Assessing the Impact of Single-Use Systems on Patient Safety: A perspective on systematic, comprehensive approach to safety evaluation
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The document discusses the impact of single-use systems (SUS) on patient safety, emphasizing the need for regulatory compliance and comprehensive risk assessment strategies to evaluate leachables and extractables associated with drug manufacturing. It highlights the importance of identifying and quantifying impurities to ensure product purity and efficacy, as well as the potential risks to patients. Additionally, the document outlines specific regulatory guidelines, methodologies for hazard assessment, and thresholds for acceptable levels of impurities in pharmaceuticals.
![Why Worry?: FDA Warning Letters
“You failed to perform leachable and extractable studies for the (b)(4)
containers used in the storage of (b)(4) intermediates.”
“You failed to demonstrate that the drug product containers and closures
used in the manufacture of your allergenic products are not reactive,
additive, or absorptive so as to alter the safety, identity, strength, quality, or
purity of the drug beyond the official or established requirements [21 CFR
211.94(a)]. Specifically, extractable and leachable studies have not been
conducted on the (b)(4) stoppers used in the manufacture of your allergenic
products.”](https://image.slidesharecdn.com/j-170515181107/85/Assessing-the-Impact-of-Single-Use-Systems-on-Patient-Safety-A-perspective-on-systematic-comprehensive-approach-to-safety-evaluation-10-320.jpg)
Assessing the Impact of Single-Use Systems on Patient Safety: A perspective on systematic, comprehensive approach to safety evaluation
- 1. Assessing the Impact of Single-Use Systems on Patient Safety: A perspective on a systematic, comprehensive approach to safety evaluation Jessica Shea MilliporeSigma
- 2. Agenda 1. Regulatory Background 2. SUS Perspective 3. Risk Assessment Strategies 4. Case Study
- 4. Regulatory Background: ICH M7 “Application of this guideline to leachables associated with drug product packaging is not intended, but the safety risk assessment principles outlined in this guideline for limiting potential carcinogenic risk can be used if warranted.“
- 5. Understand the Process’ Impact on Patient Safety Regulatory Guidance Guidance requires and best practice encourages identification and quantification of the impurities and characterization of their toxicological profile to determine their impact on patient safety. Where there is relevant risk, the drug sponsor may have to determine toxicity based on maximum dosage of potential leachables based on extractables data.1 It is the user’s responsibility to demonstrate that the product does not contain objectionable levels of extractables . . .2 1. Destry M. Sillivan - Senior Regulatory Review Officer, CBER 2. PDA Technical Report 26
- 6. Agenda 1. Regulatory Background 2. SUS Perspective 3. Risk Assessment Strategies 4. Case Study
- 7. Single Use Manufacturing Process LOW HIGHMEDIUM
- 8. Single use assemblies – PDA Recommendations Technical Report No. 66 “Single-Use Systems”, 2014
- 9. Operations downstream of Purification and Final Filling is generally considered greatest risk to patient •Must demonstrate that patient is not at risk •Must demonstrate product purity, efficacy, stability “When possible, leachables should be evaluated when the final step in the production process is sterile filtration prior to filling.” • PDA® Technical report N°26, 2008 Requirements for Final Filling Operations
- 10. Why Worry?: FDA Warning Letters “You failed to perform leachable and extractable studies for the (b)(4) containers used in the storage of (b)(4) intermediates.” “You failed to demonstrate that the drug product containers and closures used in the manufacture of your allergenic products are not reactive, additive, or absorptive so as to alter the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements [21 CFR 211.94(a)]. Specifically, extractable and leachable studies have not been conducted on the (b)(4) stoppers used in the manufacture of your allergenic products.”
- 11. Why Worry?: FDA Warning Letters “Please provide data from an extractables/leachables study conducted on the vessel, tubing and filters used for drug product manufacturing. Please ensure that the studies are conducted taking into account the nature of the non-aqueous vehicle used in your proposed drug product.” “We recommend you to conduct a leachable study for the filtration system with the drug solution to ensure the absence of leachable in the drug product after filtration.”
- 12. Agenda 1. Regulatory Background 2. SUS Perspective 3. Risk Assessment Strategies 4. Case Studies
- 13. Risk Assessment Principles: Study of Adverse Effects on Living Organisms Hazard Characterization Hazard Identification Exposure Assessment Risk Characterization Risk Management Risk Prevention Risk Mitigation Risk Communication Step 1Step 1 Step 6Step 6to
- 14. The Relationship between a Hazard and the Potential for Exposure Defines Risk
- 15. Genotoxicity • Gene mutation Chromosomal aberration • QSAR, in vitro, in vivo • Weight of evidence Local Tolerance (Skin sensitization) • LLNA, GPMT, in vitro, case reports • Skin irritation Repeat Dose Toxicity • Diff. Species • Route of exposure • NOAEL, LOAEL Reproductive Toxicity • Developmental toxicity • Fertility • NOAEL, LOAEL © Wikipedia Hazard Assessment of L&Es: Relevant Endpoints © Wikipedia
- 16. Hazard Identification to Characterization
- 17. Leachable/Extractable X (Name, Structure, CAS No.) Toxicity Data Search Inhouse studies Scientific publications ELSIE data base Reg. Authority data bases (e.g. Echa) Guidelines (e.g. ICH) No data identified Step 2Step 2 (in silico analysis) Data identified Step 3Step 3 (data evaluation) Step 1Step 1 Data Search and Collection
- 18. Step 2Step 2 QSAR Analysis • Two complementary (Q)SAR methodologies (expert rule-based and statistical) • Expert knowledge required Alert for genotoxicity Step 4Step 4 No alert for genotoxicity Step 6Step 6 In Silico Analysis
- 19. Step 3Step 3 • Quality / Reliability of Data (Documentation, Testing Guidelines, GLP, Klimisch score) • Evaluation of Toxicological Profile Substance genotoxic Step 4Step 4 Substance not genotoxic, NOAEL available Step 5Step 5 Substance not genotoxic, NOAEL not available Step 6Step 6 Data Evaluation
- 20. Step 5Step 5 With data • F1 = Extrapolation between species: • F2 = Variability between individuals: 10 • F3 = time adjustment • F4 = Severe toxicity: e.g. 10 for teratogenicity • F5 = no NOEL: e.g. 10 for LOAEL • F6 = ADME, e.g. oral to parenteral extrapolation: max. 10 NOAEL 5 12 Rat, 28 days: 10 Rat, 90 days: 5 PDE Factors from ICH Q3C Threshold for Non-Genotoxic Leachables
- 21. Step 4Step 4 • Suspected Carcinogen or no data available • TTC for genotoxic impurities (ICH M7): • PQRI - Safety Concern Threshold (SCT): Duration of Treatment ≤ 1 month >1-12 months >1-10 years >10 years Individual Impurity 120 µg 20 µg 10 µg 1.5 µg Multiple Impurities 120 µg 60 µg 30 µg 5 µg Thresholds for Genotoxic Leachables
- 22. Step 6Step 6 Cramer Class TTC Simple chemical structure; known metabolic pathway; low order of oral toxicity1 Intermediate; less innocuous than Class 1; no structural features of Class 32 No strong initial presumption of safety; may suggest significant toxicity; reactive functional groups 3 Cramer et al., 1978 Munro et al., 1996 and Kroes et al., 2004 90 µg/person/day 540 µg/person/day 1800 µg/person/day Threshold for Non-Genotoxic Leachables Without data
- 23. Step 6Step 6 Genotoxicants1 Sensitizers2 General toxicity 3 Parenteral and Ophthalmic Drug Products (PODP) Class PQRI* 1.5 µg/person/day 5 µg/person/day 50 µg/person/day Without data
- 24. Risk Assessment Principles: Study of Adverse Effects on Living Organisms Hazard Characterization Hazard Identification Exposure Assessment Risk Characterization Risk Management Risk Prevention Risk Mitigation Risk Communication Step 1Step 1 Step 6Step 6to √ √
- 26. Agenda 1. Regulatory Background 2. SUS Perspective 3. Risk Assessment Strategies 4. Case Study
- 27. 27 Final Sterilization – Single-use • Identify and evaluate • Determine which ones require further evaluation 31 Different Components in one assembly!!
- 29. 29 Toxicological Profile: Safety Factors Applied Hexylene Glycol Factor Description Factor Applied Rat → Human 5 Intraspecies Variability 10 11 days → chronic exposure 10 Bioavailability: 100% 1
- 30. 30 Exposure Assessment Process Parameters Volume Post Sterilization Flush 2 L Vials Discarded (10 mL/vial) 10 vials (0.1 L) Minimum Volume (Header Bag) 1 L Minimum Batch Size = 3.1L Amount of HG = 14.8 mg/10“ filter Concentration = 4.8 mg/L
- 31. 31 The concentration of this individual compound was placed into the worst-case model: Patient Safety Evaluation – Is there a Risk? HG Concentration (µg/mL) Dosage (mL) Patient Exposure (Total µg/dose) PDE Limit (µg/day) 4.8 10 48 10000
- 32. Conclusion • Each impurity is assessed for its hazard or inherent toxicity • Characterize of the drug product and its manufacturing process • Intended use of the drug product are considered in determining the Risk • Characterize the risk and mediate the risk if needed
- 33. Acknowledgments Special Thanks to: Thomas Broschard PhD, DABT Paul Killian, PhD George Adams Assessing safety of extractables from materials and leachables in pharmaceuticals and biologics – Current challenges an
- 34. Thank You & Questions?
Editor's Notes
- #5: Covers Genotoxic impurties
- #10: “The filter should not affect the product by removal of ingredients from it or release of substances into it.” European Commission, EUDRALEX Volume 4, “Good Manufacturing Practices, Medicinal Products for Human and Veterinary Use”, Annex 1, “Manufacture of Sterile Medicinal Products”, 2008
- #16: GPMT Gunea pig maximization test LLNA local lymph node assay No Observed adverse effect level
- #19: DEREK and Sarah two independent is from ICH M7 Toxtree and other system are available
- #20: No Observed adverse effect level
- #21: F1-F5 are factors directly from ICH Q3C, A bioavailability factor F6 is agreed upon from ELSIE member. Most dosages are not absorbed completely in oral administration therefore most companies are using this factor when considering other dosage. ADME is an abbreviation in pharmacokinetics and pharmacology for "absorption, distribution, metabolism, and excretion
- #22: All ELSIE members agree with 1.5
- #23: Without data , values are for oral administration
- #30: No Observed adverse effect Concentration
- #32: Permissible Daily Exposure - PDE