Compliance Requirements for Traditional Compounding (503A) and Outsourcing Facilities (503B)

Transcription

1 Compliance Requirements for Traditional Compounding (503A) and Outsourcing Facilities (503B) Bringing 503B into 503A to Improve Organizational Practices Ken Speidel, PharmD, RPh, FIACP, FACA Facilitator, LP3 Network Inc. Consultant, MEDISCA Network Inc. Vice President Compounding Compliance, Gates HealthCare Consulting

2 Disclosures I, Ken Speidel, declare no conflicts of interest, real or apparent, and no financial interests in any company, product, or service mentioned in this program, including grants, employment, gifts, stock holdings, and honoraria. The American College of Apothecaries is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.

3 Disclosures Ken Speidel is a Facilitator of LP3 Network Inc. s copyright program materials and a Consultant for MEDISCA Network Inc. 3

4 Copyright and Disclaimer The material in this presentation is Copyright 2017, LP3 Network Inc. DISCLAIMER: The information contained in this presentation, which may include treatment modalities, diagnostic and therapeutic information, and instructions related to regulatory guidelines and current standards of practice for pharmacy compounding, is FOR EDUCATIONAL PURPOSES ONLY and should not be taken as a treatment regimen, product indication, suggested treatment modality, or suggested standard of practice. NOTE TO MEDICAL OR ALLIED HEALTH PROFESSIONALS: Any treatments, therapies, or standards of practice must be fully investigated and prescribed by a duly licensed medical practitioner in accordance with accepted professional standards and compendia. Any regulatory or practice standard must be fully investigated by a licensed pharmacist in accordance with accepted professional practice standards and compendia. The opinions and views expressed in this presentation are those of the presenter only, and do not necessarily represent the views of LP3 Network Inc.

5 Learning Objectives At the conclusion of this program, the participating pharmacist or technician will be able to: Describe general differences between 503A and 503B practices Identify compounded preparations and drug product processing for the 503A and 503B practice. State GMP or GMP-like practices for consideration for employment into a 503A operation (503A+). Outline fundamental first-steps in making a culture change toward a GMP mindset.

6 Outline 1 Infrastructure and Operations 2 Environment 3 Preparation / Product

7 Let s Get Started 1 Infrastructure and Operations 2 Environment 3 Preparation / Product

8 Infrastructure and Operations Scope of practice 503A Formulates for one patient Compound for: Patient-specific prescription Office-use or hospital Note: This is unacceptable from a federal perspective Anticipatory compounding in limited quantities Presence or absence of a memorandum of understanding Memorandum of Understanding (MOU) Signed between State and FDA Not signed between State and FDA 30% maximum volume as interstate commerce 5% maximum volume as interstate commerce

9 Infrastructure and Operations Scope of practice 503B Manufactures for many patients Prepare medications before, with or without receipt of a prescription for an individual patient Distribute for: Office-use and hospitals No patient-specific prescription required Distribute or sell: For interstate commerce with no maximum To healthcare facilities that provide medical services directly to patients or a network of licensed providers

10 Infrastructure and Operations Personnel Mindset 503B Develop a cgmp mindset Fundamental cgmp Concept Can you apply it to 503A? Construct an ideology, an attitude and vigilant adherence to detail that is harmonized with a set of actions and behaviors in the formulation production process.

11 How do you Develop a cgmp Mindset? Look for opportunities to take 503B concepts and bring them into your 503A practice You can become 503A+

12 Infrastructure and Operations Personnel Management 503A Personnel must undergo: Training Qualification Annual refresher training and requalification Format: Written Documented outcome measures United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

13 Infrastructure and Operations Personnel Management 503B Personnel must maintain constant and consistent: Training Qualification Monitoring Fundamental cgmp Concept Can you apply it to 503A? The qualitative and quantitative specificity and rigor of personnel working in non-aseptic and aseptic manufacturing environment is essential to ensuring quality.

14 Infrastructure and Operations Personnel Management 503A+ Considerations Conduct Observational Checklists beyond USP requirements Packaging Weighing Calibrating Emergency Preparedness Drill Recall Drills HD Spill Drills Constant training (not yearly/biannually)

15 Infrastructure and Operations Personnel Management 503A+ Considerations HD Spill Observational Checklist (abbreviated) Note: If the spill is too large and dangerous ** Call Emergency Number 911, declare a Hazmat spill if appropriate for spills, you are not prepared to manage internally as the following scopes: - Immediately check yourself for contamination. If contaminated, remove contaminated protective clothing and examine your clothes for contamination which may have soaked through. If day clothing is contaminated, remove, and wash skin under running water or safety shower immediately for 15 minutes or until medical attention arrives. - Notify others and clear the area of unprotected personnel (i.e. evacuate the lab if risk of fire is high or inhalation risk exists). - DO NOT open windows to ventilate the spill as this will usually push the vapors into uncontrolled parts of the building which will require a larger evacuation and potential for widespread exposure. - If there is not a BSC/Containment or fume hood and windows are the only means of ventilation, then only open them after the liquid has been absorbed and bagged. The need for further evacuation must be assessed prior to opening the windows. - To prevent a fire safely, DO NOT operate switches on equipment or power outlets in the immediate vicinity of the spill as this could ignite any vapors. Extinguish open flames / isolate other ignition sources in the area around the spillage. - Call Emergency number if quantity of the spillage exceeds 500ml. - Only personnel trained to clean up a spillage are to be involved in the clean-up. - At least 2 persons are required for spills clean up. - Check SDS for specifics of PPE, a full cartridge respirator is located in the marked Cabinet in the shipping/receiving area. - Post notice/sign on door to restrict/prevent entry to the lab during clean up and ventilation period. - Second person (trained personal) to have fire extinguisher ready if the need arises. - Contain the spillage by using the adsorbent powder in the kit. If more is needed then an additional bag is located is located in the marked Cabinet in the shipping/receiving area. - Carefully check the limits of the spill to avoid walking into it or any spatter on the floor. - COVER SLOWLY and absorb the spill with non-combustible absorbent pads (kitty litter or proprietary powder) from the chemical spill kit starting from the outside of the spill area working towards the center. If the spill is very small, one pad may be to the appropriate size of the spill. - Collect the absorbed spillage using a dustpan and plastic spatulas or scoops and place into a white bucket / plastic bags provided. Tie the bag with a cable tie and double contain in a second bag also sealed with a cable tie. to remove hazardous vapors. - Label the waste as follows: Chemical Name & Concentration, Contaminated absorbent pads, broken glass, Chemical Spillage pads, powder (if used). - Organize for chemical waste disposal by the usual method. - The person who spilled the chemical or a witness should complete an incident report with their supervisor or a manager.

16 Infrastructure and Operations Example of Qualification and Monitoring Garbing and Gloving 503A & 503B Initial qualification includes: 3 consecutive times tested 0 colony forming units (CFU) on each test Hand hygiene and garbing procedures training Gloved fingertip/thumb sampling testing United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015). U.S. Department of Health and Human Services Food and Drug Administration (CDER, CBER, and ORA), Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Guidance for Industry, September 2004.

17 Infrastructure and Operations Example of Qualification and Monitoring Garbing and Gloving 503A Quarterly requalification 1 test (0 CFUs total for both hands) Requalification after 3 month absence Garbing and Gloving 503B Annual requalification 3 consecutive tests (0 CFUs on each test) Daily glove testing and an aseptic gowning qualification program Observational checklist Sample from front of operator (e.g., forehead, chest, left and right forearms)

18 Infrastructure and Operations Quality Mandate 503A Requires: Quality assurance (QA) and quality control (QC) program Responsible for: Written processes that, at a minimum, verifies, monitors, and reviews the adequacy of the compounding process (QA) Observation of techniques and activities that demonstrate requirements are met (QC) United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

19 Infrastructure and Operations Quality Mandate 503B Requires: Construction of an autonomous quality team Responsible for decisions to accept or reject formulations: Based upon a comprehensive set of predetermined specifications Independent of either financial or distribution pressures

20 Infrastructure and Operations Quality Mandate 503A+ Considerations Construct a Quality Team Add CAPA management processes (Correction processes required) Prevention needs to occur Acquire Compliance Software System Reminders Competency events Media fills Garbing/Gowning Licensure Environmental Certifications Maintenance Events Computerized LUMACs (Logs of Use Maintenance and Cleaning) Quality indicators Formal system for input, tracking, and trending

21 Cloud Software Infrastructure and Operations Quality Mandate 503A+ Considerations

22 Infrastructure and Operations Standard Operating Procedures (SOPs) Construct and operationalize standard operating procedures SOP 503A Requires SOPs that address USP general chapters: <795>, <797>, and <800> SOP 503B Requires process validation driven SOPs Fundamental cgmp Concept Can you apply it to 503A? In order to ensure process uniformity within an organization, and maintain it consistently, detailed and specific standard operating procedures must drive all critical processes. 503A+ Change Control SOP LUMAC Vendor Validation

23 Infrastructure and Operations Process Validation 503A Process validation is not an inherent operational component of the USP General Chapter <797> Process Validation 503B Impart consistent and complete process validation in all critical steps Process validation is defined as: Fundamental cgmp Concept Can you apply it to 503A? The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is CAPABLE of consistently delivering the expected quality products. 503A+ Operations Management Software

24 Infrastructure and Operations Verification: A Part of Validation Confirmation that a method, process, or system will perform as expected under the conditions of actual use. 1 erification 1. United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

25 Infrastructure and Operations From Receipt to Release 503A Standards require a minor process centered around trust but not a verification As per the USP General Chapter <795>: If a manufactured drug product is the source of an active pharmaceutical ingredient, then the drug product shall be manufactured in an FDA-registered facility

26 Infrastructure and Operations From Receipt to Release 503B A vendor validation process should be constructed Incorporate a process from the receipt to the release of: Materials Supplies Packaging Non-sterile ingredients Fundamental cgmp Concept Can you apply it to 503A? Confirming the identity and quality of starting materials is fundamental to building quality into the manufacturing process.

27 Infrastructure and Operations From Receipt to Release 503A+ Considerations Chemical Quality Construct a Vendor Validation SOP Construct a credentialing process and documents to be completed by vendor FDA inspected Description of their 3 rd party chemical identification process C of A process description Vendor visit Quarantine area in the receiving area Establish Criteria (checklist) for acceptance Construct substrate/equipment evaluation, acceptance and rejection SOP

28 Infrastructure and Operations From Receipt to Release 503A+ Considerations Chemical Purchasing Ensure active pharmaceutical ingredients purchased have a USP-NF monograph or; Are a component of an FDA approved drug list or; Are on the FDA-approved list of bulk drug substances that may be used to compound drug products. Ensure active pharmaceutical ingredients on the following lists are not purchased for compounding purposes: FDA list of drugs that demonstrate difficulty to compound. FDA list of drug products that have been withdrawn or removed from the market for reasons of safety or effectiveness. Assess compendial monograph requirements for the ingredient, whenever possible. Review Safety Data Sheet (SDS) of the chemical. Maintain and update the facility-specific list of hazardous substances utilized by the Pharmacy. Purchase appropriate chemical grade based on its intended use. Review Certificate of Analysis (COA) of the chemical to ensure identity, purity and quality.

29 Infrastructure and Operations From Receipt to Release 503A+ Considerations Chemical Purchasing (continued) Determine appropriate amount and container size of chemical to order. Review the need for special chemical storage conditions including but not limited to: Space. Temperature and humidity. Ventilation. Lighting. Segregation. Ensure that vendor qualification procedures have been satisfied prior to placing a purchase order. Ensure vendor is FDA registered and licensed in good standing. Review vendor sampling methods and quality control procedures, whenever possible. Consolidate orders such that all items needed from the same vendor are placed on the same order. Verify and document method of payment for all orders.

30 Infrastructure and Operations Equipment management 503A USP General Chapter <797> requires that: "The equipment used for compounding compounded sterile preparations (CSPs) must be of appropriate design and adequate size" United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

31 Infrastructure and Operations Equipment Management 503B Requires: An equipment calibration, validation, and preventative maintenance system A robust process validation system, i.e., Understand how equipment will be used to achieve the quality, integrity, strength, and sterility of each batch Initial and regular validation of each piece of equipment or group of equipment A calibration log that specifies: Frequency of calibration Points where calibration is checked Acceptable operating range

32 Infrastructure and Operations Equipment Management 503A+ Considerations Thermal mapping of temperature-related equipment Refrigerators Autoclave Dry heat oven Lower cost modified mappings can be constructed Use NIST-certified devices (National Institute of Standards and Technology) Create LUMACs (Logs of Use Maintenance and Cleaning) for critical equipment Barcode equipment to track usage and maintenance

33 Infrastructure and Operations QA/QC 503A USP General Chapter <797> requires: Written QA and QC programs Adherence to procedures in the prevention and detection of errors Addresses quality problems with appropriate corrective actions USP-related QA standards are generally less proactive and less preventative United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

34 Infrastructure and Operations Corrective Action and Preventive Action (CAPA) 503B Requires: Construction of compliance system To identify operational variances To operate a complaint system/capa plan To track and trend feedback to improve the formulation / manufacturing process CAPA system focuses on: Systematic investigation of discrepancies (failures and/or deviations) Attempts to prevent their reoccurrence (corrective action) Eliminates the cause of potential nonconforming product and other quality problems (preventive action)

35 Infrastructure and Operations Corrective Action and Preventive Action (CAPA) 503A+ Considerations Change culture to correction AND prevention Appoint a quality manager (10 hrs/week) Create a quality team Employ quality management software Track and trend

36 Outline 1 Infrastructure and Operations 2 Environment 3 Preparation / Product

37 Environment Facility Management 503A and 503B Any quality compounded/manufactured medication must be produced in a suitable environment that controls the risk of contamination and error Fundamental cgmp Concept Can you apply it to 503A? Operate and maintain all buildings/facilities with extreme vigilance with an emphasis on environmental monitoring.

38 Environment Environmental Management Requires: Comprehensive cleaning and disinfecting procedures and processes Facilities and equipment to be qualified, calibrated, cleaned, and maintained Prevent contamination and errors Critical to ensure suitability and appropriateness of use Equipment use logs Recognize the human factor in environmental management 10 Million Particles / Cu Ft. 503A+ Considerations Sterile Containment Suits Sterile Gowns/Sleeves Sterile Cleaning Utensils/Solutions, Autoclave Garb Management at Facility

39 Environment Certification 503A Sterile compounding facilities must be qualified initially using environmental air and surface sampling to establish a baseline level of environmental quality. 1 Do We Trust but Verify? 1. United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

40 Environment Certification 503B Perform triple clean 3 consecutive times (validation) 1 bactericidal agent 1 sporicidal agent Sterile isopropyl alcohol (SIPA) Time interval between cleanings (e.g., 1 week for full cleans) Sampling, incubation, and interpretation of results Failure implies excursions to action levels Reassess procedure for effectiveness Improve, if required Repeat 3 consecutive runs Results must meet acceptance criteria

41 Environment Certification 503A+ Considerations Examine certifier competency (CETA) Control and monitor certifier behaviors (SOPs) PEC and SEC smoke visualization Triple clean monthly 1. United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

42 Environment Cleaning & Sanitizing Frequency 503A Primary engineering controls (PEC) Beginning and end of each shift Before each batch Every 30 minutes Work surfaces outside PEC and floors daily Walls, ceilings, storage shelves monthly Following sampling HD Deactivation 2 % (w/w) sodium hypochlorite soap solution 1 % (w/w) sodium thiosulfate; 0.9 % (w/w) benzyl alcohol United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015). U.S. Department of Health and Human Services Food and Drug Administration (CDER, CBER, and ORA), Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Guidance for Industry, September 2004.

43 Environment Cleaning & Sanitizing Frequency 503B Horizontal surfaces daily Between batch production runs Full room cleaning weekly Monthly cleaning Following sampling

44 Environment Cleaning & Sanitizing Frequency 503A+ Considerations Internal smoke visualization Triple clean monthly Documentation Peer sign GoPro camera Sterile solutions/utensils State of control documentation Construct MFR and CR for cleaning process including dilution preparation Record lot number of cleaning solutions Checklist for cleaning process Observational checklist for operator validation Separate mop handles per room Include non-pathogenic biological indicators in cleaning validation

45 Environment Nonviable Airborne Particle Sampling 503A Every 6 months; all ISO classified environments If ISO-8 or ISO-7 action levels exceeded: Conduct route cause analysis; take corrective action If ISO-5 PEC action levels exceeded: Cease compounding activities Implement corrective action plan immediately ISO Levels and nonviable airborne particle limits applicable to 503A and 503B ISO Classification Non-viable Particles ( 0.5 µm/m 3 ) 5 3, , ,520,000 United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

46 Environment Nonviable Airborne Particle Sampling 503B Each production shift If action levels exceeded: Conduct investigation consistent with severity of the excursion Includes an evaluation of trended data Take appropriate corrective action to prevent future deviations Remote particle counting systems recommended ISO Levels and nonviable airborne particle limits applicable to 503A and 503B ISO Classification Non-viable Particles ( 0.5 µm/m 3 ) 5 3, , ,520,000 United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015). U.S. Department of Health and Human Services Food and Drug Administration (CDER, CBER, and ORA), Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Guidance for Industry, September 2004.

47 Environment Nonviable Airborne Particle Sampling 503A+ Considerations Acquire Particle Counter or.. Increase Frequency Utilize During Compounding Processes Batching (anticipatory compounding) Trend particulate levels per site over time Personnel behaviors (unwrap, wipe down, type of materials)

48 Environment Viable Airborne Particle Sampling 503A 503B At least monthly All controlled environments Active air sampling Each production shift All controlled environments Active / Passive air sampling Air classification and recommended action levels of viable airborne particle sampling ISO Designation Active Air Action Level (CFU/m 3 ) Settling Plate Action Levels (diameter 90 mm; (CFU/4 hrs) Speciation is always required to rule out pathogens United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015). U.S. Department of Health and Human Services Food and Drug Administration (CDER, CBER, and ORA), Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Guidance for Industry, September 2004.

49 Environment Viable Surface Particle Sampling 503A At least monthly; all ISO classified environments If ISO-8 or ISO-7 action levels exceeded: Conduct route cause analysis Take corrective action If ISO-5 PEC action levels exceeded: Cease compounding activities Implement corrective action plan immediately United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015). U.S. Department of Health and Human Services Food and Drug Administration (CDER, CBER, and ORA), Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Guidance for Industry, September 2004.

50 Environment Viable Surface Particle Sampling 503B Each production shift Floors, walls, and equipment surfaces Critical surfaces Sample timing, frequency, and location selected on the basis of relationship to operations performed Speciation is always required to rule out pathogens United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015). U.S. Department of Health and Human Services Food and Drug Administration (CDER, CBER, and ORA), Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Guidance for Industry, September 2004.

51 Environment Viable Surface Sampling 503A+ Considerations Initiate CAPA principles Demand certifier sample 1000L Acquire viable air sampler Increase frequency of sampling Use to validate state of control Use non-pathogenic Biological Indicators to validate the cleaning

52 Outline 1 Infrastructure and Operations 2 Environment 3 Preparation / Product

53 Preparation/Product Preparation Management 503A Pre-established table with beyond-use dates (BUDs) based on: Presence or absence of a sterility test performed with results pending Presence or absence of a preservative Storage temperature BUDs are calculated in terms of hours or days United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

54 Preparation/Product Product Management 503B Impart consistent and complete process validation in all critical steps Develop and maintain a compendial compliant program for chemicals, final product stability, and an expiration dating program Stability indicating assay (SIA) Fundamental cgmp Concept Can you apply it to 503A? The effectiveness of any procedure used to sterilize or assure the quality and stability of a manufactured product must be established through process validation. Fundamental cgmp Concept Can you apply it to 503A? There must be a robust stability program that uses appropriate and validated methods and procedures to determine the stability characteristics of the finished manufactured product and to establish appropriate storage conditions and expiration dates.

55 Preparation/Product Preparation Management 503A+ Considerations Purchase chemicals in smaller containers to reduce exposure and cross contamination Utilize nitrogen gas to be bubbled into aqueous CSPs to reduce oxidative load Destruct all non-used chemicals once removed from the original container Conduct viable air sampling during Media fills Conduct non-viable sampling during batch activities Validate formulas Incorporate process validation principles Barcode & validate all Ingredients Convert all liquids into density Peer review of all ingredients, volumes and masses Video recording of compounding process Employ compounding validation software

56 Preparation/Product Media Fill 503A Simulation of aseptic processes from complex formulations No requirement for environmental monitoring data to be correlated against the media fill test Media Fill 503B Each production run must go through a media fill procedure to validate the run Environmental monitoring data must be correlated against media fill test Where there is a change in formulation/equipment/process (Change control). United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015). U.S. Department of Health and Human Services Food and Drug Administration (CDER, CBER, and ORA), Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Guidance for Industry, September 2004.

57 Preparation/Product Media Fill Qualification 503A+ Considerations Each batch (anticipatory), complex and high clinical risk formulations have media fill process Viable surface and air testing incorporated within process Post-procedure sampling include garment forehead, trunk, abdomen, sleeves Increase requalification frequency Include in change control process Video process for review by operator and trainer

58 Preparation/Product Sterilization Processes 503A Filtration method Certified by manufacturer as suitable for pharmaceutical use Physical and chemical compatibility tested Filter integrity tested after use Terminal sterilization (dry or steam sterilization) Sterility assurance level (SAL) of 10 6 Effectiveness established and verified with each run Physicochemical indicators and integrators United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015). U.S. Department of Health and Human Services Food and Drug Administration (CDER, CBER, and ORA), Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Guidance for Industry, September 2004.

59 Preparation/Product Sterilization Processes 503B Filtration method Manufacturer retention test Physical and chemical compatibility Microbial challenge test Evaluation of product bioburden Filter integrity test Terminal sterilization (dry or steam sterilization) Sterility assurance level (SAL) 10-6 Biological indicators Physicochemical indicators and integrators Physio-chemical stability evaluated

60 Preparation/Product Sterilization Processes 503A+ Considerations Evaluate physiochemical stability of APIs/excipients and container/closures Terminally sterilize as much as possible Increase the quantity of BIs Map the position of the BIs Locate BIs within vials to simulate CSPs Include and enhance chemical integrators Sample retention Incorporate bioburden reduction for formulation process

61 Preparation/Product Finished Preparation Testing (Release?) 503A Physical inspection for physical defects; leaks, cracks, and seals Inspected against a lighted white and black background Category 2 CSPs must be sterility tested in compliance with USP General Chapter <71> Membrane filtration method is preferred; direct inoculation is the alternative CSP release prior to sterility test completion requires frequent observation of specimen and immediate recall if evidence of microbial growth Positive results imply immediate speciation Continued United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

62 Preparation/Product Release Testing 503A Category 2 CSPs made from nonsterile ingredients, except inhalation and topical ophthalmic administration, must be tested for excessive bacterial endotoxins Nonsterile ingredient certificate of analysis (COA) lists endotoxin burden Endotoxin burden is predetermined to be acceptable Material is segregated under cool and dray conditions In absence endotoxin limit in monograph or other CSP formula source, CSP must not exceed endotoxin limit calculated as described in USP General Chapter <85> for appropriate route of administration United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

63 Preparation/Product Release System 503B Develop a finished product release system The release system: Assures each batch of product conforms to predetermined specifications Contains written procedures for release of finished products Must include an established sampling plan for testing completed finished batch

64 Preparation/Product Release Testing/System 503A+ Considerations Barcoding all substances in the formulation process Barcoding all equipment used in the formulation process Convert all liquids into a mass (density) for accuracy Photograph finished preparations Develop a formulary system Increases opportunity to validate formulas Test all aliquots for potency prior to use (1 for many) Test all batches for potency Acquire color sampling for accuracy Conduct container closure evaluations on susceptible and high volume preparations

65 Preparation/Product Final Packaging and Labeling 503A Packaging materials must maintain physical integrity, sterility, and stability of CSP Container closures Inspect for defects Check for leakage, cracks in container, or improper seals Tamper-evident closures and seals recommended Light-resistant packaging materials Ensure sterility prior to use Storage area monitoring daily Temperature controlled USP General Chapter <17> Prescription Container Labeling United States Pharmacopeia. General Chapter <797> Pharmaceutical Compounding Sterile Preparations (published for public comment in Pharmacopeial Forum (PF) 41(6) [Nov. Dec. 2015] on November 2, 2015).

66 Preparation/Product Final Packaging and Labeling 503B Package type to ensure product sterility and integrity Container-closure testing Compatibility of the container-closure system with finished preparation (e.g., consider leachables, interactions, and storage conditions of the components) Stability-indicating within container Controlled storage and shipping Temperature monitoring Labelling Pre-established Conforms to requirements U.S. Department of Health and Human Services Food and Drug Administration (CDER, CBER, and ORA), Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practice, Guidance for Industry, September 2004.

67 Preparation/Product Final Packaging and Labeling 503A+ Considerations Photograph preps for MFR (what it should look like once complete) Acquire color sampling for accuracy Conduct container closure evaluations on susceptible and high volume preparations Conduct shipping validation tests Temperature tracking (USB, strips, etc.)

68 Summary Vendor Validation Ingredients and Supplies Selection Program Preparation or Product Release Testing Program Change Mindset (cgmp-like Environmental Management and Monitoring Program Components for Success Validate SOPs via Process Validation Constant and Consistent Personnel Training Autonomous Quality Team Activate CAPA 12 Tenants to cgmp 1) GMP Mindfset 2) Autonomous Quality Team 3) Process for Release/Receipt 4) Facility Vigilance 5) Process Validated of SOPs 6) Constant/Consistent Training 7) Maintain Final Prep/product check 8) Facility/ Equipment Cleaning 9) Process Validation Critical Steps 10) Facility/ Equipment Maintenance 11) Activate CAPA 12) Maintain Prep/Product Relase

69 It Depends? Where do you Begin? Changing Directions from a 503A to 503B practice Integrating concepts of 503B into a 503A 503A + 503B (concepts) = 503A+ Current regulatory status Potential market Prioritize High Risk, High Volume and Problem Prone Areas Change Culture to a Quality Culture Evolve from fire fighting to fire prevention Trend Past Data and QREs to determine areas of need/risk. Don t let history repeat itself. Learn from GMP advance knowledge Review revise formulations based on HR/HV/PP

70 Questions?

71 Need More Information? Ken Speidel, PharmD, RPh, FIACP, FACA Consultant, MEDISCA NETWORK Inc. Facilitator, LP3 Network Inc. Web: