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Shortages of Injectable Drugs: Manufacturing Issues and Potential Solutions

Shortages of Injectable Drugs: Manufacturing Issues and Potential Solutions. Lori Herz, Ph.D. Lehigh University, Professor of Practice Chemical Engineering, Bioengineering. Outline. Background and current strategies Overview of injectables manufacture Major unit operations

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Shortages of Injectable Drugs: Manufacturing Issues and Potential Solutions

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  1. Shortages of Injectable Drugs: Manufacturing Issues and Potential Solutions Lori Herz, Ph.D. Lehigh University, Professor of Practice Chemical Engineering, Bioengineering

  2. Outline • Background and current strategies • Overview of injectables manufacture • Major unit operations • Common quality and manufacturing issues • New technologies • Training, education, culture • Example: control of hospital acquired infections • Risk assessment and management tools • Example: FMECA for risk assessment in microbial cleanroom • Systems level approaches – examples of recent studies in: • Process systems engineering • Supply chain management • Enterprise-wide optimization • Summary and conclusions

  3. Background • Drug shortage – definition • Title X of FDASIA: “a period of time when the demand or projected demand for a drug within the US exceeds the supply of the drug” Strategic Plan for Preventing and Mitigating Drug Shortages FDA, Oct. 2013

  4. Current Situation • American Society of Health-Systems Pharmacists (ASHP) tracks drug shortages • Information is posted on the ASHP website • August 6, 2014 snapshot • Current shortages: 252 products • Of the 252, 74% are injectables http://www.ashp.org/menu/DrugShortages/CurrentShortages

  5. Impact on patients Examples of surveys published in medical journals • Oncology • Goldsacket. al., “Impact of Shortages of Injectable Oncology Drugs on Patient Care”, Am J Health-Syst Pharm, 2014. • Becker et. al., “Impact of Oncology Drug Shortages on Patient Therapy: Unplanned Treatment Changes”, J Oncology Practice, 2013. • McBride et.al., “National Survey on the Effect of Oncology Drug Shortages on Cancer Care”, Am J Health-Syst Pharm, 2013. • 243 responses • 93% reported delays in treatment or changes in regimen • 16% reported near miss errors due to changes • Anesthesia • Burgert, “An Analysis of Communication-Centered Policy Alternatives to Address the Anesthesia Drug Shortage”, Health Policy and Technology, 2014. • Gastroenterology • Meneeset. al., “Drug Shortages in America: What about the Gastroenterologist?”, Gastrointestinal Endoscopy, 2013. • Infectious disease • Gundlapalliet. al., “Perspectives and Concerns Regarding Antimicrobial Agent Shortages among Infectious Disease Specialists”, Diagnostic Microbiology and Infectious Disease, 2013. • Industry-wide • McLaughlin et. al., “Effects on Patient Care Caused by Drug Shortages”, JMCP, 2013.

  6. Causes of shortages • Quality issues caused majority (56%) of shortages • Quality failures can disrupt the supply • 2nd leading cause (20%) was delays and capacity issues • Sometimes, capacity-related shutdowns Reported reasons for shortages in 2011 (Fig. 1) Ref: Woodcock and Wosinska, 2012

  7. Economic drivers of manufacturing quality problems • Quality not rewarded • Purchasers consider only price • Product complexity • Defects in sterile products can be hard to detect • Non-uniform & episodic • Contamination may increase after production • Other contributing factors result in quality problems • Aging facilities • Less automated • Fewer technology innovations (isolators) Ref: Woodcock and Wosinska, 2012 (Fig 2)

  8. Actions taken by FDA • Note: Most of these items are not trivial to implement Ref: Kweder and Dill , 2013 (Fig 5)

  9. FDA Strategic Plan for Preventing and Mitigating Drug Shortages, Oct. 2013 • Goal #1: Strengthen mitigation response • Goal #2: Develop long-term prevention strategies • Develop methods to incentivize and prioritize manufacturing quality • “Manufacturing processes and technologies must keep pace with advances in research & development” • Use regulatory science to identify early warning signals of shortages • Explore risk-based approaches • Work with stakeholders to identify vulnerabilities • Increase knowledge to develop new strategies to address shortages • Work with professional societies and manufacturers

  10. Partnerships with professional societies - Developing quality metrics • International Society of Pharmaceutical Engineers (ISPE) • 2013 Whitepaper: Proposals for FDA Quality Metrics Program to support risk-based inspection program • Examples of metrics: Rates of • Batch reject, rework & reprocessing, out-of-specifications, critical complaints, on-time annual product reviews • Parenteral Drug Association (PDA) • 2013 Points to consider: Pharmaceutical Quality Metrics • Recommended quality metrics – trend metrics • Rates of complaints, batch rejects, and out-of-specifications

  11. Compound Key steps in injectables manufacture ISO 8 Filter Prep containers Fill Prep stoppers Stopper ISO 5 Lyophilize (freeze dry) Produce Water for Injection Seal Produce clean steam Inspect unclassified Autoclave Label & package

  12. Cleanrooms • Designed and controlled to prevent particle and microbial contamination • Pressure differentials, HEPA filters, unidirectional airflow, airlocks • Personnel • Gowning, aseptic technique, monitoring, flow of people and materials http://www.vgcc.edu/News/indNews.cfm?recNo=1339

  13. Compounding http://www.walkerep.com/products/products-by-industries/pharmaceutical--biotech.aspx

  14. Containers & closures • Maintain sterility & product integrity • Different combinations • Vial + stopper + seal • Ampoule • Syringe + stopper • Parts are cleaned & sterilized. Common methods: • Vials: wash + dry heat sterilization • Syringes: wash + irradiation • Stoppers: wash + steam sterilize • Visually inspect for defects Pictures: http://www.pharmaceutical-technology.com/contractors/contract/one2one/one2one1.html

  15. Filling– ISO 5 • Dispense sterile liquid product into containers • Filling needles are attached to dosing pumps • 3-10+ pumps operate simultaneously http://www.steriline.it/prodotti_filling_machines.php?cat=vials 15

  16. Visual inspection • Purpose: detection of particulates • Manual and/or automated http://www.boschpackaging.com/en/pa/products/industries/pd/product-detail/aim-2022-5022-7022-19521.php?ind=1675&mt=15319

  17. Common quality issues: contamination

  18. More quality and manufacturing issues • Equipment failure • Age, frequent use • Delays • Unexpected maintenance, frequent product changeover • GMP violations • Not following procedures, documentation errors, incomplete/open investigations, inadequate training • Environmental monitoring out-of-specification

  19. Outline • Background and current strategies • Overview of injectables manufacture • Major unit operations • Common quality and manufacturing issues • New technologies • Training, education, culture • Example: control of hospital acquired infections • Risk assessment and management tools • Example: FMECA for risk assessment in microbial cleanroom • Systems level approaches – examples of recent studies in: • Process systems engineering • Supply chain management • Enterprise-wide optimization • Summary and conclusions

  20. Filling line isolators and restricted access barriers (RABS) • Alternatives to traditional cleanroom • Keeps people out of the process • Isolator: closed process • RABS: semi-closed; some personnel interventions Pictures: http://www.steriline.it/prodotti_isolators_filling_lines.php http://www.steriline.it/prodotti_isolators_crabs.php

  21. Closed-vial technology: Verjans, 2012; Verjanset al, 2012 • Alternative to current standard of fill + stopper • Advantages • Fill while vial is closed: reduced risk of microbial contamination • Eliminates process steps: component cleaning, sterilization, and siliconization • Utilizes new process technologies: vial polymers, needle design, laser seal Fig. 1: Verjans, 2012

  22. Reduction in number of process stepsExample: stopper preparation • Ready-to-sterilize • Washed by supplier • Ready-to-use • Washed and sterilized by supplier • Integration of washing + sterilization + transfer steps • Use of equipment that performs multiple steps

  23. Personnel training: requirements and pitfalls • 21 CFR 211.25 • Personnel must be trained to do their specific jobs • Quality Systems Approach to Pharmaceutical cGMP, 2006 – Management expectations • Support a problem-solving, communicative culture • Act on employee suggestions for improvement • Despite regulations, training problems are frequently observed • Types of problems (Jones, 2000) • Training is evaluated less than materials, components, products, and processes • “Poor, inadequate, and ineffective training has an insidious way of being perpetrated….”

  24. Hospital acquired infections: Parallels to manufacturing of injectables • Fitzpatrick M. et al, 2011 • Nearly 2MM US patients get HAI’s • Hygiene practices are related to • Workload, stress, physical environment (i.e. sink location) Sydor and Perl, 2011

  25. Elements of successful educational program: hand hygiene Key features Useful content HAI rates and cost Risks to patients and healthcare workers When to wash hands, with examples Methods of hand cleaning – soap & water, sanitizer Glove use • Continuity – on-going education & continuous reinforcement • Leadership commitment • Performance feedback & reminders (signage) • NOT: printed educational materials why when how Mathai et al, 2010

  26. More lessons learned from HAI studies • Simple solutions can be most effective • Hand hygiene is the most important measure to prevent HAI transmission • Analogous to aseptic technique • Education and training • The why is important, not just the how & when • More education in science and engineering of manufacturing • Share the data • Providing healthcare workers with surveillance data has been a catalyst for employee-driven quality programs Sydor and Perl, 2011. Mathai et al, 2010

  27. Innovative learning toolOperator training simulator (OTS) • Virtual training prior to real-world situations • Currently used for flight & surgical training • Gerlachet al, 2014 • OTS for cell growth and recombinant protein production • Students trained in OTS (or not) prior to lab training • OTS trained students followed SOP more correctly and were better able to interpret data and recollect events Fig 1

  28. Risk management & risk assessment • ICH Q9: Quality risk management • “Systematic process for the assessment, control, communication and review of risks to the quality of the drug (medicinal) product across the product lifecycle” • Tools: FMEA, FMECA, FTA, HAZOP, etc. ICH Q9, Fig. 1 FMECA: failure mode, effects, and criticality analysis

  29. FMECA: Microbial risk assessment in pharma cleanrooms, Whyte and Eaton, 2004 • Model microbial contamination of product via air and surface contact • Performed risk assessment to identify parts of the manufacturing process with the highest level of risk • Identified sources of risk (Fig 1)

  30. Microbial risk assessment: Whyte and Eaton, 2004 Table 5: Risk scores and risk ratings throughout the manufacturing process

  31. Outline • Background and current strategies • Overview of injectables manufacture • Major unit operations • Common quality and manufacturing issues • New technologies • Training, education, culture • Example: control of hospital acquired infections • Risk assessment and management tools • Example: FMECA for risk assessment in microbial cleanroom • Systems level approaches – examples of recent studies in: • Process systems engineering • Supply chain management • Enterprise-wide optimization • Summary and conclusions

  32. Systems approaches Enterprise-wide optimization • Engineering principles • Integration of functional areas • Models of systems • Mathematically complex and computationally intensive. Examples: • Mixed integer linear programming (MILP) • Stochastic models Process systems engineering Supply chain management • Process systems engineering (PSE) – chemical engineers • Focus: technical aspects of manufacturing process • Supply chain management (SCM) • Focus: logistics of raw materials, manufacturing, storage, and distribution • Enterprise-wide optimization (EWO) • Integrated approach to PSE and SCM

  33. PSE Approach: Parenterals production at Roche Sugiyama and Schmidt, 2012a • Applied process modeling and optimization to measure product losses and increase production • Products: Monoclonal antibodies filled into vials (liquid and lyo) and pre-filled syringes Fig. 2: Mass balance From the process flow diagram, or map, yields at each step were calculated

  34. Sugiyama and Schmidt, 2012aPrioritizing causes of yield loss (Fig 3) • Focused on (1) visual inspection operation and (2) pre-run filling losses

  35. Sugiyama and Schmidt, 2012a: Actions • Reduced pre-run filling losses • Performed study to determine number of samples to discard • Reduced scratches on glass vials • Changed equipment used to transport vials • Coated table in isolator to reduce friction • More detailed reporting of defect type (Fig 6, right) • Engaged numerous areas of expertise • Ground-level operations improvement

  36. PSE in the pharma industryTroup and Georgakis, 2013; Gernaeyet al, 2012 • PSE areas / tools • Process analytical technologies (PAT) • Design, data acquisition, and analysis • Process analyzers and control • Continuous improvement & knowledge management tools • Process monitoring • Plant wide information systems • Modeling and optimization methodologies • Observations • Focus has been in manufacture of small molecule API, solid dosage forms, and some biologics API • Literature in PSE applications in injectables is minimal • Opportunity is great

  37. Models for global supply chain planning Sousa et al, 2011 • Multiple products and sites • Known information • Forecast, costs, tax rates, SC structure (locations) • Decisions determined by model • Where to allocate manufacture of primary (API) and secondary products (drug product) • Production amounts and inventory levels for each site • Computing – readily available, inexpensive • Windows XP, 1 GB RAM, 3.4 Pentium 4 Processor • GAMS 22.8* with CPLEX 11.1 solver* * http://www.gams.com/ ; http://www-01.ibm.com/software/commerce/optimization/cplex-optimizer/

  38. Sousa et al, 2011: Example problems and results Fig 8: Product allocations for Products I1-I10 (y-axis) at Sites C1 – C10 Total computation time ~ 4h

  39. Enterprise-Wide Optimization (EWO): Grossmann, 2005 • Integration of information with IT tools • SAP, Oracle: Real-time information sharing • Aspentech: Optimization tool • Challenges for developing new tools • Modeling • Operations complexities and uncertainties • Multi-scale decision making • Long-term: investment, sourcing • Medium-term: production planning • Short-term: scheduling, process control • Algorithms and computer architecture SCM Logistics & planning Linear models EWO Manufacturing facilities & planning, scheduling, control of manufacturing Non-linear models Some progress has been made, but more is needed.

  40. Management of multiple systemsTechnology roadmapping: Choudhury and Thien, 2012 • Tool to align changes in technology, organization, and business to “transform and coordinate PSE” across the organization • How to identify, select, acquire, develop, and implement technological changes Exhibit 5

  41. Summary and conclusions • Shortages of injectable drugs continue to be an issue for manufactures and hospitals/clinics • Quality and manufacturing issues are leading causes of shortages • Multiple solutions and approaches are needed • New technologies in manufacturing operations • Ground level evaluation of processes • Culture of training and education • Systems level evaluations • Production; multiple functional areas • Minimally utilized for injectables • Involvement at all levels of the organization • Implementation is challenging • Evaluation: Will they add value? • Partnerships with academia

  42. References • “Application of Hazard Analysis and Critical Control Point (HACCP) Methodology to Pharmaceuticals”, World Health Organization, WHO Technical Report Series, No. 908, 2003. • FDA Strategic Plan for Preventing and Mitigating Drug Shortages, Oct. 2013 • Fitzpatrick M, Everett-Thomas R, Nevo I, Shekhter I, Rosen LF, Scheinman SR, Arheart KL, Birnbach DJ. “A Novel Educational Programme to Improve Knowledge Regarding Health Care-Associated Infection and Hand Hygiene”. International Journal of Nursing Practice, vol. 17,2011, p.269–274. • Gernaey K, Cervera-Padrell C, and Woodley J. “A Perspective on PSE in Pharmaceutical Process Development and Innovation”. Computers and Chemical Engineering, vol. 42, 2012, p. 15-29. • Gallup D, Domenick K, Gillis M. “Personnel Training in Pharmaceutical Manufacturing”, in Pharmaceutical Manufacturing Handbook: Regulations and Quality, John Wiley and Sons, 2008. • Gerlach I, Brüning S, Gustavsson R, Mandius CF, Hass V. “Operator Training in Recombinant Protein Production Using a Structured Simulator Model”. Journal of Biotechnology, vol. 177, p. 53-59. • Grossmann I. “Enterprise-wide Optimization: A New Frontier in Process Systems Engineering”. AIChE Journal, vol. 51, 2005, p. 1846-1857. • ICH Guideline Q9, “Quality Risk Management”, 2005. • ICH Guideline Q10, “Pharmaceutical Quality System”, 2008. • Int’l Society of Pharmaceutical Engineers (ISPE) Proposals for FDA Quality Metrics Program – Whitepaper , 2013 • Jones D. “Evaluating the Effectiveness of cGMP Training”. Pharmaceutical Online, 2000. http://www.pharmaceuticalonline.com/doc/evaluating-the-effectiveness-of-cgmp-training-0001

  43. References • Kweder, SL and Dill, S. “Drug Shortages: The Cycle of Quantity and Quality”, Clinical Pharmacology and Therapeutics, vol 93, 2013, p. 245-251. • Mathai E, Allegranzi R, Seto WH, Chraiti M-N, Sax H, Larson E, Pittet D. “Educating Healthcare Workers to Optimal Hand Hygiene Practices: Addressing the Need”. Infection, vol. 38, 2010, p. 349-356. • Parenteral Drug Association (PDA) Points to consider: Pharmaceutical Quality Metrics , 2013 • Pietrowski R, “Risk Management and Microbiological Auditing”, in Guide to Microbiological Control in Pharmaceuticals and Medical Devices, 2nded, CRC Press, 2007. • Sandle T, “Risk Management in Sterile Environments”, in Pharmaceutical Manufacturing Special Report, Aseptic Manufacturing: A Roadmap to Excellence, 2013. http://www.pharmamanufacturing.com/assets/wp_downloads/pdf/dpt.pdf • Shah N. “Pharmaceutical Supply Chains: Key Issues and Strategies for Optimisation”. Computers & Chemical Engineering, vol. 28, 2004, p. 929-941. • Sousa R, Liu S, Papageorgiou L, Shah N. “Global Supply Chain Planning for Pharmaceuticals”. Chemical Engineering Research and Design, vol. 89, 2011, p. 2396-2409. • Sugiyama H and Schmidt S. “Model-Based Optimization in Pharmaceutical Technical Operations – Yield Measurement and Increase in Roche’s Parenterals Production Kaiseraugst”. Proceedings of the 22nd European Symposium on Computer Aided Process Engineering, 2012. • Sugiyama H and Schmidt S. “Realizing Continous Improvement in Pharmaceutical Technical Operations – Business Process Model in Roche’s ParenteralsProduction Kaiseraugst”. Proceedings of the 22nd European Symposium on Computer Aided Process Engineering, 2012.

  44. References • Sydor E, Perl M. “Hospital Epidemiology and Infection Control in Acute-Care Settings”. Clinical Microbiology Reviews, 2011, p. 141-173. • Thomas P, “Workforce Training: Embracing the “Necessary Evil”. Pharmaceutical Manufacturing, 2010. http://www.pharmamanufacturing.com/articles/2010/150/ • Troup G and Georgakis C. “Process Systems Engineering Tools in the Pharmaceutical Industry”. Computers and Chemical Engineering, vol. 51, 2013, p. 157-171. • Varma V, Reklaitis G, Blau G, and Pekny J., “Enterprise-wide Modeling & Optimization – An Overview of Emerging Research Challenges and Opportunities”. Computers & Chemical Engineering, vol. 31, 2007, p. 692-711. • Verjans B, Gilbert A, Baleriaux P. “In-Depth Validation of Closed Vial Technology”. BioPharm International, vol. 9, 2012, p. 30-42. • Verjans B, “Using Closed Vial Technology in Aseptic Filling”. Pharmaceutical Technology, 2012, s36-40. • Whyte W and Eaton T. “Microbiological contamination models for use in risk assessment during pharmaceutical production”. European Journal of Parenteral and Pharmaceutical Sciences, vol. 9, 2004, p. 11-15. • Whyte W and Eaton T. “Microbial risk assessment in pharmaceutical cleanrooms”. European Journal of Parenteral and Pharmaceutical Sciences, vol. 9, 2004, p. 16-23. • Woodcock, J. and Wosinska, M. “Economic and Technological Drivers of Generic Sterile Injectable Drug Shortages”, Clinical Pharmacology and Therapeutics, vol 92, 2012, p. 170-176.

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