Bringing 503B into 503A to Improve Organizational...

© 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


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.


Disclosures

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

3


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.


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.


Environment

Infrastructure and Operations1

2

3 Preparation / Product

Outline


Let’s Get Started

Environment


2



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



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



• 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.


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+”



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).



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.



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


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.



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.



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



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




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



• 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



• 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


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



• “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).



• 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



• 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.



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


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.


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.



• 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




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



• 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



• 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




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



• 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


Environment


2


Outline


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.


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


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



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


Environment

• Examine certifier competency (CETA)• Control and monitor certifier behaviors (SOPs) • PEC and SEC smoke visualization• Triple clean monthly

Certification – 503A+ Considerations



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



Environment

• Horizontal surfaces – daily • Between batch production runs• Full room cleaning – weekly • Monthly cleaning• Following sampling

Cleaning & Sanitizing Frequency – 503B


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


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



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



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


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



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



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



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


Outline

Environment


2



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



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.


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


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



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


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



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


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


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



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



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


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


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



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.


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


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


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


Questions?


Need More Information?

Ken Speidel, PharmD, RPh, FIACP, FACAConsultant, MEDISCA NETWORK Inc.

Facilitator, LP3 Network Inc.Web: www.lp3network.com

Email: [email protected]

http://www.lp3network.com/

mailto:[email protected]

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