documentation Strategy Deliverables: Separate reports or sections in one report Ingredient/Product Risk Assessment Packaging Risk Assessment Manufacturing Risk Assessment Material CoA Supplier Questionnaire Product Formulation Rationale for Target Elements Ingredient Test Results Product Test Results Calculations Materials of Construction Potential Leachables Review of Process Materials of Contact Methods and Specifications Regulatory Submission Risk Assessment Summary & Control Strategy 22 5/11/2016

23 Change Control Include EI assessment as part of change control procedures Process Changes (Validation Report) Material Changes Include EI as part of the Vendor Certification Program Changing one material can affect many processes or products Documentation strategy feeds into the Change Control and Lifecycle Management strategy. (e.g., effect of packaging material change or excipient supplier change). 23 5/11/2016

24 Life-Cycle Management 24 5/11/2016

25 Case Study: Teflon Stir Bar Problem: Occasional Out-of Trend (high) results are observed for Cobalt for a parenteral preparation (PDE 5 µg/day). Root Cause Investigation: Occurred during a validation study, so there were data suggesting the high recovery result was suspect Problem isolated to Teflon-coated, ALNICO magnetic stirring bar used in the microwave digester (ALNICO acronym : Aluminum-Nickel-Cobalt) Apparently with some low and unpredictable frequency the stir bars fail and result in a high Co values Lesson Learned : Due to the nature of trace analysis, false positives will occur. CAPA : While it may not possible to completely prevent reoccurrence, once the root cause has been identified measures can be put in place to remediate the suspect result (contamination or real result). 25 5/11/2016

26 Lab Best Practices Clean and Green 1. As little as 50 picograms of certain elements can have an adverse effect on results. 2. Even a clean room does not cover all sources of contamination. 3. PPE, like gloves, serve to minimize contamination. 4. Consider using plasticware instead of glassware. Pre-treat Pyrex digestion vessels using the digestion acids and cycle before use. 5. Store items in zippered plastic bags to minimize contamination. 26 5/11/2016

27 Lab Best Practices 6. If bottle top dispensers are used, before use dispense some of the liquid to rinse the dispenser tip to minimize contamination. 7. Use plastic spatulas or coated spatulas (Teflon, PTFE) to dispense solids. 8. Keep items and samples covered as they move about the laboratory. 9. Use high purity acids. Trace metal grade acids are usually suitable and a good alternative to ultra high purity grade acids which are expensive. 10. For very low level detection, KED mode can eliminate interferences due to residual carbon (e.g., vanadium). 27 5/11/2016

28 THANK YOU FOR YOUR ATTENTION! Acknowledgements: Thanks to my colleagues at Mallinckrodt Pharmaceuticals: Dr. David A. Fay Christy M. Nichols Eileen L. S. McClendon Jared L. Zobrist Roy Alexander s 3-D Periodic Table More than you ever wanted to know about periodic tables: The INTERNET Database of Periodic Tables, The Chemogenesis Web Book, /11/2016