Transcript Compliance insight, Inc.

“COMPOUNDING QUALITY ACT”:
AN INTRODUCTION TO SEC 503 B OF
THE FD&C ACT
An Overview of the
cGMP regulations
21 CFR Parts 210 and 211
and the FDA July 2014
“Current Good Manufacturing Practice –Interim Guidance for
Human Drug Compounding Outsourcing Facilities Under Section
503B of the FD&C Act”
Copyrighted 2015, Compliance Insight, Inc.
PRESENTED BY:
DOYLE C. SMITH, MS, FAAM
COMPLIANCE INSIGHT, INC.
• FDA Compliance Specialists
• Our mission: Actively engage and align with our clients to move beyond the
regulations to compliance that makes sense
• Our approach: Industry Professionals and former FDA Inspectors represent the client;
effectively mitigating and resolving FDA issues in a practical, straight-forward
manner
• Our vision: Your first and best choice for decisive insight into GxP compliance!
Insight beyond the regulations!
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CRITICAL PATH TO ASEPTIC REQUIREMENTS
Compounding Outsourcing Facilities
and 503 B
Also applies to aseptically
compounded drugs made in a 503 A
Establishment
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STERILE AND ASEPTIC
• Sterile: terminally sterilized; for injection
• Aseptic: Produced under highly controlled aseptic/sterile;
bioburden conditions; Sterility assurance level (SAL) is the
probability of a single unit being non-sterile is less than 10-6
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STERILIZATION
• Steam Sterilization: Autoclave @ 121 ° C for 15 minutes
• Dry Heat Sterilization: Dry heat chamber - 160°C for 120 minutes
• Gas Sterilization: ETO (Ethylene Oxide) Chamber; Preconditioning,
ETO and humidity injection, Aeration
• Irradiation (Gamma ray): Cobalt source; Gamma dose, time,
penetration
• Each requires STERILE PROCESS VALIDATION to demonstrate
sterilization of the material to 10-12
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INFORMATION & BACKGROUND
• The Drug Quality & Security Act adds new Section 503 B
to the FD&C Act. FDA, not state Pharmacy Boards,
enforce the FD&C Act
• A facility may register as a 503 B outsourcing facility with
FDA, and must:
• comply with the Compound Quality Act 503 B
requirements
• comply with the cGMP requirements for finished
pharmaceutical drug products established in 21 CFR
Parts 210 & 211
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INFORMATION & BACKGROUND
• Outsource faclities will be inspected by FDA in accord with the
cGMP requirements set forth in 21 CFR Part 211 – cGMP FOR
FINISHED PHARMACEUTICALS
• Failure to meet cGMP requirements will cause the drug to be
adulterated under section 501(a)(2)(B) of the FD&C Act…..
• A drug is considered to be adulterated if the methods used
in, or the facilities or CONTROLS, used for its manufacture,
process, packing, or holding do not conform to, or are not
operated or administered in conformity with cGMP……..
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INFORMATION & BACKGROUND
• Managing the risk of, and establishing the safety of bulk drug
substance, ingredients and components used to compound
drugs
1. FDA intends to develop specific cGMP regulations applicable
to outsourcing facilities. -2. Until that time the Interim Draft Guidance (JULY 2014) provides
FDA’s expectations regarding outsourcing facilities AND THE
cGMP requirements of 210 & 211
3. FDA inspection and enforcement efforts will focus on those
aspects that pose the HIGHEST RISK – 211 parts that relate to
sterility assurance, and strength (Super & Sub)
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CGMP REGULATIONS FOR OUTSOURCING
• Develop specific regulations applicable to outsourcing
facilities and practices
• Interim draft guidance reflects FDAs intent to recognize
differences between outsourcing facilities and drug
manufacturers
• Develop cGMP requirements to the nature of compounding
operations
• Maintain minimum standards to protect the public from risks of
contaminated / substandard drug products
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HOW A PHARMA COMPANY WORKS
Raw Materials
Documentation and
Control is key factor!!
Containers
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CGMPS – THE MYSTERY – THE NEW
• Title 21 of the CFR – Code of Federal Regulations – implementing
instructions to enforce the Federal Law!!!
• Dealing with drug manufacturing – sections 210 and 211
• “c” – stands for CURRENT
• Always changing – Never finalized
• Are a road map to success - e.g., keep out of regulatory trouble
• Guidelines - are published to “clarify” FDA’s minimum
requirements to meet the FDA implementing regulations
• e 21 of the CFR – Code of Federal Regulations – Implement Federal Law!!!
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503 B FACILITY DESIGN - 211.42
 Aseptic Processing area - must be ISO 5 (100 particles/ft3) or
better - the adjacent area should at least ISO 7 (10,000
particles/ft3)
 If an isolator is used, the adjacent area should meet at least ISO
8 (100,000 particles/ft3)
 All materials entering the clean suite need to be sterile
 HEPA filters – must be clean, probed & sealed every 6-months
 Cascading air movement is known and monitored daily and
requalified annually
 Particle counting - viable, by procedure and validated test
- non-viable, sampling within 6” of fill area
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MICROBIOLOGICAL CONTAMINATION CONTROL §211.113
• There shall be written procedures to prevent microorganisms
in drug products not required to be sterile
• There shall be written procedures to prevent microorganisms
in sterile drug products.
• Such procedures shall include validation of all aseptic
and sterilization processes
• Mapped, load patterns,
• Monitored and documented
• Requalified at specified intervals
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CONTROL MICROBIOLOGICAL CONTAMINATION
• Terminally sterilized drug validation should demonstrate at least a
10-6 sterility assurance level (SAL) using an appropriate bioindicator
• Aseptic processing validation may be demonstrated by media fills
simulating actual process with adequate personnel
• Aseptic processing of sterile powders may be demonstrated by
media fills
• Filter sterilized drug, prefiltration bioburden & endotoxin limits
should be established & measured prior to sterile filtration
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MICROBIAL CONTROL
• Media fill studies should closely SIMULATE the aseptic
manufacturing operations and staff requirements
• Worst-case activities
• Conditions that provide challenge to aseptic operations
• Lyophilization as applicable
• Aseptic assembly
• Sample collections
• Etc.
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PACKAGING AND LABELING CONTROL
• 211.122 Materials examination and usage criteria
• 211.125 Labeling issuance – control of printing, issuance &
reconcile quantities
• 211.130 Packaging and labeling operations
• 211.134 Drug product inspection - labeling
• 211.137 Expiration dating and lot number
• Batch record must reflect examination for correctness of
labels
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LABORATORY CONTROLS
• 211.160 General requirements – methods must be validated
and stability indicating
• 211.165 Test and release to meet established specifications
• 211.166 Stability testing program
• 211.167 Special testing requirements – contract service
• 211.170 Reserve samples – API (bulk) & finished
pharmaceutical 2 x release (5).
• 211.176 Penicillin contamination – separate facility
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211.165 TESTING FOR RELEASE
• Finished drug product specifications should include at a
minimum• Identity and strength of the active ingredient(s)
• Sterile or non-pyrogenic drugs, sterility and a limit for
endotoxins
• Established Release procedures
• Agency does not intend take action re: release described
above under certain conditions
• Id test & sterility
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PERSONNEL
• Knowledgeable – process asepsis §211.25
• Training
• Health issues – personal §211.28
• Behavior – aseptic technique
• Understanding the impact of their job on patients health
• Gowning
• Qualification & requalification –equipment, staff, process
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MANAGEMENT
• Procedures, change control, deviations & excursions are
investigated & documented
• Master production records
• Data collection and review
• Ownership
• Quality unit
• Quality Reviews
• Audit
• Providing appropriate tools, facilities, space
• Product release
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EQUIPMENT, SYSTEMS & PROCESSES
• All equipment and systems require
• Equipment ID, qualification, calibration & maintenance
• Validation of systems
• Environment – Qualification HVAC system with HEPA filtering,
cascading air pressure & direction. Re-balance annually
• Air flow in clean rooms and aseptic fill equipment qualification
• Cleaning validation and certification
• Water system qualification and frequent monitoring,
dishwasher
• Glove Box? and Isolator Technology?
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ASEPTIC PROCESS
• Material and people flow
• Aseptic technique for manipulations
• Product filtration - 0.2 micron retention
• Equipment integrity (velocity and leak testing)
• Cleaning, sanitization, & disinfection
• Requalification
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ENVIRONMENT
• HEPA certification, monitoring & documentation
• Layout of operations (cascading air qualities)
• At rest verses dynamic – smoke studies
• Non-viable particulate counting
• Viable “particulate” counting
• Settle plates or other microbial monitoring of the area
(room, walls, work area etc.)
• Microbial monitoring plate/ membrane/ swab controls
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MATERIALS
• Reliable supplier • Supplier Qualification – CoA validation & certificate of
compliance (CoC)
• Components (what is a component in FDA speak) - §210.3
• Water for manufacturing and water for final rinse (WFI - PW)
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MATERIALS CONTINUED
• Receipt, acceptance and release of components
• Identification
• Potency
• Sterility
• Pyrogen levels
• Bioburden levels
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MATERIALS CONTINUED
• Storage
• Inventory (FIFO), receiving documentation, release & use
log
• Retest or expiry date of bulk substance and component
materials / supplies
• Appropriate identification and labeling
• Qualification and requalification of suppliers CoA/ CoC
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TESTING
• Component: specification
• Identity
• Bioburden level
• Pyro-Burden
• Potency
• CoA
• Material release by QA after meeting specifications
• Compounded materials purported to be sterile:
• Sterility: - Free from contamination
• Pyrogen level
• Potency
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TESTING CONTINUED
• Testing must be done using a validated test method: USP or
other
• Testing must be done by a qualified lab, internal or third
party
• Data must be reviewed by the outsourcing facility prior to
release.
• Each lot is to be “released”
• EXPIRY: Micro testing of “sterile“ products, may add 14 days
from date of sterility test completion.
Copyrighted 2015, Compliance Insight, Inc.
CORRECTIVE ACTION & PREVENTATIVE ACTION
• All deviations or failure must be investigated and documented
§211.192
• Failure to:
• follow SOPs, production instructions, etc.
• meet established specifications (OOS)
• meet established tolerances
• Batch record deviations or excursions for equipment, process
step or operator failure / error
• Environmental failure or excursions
• Power failure Copyrighted 2015, Compliance Insight, Inc.
CAPA CONTINUED
• The investigation issues and data will be written and
provide a summary conclusion and determine a root
cause.
• There may be immediate and long term CAPA
recommendations
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IMPROVEMENT
• Using the ANNUAL PRODUCT REVIEW and investigations in
a continuous improvement model to make process /
product improvements is part of the cGMPs & Quality by
Design (QbD).
• “in Control” means not only do you have SOPs and
records but that you continuously address the systems
short comings and improve the system/process. This is the
FDA’s expectation of “In Control”.
• Quality Reviews: Quarterly or Bi-annually
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AND BEYOND ----CONCEPT OF CONTINUOUS IMPROVEMENT
Copyrighted 2015, Compliance Insight, Inc.
YOUR NEXT STEPS
• Call our Partnership Development Team members based upon your location
• Southeast US – Shawn Ferris at 910-726-2943 or [email protected]
• Northeast US – Bill O’Boyle at 862-236-5533 or [email protected]
• Central and Western US, Canada – contact the corporate office at 513-860-3512
or [email protected]
• Establish a CDA
• Allows us to openly discuss your needs via a conference call
• No obligations to use our services
• We start working immediately to meet your goals
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For more information about this presentation, contact us at:
[email protected]
www.Compliance-Insight.com
513-860-3512
Copyrighted 2015, Compliance Insight, Inc.