Pre-Filled Syringe Recalls and Inspections Karen Hirshfield, R.Ph CAPT USPHS Recalls and Shortages Branch Division of Manufacturing and Product Quality Office of Compliance, Center for Drug Evaluation and Research Food and Drug Administration 1 Agenda Benefits/Challenges of glass containers as primary packaging Recall Definitions FDA Responsibilities Trends for PFS recalls Case Studies Inspectional Observations Corrective and Preventive Actions FDA expectations 2 1
Glass has been used for thousands of years to store sensitive medicinals Ancient Roman Apothecary Containers 3 And in modern history for pharmaceuticals Early 20 th Century Drug Bottles 4 2
Pre-Filled Syringe 5 Benefits vs. Challenges Glass Containers as Primary Packaging Benefits Inert Low costs Widely available Mature technology Well understood Challenges Glass is brittle and breaks More complex container-closure integrity Moving from simple to complex delivery systems increases complexity Product stability More components New materials and 6 manufacturing processes 3
Benefits of Using PFS vs. Glass Vials Fewer aseptic manipulations Fewer opportunities for error More accurate dosing Easier to use 7 Glass does not spontaneously break by itself. 8 4
What happens when the glass breaks Nonconformance to specifications Violation of FDA laws Product liability Risk to the consumer Possible recall 9 What is a Recall? A firm's removal or correction of a marketed product that the FDA considers to be in violation of the laws it administers Voluntary Action Effective method to remove or correct consumer products from marketplace Alternative to FDA initiated court action for removing violative products from the market (e.g., seizure) 10 5
Firm Initiated Types of Recalls Firm decides to recall product on its own FDA requested Based on risk of illness or injury and/or gross consumer deception Firm aware of defect but not acting on its own initiative When necessary to protect public health 11 When Are Recalls Initiated? Manufacturers and/or distributors may initiate a recall at any time Firms may also initiate a recall following notification of a problem by state agency in response to a formal request by FDA 12 6
Health Hazard Evaluation Evaluation of health risk-factors should include: If disease or injury already has occurred following the use of a defective drug product Assessment to various patient populations (e.g., children, elderly, immunosuppression) Likelihood of occurrence Assessment of immediate and long-range consequences HHE is used to Classify a Recall 13 Recall Classifications Class I recall: reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death. Class II recall: may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote. Class III recall: not likely to cause adverse health consequences. 14 7
FDA Recall Responsibility Review Recall Letter Notify firm of Classification/Hazard determination Sets appropriate level of recall (consumer, retail, or wholesale) Recommend extent of firm s effectiveness checks Audit effectiveness of recall through FDA visits of consignees Witness product destruction/review reconditioning plan Determine need for Public/Press notification Assure appropriate risk statements included Notify public of recall actions via Enforcement Report Notify appropriate review divisions when recall defect impacts new drug process (i.e., unknown impurity/degradations) Track and trend recalls and defects leading to recalls 15 Where to find recall information www.fda.gov 16 8
17 Drug Recalls FY 2000 FY 2009 18 9
PFS Recalls Since January 2005 there have been 12 CDER recalls involving syringes 2 Class I recalls both compounded Product mix-up Contaminated 8 Class II recalls Lack of efficacy Improper storage temperatures Syringe malfunction 2 Class III recalls mislabeled 19 Case Studies 20 10
Case Study I Existing Pre-Filled Syringe (PFS) product moved to autoinjector New requirements are studied, validated and implemented After many trouble-free ee product lots, unexpected on-line breakage was detected with the device assembly process 21 Case Study I Investigations could not find a root cause New visual inspections implemented Continued investigations still could not find a root cause Affected lots released 22 11
Case Study I Increase in product complaints received Normal complaint rate increases 7X On-line breakage unexpectedly disappears Complaints started to trend down but did not return to historical values 23 Case Study I Investigation closed out with no known root cause but speculates multi-factorial problem Regulatory inspection begins Regulatory body focuses on glass breakage complaints 24 12
FDA 483 Observations Responsibilities and procedures applicable to the quality control unit (QCU) are not fully followed QCU failed to implement adequate supplier controls to ensure that received components conform with quality requirements QCU inspected and released for commercial use the affected syringe lots even though the component was identified as the potential root cause of the product defect [related to consumer complaints] 25 FDA 483 Observations Failure to apply adequate and reliable procedures to ensure that critical components received from the supplier were appropriate for their intended use and meet with the requirements of safety and effectiveness of the final drug product Failure to develop and establish specification and/or inspection criteria i in collaboration with the syringe manufacturing supplier to ensure that quality commitments were met Failure to submit a timely defect report 26 13
Case Study I Outcome HHE determined that the introduction of glass splinters onto the skin could: become sites of localized infection (i.e., cellulites, localized abscess) the product could become potentially contaminated with pathogens due to the microfractures the defective syringes could deliver a subtherapeutic dose, which could cause a flare of the patients' underlying disease Class II recall of 37 lots equaling approximately 3 million syringes was conducted 27 Firm s Corrective Action and Preventive Action (CAPA) A Process Monitoring Program was instituted to better identify, track, and correct glass breakage in the manufacturing process to detect glass issues early and to force remediation of glass issues quickly using a statistical process 28 14
Firm s CAPA Three improvements to the Process Monitoring Program involved: 1. Consistent preventive checks 2. Continuous monitoring and immediate, consistent, effective and efficient remediation of significant events 3. Increase of post-detectability If an off set observed a Non Conformance investigation initiated and completed. 29 Case Study II Increase in the numbers of complaints involving cracked syringes (above baseline) Evaluation aua of the esample pedee determined edthat the cracked body of the syringe was caused by immense forces and only the label was holding the syringe together 30 15
Case Study II Fractures originated on the inside surface of the syringe Unlikely that the defect was created by impact Root cause was attributed to either e the glass forming process or in the filling process 31 FDA-483 Observations Not all adverse drug experiences that are both serious and unexpected have been reported to FDA within 15 calendar days of initial receipt of the information Investigations were not closed within timeframe specified by the firm s SOP 32 16
Investigation extended to Glass supplier Syringe assembler Product Manufacturer Packager Firm s CAPA Hired a third party Glass Specialist to help determine root cause 33 FDA Expectations ti 34 17
Guidance for Industry Quality Systems Approach to Pharmaceutical CGMP Regulations http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm070337.pdf 35 FDA Expectations Corrective and Preventive Action (CAPA) is a well-known CGMP regulatory concept that t focuses on investigating, understanding, di and correcting discrepancies while attempting to prevent their recurrence. Quality system models discuss CAPA as three separate concepts: Remedial corrections of an identified problem Root cause analysis with corrective action to help understand the cause of the deviation and potentially prevent recurrence of a similar problem Preventive action to avert recurrence of a similar potential problem 36 18
FDA Expectations Corrective Action Corrective action is a reactive tool for system improvement to ensure that significant problems do not recur. Both quality systems and the CGMP regulations emphasize corrective actions. Quality systems approaches call for procedures to be developed and documented to ensure that the need for action is evaluated relevant to: the possible consequences the root cause of the problem is investigated a selected action is taken within a defined timeframe the effectiveness of the action taken is evaluated. 37 FDA Expectations Corrective Action (cont.) It is essential to determine what actions will reduce the likelihood of a problem recurring. Examples of information sources include: Nonconformance reports and rejections Returns Complaints Internal and external audits Data and risk assessment related to operations and quality system processes It is essential to document corrective actions taken (CGMP also requires this; see 211.192). 38 19
FDA Expectations Preventive Actions Being proactive is an essential tool in quality systems management. Succession planning, training, capturing institutional knowledge, and planning for personnel, policy, and process changes are preventive actions that will help ensure that potential problems and root causes are identified, possible consequences assessed, and appropriate actions considered. The selected preventive action should be evaluated and recorded, and the system should be monitored for the effectiveness of the action. Problems can be anticipated and their occurrence prevented by reviewing data and analyzing risks associated with operational and quality system processes, and by keeping abreast of changes in scientific developments and regulatory requirements. 39 FDA Expectations Failure investigations should be done when problem is detected Pay attention to safety signals Swift action should be taken Do not continuously inspect quality into the product Visual inspections cannot replace a validated and robust process 40 20
FDA Expectations Root Cause investigation should include analysis of at least the following systems: Equipment Procedures Processes Personnel Raw Material/Component (suppliers) Implement corrective actions quickly If product recall is necessary it is important to bracket the defect based on the root cause the sooner the better 41 FDA Expectations Pharmaceutical companies and glass container manufacturers need to establish a final product quality specification that is based on patient safety and product requirements, which may include: - Develop dimensional design of glass containers - Establish sampling plans - Define glass container lots - Define Acceptable Quality Limits (AQL) - Establish classification and disposition of nonconformities - Establish recommendation criteria for reinspection Reference: PDA Journal of Pharmaceutical Science and Technology, Technical Report No. 43 42 21
FDA Commissioner's Enforcement Initiatives August 2009 announced key initiatives FDA would take regarding enforcement actions Warning Letter and Recall Follow-Up Inspections After a WL is issued or a recall with significant health implications occurs, FDA will make it a priority to follow-up promptly and with appropriate action, such as an inspection or investigation Intended to ensure that appropriate p corrective actions have taken place and to assure that the root cause of the problem which led to the violative conditions has been identified and addressed http://www.fda.gov/newsevents/speeches/ucm175983.htm 43 In Summary Implement a comprehensive Quality System to build quality into the process and product Understand the properties of glass and other packaging components Assure the container/closure suppliers continue to meet all specifications and quickly convey any changes to their processes Investigate out-of-specification findings and consumer complaints and implement corrective actions quickly 44 22
Acknowledgements Mark Browning, RPh, JD, Recall and Shortage Coord. Milind Ganjawala, PhD, FDA Recall and Shortage Coord. April Inyard, PhD., FDA Staff Fellow Donald Obenhuber, PhD, FDA Microbiologist Timothy Pohlhaus, PhD, FDA Staff Fellow Lynn Torbeck, FDA Contractor, Torbeck and Associates Martin VanTrieste, VP Quality, Amgen, Inc. 45 23