bringing 503b into 503a to improve organizational...
TRANSCRIPT
© 2017 LP3 Network Inc.
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
© 2017 LP3 Network Inc.
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.
© 2017 LP3 Network Inc.
Disclosures
Ken Speidel is a Facilitator of LP3 Network Inc.’s copyright program materials and a Consultant for MEDISCA Network Inc.
3
© 2017 LP3 Network Inc.
Copyright and Disclaimer
The material in this presentationis 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 currentstandards of practice for pharmacy compounding, is FOR EDUCATIONAL PURPOSES ONLY and shouldnot be taken as a treatment regimen, product indication, suggested treatment modality, or suggestedstandard 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 medicalpractitioner in accordance with accepted professional standards and compendia. Any regulatory orpractice standard must be fully investigated by a licensed pharmacist in accordance with acceptedprofessional practice standards and compendia. The opinions and views expressed in this presentationare those of the presenter only, and do not necessarily represent the views of LP3 Network Inc.
© 2017 LP3 Network Inc.
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.
© 2017 LP3 Network Inc.
Environment
Infrastructure and Operations1
2
3 Preparation / Product
Outline
© 2017 LP3 Network Inc.
Let’s Get Started
Environment
Infrastructure and Operations1
2
3 Preparation / Product
© 2017 LP3 Network Inc.
Infrastructure and Operations
Scope of practice – 503AFormulates 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 30% maximum volume as interstate commerce
Not signed between State and FDA
5% maximum volume as interstate commerce
© 2017 LP3 Network Inc.
Infrastructure and Operations
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
Scope of practice – 503B
© 2017 LP3 Network Inc.
Infrastructure and Operations
• Develop a cGMP mindset
Personnel Mindset – 503B
Fundamental cGMP Concept – Can you apply it to 503A?Construct an ideology, an attitude and vigilant adherence to detail that isharmonized with a set of actions and behaviors in the formulation productionprocess.
© 2017 LP3 Network Inc.
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+”
© 2017 LP3 Network Inc.
Infrastructure and Operations
Personnel must undergo:• Training• Qualification• Annual refresher training
and requalification
Format:• Written• Documented outcome
measures
Personnel Management – 503A
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).
© 2017 LP3 Network Inc.
Infrastructure and Operations
Personnel must maintain constant and consistent:• Training• Qualification• Monitoring
Personnel Management – 503B
Fundamental cGMP Concept – Can you apply it to 503A?The qualitative and quantitative specificity and rigor of personnel working innon-aseptic and aseptic manufacturing environment is essential to ensuringquality.
© 2017 LP3 Network Inc.
Infrastructure and Operations
Conduct Observational Checklists beyond USP requirements• Packaging• Weighing• Calibrating• Emergency Preparedness Drill• Recall Drills• HD Spill Drills• Constant training (not yearly/biannually)
Personnel Management – 503A+ Considerations
© 2017 LP3 Network Inc.
Infrastructure and OperationsHD Spill Observational Checklist (abbreviated)Personnel Management – 503A+ Considerations
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.
© 2017 LP3 Network Inc.
Infrastructure and Operations
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
Example of Qualification and MonitoringGarbing and Gloving – 503A & 503B
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.
© 2017 LP3 Network Inc.
Infrastructure and Operations
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)
Example of Qualification and Monitoring
© 2017 LP3 Network Inc.
Infrastructure and Operations
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)
Quality Mandate – 503A
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).
© 2017 LP3 Network Inc.
Infrastructure and Operations
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
Quality Mandate – 503B
© 2017 LP3 Network Inc.
Infrastructure and Operations
• 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
Quality Mandate – 503A+ Considerations
Cloud Software
Infrastructure and OperationsQuality Mandate – 503A+ Considerations
© 2017 LP3 Network Inc.
Infrastructure and Operations
• 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
Standard Operating Procedures (SOPs)
Fundamental cGMP Concept – Can you apply it to 503A?In order to ensure process uniformity within an organization, and maintain itconsistently, detailed and specific standard operating procedures must drive allcritical processes. 503A+ – Change Control SOP – LUMAC – Vendor Validation
© 2017 LP3 Network Inc.
Infrastructure and OperationsProcess 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 stagethrough commercial production, which establishes scientific evidencethat a process is CAPABLE of consistently delivering the expectedquality products. 503A+ – Operations Management Software
© 2017 LP3 Network Inc.
Infrastructure and Operations
• “Confirmation that a method, process, or system will perform as expected under the conditions of actual use.”1
Verification: A Part of Validation
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).
© 2017 LP3 Network Inc.
Infrastructure and Operations
• 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
From Receipt to Release – 503A
© 2017 LP3 Network Inc.
Infrastructure and Operations
• A vendor validation process should be constructed• Incorporate a process from the receipt to the release of:
– Materials– Supplies– Packaging– Non-sterile ingredients
From Receipt to Release – 503B
Fundamental cGMP Concept – Can you apply it to 503A?Confirming the identity and quality of starting materials isfundamental to building quality into the manufacturing process.
© 2017 LP3 Network Inc.
Infrastructure and Operations
Chemical Quality• Construct a Vendor Validation SOP
– Construct a credentialing process and documents to be completed by vendor
• FDA inspected• Description of their 3rd 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
From Receipt to Release – 503A+ Considerations
© 2017 LP3 Network Inc.
Infrastructure and OperationsFrom Receipt to Release – 503A+ ConsiderationsChemical 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.
© 2017 LP3 Network Inc.
Infrastructure and OperationsFrom Receipt to Release – 503A+ ConsiderationsChemical 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.
© 2017 LP3 Network Inc.
Infrastructure and Operations
• USP General Chapter <797> requires that:– "The equipment used for compounding compounded sterile
preparations (CSPs) must be of appropriate design and adequate size".1
Equipment management – 503A
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).
© 2017 LP3 Network Inc.
Infrastructure and Operations
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
Equipment Management – 503B
© 2017 LP3 Network Inc.
Infrastructure and Operations
• 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
Equipment Management – 503A+ Considerations
© 2017 LP3 Network Inc.
Infrastructure and Operations
• 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
QA/QC – 503A
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).
© 2017 LP3 Network Inc.
Infrastructure and Operations
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)
Corrective Action and Preventive Action (CAPA) – 503B
© 2017 LP3 Network Inc.
Infrastructure and Operations
• Change culture to correction AND prevention• Appoint a quality manager (10 hrs/week)• Create a quality team • Employ quality management software• Track and trend
Corrective Action and Preventive Action (CAPA) –503A+ Considerations
© 2017 LP3 Network Inc.
Environment
Infrastructure and Operations1
2
3 Preparation / Product
Outline
© 2017 LP3 Network Inc.
Environment
• Any quality compounded/manufactured medication must be produced in a suitable environment that controls the risk of contamination and error
Facility Management 503A and 503B
Fundamental cGMP Concept – Can you apply it to 503A?Operate and maintain all buildings/facilities with extremevigilance with an emphasis on environmental monitoring.
© 2017 LP3 Network Inc.
EnvironmentRequires:• 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.
Environmental Management
503A+ Considerations• Sterile Containment Suits• Sterile Gowns/Sleeves• Sterile Cleaning Utensils/Solutions, Autoclave• Garb Management at Facility
© 2017 LP3 Network Inc.
Environment
• “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?
Certification – 503A
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).
© 2017 LP3 Network Inc.
Environment
• 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
Certification – 503B
© 2017 LP3 Network Inc.
Environment
• Examine certifier competency (CETA)• Control and monitor certifier behaviors (SOPs) • PEC and SEC smoke visualization• Triple clean monthly
Certification – 503A+ Considerations
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).
© 2017 LP3 Network Inc.
Environment
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
Cleaning & Sanitizing Frequency – 503A
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.
© 2017 LP3 Network Inc.
Environment
• Horizontal surfaces – daily • Between batch production runs• Full room cleaning – weekly • Monthly cleaning• Following sampling
Cleaning & Sanitizing Frequency – 503B
© 2017 LP3 Network Inc.
Environment
• 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
Cleaning & Sanitizing Frequency – 503A+ Considerations
© 2017 LP3 Network Inc.
Environment
• 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
Nonviable Airborne Particle Sampling – 503A
ISO Levels and nonviable airborne particle limits applicable to 503A and 503B
ISO Classification Non-viable Particles (≥ 0.5 µm/m3)5 3,520
7 352,000
8 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).
© 2017 LP3 Network Inc.
Environment
• 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
Nonviable Airborne Particle Sampling – 503B
ISO Levels and nonviable airborne particle limits applicable to 503A and 503B
ISO Classification Non-viable Particles (≥ 0.5 µm/m3)5 3,520
7 352,000
8 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.
© 2017 LP3 Network Inc.
Environment
• 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)
Nonviable Airborne Particle Sampling – 503A+ Considerations
© 2017 LP3 Network Inc.
Environment
503A
• At least monthly• All controlled environments• Active air sampling
503B
• Each production shift• All controlled environments• Active / Passive air sampling
Viable Airborne Particle Sampling
Air classification and recommended action levels of viable airborne particle sampling
ISO Designation Active Air Action Level (CFU/m3)
Settling Plate Action Levels(diameter 90 mm; (CFU/4 hrs)
5 ≥ 1 ≥ 1
6 ≥ 7 ≥ 3
7 ≥ 10 ≥ 5
8 ≥ 100 ≥ 50
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.
© 2017 LP3 Network Inc.
Environment
• 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
Viable Surface Particle Sampling – 503A
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.
© 2017 LP3 Network Inc.
Environment
• Each production shift– Floors, walls, and equipment surfaces– Critical surfaces
• Sample timing, frequency, and location selected on the basis of relationship to operations performed
Viable Surface Particle Sampling – 503B
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.
© 2017 LP3 Network Inc.
Environment
• 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
Viable Surface Sampling – 503A+ Considerations
© 2017 LP3 Network Inc.
Outline
Environment
Infrastructure and Operations1
2
3 Preparation / Product
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Preparation Management – 503A
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).
© 2017 LP3 Network Inc.
Preparation/Product
• 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)
Product Management – 503B
Fundamental cGMP Concept – Can you apply it to 503A?The effectiveness of any procedure used to sterilize or assure the quality andstability 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 validatedmethods and procedures to determine the stability characteristics of the finishedmanufactured product and to establish appropriate storage conditions and expirationdates.
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Preparation Management – 503A+ Considerations
© 2017 LP3 Network Inc.
Preparation/Product
• Simulation of aseptic processes from complex formulations• No requirement for environmental monitoring data to be correlated
against the media fill test
Media Fill – 503A
• 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).
Media Fill – 503B
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.
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Media Fill Qualification – 503A+ Considerations
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Sterilization Processes – 503A
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.
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Sterilization Processes – 503B
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Sterilization Processes – 503A+ Considerations
© 2017 LP3 Network Inc.
Preparation/Product
• 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 speciationContinued…
Finished Preparation Testing (Release?)– 503A
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).
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Release Testing – 503A
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).
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Release System – 503B
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Release Testing/System – 503A+ Considerations
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Final Packaging and Labeling – 503A
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).
© 2017 LP3 Network Inc.
Preparation/Product
• 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
Final Packaging and Labeling – 503B
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.
© 2017 LP3 Network Inc.
Preparation/Product
• 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.)
Final Packaging and Labeling – 503A+ Considerations
© 2017 LP3 Network Inc.
Summary
Components for Success
Change Mindset (cGMP-Like
Environmental Management and
Monitoring Program
Constant and Consistent Personnel Training
Autonomous Quality Team
Activate CAPA
Validate SOPs via Process Validation
Preparation orProduct Release Testing Program
Vendor Validation Ingredients and
Supplies Selection Program
12 Tenants to cGMP1) GMP Mindfset2) Autonomous Quality Team3) Process for Release/Receipt4) Facility Vigilance5) Process Validated of SOPs6) Constant/Consistent Training7) Maintain Final Prep/product check8) Facility/ Equipment Cleaning9) Process Validation Critical Steps10) Facility/ Equipment Maintenance11) Activate CAPA12) Maintain Prep/Product Relase
© 2017 LP3 Network Inc.
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
It Depends?
• 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
Prioritize High Risk, High Volume and Problem Prone Areas
© 2017 LP3 Network Inc.
Questions?
© 2017 LP3 Network Inc.
Need More Information?
Ken Speidel, PharmD, RPh, FIACP, FACAConsultant, MEDISCA NETWORK Inc.
Facilitator, LP3 Network Inc.Web: www.lp3network.com
Email: [email protected]