The Current State of Compounding Standards: What Happens Next? Eric S. Kastango, MBA, RPh, FASHP Clinical IQ, LLC & CriticalPoint, LLC Madison NJ

Transcription

1 The Current State of Compounding Standards: What Happens Next? Eric S. Kastango, MBA, RPh, FASHP Clinical IQ, LLC & CriticalPoint, LLC Madison NJ

2 Disclosure Information The Current State of Compounding Standards: What Happens Next? Eric S.Kastango, MBA, RPh, FASHP I have the following financial relationships to disclose: Consultant for: USP Pharmacopeial Convention (USP) Royalties from Wolters Kluwer AND I will not discuss off label use and/or investigational use in my presentation.

3 Learning Objectives At the completion of this activity, you will be able to: Describe the concepts in recent compounding legislation affecting state and federal oversight of sterile compounding. Describe the current and future-state requirements dictating compounding standards Describe the current and future-state requirements for determine the beyond-use dating of compounding sterile preparations

4 History of Compounding Pharmacy compounding is simply the art and science of preparing customized medications that are not otherwise commercially available. Compounding is performed by or under the supervision of a pharmacist pursuant to an order from a licensed prescriber for an individual patient. Compounding is an essential element of pharmacy.

5 1975 NCC LVP Yesterday FDA Alert Letter ASHP Urgent Attention Letter ASHP National Survey ASHP TAB USP <1206> ASHP National Survey FDAMA signed into law by President Clinton ; Contained new section 503A regarding pharmacy compounding 2000 ASHP Guidelines revised 2002 Supreme Court held unconstitutional certain advertising restrictions in section 503A ASHP National Survey

6 Today 2004 January 1, USP <797> first published November, NIOSH Alert published 2008 USP <797> revised, new standard effective June st CriticalPoint National USP <797> Compliance Survey 2012 CDC and CMS recognizes USP <797> NECC tragedy 2 nd CriticalPoint USP <797> Compliance Survey rd CriticalPoint USP <797> Compliance Study The Drug Quality and Security Act becomes law 2014 FDA published 503A and 503B guidance 4 th CriticalPoint USP <797> Compliance Study 2015 USP publishes USP 800-two public comment periods USP publishes proposed revisions to USP 797 FDA issues a series of draft guidance documents 5 th CriticalPoint USP <797> Compliance Study

7 Study the past if you would define the future Confucius

8 Who s been involved in compounding contaminated drugs? What do these entities have in common? Retail/Community-based Homecare/Home Infusion Hospital Commercial outsourcer They all: are licensed as pharmacies by their respective state boards of pharmacy considered compounding pharmacies by the FDA represent the full spectrum of practice settings run by pharmacists

9 What s the damage? Since 2001 over 25 pharmacy compounding incidents with 1,049 adverse events, including 89 deaths, have been reported. Contamination of sterile preparations was the most common compounding error, though others were the result of pharmacists' and technicians' miscalculations and mistakes in filling prescriptions.

10 Our patients have never had a problem.

11 Brutal Facts (continued) Year State Description 2005 New Jersey, California Up to 25 patients contracted Serratia marcescens infections due to contaminated magnesium sulfate minibags prepared by a compounding pharmacy 2005 Minnesota 2 patients were blinded after receiving a compounded trypan blue ophthalmic injection contaminated with Pseudomonas aeruginosa and Burkholderia cepacia; the injectable product is a commercially available product 2005 California Sterile talc vials with unwashed stoppers were not sterility tested before distribution from an outsourcing compounding pharmacy 2005 Maryland 10 patients died after exposure to cardioplegia solution from 2 lots contaminated with gram-negative rods

12 Brutal Facts (continued) Year State Description 2006 Nevada 1 baby died from a 1,000-fold zinc overdose (mcg and mg zinc sulfate confused) compounded in a hospital pharmacy 2006 Ohio 1 child died after a compounding error led to administration of chemotherapy in 23.4% sodium chloride injection instead of 0.9% sodium chloride 2007 Washington, Oregon 2, possibly 3, patients died after receiving an intravenous colchicine product compounded at a concentration higher than standard (4 mg/ml vs. 0.5 mg/ml) in a compounding pharmacy 2009 Florida 21 horses died after receiving a compounded substitute vitamin supplement containing vitamin B, potassium, magnesium, and selenium (product not approved in the US)

13 Brutal Facts (continued) Year State Description 2010 Illinois 1 child died after receiving more than 60 times the amount of sodium chloride prescribed due to a 2011 California, Florida, Tennessee compounding error in a hospital pharmacy 16 patients being treated for wet macular degeneration developed severe eye infections due to contamination of AVASTIN (bevacizumab) during compounding; one patient blinded, another patient developed brain infection 2011 Alabama 9 patients among 19 died when PN solutions that were administered were contaminated with Serratia marcescens during compounding using non-sterile components to prepare amino acids 2012 California 9 patients developed fungal endophthalmitis after use of the compounded product Brilliant Blue-G (BBG) or receiving injections of triamcinolone-containing products dispensed from the same compounding pharmacy

14 NECC Date Location Cause Injuries New England Compounding Center (NECC) Meningitis Outbreak Death(s) 64 September 21, 2012 October 23, 2013 (no further CDC updates expected) USA (20 States) Fungal meningitis contamination of steroid medication 751 total case count; 384 meningitis and spinal infection; 7 stroke; 325 paraspinal/spinal infection; 33 peripheral joint infection; 2 spinal and peripheral joint Some patients recovering from the meningitis are falling ill again. Sufferers of the new infection are now coping with epidural abscesses and infections near the injection site. More than 20 lawsuits filed against NECC, 25 count indictment against Litigation The scale 14 of the meningitis outbreak makes this event the worst among a series of fatal or harmful infections and overdoses linked to pharmacy compounding practices in the US rivaling other key drug safety issues in the past that have led to substantial drug safety legislation.

15 Brutal Facts Continue Since NECC: 2013 & 2014 Year State Description 2013 Connecticut FDA announced that a compounding pharmacy in New Jersey was voluntarily recalling all of its products after a Connecticut hospital reported that 5 bags of magnesium sulfate from the pharmacy were contaminated with mold. The pharmacy has since been closed by the NJ Division of Consumer Affairs Georgia, Louisiana, South Carolina and Indiana Texas A compounding pharmacy in Augusta, Georgia, is voluntarily recalling 79 lots of bevacizumab-filled syringes (Avastin, Genentech) intended for retinal injections because of the risk for eye infection, the US Food and Drug Administration (FDA) announced yesterday. A batch of compounded IV Calcium Gluconate found to be contaminated with Rhondococcus equii. 15 infected patients, 2 deaths (relationship to drug not known) 2014 Oregon A patient died after being given rocuronium instead of fosphenytoin. The order was correct, the bag was labeled correctly, it was independently checked by a 2 nd person however the rocuronium vials were not noticed and the error went undiscovered.

16 FDA Inspection of Compounding Pharmacies Figures do not include pharmacies dedicated to producing veterinary drugs. Note: years represent fiscal years October 1 September 30. Fiscal year 2014 includes data through 9/12. Source: US Food and Drug Administration, USA Today Research. Table excerpted from: Eisler P and Schmaars C. Safety, sanitary problems prompt scores of drug recalls. USA Today. October 7, 2014 retrieved from on October 7, 2014.

17 Used with permission, Ridgewood Medical Media, LLC Used with permission

18 USP Compounding Standards Chapter <797>: Sterile Compounding Official on January 1, 2004 Revised chapter official on June 1, 2008 Proposed changes published September 25, 2015 Nationally enforceable 28 states require compliance More states are modifying regulations Codify USP <797> Adopt portions Develop own regulations No action Chapter <795>: Nonsterile Compounding Proposed Chapter <800>:Hazardous Drugs

19 State Regulation of Pharmacy Compounding All states license pharmacists to compound Each state has varying degrees of regulations and oversight and enforcement of compounding practices Only 28 states require direct compliance with USP 797 after 11 years Until USP <797>, no consistent and enforceable compounding standard of practice existed

20 Overall Compliance Scores 2011 vs 2014 based on State Regulations 86.0% Over 4 year period, overall compliance scores grouped by state regulatory status: Overall compliance improvement (all states) 7.4% 85.4% 81.0% Red states improved by 10.0% Yellow states improved by 8.4% 81.6% 81.3% Green states improved by 11.1% 80.3% 76.0% 74.3% 73.9% 71.0% 71.6% 71.9% 66.0%

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22 Thought You can avoid reality, but you cannot avoid the consequences of avoiding reality. Ayn Rand ( ) 2014, Clinical IQ, LLC. Provided under limited license from Clinical IQ, LLC

23 Proposed USP <797> Summary of Major Changes: 3 risk levels changed to 2 categories distinguished by conditions under which they are made and time within which used Quarterly requirement for Personnel Monitoring (visual observation of hand hygiene and garbing, MFT and ongoing GFS) BUD and Storage times changed with a maximum BUD of 45 days regardless of sterility testing Master formulation and compounding records will be required for all batch and non-sterile compounding New placement requirements on use of isolators Removal of HD handling section and cross-referenced to USP 800 Quarterly requirement for Viable Air sampling and Surface sampling Introduction of In-Use time (time before which conventionally manufactured product or compounded dilution bag must be used after it is punctured) New guidance for sterility testing of CSP prepared in batch sizes of less than 40. (10% rule) Requirement for sterile gloves and sterile sleeves, sterile wipers and cleaning tools that need to be re-sterilized but not sterile disinfectants

24 Briefing of Proposed Changes Reorganized, redundancies eliminated, and requirements clarified Minor editorial changes have been made to update the chapter to current USP style. Organized in a similar manner as 21 CFR Part 211 US FDA CGMPs Key procedures placed in boxes for reference All sample documents and media procedures removed Hazardous Drug requirements referred to USP <800> Allergen extracts no longer given a carve-out Radiopharmaceuticals still need to comply with USP 797 Administration is still out of scope defer to CDC guidance

25 Definitions and Practice Issues Current USP Chapter <797> rejects this statement Compounding does not include mixing, reconstituting, or similar acts that are performed in accordance with the directions contained in approved labeling provided by the product's manufacturer and other manufacturer directions consistent with that labeling [21 USC 321 (k) and (m)]. For one patient for immediate administration a function of medication administration This is fundamentally low-risk compounding Batching <797> applies

26 Current BUD Paradigm Applied only to pre-administration activities (handling, compounding and storage) Once CSP was administered, then USP 797 was no longer applicable Chemical Stability must be assured during the use of the CSP Not capped: USP 71 Sterility Test passed has allowed BUD to chemical stability of the drug. Not Closure-Container Integrity Test required Current USP 797 is silent on the requirements for compounding multi-dose vials/containers USP <51> Antimicrobial Effectiveness Test

27 New Proposed BUD Paradigm NEW DEFINITION: The date or time after which a CSP cannot be used and must be discarded. The BUD is determined from the time the CSP is compounded. One day is equivalent to 24 hours. BUDs is capped to 42 days refrigerated Closure-Container Integrity Test required for frozen CSPs CSPs that are made as a MDV must undergo USP <51> Antimicrobial Effectiveness Testing

28 Proposed USP 797: Category 1 CSPs PEC placement Sterility Testing Endotoxin Testing BUD Not in ISO classified air Not required Not required 12 hours room temperature or 24 hours refrigerated

29 Terminally Sterilized CSPs Aseptically Prepared CSPs Proposed USP 797: Storage for Category 2 CSPs PEC placement Sterility Testing Endotoxin Testing Storage BUD Assignment Placed in ISO classified air Based on BUD Assignment below Required if sterile components are used > 12 hour room temperature or > than 24 hours refrigerated Method Sterility Testing Preservative Added Controlled Room Refrigerated Frozen No No Made from 1 or more non sterile components 4 days 7 days 45 days Made with only sterile components 6 days 9 days 45 days Yes (USP 51) 28 days 42 days Yes No 28 days 42 days Yes (USP 51) 42 days 42 days No No 14 days 28 days Yes Yes (USP 51) 28 days 42 days No 28 days 42 days Yes (USP 51) 42 days 45 days 45 days

30 How to Provide Comments to USP Go to and search for USP <797> Download the proposed revisions Comments must be submitted on Comment Submission Template by to by January 31, 2016 Be sure to include line numbers for your comments If you have any questions, contact the Healthcare Quality Standards team at

31 Summary Patients will always be at risk of compounding errors State Boards of Pharmacy are responding the challenges in providing regulations and oversight for 503A pharmacies Employees must skilled, educated and trained! A knowledgeable workforce is necessary for success. Employee Vigilance and adherence to robust work practices are required to maintain a state of control. Building a compliant facility isn t enough! Maintaining the facility and regularly measuring and adjusting its performance during regular service from certification professionals is necessary. Environmental Sampling provides the ongoing evidence of the effectiveness of the facility, cleaning and work practices in achieving an environment that is suitable for compounding sterile preparations.

32 Resources USP website: Pharmacy OneSource USP 797 webinars webinars/ CriticalPoint e-learning lesson Pharmacy, Purchasing and Products Magazine

33 Thank you My contact information: Eric S. Kastango, MBA, RPh, FASHP 235 Main Street, Suite 292 Madison, NJ