503B Outsourcing Facilities: Health-System Evaluation Strategies and An Update on FDA Guidance PharMEDium Lunch and Learn Series 1 ProCE, Inc. www.ProCE.com 1 503B Outsourcing Facilities: Health‐System Evaluation Strategies and An Update on FDA Guidance December 14, 2018 Featured Speaker: Kevin Hansen, PharmD, MS, BCPS Assistant Director of Pharmacy Cone Health, Moses H. Cone Memorial Hospital Greensboro, North Carolina LUNCH AND LEARN 2 CE Activity Information & Accreditation ProCE, Inc. (Pharmacist and Tech CE) 1.0 contact hour Funding: This activity is self‐funded through PharMEDium. It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Hansen is a Speaker for Acurity, ASHP, Baxter, and PharMEDium, and a content contributor and reviewer of a publication/article for Equashield.
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503B Outsourcing Facilities: Health-System Evaluation Strategies and An Update on FDA GuidancePharMEDium Lunch and Learn Series
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503B Outsourcing Facilities: Health‐System Evaluation Strategies and An Update on FDA Guidance
December 14, 2018
Featured Speaker: Kevin Hansen, PharmD, MS, BCPSAssistant Director of PharmacyCone Health, Moses H. Cone Memorial HospitalGreensboro, North Carolina
LUNCH AND LEARN
2
CE Activity Information & Accreditation
ProCE, Inc. (Pharmacist and Tech CE)
1.0 contact hour
Funding: This activity is self‐funded through PharMEDium.
It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Hansen is a Speaker for Acurity, ASHP, Baxter, and PharMEDium, and a content contributor and reviewer of a publication/article for Equashield.
503B Outsourcing Facilities: Health-System Evaluation Strategies and An Update on FDA GuidancePharMEDium Lunch and Learn Series
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Go to www.ProCE.com/PharMEDiumRx
Login to CE Center
Complete online self‐assessment and evaluation to obtain CE credit
Live CE Deadline: January 11, 2019
CPE Monitor– CE is uploaded to NABP/CPE Monitor upon completion of CE process
(user must complete the “claim credit” step)
Online Evaluation, Self-Assessmentand CE Credit
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Code will be provided at the end of today’s activityAttendance Code not needed for On‐Demand
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503B Outsourcing Facilities: Health-System Evaluation Strategies and An Update on FDA GuidancePharMEDium Lunch and Learn Series
Kevin Hansen, PharmD, MS, BCPSAssistant Director, PharmacySterile Products, Special Formulations, Perioperative ServicesMoses H. Cone Memorial Hospital | Cone HealthGreensboro, North Carolina
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• I have no relevant financial relationships to disclose with regards to this presentation
•The views/opinions expressed in this presentation are of my own and not that of my employer
Disclosures
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Technicians1. Outline the impact regulatory systems and changes may have on
sterile compounding practices2. Identify insanitary conditions in compounding facilities3. Discuss importance of proper training and competency programs
Pharmacists1. List Food, Drug and Cosmetic (FD&C) Act exemptions for 503A,
503B, and manufacturing facilities2. Outline the impact regulatory systems and changes may have on
sterile compounding practices3. Describe evaluation strategies to outsource to a 503B facility4. Discuss importance of proper training and competency programs
Learning Objectives
503B Outsourcing Facilities: Health-System Evaluation Strategies and An Update on FDA GuidancePharMEDium Lunch and Learn Series
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• ANDA: Abbreviated New Drug Application
• API: Active Pharmaceutical Ingredient• BUD: Beyond Use Date• CGMP: Current Good Manufacturing Practices
• COA: Certificate of Analysis• EM: Environmental Monitoring• FDA: Food and Drug Administration• FD&C: Food, Drug, and Cosmetic Act• HRO: High Reliability Organizations• ISMP: Institute for Safe Medication Practices
• ISO: International Organization for Standardization
• MOU: Memorandum Of Understanding
• NDA: New Drug Application• QA: Quality Assurance• QC: Quality Control• REMS: Risk Evaluation and Mitigation Strategies
• SBOP: State Board of Pharmacies• USP: United States Pharmacopeia
“Unfortunately, there are too many people in health care who feel that if it hasn’t happened to them, the
adverse experiences of others do not apply.”‐ Michael Cohen, MS, FASHP (ISMP)
V(value)
Q(quality)
S(service)
$(cost)
=+
The traditional ‘Value Equation’ does not put quality at the forefront for patient care
Require more strict regulation that demands a focus on quality
AccessAchievable
Strict Compounding Regulations
Considerations:1. Science/evidence based2. Standardized3. Accountability4. Doesn’t restrict patient access5. Achievable or scalable to
different practice settings
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• Address manufacturing standards for outsourcing facilities
• Regulate compounding from bulk drug substances
• Restrict compounding of drugs that are essentially copies of FDA‐approved drugs
• Solidify the FDA’s partnership with state regulatory authorities
• Provide guidance on other activities that compounders undertake
• Aims to protect patients from unsafe, ineffective, and poor quality compounded drugs, while preserving access to lawfully‐marketed compounded drugs for patients who have a medical need for them.
• Goals• Preserve patient access• Protect consumers• Make it more feasible for compounding pharmacies to become outsourcing facilities
FDA 2018 Compounding Policy Priorities Plan
FDA Human Drug Compounding Progress Report 2017
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503A 503B Manufacturing
Exemptions:• CGMP [501(a)(2)(B)]• Labeling with adequate directions for use [502(f)(1)]• NDA/ANDA [505]
Exemptions:• Labeling with adequate directions for use [502(f)(1)]• NDA/ANDA [505]• Track and trace [582]
NO EXEMPTIONS
Conditions:• Prescription for individual patients• Pharmacist / licensed physician• State licensed pharmacy or federal facility• Limited quantities before receipt of prescription• USP compliance• Specific bulk drug substances (503A list)• No drugs that have been withdrawn/removed from market• Limited compounding of ‘essentially copies of commercially
available drug products’• No compounding of ‘demonstrable difficult to compound’
drugs• Limited distribution• State with memorandum of understanding (MOU) with
FDA
Conditions:• Reporting drugs compounded, adverse events to FDA• Specific bulk drug substances (503B list)• Ingredients must meet certain requirements• No drugs that have been withdrawn/removed from market• No compounding of ‘essentially copies of commercially
available products’• No compounding of ‘demonstrable difficult to compound’
drugs• Demonstrate REMS requirements for applicable drugs• Drugs not sold or transferred by other entities (other than
outsourcing facility)• Paid all applicable establishment and reinspection fees• Specific labeling requirements• All drugs compounded must be in accordance with 503B• CGMP
FD&C Act: Exemptions and Conditions
FDA Guidance Public Docket 3/6/2015 ‐https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm435070.htm
FD&C Act
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In Between Similar to manufacturingSimilar to 503A
Compounding Spectrum
503A 503B Manufacturing
Compounding Manufacturing
Limited Mass scale
Preparation
Production
Risk‐Based TestingQA
Yes NoPrescriptions
Limited BroadDistribution
SBOP FDAOversight
USP, SBOP CGMP, FDAStandards
No YesFDA Drug Approval
Infrequent RoutineQC
Minimum FullLabeling
Where does 503B fit in?
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FDA Compounding Guidance Documents
Draft Final
503A
• Memorandum of understanding (revised)• Hospital and health system compounding
• Compounding under 503A• Compounding using bulk drugs• Compounding ‘essentially copies’ of approved drugs• Compounding and repackaging of radiopharmaceuticals• Prescription requirements
503B
• CGMP (revised)• Evaluation of bulk drugs
• 503B Registration• Fees for 503B• Considerations for registering as a 503B• Adverse event reporting• Electronic drug product reporting• Compounding using bulk drugs• Compounding ‘essentially copies’ of approved drugs• Facility definition• Compounding and repackaging of radiopharmaceuticals
Both
• Insanitary Conditions (revised) • List of drugs that have been withdrawn/removed from market
• Repackaging of certain drugs• Mixing, diluting, repackaging biologic products
• 21 CFR Parts 210 and 211 outline ‘full’ CGMP regulations
• FDA guidance document (draft) indicates:“FDA Intends to promulgate more specific CGMP regulations for outsourcing facilities. Until final regulations are promulgated, this guidance describes FDA's expectations regarding outsourcing facilities and the CGMP requirements in 21 CFR parts 210 and 211 during this interim period.”
• Focus: sterility assurance, strength, labeling, preventing drug mix‐ups
• Under section 501(a)(2)(B), a drug is deemed to be adultered if:“[T]he methods used in, or the facilities or controls used for, its manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with current good manufacturing practice to assure that such drug meets the requirements of this [Act] as to safety and has the identity and strength, and meets the quality and purity characteristics, which it purports or is represented to possess…”“… the term “current good manufacturing practice” includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety or raw materials, materials used in the manufacturing of drugs, and finished drug products”
• The revised guidance provides these same principles of CGMP, however in a risk‐based approach. The most critical aspects of ensuring quality of drug products include:
≤ 1,000 units Default BUD, which may be further limited by literature or other scientific information. See Appendix B for the conditions that must be met.
Data‐driven stability program. See Appendix B for the conditions that must be
met> 1,000 units N/A. Default BUDs are notapplicable to larger aggregate batch sizes.
503B CGMP Guidance (Revised): Stability/Expiration Dating for Compounded Drug Products
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503B CGMP Guidance (Revised):Default BUDs
Processing Conditions Contains a Preservative?
Controlled Room Temperature
Refrigerator Freezer
• Finished drug product is aseptically processed; and
• A sterility test has not been completed before release
No 6 days 9 days 45 days
Yes 28 days 42 days 45 days
• Finished drug product is terminally sterilized;
• A validated sterilization cycle that uses physical, chemical, or biological indicators is employed; and
• A sterility test has not been completed before release
No 14 days 28 days 45 days
Yes 28 days 42 days 45 days
• Finished drug product is aseptically processed or terminally sterilized and has a completed, passing sterility test before release
No 28 days 42 days 45 days
Yes 42 days 42 days 45 days
1.) Default BUD (No Testing) for Sterile Drug Products(Aggregate Batch Size ≤ 1,000 units) 2.)
3.)
Literature or other scientific information, including relevant commercially available product labeling for a similar drug (i.e. components, dosage form, route of administration, primary container‐closure type), does not indicate that the drug product may not be physiochemically stable over the time period listed
1. Batch size ≥ 60 units or once 60 units are produced Y Y Y Y Y Y Y Y Y Y
2. Batch size < 60 units, if omitted tests are performed once 60 units are produced
Y Y Y Y
3. Batch <10 units compounded pursuant to prescription for single patient and label bears BUD per ‘Default BUD’, if omitted tests are performed once 60 units are produced
Y Y Y
Other conditions listed, including:• Potency method used• Solutions and TPNs• Terminal sterilization
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FDA Guidance: Insanitary Conditions (503A/503B)Examples(non‐exhaustive list)
Sterile/Non‐Sterile: Vermin, visible microbial (i.e. mold) and non‐microbial (i.e. rust, hair) contamination, cross‐contamination with beta‐lactams, hazardous drugs, or highly potent drugs, production during adjacent construction without adequate controlsSterile: improper gowning, failing to disinfect/change gloves frequently, non‐sterile gloves, exposed hands, wrists, legs, hair, or mouth; manipulations outside of ISO 5 area, movement of personnel in/out of cleanroom, moving too quickly, blocking first air, non‐sterile tools, touch contamination outside ISO 5 area, unsealed ceiling tiles, leaking HEPA filters, presence of sinks/drains in cleanrooms, non‐sterile disinfecting agents, infrequent use of sporicidal agent, insufficient disinfectant dwell time, frequent pressure reversals from areas of less clean air to areas of higher cleanliness
Identification • Conduct routine environmental monitoring• Certify the ISO 5 area every 6 months• Measure pressure differentials during operations• Conduct media fill studies to closely simulate aseptic operations (worst‐case)
Corrective Actions Certain insanitary conditions deemed to be particularly serious requiring ceasing sterile operations and recall of purportedly sterile drugs until the conditions have been corrected (see red text above).
Compounding from bulk drug substances involves more complexand numerous interrelated manipulations by the compounder compared to compounding only using FDA‐approved drug products.
Compounding from Bulk Drug Substances
Risks associated with compounding with bulk drug substances:
• Bulk drug substances are not FDA‐approved products
• Compounder must address risks related to ingredient quality
• Bulk drugs are non‐sterile
• Will require sterilization steps if producing sterile drugs as final form
• Terminal sterilization may impact potency and impurities
• Increases potential for errors and mix‐ups
• Need to consider powder flow properties, hygroscopicity, and liquid viscosity for handling/weighing
• Cross‐contamination more likely
Bulk Drug Substance / Active Pharmaceutical Ingredient (API)
“any substances that is intended for incorporation into a finished drug product and intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of a disease, or to affect the structure or any function of the body”
• Category 3: nominated without adequate support [not eligible, unless re‐submitted with supporting information]
Compounding from Bulk Drug Substances (503B)
• Bulk drug substances with ‘clinical’ need:• There is a clinical need to compound using bulk drug
substance• The drug product must be compounded using the bulk
drug substance• Can compound category 1 bulk drug substances if conditions
are met:• Appears on category 1 list for specific registration (503A vs
503B)• Original manufacturer of bulk drug substance is registered
under section 510 of the FD&C Act• Substance is accompanied with a valid COA• Complies with USP or NF monograph (if applicable)• Drug product compounded is in compliance with all other
Domperidone 503A Used by lactating women to enhance breast milk production and for severe gastrointestinal motility disorders. Not FDA approve drug. Available in other countries.
Serious risk of life‐threatening cardiac arrhythmias and sudden cardiac death in all populations, including healthy lactating women.
Quinacrine HCl for intrauterine administration
503A Used for female sterilization. Banned in many countries due to concerns about lack of informed consent and long‐term safety. Not FDA approved drug. Benefits do not outweigh risks.
A known mutagen and associated with serious adverse reactions such as aplastic anemia, hepatitis, severe dermatitis, exacerbation or worsening psoriasis, and psychosis. Increased risk for life‐threatening reproductive tract malignancies.
Cesium chloride 503A Used by cancer patients seeking alternative treatment. Not FDA approved drug.
Poses significant safety risks and is potentially associated with death. Can cause arrhythmias and hypokalemia.
Germanium sesquioxide
Both Used in the treatment of cancer and chronic illnesses. Not FDA approved drug. Delaying treatment with FDA‐approved products with well‐established safety/efficacy raises significant patient safety concerns.
Likely to be contaminated with highly toxic inorganic forms of germanium salts which can be toxic to the kidneys. Has resulted in nephrotoxicity and death, even at recommended levels.
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503B Facility Definition
The section 503A establishment may be located near the outsourcing facility or in the same building, provided the compounding in the outsourcing facility is completely segregated from compounding by the section 503A establishment.
Conditions:1. Do NOT share any common rooms2. Do NOT share any fixed equipment or
supplies for use in compounding3. Have separate entrances and exits4. Do NOT share an internal pass‐through5. Separated by permanent physical barriers
Guidance in Whether to Register as a 503B Outsourcing Facility
• ALL drugs compounded at outsourcing facility must be in accordance with section 503B
• Must engage in compounding of STERILE human drugs• FDA compounding definition does NOT include REPACKAGING• Does NOT include BIOLOGICS (under Public Health Service Act)
Important to know scope of compounding at the facility and any other activities that may be occurring in or adjacent to facility
“…everything the inspectors observe may be evidence that can be used against the pharmacy and individuals present in the pharmacy, and may result in civil, criminal, and administrative fines, penalties, and/or possible jail time”
Kulkarni, D. IJPC Sep/Oct 2013: 358‐362
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FDA 483: Top Inspection Observations and Actions
Rank Short Description
1 Procedures not in writing, fully followed
2 Scientifically sound laboratory controls
3 Investigations of discrepancies, failures
4 Absence of written procedures
5 Written procedures not established/followed
6 Testing and release for distribution
7 Computer control of master formula records
8 Procedures for sterile drug products
9 Calibration / inspection / checking not done
10 Lack of written stability program
Top Inspection Observations (503A/503B)FDA Actions
• FDA form 483: issued to firm/company management at the conclusion of an inspection when an investigator has observed any conditions that may constitute violations of the FD&C Act
• Observations are based on investigators judgement
• Not all‐inclusive; only responding to what they saw
• Corrective action planning and implementation required
• FDA Warning Letter:• FDA officials reviewed observation and determined a serious violation may exist
• Often cite ‘insanitary conditions’
• Must respond within 15 days• Both are public information
FDA Form 483 and Warning Letters
483
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• How to access?• FDA.gov > Home > Drugs > Guidance, Compliance & Regulatory Information > Compounding > Compounding: Inspections, Recalls, and other actions
• What to do with them?• Evaluate observations and severity of findings• Insanitary conditions are significant findings
• What next?• Review written response letter from firm’s to determine if observations are adequately addressed
• Review ‘close‐out’ letter (if applicable) to see if the FDA was satisfied with the firms response and demonstration of corrected actions
How can health‐systems evaluate 503B Outsourcing Facilities• ASHP Outsourcing Vendor Assessment Tool• Regulatory and quality document review• Outsourcing policies and procedures• Physical on‐site assessment• Formulary generation• Periodic re‐assessment
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High Reliability Organizations are those that operate in complex, high‐hazard domains for extended periods without serious accidents or catastrophic failures.
High Reliability Organizations
?
Weick et al 2007; Hines et al 2008; Chassin et al 2013; Rochlin 1999
Preoccupation with Failure• Aware and thinking about potential for failure
• Know that new threats emerge regularly• Alert to small signs of potential problems• Near misses viewed as opportunities to learn• Absence of accidents leads to heightened sense of vigilance for next possible failure
Weick et al 2007; Hines et al 2008; Chassin et al 2013; Rochlin 1999
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Preoccupation with Failure
Reluctance to Simplify
Sensitivity to Operations
Deference to Expertise
Commitment to Resilience
High Reliability Organizations: Characteristics
1
2
3
4
5
Reluctance to Simplify• Resist understanding of how/why things succeed or fail in the environment
• Understand the work is complex/dynamic• Seek underlying rather than surface explanations
• Recognize value of standardization of workflows to reduce variation
• Appreciate complexity inherent in teams, processes, and relationships involved in daily operations
Weick et al 2007; Hines et al 2008; Chassin et al 2013; Rochlin 1999
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Preoccupation with Failure
Reluctance to Simplify
Sensitivity to Operations
Deference to Expertise
Commitment to Resilience
High Reliability Organizations: Characteristics
1
2
3
4
5
Sensitivity to Operations• Strive to maintain high awareness of operational conditions
Since the 2012 outbreak of fungal meningitis, the FDA has overseen more than 200 recalls conducted by compounders, most as a result of FDA inspectional
• Create policy for Procurement of Compounded Medications• 503B Outsourcing Facilities• 503A Outsourcing (retail/community compounding pharmacy)
• Policy includes:• Vendor assessment• Minimum qualifications• Documents to request/review• On‐site inspection requirements• Vendor status: expedited, full• Approved institutional vendor list• Approved institutional list of products• Re‐assessment periods
Outsourcing Policies and Procedures
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What to look for during an on‐site assessment:• FDA insanitary conditions• Flow of product (unidirectional ideal)• Flow of people (unidirectional ideal)• Aseptic technique of staff performing admixing• What is stored in the cleanroom• Use of automation and technology• Proper garb/attire• Observation / verification methods of products
Physical On‐Site Assessment of Outsourcers
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• How do pilots get trained?• Certifications
• Practical exams
• Training on specific type of aircraft
• Virtual flight trainers
• Obtain certain number of hours in specific type of aircraft
• Maximum hour requirements
Training and Competency for Sterile Compounding
• What if we applied same methodology to training sterile compounding?
• Certifications
• Practical exams
• Training on specific type of dosage forms (syringes, bags, epidurals, etc.)
• Virtual compounding labs
• Obtain certain number of hours compounding certain dosage forms
• Maximum hour requirements
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• The National Institutes of Health (NIH) Competencies Proficiency Scale
• Used to measure one's ability to demonstrate a competency on the job
Training and Competency for Sterile Compounding
Fundamental Awareness Basic Knowledge Common knowledge or understanding of basic techniques/concepts
Novice Limited Experience Experience in classroom and/or experimental scenarios or as a trainee on‐the‐job. Needs help performing this skill
Intermediate Practical Application Able to successfully complete tasks as requested. Help from expert may be required from time‐to‐time, but usually independent
Advanced Applied Theory Performs skill without assistance. Recognized as ‘person to ask’ when difficult questions arise
Expert Recognized Authority Known as expert in this area. Can provide guidance, troubleshooting, and answer questions related to this skill