Compliance, FDA Inspection
and Product Quality
Jim Li, Ph.D. MBA
Presentation Overview
Š Regulations and Guidance:
– DP: 21 CFR Parts 210 & 211
– DS: ICH Q7A
Š System based approach
Š FDA expectation in GMP compliance
– Types of FDA inspection
– Inspection process
– Common violations
– Examples of observation
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GMP Regulations and Guidance
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21 CFR Parts 210 and 211
• 21 CFR Parts 210 and 211
• Title 21 Food and Drugs, Code of Federal Regulations
• Issued by FDA
• GMP Regulations for finished pharmaceuticals:
• OTC, Rx, IND, NDA, medical gases
• Establish “what to” do, not “how to”
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Minimal standards
Maximum flexibility
Specific enough to address problems
Technology neutral
Scalable
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Part 210: cGMP General
1. Status of current good manufacturing practice regulations
• minimum requirements for methods, facilities or controls,
manufacture, processing, packing, or holding of a drug
• Failure to comply renders a drug adulterated
2. Applicability of cGMP regulations.
• 211-226, 600-680 and 1271 are supplement each other
• A person is subject to those regulations applicable to the operations
in which he or she is engaged
• Phase 1 drug is subject to the 21 U.S.C. 351(a)(2)(B) but exempt
from part 211.
• If used, in phase 2 or 3 study or lawfully marketed, must comply
3. Definitions
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Part 211
Subparts
A. General Provision
B. Organization and Personnel
C. Building and Facilities
D. Equipment
E. Control of Components and Drug Product
Containers and Closures
F. Production and Process Controls
G. Packaging and Labeling Controls
H. Holding and Distribution
I.
Laboratory Controls
J. Records and Reports
K. Returned and Salvaged Drug Product
Paragraphs
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General Principles
• Quality built into product
• By “taking care” in making medicine
• Can’t test quality into product
• Without/inadequate cGMP
• Product adulterated (defects need not be shown)
• Non-compliance = eventual problems
• Current = dynamic
• Standards evolve over time
• Good practices
• Minimal standards, not best practices
• Feasible and valuable
• No “percentage” in practice threshold
• Enforceable even nobody is doing it
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ICH Q7A: GMP Guidance for APIs
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For manufacturing of API used in human drug products
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Include receipt of materials, production, packaging, repackaging,
labeling, relabeling, quality control, release, storage and
distribution of APIs and the related controls.
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Scope: chemical synthesis, extraction, cell culture/fermentation,
recovery from natural sources, or any combination.
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Sterile API: only up to the point prior to APIs rendered sterile.
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Excludes vaccines, whole cells, whole blood and plasma, blood
and plasma derivatives, and gene therapy APIs.
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Specific guidance for APIs used in clinical materials
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GMP does not apply to steps prior to the introduction of the
defined API starting material.
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Content of ICH Q7A
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Quality Management
Personnel
Building and Facilities
Process Equipment
Documentation and Records
Materials Management
Production and In-Process
Controls
Packaging and Identification
Labeling of APIs and
Intermediates
Storage and Distribution
Laboratory Controls
Validation
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Change Control
Rejection and Re-Use of
Materials
Complaints and Recalls
Contract Manufacturers
(Including Laboratories)
Agents, Brokers, Traders,
Distributors , Repackers ,
and Relabelers
Specific Guidance for APIs
Manufactured by Cell
Culture/Fermentation
APIs for Use in Clinical
Trials
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Systems Based GMP Approach
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Systems Based GMP
• Activities in drug firms can be organized into systems
that are sets of operations and related activities
• Control of all systems helps to ensure the firm will
produce drugs that are safe, have the identity and
strength, and meet the quality and purity
characteristics as intended
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Six Systems
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System Based Inspection
Inspection of Systems
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≥ 2 systems, with QS as mandatory,
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Numbers of systems covered depends on the purpose of an
inspection
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Inspection of certain number of systems provide the basis for an
overall cGMP decision
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Coverage of a system in sufficient details so that the outcome
reflects the state of control in that system for every profile class
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If a particular system is adequate, it should be adequate for all
profile classes
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Complete inspection of one system may necessitate further
follow-up of some items within another system
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Expectation to Systems
Common to All Systems
• Written procedures
• Adherence to procedures verified through
observation where possible
• Personnel qualification and training
• Investigation into any unexpected discrepancies
• Records for production, control and distribution
• Change control
• Computer qualification, validation, and security
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Quality System
This system assures overall compliance with cGMP,
internal procedures and specifications
• Quality control unit and all of its review & approval
duties (e.g. change control, reprocessing, batch
release, annual record review, validation protocols &
reports, etc.)
• All product defect evaluations and evaluation of
returned and salvaged drug products
See 21 CFR 211 Subparts B, E, F, G, I, J and K.
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Pharmaceutical Quality System Model
GMP
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Quality System Inspection Coverage
• Product reviews
• Complaint
reviews
• Returns &
salvage
• Rejects
• Discrepancy &
failure
investigations
• Stability failures
• Change control
• Validation status
• Reprocess &
rework
• Training/qualificat
ion
• Quarantine
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Facilities and Equipment System
Measure & activities which provide an appropriate physical
environment and resources used to produce drugs of drug
products
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Buildings and facilities along with maintenance
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Equipment qualifications
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Equipment calibration & preventative maintenance
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Cleaning & validation of cleaning procedures
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Utilities that are not intended to be incorporated into the product
such as HAVC, compressed gases, steam and water systems
See 21 CFR Subparts B, C, D and J
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Facilities and Equipment Coverage - Facilities
• Cleaning & maintenance
• HVAC to prevent cross contamination
• Layout to prevent mix-ups and contamination
• Lighting, sewage & refuse disposal, potable water,
washing & toilet facilities
• Sanitation of the building
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Facilities and Equipment Coverage - Equipment
• IQ/OQ
• Design, size, location
• Surface not reactive, additive, or absorptive
• Cleaning procedures and validation
• Calibration and maintenance
• Identification
• Controls to prevent contamination
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Materials System
Measures & activities to control finished products,
components, including water or gases, that are
incorporated into the product, containers and
closures
• Validation of computerized inventory control
processes
• Drug storage
• Distribution controls
• Records
See 21 CFR 211 Subparts B, E, H and J
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Materials System Coverage
Identification &
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Retesting
inventory
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FIFO
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Storage conditions
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Water & process
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Quarantine
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Sampling
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Testing
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gas
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Distribution
records
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Rejection
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Production System
Measures & activities to control the manufacture of
drugs and drug products
• Batch compounding
• Dosage form production
• In-process sampling and testing
• Process validation
• Establishing, following, and documenting performance of
approved manufacturing procedures
See 21 CFR Subparts B, F, and J
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Production System Coverage
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Charge-in of
components
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Identification of
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Time limits
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Process validation
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Other validation
equipment status
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Formulation
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Master & batch records
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Yields
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In-process controls
• Cleaning, sterilization,
& depyrogenation
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Environmental
control & monitoring
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Packaging and Labeling System
Measures & activities that control the packaging and
labeling of drugs and drug products
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Written procedures
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Label examination and usage
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Label storage and issuance
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Packaging and labeling operations controls
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Validation of these operations
See 21 CFR Subparts B, G and J
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Packaging and Labeling System Coverage
• Acceptance of materials
• Storage
• Control of different labeling
• Visual identification
• Control of filled unlabeled containers
• Packaging records
• Specimens of label
• Issuance of labeling
• Examination of finished labeled product
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Packaging and Labeling System Coverage
• Lot numbers
• Separation between packaging and labeling lines
• Monitoring of printing devices
• Line clearance
• Expiration dates
• Temper-evident packaging requirements
• Validation
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Laboratory Control System
Measures & activities related to:
• Laboratory procedures
• Testing
• Analytical methods development and validation or
verification
• Stability program
See 21 CFR 211 Subparts B, I, J and K
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Laboratory Control System Coverage
• Staff
• Equipment & facility
• Calibration &
maintenance
• Reference
standards
• System suitability
• Methods validation
& verification
• Procedures
• OOS
• Records
• Stability
• Reserve samples
• Samples
• Raw data
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State of Control
• If quality, identity, strength and purity of the products from
a system cannot be adequately assured the system is out
of control .
• If any system is out of control, the firm is considered out
of control
• Findings of deficiency may be used as evidence for taking
appropriate advisory, administrative and/or judicial actions
• If one or more systems is/are out of control The outcome
will be classified official action indicated (OAI)
• Type of action is based on the seriousness and/or the
frequency of the problem
• Significant and/or a trend of deficiencies may result in the
issuance of a Warning Letter or other regulatory actions
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Types of GMP
Inspections
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Type of Inspection
• Surveillance Inspections
• For-Cause Inspections
• Pre-approval Inspections
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Surveillance Inspections
Full Inspection
• A broad and deep evaluation of the firm‘s CGMP
compliance
• Conducted when
• Little or no information is known
• There is doubt about the CMGP compliance in the firm
• Follow up to previous regulatory actions.
• At least four systems, one must be Quality System
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Surveillance Inspections
Abbreviated Inspection
• An update evaluation of a firm’s CGMP
• Conducted when a firm has
• a record of satisfactory CGMP compliance
• no significant recall, product defect or incidents
• little shift in the manufacturing profiles within last two years
• At least two systems, one must be Quality System
• Optional systems are rotated in next Inspections.
• For a contract lab, two systems may be considered a Full
Inspection
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Surveillance Inspections
Post-Approval Inspection
• Audit for changes in the production and control
practices that occur after approval
• Confirm that the approved applications have been
appropriately supplemented to reflect those
changes
• Cover approved products regardless of whether
or not these products were covered under the preapproval program
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Common Problems Found in Post-Approval FDA Audit
Scale up not documented/validated prior to
commercial distribution
Lack of data supporting processes and controls, and
changes thereto
Lack of controls and records
Inadequate, or lack of, validation
Inadequate change control procedures
Unauthorized process changes
Inadequate stability data, unfulfilled stability testing
commitments, Unreported stability test failures
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Common Problems Found in Post-Approval FDA Audit
Unfulfilled application commitments
Unreported/unapproved changes in manufacturing or
testing/QA procedures
Improperly reported or fraudulent changes
Non-permitted change to new suppliers, testing, or
contract laboratories
Using unapproved suppliers, testing, or contract
laboratories
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For-Cause Inspection
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Evaluate corrective actions after a regulatory action
Cover areas found deficient and subjected to corrective actions
Focus on systems for determination on overall compliance
Firm is expected to address all of its operations in its corrective
action plan, not just the deficiencies in the FDA-483
Full Inspection is used for a compliance inspection, especially if
Abbreviated Inspection was used during the violative inspection
In addition, For-cause inspection may be conducted under
following situations
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Field Alert Reports (FARs)
industry complaints
recalls
indicators of defective products
etc.
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Pre-Approval Inspection
Inspection conducted before approval of a NDA/ANDA
and CMC supplement to assure
1. Readiness for commercial manufacturing
2. Conformance to application
3. Data integrity audit
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The objectives determine the scope of inspection coverage
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At least 1 objective will be addressed during a PAI
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Pre-Approval Inspection
(PAI)
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Priority PAI
Priority PAI criteria:
1. Firm first time in an application
2. First application filed by applicant for DP
3. First ANDA for an approved drug
4. Product containing a NME
5. Product content assay has narrow range, or requires titrated dosing
6. Product or API manufactured by a substantially different process
7. API deviation is high risk (from animal tissue) or intended use
changed
8. Numerous submissions/changes
9. Profile class status not updated in last 2 years (3 years for testing lab,
4 years for packaging & labeling )
If any one of the criteria is met, a PAI may be performed.
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Rationales for Not Conducting a
Priority PAI
• Facility has an acceptable profile for a similar
product with a higher manufacturing complexity
• Facility has an unacceptable profile and a
withhold recommendation is appropriate
without need for a follow-up inspection
• Another recognized regulatory authority’s
inspection report may be considered for
international facilities
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Discretionary PAI
• Rationales for a Discretionary PAI
ƒ Multiple applications filed in short period of time involving
a single establishment
ƒ Significant deficiencies were found during the last PAI
ƒ Additional potentially adverse information regarding the
compliance status not yet known, i.e. an expected
enforcement action recommendation during an ongoing
inspection, multiple recalls, or new firm management
• District Office or ICB determine the
objective(s) of Discretionary PAI
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FDA Organization
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Roles of ORA
• Responds to inspection requests
• Inspects sites in accordance with the PAI
program
• Reports findings
• Provides a recommendation on site
acceptability to the OC/CDER
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Roles of DMPQ
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Evaluates establishments
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Receive and process EER and monitor inspection status
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Determines if a PAI must be conducted
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Reviews inspection reports and recommendations
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Provides a site acceptability decision to other CDER offices,
including initiation of regulatory actions
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Assures uniform application of compliance decisions and CGMP
policy
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For international establishments, the ICB serves as the
compliance office
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Facilitate interaction between reviewers and investigators
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Provide technical assistance to ORA, and participate, as needed,
as member of inspection team
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Roles of Review Offices
CDER ONDQA, OGD, OBP, NDMS, OC/BMT
• Perform review of submitted information: test methods,
manufacturing and control strategy
• Establish specifications and other regulatory
commitments where needed to support application
approval decisions
• May participate inspection
CDER OND
• Determines and issues the final decision on NDAs and
BLAs
CDER OGD
• Determines and issues the final decision on ANDAs
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Inspection Team
• At least one investigator and one analyst,
when possible
• Application reviewer or CGMP subject expert
• DFI national expert or Pharmaceutical
Inspectorate
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PAI Process: Initiation
District Offices
1. Approval
2. Withhold
3. Assigned to IB
Inspection
Domestic
-NDA
-ANDA
-Supplement
Review Offices
1. Enter into
EES
2. Generate EER
OC DMPQ
1. Profile review
2. 10-day letter
3. Review EER for
foreign firm
International
ORA DFI
Inspection
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PAI Process: Inspection & Response
Ac
le
tab
p
ce
Un
ac
ce
pta
ble
DMPQ/OC
District Office
Response
Follow-up
Firm
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Outcomes of Inspection
Outcomes:
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NAI (No Action Indicated)
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VAI (Voluntary Action Indicated)
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OAI (Official Action Indicated)
Regulatory and/or Administrative Actions
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Application Integrity Policy
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Application withdrawal
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FDA-requested recall
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Warning letter
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Import alert/detention
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Consent decree
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Seizure
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Injunction
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Prosecution
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Case Example 1
FDA 483 Observation:
• “There is no data to support the following steps/
parameters during manufacture and packaging:
ƒ Process controls and acceptance limits have not been
established for manufacturing steps, such as the pre-blend roll
compaction and milling steps;
ƒ There is a lack of scientific rationale and data to support the
blend time parameters for the scale up manufacturing process
from the submission batch size of 150,000 tablets to the
proposed commercial size of 1,000,000 tablets.”
Recommendation:
Withhold
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Case Example 2
FDA 483 Observation:
• “The firm failed to establish acceptance level and
rejection level criteria for “particles” found in the
NF-Parenteral XXXXX manufactured by the firm.
For example, particles were observed in samples
from batch numbers; ZZZZZ validation batches
and YYYYY, a post validation batch.”
Recommendation:
Withhold
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Case Example 3
FDA 483 Observation:
• “Laboratory records do not include complete
data derived from all tests, examinations, and
assay necessary to assure compliance with
established specifications and standards…
• Established test procedures are not followed
and documented at the time of
performance………”
Recommendation:
Withhold
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Case Example 4
FDA 483 Observation:
• “Changes to the validated process were not approved
by the Quality Unit prior to production. Specifically,
the production manager issued written procedures for
the manufacture of batch XXXX that caused the batch
to be manufactured below the specifications
approved by the Quality Unit during the validation of
the process……..”
Recommendation:
Withhold
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Case Example 5
FDA 483 Observation:
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“The use of instruments not meeting established
specifications was observed. Specifically, failure
to qualify equipment prior to use for the following
pieces of equipment used in the testing of XXXX
API and stability samples.
ƒ There are no calibration records for the Nicolet 360 FTIR
spectrophotometer.
ƒ There are no calibration records for Water HPLC instrument
for years of 2006 and 2007.
ƒ The VWR 1330G #1 oven used for analysis of non-volatile
residue has not been calibrated.”
Recommendation:
Withhold
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Discussion & Question