FDA
FDA cGMP
cGMP
China
China
Training
Training Program
Program
December
-7, 2005
December 55-7,
2005
Ying
Ying Jie
Jie Convention
Convention Center
Center
Beijing
Beijing University
University Beijing
Beijing
cGMP in the USA
Nicholas Buhay
Deputy Director
Division of Manufacturing & Product Quality
Office of Compliance, CDER, FDA
Introduction to
Drug
Current Good Manufacturing Practice
Of US FDA
An
An Outline
Outline
• Legal bases for cGMP
• cGMP legal principles
• cGMP Implementation Tools
• cGMP Resources
• Overview of cGMP Requirements
• Integrity of Records and Data
FD&C
FD&C Act;
Act; 501(a)(2)(B)
501(a)(2)(B)
“A drug shall be deemed adulterated if:
... the 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
...”
more...
FD&C
FD&C Act;
Act; 501(a)(2)(B)
501(a)(2)(B)
“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.”
cGMP
cGMP legal
legal principles
principles
• Quality built into product
– By “taking care” in making
medicine
– Can’t ‘test’ into product the quality
• Without/Inadequate cGMP
– Product(s) adulterated(defects
need not be shown)
– Firm and its management are
responsible
cGMP
cGMP legal
legal principles
principles
• Non-compliance = eventual problems
– Superpotency/subpotency
– Contamination
– Misbranding
– Bioavailability
– Safety and efficacy
cGMP
cGMP Legal
Legal Principles
Principles
• Scope
– Ingredients (APIs + excipients)
– Finished dosage forms administered
to humans/animals
»OTC, Rx products
»Biologics, veterinary drugs
»Drugs undergoing study(IND, etc)
– Manufacturers, test laboratories,
packagers(including pharmacies)
cGMP
cGMP legal
legal principles
principles
• Excluded from the cGMP
requirement
– Positron emission tomography, per
FDAMA (own cGMP to be developed)
– Drug products compounded per Section
503 Pharmacy Compounding (FDAMA)
cGMP
cGMP Legal
Legal Principles
Principles
• Current = dynamic
– Standards evolve over time
• Good practices
– Minimal standards
– Not “best practices”
» Unless “best” is, in fact, current minimal
cGMP
cGMP Legal
Legal Principles
Principles
• Feasible and valuable
– No threshold for “percentage” in
practice
»Doesn’t have to be “predominant”
– Enforceable even if nobody is doing it
»Stronger case if someone is doing it
The
The cGMP
cGMP Regulation
Regulation
• cGMP for Finished Pharmaceuticals 21 CFR
210, 211
– First issued: June 1963
– Today’s version: September 1978
– Scope
»Dosage forms for human/vet/biologics
»OTC, Rx, IND, NDA, Medical Gases
»Not: pharmacies, ingredients, nonclinical research, etc
The
The cGMP
cGMP Regulation
Regulation
• cGMP for Finished Pharmaceuticals
21 CFR 210, 211
– Substantive
» Force and effect of law
– Constitute major part of (not
entire) cGMP
more...
The
The cGMP
cGMP Regulation
Regulation
• cGMP for Finished Pharmaceuticals 21 CFR
210, 211
– Establish “what to” do, not “how to” do
»Minimal standards
»Maximum flexibility
»Specific enough to address
problems
• e.g., Penicillin contamination
control
»Technology neutral
»Scalable
cGMP
cGMP Implementation
Implementation
Tools
Tools
• Compliance Policy Guides
– Specific actions we do related to cGMP
– Examples:
» Sub Chapter 410 Bulk Drugs
• The regulations for finished
pharmaceuticals will be applied as
guidelines for bulk drugs
» Sub Chapter 420 Compendial (USP)/Test
Requirements Ex:USP not required for release
test
» Other Sub Chapters
• Labeling and Repackaging
• Stability/Expiration
• Process Validation
• Etc
cGMP
cGMP Implementation
Implementation
Tools
Tools
• cGMP Guidance Documents
– Principles:
»Not requirements
»Agency “current thinking”
»Detailed, technical
»Expression of “How to” meet “what
to” do (requirements)
– Shape industry behavior
»offers routes to efficiency in meeting
cGMP requirement, evaluation of
compliance
cGMP
cGMP Implementation
Implementation
Tools
Tools
• cGMP Guidance Documents
(Examples)
– General Principles of Process
Validation
– Compressed Medical Gases
– Sterile Drug Products Produced by
Aseptic Processing
– Guideline on the Preparation of
Investigational New Drug Products
more...
cGMP
cGMP Implementation
Implementation
Tools
Tools
• cGMP Guidance Documents
– Investigating Out of Specification
Test Results for Pharmaceutical
Production
– Manufacturing, Processing or
Holding of Active Pharmaceutical
Ingredients
cGMP
cGMP Implementation
Implementation
Tools
Tools
•
cGMP Compliance Programs –Instructions to FDA
inspectors
– Drug Manufacturing Inspections Program
» Systems-based assessment of site
– Preapproval Inspection Program
» Points to inspect
» Laboratory support
» Regulatory approaches
cGMP
cGMP Implementation
Implementation
Tools
Tools
• cGMP Guides to Inspection of….
– Help field investigators apply
cGMP
»Uncover need for cGMP changes
»Specific to topics (e.g., cleaning
validation)
cGMP
cGMP Resources
Resources
• Internet WWW site by DMPQ
– http://www.fda.gov/cder/dmpq
»cGMP regulations and ongoing
changes
»Preamble to the cGMP regulation
»Division subject contacts
»Medical gases
»Active pharmaceutical ingredients
»Human Drug cGMP Notes/Policy
»etc.
Overview
Overview of
of cGMP
cGMP
requirements
requirements in
in the
the
regulation
regulation
• cGMP Regulations
– 21 CFR 210
» Status of the regulations
» Applicability of the regulations
» Definitions
• Batch
• Lot
• In-process material
• Quality control unit
• Representative sample
• etc
Overview
Overview of
of cGMP
cGMP
requirements
requirements in
in the
the
regulation
regulation
• cGMP Regulations
– 21 CFR 211
» Subpart A General Provisions
» Subpart B Organization an Personnel
» Subpart C Buildings and Facilities
» Subpart D Equipment
» Subpart E Control of Cmpnts/Cntr/Closures
» Subpart F Production and Process Controls
» Subpart G Packaging and Labeling Controls
more...
Overview
Overview of
of cGMP
cGMP
requirements
requirements in
in the
the
regulation
regulation
• cGMP Regulations
– 21 CFR 211
»Subpart A General Provisions
• this is minimum cGMP
Overview
Overview of
of cGMP
cGMP
requirements
requirements in
in the
the
regulation
regulation
• cGMP Regulations
– 21 CFR 211
»Subpart B Organization and Personnel
• There shall be a quality control unit
• quality control unit responsibility to
approve/reject
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
» Subpart C Buildings and Facilities
• buildings shall be….suitable
• operations to be in specifically defined
areas….separate…. Or such other control
systems for ….operations as are necessary
to prevent contamination or mix-ups….
(see list, includes aseptic processing)
• “separate” facilities for penicillin
• building….shall be….clean and sanitary
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
»Subpart D Equipment
• surfaces ….shall not be reactive,
additive, or absorptive
• Equipment….shall be cleaned,
maintained and sanitized….
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
» Subpart E Control of Components, Containers
and Closures
• containers and closures ….handled in a
manner to prevent contamination.
• Testing or examination of c/c/c’s
• test to identify each component
• tests on components for conformance with
specs
• test c/c/c’s microscopically, for
adulterants, microscopically
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
» Subpart F Production and Process Controls
• written procedures for production and
process control
• formulated not less than 100 %
• portions of components identified,
examined by a 2nd person before
dispensed for use in manufacture
• sampling and testing of in-process
materials and products, some specified
• time limits
• reprocessing allowed, but controlled
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
» Subpart G Packaging and Labeling Controls
• examination, approval of labels, labeling
• strict control over labeling issue, and
return to stock
• written procedures, physical separation of
labeling operations
• examination of materials before use
• inspection of facilities immediately before
• tamper resistant packaging (for OTC
products)
• expiration dating
Overview
Overview of
of cGMP
cGMP
requirements
requirements
•
cGMP Regulations
– 21 CFR 211
» Subpart H Holding and Distribution
» Subpart I Laboratory Controls
» Subpart J Records and Reports
» Subpart K Returned and Salvaged Drug
Products
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
»Subpart H Holding and Distribution
• quarantine before release
• store under appropriate conditions
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
»Subpart I Laboratory Controls
• establish specs, standards,
sampling plans, test procedures
• calibration, of laboratory equipment
• test each batch of drug product
• adequate acceptance criteria
• validate test methods
• conduct stability program
more....
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
» Subpart I Laboratory Controls
• Special tests
– sterility and pyrogenicity
– ophthalmic ointments for
foreign/abrasive particles
– controlled release products for rate of
release
• keep reserve samples
• test non-penicillin products for penicillin
when reasonable possibility of exposure to
presence of penicillin
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
»Subpart J Records and Reports
• keep records, make available for
inspection
• conduct annual review of each drug
product for changes to specs,
control procedures
• keep equipment cleaning and use
log
• keep component, container,
closure and labeling records
more....
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
» Subpart J Records and Reports
• have SOP for master production and
control record, maintain record
• use batch production and control records
for manufacture, keep records
• records to be reviewed/approved by qual
control unit
• complete data derived from all tests
necessary to assure compliance
more....
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
»Subpart J Records and Reports
• distribution records, with lot
numbers(except medical gases)
• complaint files
Problem
–
Drug Regulatory Program depends heavily on the
reliability (i.e. truthfulness, completeness and
accuracy) of data & information in records
–
Applications for approval [AIP]
–
Manufacturing Controls documentation [non-AIP]
–
Historical experience with broad scale unreliability of
data in records or in conduct related to records
Data
Data and
and records
records that
that
are
are not
not acceptable
acceptable or
or
are
are misleading
misleading
What are some characteristics of data that lack integrity?
» Untrue, made up, false, no source in an event
» Omission of significant data from the submission that
is determined to be material to the review process.
Data that is not submitted, but should have been
» Inaccurate (e.g. First data failed specs, retest data
passes specs, no lab investigation, but retest data is
submitted to the application.)
Records
Records Must
Must be
be True
True
• All data and information in records submitted to FDA &
supporting documents in the possession of the applicant
are accurate & true representations of –
– Actual tests performed & the test results
– Actual manufacturing & quality control steps &
procedures associated with the development and
manufacture of the submission batch (clinical/pilot or
biobatch)
– any other actions and conditions associated with the
application
Wrongful Acts
ÎAny act or conduct that subverts the integrity of the review
process, including, but not limited to the following:
–
submitting fraudulent applications
–
offering or promising a bribe or illegal gratuities
–
–
making an untrue statement of a material fact (e.g. false
statement, a misstatement or an omission of a fact)
submitting unreliable data which results from system-wide
or firm-wide behavior
Wrongful Acts (continued)
ÎAn untrue statement of material fact is a false statement,
a misstatement or an omission of a fact that is important
in the review process.
ÎSystem-wide incompetence is also a wrongful act
ÎWhen an untrue statement of material fact or system-
wide incompetence is found, several steps are required to
the invoke the AIP including:
–
–
Documentation of a pattern or practice of wrongful
acts.
Ensuring that the untrue statements are material
facts.
Pattern or Practice
ÎPattern- More than one instance of errors or acts
involving the subject matter important to the
evaluation of an application
ÎPractice- An act or process of doing something
affecting subject matter important to the evaluation
of an application
ÎA practice can be one or more acts or processes. A
pattern or practice can occur in one or more
applications.
If submitted to an
Application
ÎThe AIP procedures broadly define the term,
“application” to include, but not be limited to, any
application, amendment, supplement or other
submission made by an applicant.
ΓSubmitted” is an understandable term and includes
documents received by the review branch.
ÎWrongful acts also include omissions of data and/or
information that should have been submitted to an
application.
Food, Drug, and Cosmetic Act
Section 505(e) (excerpt below)
Numbered Part 5
– The
Secretary shall, after due notice
and opportunity for hearing to the
applicant,withdraw approval of an
application with respect to any drug
under this section, if the Secretary
finds….
– (5)
that the application contains any
untrue statement of a material fact
TO INVOKE AIP
ÎDocumentation of a pattern or practice
of wrongful conduct that raises
significant questions about the reliability
of data submitted to an application
- wrongful acts
- pattern or practice
- unreliable data
Restore FDA’s
Confidence in Data???
ÎCooperation with investigators
ÎIdentification of involved individuals
ÎCredible internal review & actions
ÎProblem analysis/identify all instances of wrongful acts
ÎUse of impartial auditor/Outside consultant
ÎAudit Plan, audits, audit reports
ÎOther measures as FDA deems appropriate
Restore FDA’s Confidence in
Data
ÎCorrective Action Operating Plan:
ÎAnalysis of audit findings
ÎImplementation of auditor recommendations
ÎActions taken to correct fraud/wrongful acts, e.g.
ÎWithdraw applications & recall products
ÎTimetable
ÎIdentification of persons assigned to complete and
verify corrective actions
ÎComprehensive ethics program
ÎProcedures for monitoring effectiveness of the plan
ÎTraining in the requirements of the Act and 18 USC
1001
Corrective Actions Plan
Evaluation
Monitor applicant’s actions/inquiries during
internal review
ÎInspection to assess actions taken by
applicant to determine if
ÎInternal Review performed adequately
ÎCorrective Action Operating Plan
implemented adequately
ÎSubmit recommendation to CDER to remove
site from the policy
ÎExpect a long time to pass before restoration
Overview
Overview of
of cGMP
cGMP
requirements
requirements
• cGMP Regulations
– 21 CFR 211
»Subpart K Returned and Salvaged
Drug Products
• if conditions cast doubt returned
product shall be destroyed unless
proved ok by test, examination,
investigation
• salvage only if evidence from tests
and inspection show all standards
met
Input
Input for
for cGMP
cGMP Changes
Changes
• Establishment inspections
– Industry changes/problems
• Defect reports/complaints/recalls
• Litigation
• Agency application reviews
• Trade/scientific literature
• Citizen petitions
Management
Management of
of cGMP
cGMP
Regulatory
Regulatory Program
Program
• FDA/CDER
– OC/Division of Manufacturing
and Product Quality
–
–
–
–
maintenance of the regulation
definitive interpretation
manage guidance development
develop, operate, evaluate
programs
– train FDA/outreach to industry
We
We Have
Have Discussed
Discussed
• Legal bases for cGMP
• cGMP legal principles
• cGMP Implementation Tools
• cGMP Resources
• Overview of cGMP requirements
• Integrity of Records and Data
Nicholas Buhay
Deputy Director
Division of Manufacturing
and Product Quality, HFD-320
Center for Drug Evaluation and Research
Phone: 301-827-8940
Fax: 301-827-8907
E-mail: buhay@cder.fda.gov
Montrose Metro Centre II Room 438
11919 Rockville Pike
Rockville, MD 20852
FDA CGMP
China
Training Program
December 5-7, 2005
Ying Jie Convention Center
Beijing University Beijing
Counterfeit Drugs
Nicholas Buhay
Deputy Director
Division of Manufacturing & Product Quality
Office of Compliance, CDER, FDA
Counterfeit Drugs
• Not permitted:
– Doing any act to cause a drug
to be a counterfeit
– Sale or dispensing a counterfeit
– Holding for sale or for
dispensing a counterfeit
2
Counterfeit Drugs
• A drug, or container or labeling of
it, that falsely represents the drug
to be
– To be the product of another
manufacturer, processor, packer, or
distributor
– To have been packed or distributed by
another manufacturer, processor,
packer, or distributor
3
Counterfeit Drug
• Not permitted:
Why????
– Product lacks assurance of
safety and efficacy
4
Counterfeit Drug
• Assurance of Safety and Efficacy
results from
– Knowledge of the pedigree (heritage) of
the shipment
– Opportunity for regulatory attention to
confirm
• Inspection of conditions and practices in
manufacture
• Samples and tests
• Review of information
5
Unapproved Drugs
• In USA, components (API + non-active
ingredients) are specified by source
factory in the approval of a new drug
application (NDA or ANDA)
• Sometimes, also precursor chemicals
are specified by source factory
6
Unapproved Drugs
• The use of other materials different
from materials from the specified
source factory may be
counterfeiting, but
• Definitely the product made is an
‘unapproved new drug’
7
Example:
• Tablets look like ‘Viagra’ but
• Tablets not manufactured, processed
or distributed by manufacturer
approved by FDA
8
Example
• Acetaminophen API made by factory
in Milan but,
• Label says product made by factory
in Beijing
9
Example
• Buspirone API made by factory in India and,
• Tablet manufacturer in USA uses the
buspirone API to make buspirone tablets
but,
• Manufacturer’s FDA approved Abbreviated
New Drug Application (ANDA) specifies
tablet manufacturer must use only
buspirone made by factory in Canada
10
Example
• Importer in New York buys methylphenidate
made in factory in Guangdong and,
• Puts it into different drum labeled with
name of factory in South Africa
– Also, puts C of A data onto South Africa factory
letterhead document
11
Example
• The government of Russia orders
Captopril Tablets to be made in a
factory in Ireland and,
• A multinational company operated
factories in Ireland and in Puerto
Rico and,
• Captopril Tablets made in Puerto
Rico factory of the company are
shipped to Russia to fill the order
12
Example
• A company in China operates two
factories, one in Shanghai and one in
Tianjin, and,
• The factory in Tianjin is approved in an
ANDA by FDA as source factory for
cefuroxime but,
• The company sells cefuroxime made in the
Shanghai factory for use in making the
approved drug tablets
– The company writes batch records showing
manufacture of this cefuroxime in the Tianjin
factory
13
Example
• A multinational company operates factories
in France and Italy; an FDA approved ANDA
approves total synthesis of cefaclor in the
Italy factory, but
• The company orders the factory in France
to make a specified precursor and sends it
to the Italy factory and,
• The Italy factory uses the precursor to
complete the synthesis of cefaclor
• Italy factory sends cefaclor to USA
– Italy factory makes batch records showing
complete synthesis
14
??Problem: Complex
distributiona
•
•
•
•
API source factory to
Trader (s) to
Importer to
Finished Pharmaceutical
Manufacturer
• Carriers
15
??Solution
• Limit distribution system?
• Markers?
• Characterization/Identification?
• Maintain ‘pedigree’?
16
Pedigree
• Process specific
• Lot specific
• Shipment specific
17
Pedigree
• Documentation
–
–
–
–
–
–
–
–
–
Batch records
Labels
Certificate of Analysis
Sales
Shipping
Declaration (Gates)
Receipt
Storage
Use
18
Pedigree
• Modern Technology
– Packaging
– Shipping
– Electronics
19
Summary
• Counterfeiting of products are
– Manufactured under unknown conditions and
practices
– Manufactured with unknown process
– Undesirable product event (adverse reaction,
product defect, etc) cannot be resolved
• Regulatory oversight process is
undermined
• Loss of assurance
20
Concern validated
• Actual event:
– Haiti 1996
– Contaminated “Acetaminophen Syrup”
product
• 3% Glycerin
• Water, sugars
• 14% Ethylene glycol (engine antifreeze)
• 80 children died
21
Concern validated
• Source of contamination
– “Synthetic Glycerin” component
material
– Used by Haiti manufacturer factory
– Importer in Haiti
– Trader in Netherlands (applied label to
read ‘Glycerin USP’
– Trader in China
– Manufactured in China (factory
unknown)
22
??Cause
•
•
•
•
Manufacturer?
Trader (s)
Importer?
Terror??
23
FDA Approach to Thwarting
Counterfeiting
Multi-Pronged Approach
• Technology
• State and Federal Regulatory
Action
• Secure Business Practices
• Education and Reporting
• International Collaboration
24
Technology
• Authentication Technologies
• Track and Trace Technologies
• No magic bullet – must use
layered approach
• Technology alone probably
insufficient without secure
business practices
25
Authentication Technology
• Inks, Holograms, Taggants etc.
• FDA recommends use of one or
more on products/packaging,
particularly those likely to be
counterfeited
• Manufacturers to use on a product
specific basis after doing a
cost/benefit analysis
• No requirements for any
particular technology
26
Track and Trace Technology
Requires:
• Mass Serialization
• Infrastructure – hardware and
software
Can be accomplished with:
• Radiofrequency Identification
(RFID) Technology
• 2D Bar Codes
27
Conclusion
Counterfeit Drugs will be an ongoing
problem
•
Sophistication
FDA’s multi-pronged approach will
make deterring and detecting
counterfeits more feasible
•
Layered approach
28
Conclusion
•
•
•
•
Don’t counterfeit
It is a social threat
It is a business threat
Participate in development of
distribution integrity
29
Conclusion
• We must protect our
children, our sick, our
revered elders
• We will be watching
• We will appreciate your help
30
FDA cGMP Inspections
Peking University 2005
Robert C. Horan, PhD
FDA Pharmaceutical Inspectorate
New York District
FDA Inspections
„
Periodic (biennial) comprehensive cGMP
„
Pre-Approval Inspection(PAI)
„
“For cause”
„
„
Inspection may involve more than one
assignment and will verify corrections to
previous inspections.
All inspections cover GMPs
Foreign Inspections by
Country in FY 2004
India
14%
Others
19%
Germany
14%
Ireland
4%
Spain
4%
Switzerland
4%
Italy
10%
Japan
5%
France
5%
China
7%
Canada
7%
United Kingdom
7%
Foreign Inspection in FY 2004
by Firm Type
Both API and Dosage
9%
Control Lab
2%
Micronizer
1%
Intermediates
10%
API
51%
Dosage
27%
FDA cGMPs for 21st Century
Initiative
Announced 8/2002; objectives include:
„
„
„
„
Encourage adoption of new technologies
Promote industry use of modern quality system
approaches
Encourage risk-based approaches which focus
on critical elements
Ensure FDA review, compliance and inspection
policies based on state-of-art pharmaceutical
science
FDA cGMPs for 21st Century
Initiative
„
Systems Based Inspections
„
Risk-Based Approach to Manufacturing and Regulation
„
Pharmaceutical Inspectorate
„
PAT Guidance document/ PAT Team
„
Quality Systems Guidance document
„
„
Process Validation (Compliance Policy Guide revised;
Guidance being revised)
21 CFR Part 11 Electronic Records Guidance (riskbased; geared toward GMP documents)
Pharmaceutical Inspectorate
„
„
„
Cadre of most experienced investigators who are
dedicated to drug inspections
Intensively trained along with quality reviewers
and compliance staff in FDA headquarters (HQ)
Overall goal is to have PI work closely with HQ
personnel – more efficiently integrate review
and inspection functions
Pharmaceutical Inspectorate
„
FDA Review staff, Compliance Officers and
PI candidates attended training modules
which focused on:
¾
Current Regulatory Programs
¾
Advanced Quality Systems
¾
PAT and Modern Pharmaceutical Technology
¾
Risk Management
Pharmaceutical Inspectorate
„
Field Investigators (18) from across U.S.
make up the Pharmaceutical Inspectorate
Screening process with certification board
¾ Completed training with HQ personnel
¾ One month detail working with HQ staff
¾ Level III certification (highest level)
¾ Conduct PAIs, complex drug inspections
¾
Process Analytical Technology
„
„
PAT is a system for designing, analyzing
and controlling manufacturing through
“real time” measurements of critical
quality attributes of raw and in-process
materials and processes, with the goal of
ensuring final product quality.
See FDA Guidance document on PAT
Process Analytical Technology
Examples of PAT applications:
„
„
Continuous real time measurements of
content uniformity of tablets during
production (using near Infra-Red)
Near IR measurement of moisture level
during API drying process to determine
actual end of operation for each batch
Process Analytical Technology
„
A process is generally considered well
understood when:
¾
¾
„
All critical sources of variability are identified
and explained
Variability is managed by the process
“Quality cannot be tested into products;
it should be built-in or should be by
design.”
Process Validation
Life Cycle Approach
„
„
„
Process validation begins with process
development and continues beyond the initial
“validation” batches for as long as product is
manufactured/marketed
Sources of critical variability identified and
controlled
Quality System role in maintaining validated
state (quality built in; not tested into product)
Process Validation
„
FDA Compliance Policy Guide
“Process Validation Requirements for Drug
Products and Active Pharmaceutical Ingredients
CPG 7132c.08”; revision date 12 March 2004
„
FDA Industry Guideline on Process
Validation – currently being revised
System Inspections
„
Quality
„
Facilities and Equipment
„
Materials
„
Production
„
Packaging/Labeling
„
Laboratory Controls
Most Common GMP
Deficiencies by System
– API/ Dosage Inspections for 2004/5
Materials
6%
Packaging and Labeling
1%
Laboratory
19%
Facilities & Equipment
17%
Production
11%
Quality
46%
“State of Control”
„
„
„
Detailed inspection of a system so that the
findings reflect the state of control in that
system for every product (profile) class
If one of the six systems is out of control, the
firm is considered out of control
A system is considered out of control based on
GMP deficiencies which suggest lack of
assurance of quality
Quality System
„
Quality must be built into the process
„
Quality is not tested into the product
„
Assurance of Quality comes from
- Design of robust process based on thorough
knowledge of that process and the sources of
variability
- Effective Quality System in place
Role of Management in QS
‰
‰
Management is responsible for:
¾
Organizational structure
¾
All Processes
¾
All Procedures
¾
Facilities & Resources
In short, everything to insure product quality,
customer satisfaction and continuous
improvement
Quality System Responsibilities
‰
Assures overall compliance with cGMPs
‰
Review and approval duties for:
1)
Product Quality Reviews (at least annually)
2)
Complaint reviews
3)
Discrepancy/ failure investigations
4)
Change Control
5)
CAPA (Corrective And Preventive Action)
Quality system (continued)
6)
7)
8)
9)
10)
11)
Reprocess/ Rework
Validation/ Revalidation
Rejects
Stability Failures/ Out of trend data
Quarantine products
Documented GMP & Job Related Training
Laboratory Control System
„
„
„
„
Adequate lab facilities under the Quality Unit which is
independent from Production
Adequately staffed laboratories (supervisory and bench
personnel)
Written specifications for raw materials, intermediates,
APIs, labels & packaging
Written procedures for sampling, testing, approval or
rejection of materials and for the recording and storage
of data
„
Change control for written procedures
„
Method validation/ revalidation
Laboratory Control System
„
Reference Standards (primary; secondary)
„
Equipment Qualification
„
„
„
Calibration: written procedures, schedule,
documentation
Validation and Security for computerized
handling of test results and related data; system
for assuring integrity of all lab data
Laboratory controls followed and documented
Laboratory Control System
„
„
„
Written procedure (SOP) covering out of
specification “oos” results
Investigation of “oos” results conducted in a
timely manner as per SOP and documented
(complete records maintained). Conclusions
from “oos” investigations documented and
corrective actions/ need for addition
investigation identified and implemented.
“oos” review included in Product Quality Reviews
Laboratory Control Records
„
Description of samples
„
Identification of method used
„
Raw data for sample/ standard preparation, reagents
„
Complete record of all data from testing
„
Record of all calculations
„
„
„
Statement of the test results; how compare with
established acceptance criteria
Signature of the person who performed each test; dates
tests performed
Date/ signature of second qualified person who reviewed
original test records for accuracy, completeness and
compliance with established standards
Production System
„
Training (documented; job-related)
„
Master production and control records
„
Batch production and control records
„
Change control procedure
„
„
Contemporaneous, accurate and complete batch
production documentation
Implementation and documentation of inprocess controls, tests, and examinations
Production system (continued)
„
„
„
„
Adequate written procedures & practice
for charge-in of materials
Identification of equipment with contents,
stage of manufacturing, status
Equipment cleaning records
Established time limits for completion of
production steps/stages
Production system (continued)
„
„
„
„
Deviations investigated and documented
contemporaneously with investigation
Process validation based on knowledge of process
(scientific basis for identifying critical steps/critical
process parameters/control points)
Justification and consistency of in-process
specifications and final product specifications
Data/information documented and available to
Quality Unit for review (trending, investigations etc.)
Facilities & Equipment System
FACILITIES
„
„
„
Location, design, construction appropriate to
facilitate cleaning, maintenance, operations
Layout and air handling designed and
constructed to prevent cross-contamination
Flow of materials & personnel designed to
prevent mix-ups or contamination
Facilities & Equipment System
„
Defined areas or other control systems to
prevent mix-ups or contamination
¾
Incoming materials (id, quarantine)
¾
Sampling area (prevent contamination)
¾
Quarantine (intermediates, APIs)
¾
Released materials
¾
Rejection
Facilities & Equipment System
EQUIPMENT
„
Appropriate design, size, location, non-reactive product
contact surfaces
„
Identification clearly marked
„
Qualification (DQ, IQ,OQ, PQ)
„
Calibration
„
Preventive Maintenance schedule and procedures
„
Cleaning procedures and validation
„
Records of use, cleaning, maintenance
Facilities & Equipment System
„
Lubricants, heating fluids or coolants (not
contact/alter product quality)
„
Closed or contained equipment
„
Inspection prior to use
*****************************************
„
Separate facilities or containment where needed
(penicillins, highly potent compounds etc.)
Utilities
„
„
„
„
„
Qualified and appropriately monitored; drawings
should be available
Designed and constructed to prevent
contamination or cross-contamination
Recirculated air to production (same concern)
Permanently installed pipework should be
appropriately identified
Drains of adequate size with air break
Water
„
„
„
„
Process water at minimum meeting WHO
guidelines for potable water
Justify quality of water used to achieve stated
API quality and establish specifications
Water treatment facilities validated
API to be used for incorporation into sterile
dosage form – water used in later stages should
be monitored and controlled for total microbial
counts, objectionable organisms and endotoxins
Materials System
„
Written procedures for receipt, identification,
quarantine, storage, handling, sampling, testing
and approval or rejection of materials
„
System to evaluate suppliers (critical materials)
„
Purchased against agreed specification
„
Change control process for changing suppliers
„
Upon receipt check for correct labeling, seals
„
Before co-mingling bulk material, id/test
„
Assurances obtained from non-dedicated tankers
Materials System
„
„
„
„
Identification on large storage containers and
associated manifolds, filling and discharge lines
Code given to received batches; status identity
At minimum, a specific identity test on incoming
batches; COA
Supplier evaluation should include three fully
tested batches; one fully tested batch/year
„
Written sampling plan with justification
„
Prevent contamination of sampled containers
Materials System
„
Stored in manner to prevent degradation,
contamination, no adverse effect on quality
„
Drums, bags, boxes off the floor
„
First in, first out
„
„
Rejected materials identified and controlled
under a quarantine system
Established re-test/ re-evaluation periods
Packaging & Labeling System
„
„
„
„
Written procedures for receipt, identification,
quarantine, sampling, examination and/or
testing P&L
P&L should conform to specifications
Records maintained for each shipment (showing
receipt, examination & result)
Containers protective, clean, not alter product
quality; if re-used, cleaned & labeling defaced
Labeling
„
„
Access to label storage area limited
Written procedures for reconciliation;
investigation if discrepancy
„
All excess labels with batch #, destroyed
„
Obsolete labels destroyed
„
„
Printing devices controlled to insure accuracy of
label (against batch record)
Print labels checked against master and a copy
placed into the batch record
Packaging/Labeling Operations
„
Documented procedures to assure correct
packaging materials/ labels used
„
Operations designed to prevent mix-ups
„
Labels: API name, batch #, storage conditions
„
„
„
„
Shipped API: Name/ address manufacturer;
special transport conditions; expiry/ retest date
Documented clearance before operations
Packaged/ labeled intermediates or APIs
examined as part of packaging (documented)
Seal employed to assure package integrity
APIs are Drug Substances
„
„
„
FDA Food, Drug and Cosmetic Act definition of
drug includes “articles intended for use in the
diagnosis, cure, mitigation, treatment or
prevention of disease in man or other animals”
(no distinction between APIs & dosage forms)
Before ICH Q7A, FDA used dosage drug
regulations as guidance for API inspection
Still true (see next slide) , however, ICH Q7A
provides guidance on the application of those
cGMPs to APIs)
From current FDA Compliance Program
56002 for Drug Manufacturing Inspections:
(This is the compliance program for FDA
Investigators; this revision introduced Systems
Inspections)
“The cGMP regulations are not direct
requirements for manufacture of APIs…….but
they are guidance for cGMP in API manufacture.”
Current FDA Compliance Guide
on Process validation
From FDA Compliance Policy Guide “Process Validation
Requirements for Drug Products and Active Pharmaceutical
Ingredients CPG 7132c.08”; revision date 12 March 2004:
Validation of manufacturing processes is a
requirement of the Current Good Manufacturing
Practice (cGMP) regulations for finished
pharmaceuticals, and is considered an enforceable
element of current good manufacturing practice for
active pharmaceutical ingredients (APIs) under the
broader statutory cGMP provisions of the Federal
Food, Drug, and Cosmetic Act”.
Differences API/ Dosage Form
„
APIs involve purification steps
„
GMP controls tighter for later API steps
„
„
API impurity profile is critical focus and
steps which produce or remove impurities
require greater control and validation
Dosage forms do not involve purification
Similarities APIs/Dosage Forms
„
„
„
Require demonstrated knowledge of
process and application of appropriate
GMP controls to assure safety, identity,
strength, quality and purity.
Systems in control to be in compliance
Life Cycle Approach to Validation (beyond
the initial “conformance batches”)
Similarities include….
„
Processes for specific products vary in
complexity (either API or dosage can involve
complex or simple processes)
„
In-process controls
„
Finished product controls
„
Critical steps/ critical process parameters
„
Process validation
„
Quality assurance for consumer is based on
understanding & control of sources of process/
product variability
More Similarities…..
„
„
„
Science based approach for the
establishment of processes
Knowledge of process based on Process
Development work
¾
Design Of Experiments (DOE)
¾
Quality System (review/ trending)
Continuous Improvement possible within
well characterized process
FDA CGMP
China Training Program
December 5-7, 2005
Ying Jie Convention Center
Beijing University Beijing
Solid Oral Dosage Forms
Nicholas Buhay
Deputy Director
Division of Manufacturing & Product Quality
Office of Compliance, CDER, FDA
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Solid Oral Dosage Forms
Discussion of Manufacturing
Considerations and Current Good
Manufacturing Practice
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
FORMS
•
•
•
•
•
Powders
Pills
Troche
Capsules
Tablets
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Most Common Dosage Forms
•
•
•
•
•
Convenient
Relatively Stable
Easily Administered
Palatable
Flexible
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Capsules
• Hard Gelatin
• Soft Gelatin
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Hard Gelatin Capsules
• Empty Capsule
Storage
– Controlled temperature
and humidity
• Too moist - capsules
become tacky
• Too dry - capsules
become brittle and
change dimensions
• 30 to 45% R.M. ideal
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Operations
•
•
•
•
Rectify the capsule
Separate body from cap
Fill the body
Replace the cap
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Capsule Filling Machine
• Hand Operated
• Semi-automatic
• Fully automatic
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Process Variables
•
•
•
•
•
Speed
Humidity
Bulk Powder Level
Weight Variation
Gelatin Moisture Content
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Compressed Tablet
• Un-coated
• Immediate Release
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Multiple Compressed
• Layered
• Compression Coated
– Tablet Within a Tablet
– Two Part
– Three Layer
– Function as Film/Sugar
Coated
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Repeat-Action
Active ingredient in the tablet core
and in the coating.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Delayed-Action/Enteric Coated
• Coating protects core in the stomach
• Drug released in the upper GI tract after the
stomach
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Film Coated
• Solvent Based
• Aqueous Based
• Alternative to Sugar Coated
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
INGREDIENTS
• Active
• Non-Active
– Drug Substance
–
–
–
–
–
–
–
–
Diluents
Binders
Lubricants
Disintegrants
Coloring
Flavoring
Antiadherents
Glidants
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Drug Substance
• Fully Characterized
– Physical
Specifications
(Including Particle size
distribution, density,
isomerism and
Morphology)
– Chemical
Specifications
(Including Impurity
and Degradation
Profile)
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
DILUENTS
•
•
•
•
•
Lactose
Starch
Mannitol
Calcium Sulfate
Sorbitol
•
•
•
•
•
Dicalcium Phosphate
Kaolin
Sodium Chloride
Powdered Sugar
Microcrystalline
Cellulose
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
DISINTEGRANTS
•
•
•
•
•
Starch
Microcrystaline Cellulose
Alginic Acid
Gums
Crospovidone
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Binders
•
•
•
•
•
•
Starch Paste
Glucose
Gelatin Solution
Acacia
Sucrose
Sodium Alginate
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
LUBRICANTS
•
•
•
•
•
•
Magnesium Stearate
Calcium Stearate
Talc
Stearic Acid
Sodium Lauryl Sulfate
Sodium Acetate
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Observations
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
-) Testing standards for raw
materials used in the manufacture
of ***** 40 mg tablets do not
include specifications for physical
characteristics.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
-) ***** raw material is not
sufficiently characterized to
determine its suitability for the
manufacturing process. Various
lots have passed all acceptance
criteria, but have been identified as
the causative factor in granulation
and tableting deviations.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
-) …..The affect of particle size
distribution, surface area and the
particle morphology of the bulk
drug substance, on the granulation
process were not fully
evaluated…..
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
There was a failure by QA to
identify two separate lots of diluted
Isosorbide Dinitrate bulk drug
substance, received from the
supplier in the same shipment...
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
-) The investigation into the
acquisition and release of
aluminum stearate of the wrong
grade obtained from an unapproved
source failed to identify that the
wrong grade of material was
ordered from the vendor.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
GRANULATING
• Wet Granulation
• Direct Compression
• Dry Granulation
– Slugging
– Roll Compaction
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Wet Granulation
• Advantages
• Disadvantages
– Improved
Compressibility
– Improved uniformity
– Decreased segregation
– Flexibility
– Process complexity
– Cost
– Possible affect on drug
substance
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Wet Granulation Manufacturing Steps
W eighing
Mixing
Granulation
Screening
Drying
Screening
Lubrication
Compression
Oral
Solid Dosage Forms/Michael
O'Meara/ 2004
Wet Granulation
• Specific Manufacturing Instructions
• Amounts, Rates and Timing of Granulating
Fluid Additions
• Mixer Speeds and Configuration
• Specified End Points - Motor Load,
Appearance, Texture
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
FDA 483 Observation
...some granulation batches have required
on the spot changes in established
procedures for water addition and/or mix
time to compensate for over and under
granulation problems, the addition of a wet
milling step or hand processing to break up
lumps in over granulated batches, an
additional drying step...
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Dry Granulation
• sensitive to
• Useful when ingredients are
moisture or heat
• Blended ingredients are either compressed
into “slugs” or roll compacted into “sticks”
or sheets
• Slugs or sticks are screened/milled
• Granulation is blended with lubricant and
disintegrants then compressed
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Roller Compactor
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Direct Compression
• Ingredients are milled and/or screened, then
mixed, then compressed into tablets.
• Few Manufacturing steps
• Greater potential for segregation
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Mixers & Blenders
•
•
•
•
•
Pony/Planetary Mixer
High Shear Mixer
Ribbon Blender
Screw Blender
Tumble Blenders
–
–
–
–
Twin Shell
Double Cone
Drums
Other
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Mixing Process Validation
• Validation of the reliability of mixing
operations is a very significant control
expected
• Sample from the blender (if possible)
• 10 individual assays
• Sample size
– Approximate unit dose
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Planetary Mixer
• Good horizontal mixing
• Cross contamination risk
• Poor vertical mixing
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Ribbon Blender
• Horizontal and vertical mixing
• Dead zones
• Cleaning issues
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Screw Blenders
• Three Distinct Intermixing Action
– Screw produces lifting action
– Orbiting screw moves material from the walls
of the blender into the center of the vessel
– Material lifted by the screw gravitates
downward
– No picture
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Tumble Blenders
• Shell blenders
• Twin Shell and Double Cone
– Low energy mixing
• clumping and segregation
– Working capacity
– Cleaning
– Liquid Dispersion Granulation
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
High Shear Mixers
• Very efficient
• Ideal for wet
granulation
• Amount and addition
rate of granulating
fluid must be strictly
controlled
• End points can be
measured
• Single pot production
• Heat
• Cleaning
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
OTHER BLENDERS
• Drum
• Bags
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Inspection Observations
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
there were no blend time studies
conducted to assure uniformity of
granulation for the pre-blend or
final blend steps…In addition,
production batch records do not
specify a finite time for blend steps.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
one of six granulation samples
obtained from the blender, at final
blend step, assayed below
specification.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
- Content uniformity of the
preservative was not included in
the validation study for ***.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
- During the processing of ***
500mg tablet batch ***, an
operator was observed inverting a
drum of granulation several times
prior to placing it above the tablet
press granulation hopper. This step
is not part of the established
process, but is reportedly common
practice.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
- ******* 40 mg tablets are not manufactured
in accordance with the approved filed process.
The current manufacturing process includes an
additional 5 minutes of blending with intensifier
bar prior to the granulation step, an additional 3
minute blending step (drum mix) during the
tableting operation, and pre-compression and
dissolution evaluation steps, none of which are
represented in the filed process.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
DRYING
• Fluid Bed
• Tray
• Vacuum
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Fluid Bed Drying
• Efficient
• Uniform drying
• Process Variables
– Temperature
– Air velocity
– Filter pore size
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Fluid Bed Granulating
• Process Variables
– Droplet size and spray
rate
– Inlet air temperature,
humidity and velocity
– Location of spay
nozzle
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oven/Tray Drying
• Drying is less uniform
than with fluid bed
• End point
determination
• Cross contamination
issues
• Cleaning
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Vacuum Drying
• Jacketed tumble dryer
• Heat applied to vessel walls
• Vacuum draws off moisture/solvent
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Milling
• Process Variables
–
–
–
–
–
–
Feed rate
Inlet feed throat design
Blade type
Rotor speed
Screen type
(Overhead)
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Transfer & Storage
•
•
•
•
•
Post blending segregation
Floor vibration
Chutes and collars
Equipment Vibration
Segregation ????
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Compression
• Start up tablets
• In process testing
–
–
–
–
–
–
hardness
friability
size
shape
disintegration
thickness
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Tablet Presses
•
•
•
•
Single Punch
Rotary Press
High Speed Rotary Press
Multi-layer Rotary Press
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Tooling
• Quality Control
• Accountability
– unique identifier
– security
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Problems
• Sticking and Picking
– granulation moisture
– lubricant
– punch face
• Capping
– Fines
– Air
– punch-die clearance
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Problems
• Lamination
• Chipping & Cracking
– Tooling
– granulation procedure
– formulation
• increase binder
• lubricant
– tooling
– granulation
• fines
• granule size
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Common controls
• Hardness
• Friability
– Force required to break
a tablet
– Ability to withstand
abrasion and trauma
without crumbling
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Common controls
• Disintegration
• Dissolution
– The time it takes for a
tablet to disintegrate in
an aqueous medium
– How the formulation
releases the drug
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Inspection Observations
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
The investigations into a capping
problem associated with seven
production batches of XXX Tablets
identified by MDIR's for one year
are incomplete, in that; there was
no evaluation of the granulation nor
of the raw materials used.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
The manufacturing process for XXX
Extended Release Tablets is not
validated in that :
a) the 45 station Stokes BB2 rotary
tablet press (firm's ID # xxx ) was not
qualified to assure the capability and
controls for this piece of equipment
were suitable to meet requirements
established for manufacture of this
product.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
MDIR's were not generated, nor
investigations conducted to determine
cause, identity of content, and quantity
of "chunks" of granulation which had
to be occasionally removed from the
tablet press screen during compression
of xxx, batch xxx, nor of "lumpy"
granulation observed in the hopper of
the press during granulation of xxx,
batch xxx.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
- Development history supports an
in-process disintegration limit
lower than the current value of < 15
min. An unusual dissolution
profile in a development batch was
associated with in-process
disintegration times > 9min.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
- The ***** 40mg tablet
manufacturing process is not
validated in that:
a) Tableting parameters are set
batch to batch based on precompression dissolution test
results.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
b) Critical physical
characteristics of raw materials
have not been identified.
c) Validation lots did not
include specifications for the
physical characteristics of
blends and granulations.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
d) Final blend samples taken for
physical characteristics analysis
were composite.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
- The agency was not notified, in
accordance with NDA Field Alert
reporting requirements, when it
was determined that lot **** failed
dissolution testing at the 1 month
stability station.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
- The operating speed for the Perry
Powder Filler when filling XXX is
listed as 95 bottles per minute
(BPM) in the Line Set-up Standard
Sheet, which is outside the 80 to 90
BPM range used in the validation
batches.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
COATING
•
•
•
•
•
Protect drug from the environment
Mask taste
Improve appearance
Separate ingredients
Provide multiple release profiles
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Equipment
• Standard coating pan
• Perforated coating pan
• Fluidized bed
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Standard Pans
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Perforated Pans
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Fluid Bed
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Types
• Film
• Enteric
• Sugar
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Film Coating Materials
• Polymers -
Hydroxypropyl methylcellulos
Povidone
Polyethyleneglycol
• Enteric Materials Cellulose acetate phthalate
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Sugar Coating Materials
• Sealant - Shellac
• Sugar - Syrup and color
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Process Variables
•
•
•
•
Pan design
Pan speed & load
Air quality
Temperature
•
•
•
•
Airflow rate
Spray rate
Spray pattern
Nozzle to bed distance
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
There are no written SOP's for
conducting batch record reviews to
assure consistency and
completeness of those reviews...
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
A sticky note, attached to the official
lab report, both dated with the same
day, contained unacceptable test results
of an individual tablet relative to a
dissolution profile test conducted
during the initial validation batch xxx,
for product XXX. The values for this
tablet were not included on the final
lab report.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
- 80% of the Aluminum Stearate
used in the formula for ***** lot
***** was an unapproved grade
obtained from an unapproved source.
This lot has been distributed. The
following two lots, ***** & *****,
which were manufactured using 100%
of the unapproved material were
rejected for failing to meet
specification.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
- There was no investigation
conducted following the rejection of
86 kg of XXX 40mg tablets from lot
***** (a post validation lot) when the
2 hour compression trial sample failed
dissolution testing; there was also no
QA Management evaluation of the
incident or its impact on the validation
status of the process.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
The local Quality Unit review has
failed to assure the accuracy and
completeness of validation reports,
manufacturing documents, and
analytical reports. For example:...
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
The local QA unit failed to follow
the procedure (***.*) to notify
senior corporate officials of
significant quality issues so that
resources could be allocated to
resolve problems...
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Laboratory procedures do not provide
for the expeditious analysis of stability
samples that require multi stage
testing. For example, stage one
dissolution testing for stability sample
*** was initiated on August 9, but
stage three testing, indicating a
stability failure, was not completed
until October 5.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Specifically, the manufacturing process for
lots of *** mg tablets manufactured
between *** and *** was not validated in
that approximately 9 of 39 lots were
rejected due to dissolution failures. Changes
made to the manufacturing process during
this time did not resolve the dissolution
failures. Approximately 21 lots
manufactured during this time were released
for commercial distribution.
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Summary
• Process Analysis
• Process Variables
• Process Controls
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Summary
•
•
•
•
•
•
•
Evaluate material
Evaluation of site for cross-contamination
Consider operations (steps) in process
Consider equipment for operations
Determine process controls
Demonstrate process reliability (validation)
Commit to continuous monitoring of
manufacturing experience
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Inspection References
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
GUIDE TO INSPECTIONS OF
DOSAGE FORM DRUG
MANUFACTURER'S - CGMP'S
October, 1993
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
GUIDE TO INSPECTIONS OF
ORAL SOLID DOSAGE
FORMS PRE/POST
APPROVAL ISSUES FOR
DEVELOPMENT AND
VALIDATION
January, 1994
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
GUIDE TO INSPECTIONS
VALIDATION OF CLEANING
PROCESSES
May 1987
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
GUIDE TO INSPECTIONS OF
PHARMACEUTICAL
QUALITY CONTROL
LABORATORIES
July, 1993
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
EXPIRATION DATING AND STABILITY
TESTING FOR HUMAN DRUG PRODUCTS
Inspection Technical guide 41
(http://www.fda.gov/ora/inspect_ref/itg/itg4
1.html)
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
CGMP Guidance: Answers to
Frequently Asked Questions
Notes
Human Drug CGMP Notes (3/1995-7/2000)
• Human Drug CGMP Notes (1/1993-12/1994)
–
–
–
–
–
–
–
–
[CNOTES vol. 1 no. 1 Feb 1993]
[CNOTES vol. 1 no. 2 May 1993]
[CNOTES vol.1 no. 3 Sept 1993]
[CNOTES vol.1 no. 4 Dec 1993]
[CNOTES vol. 2 no. 1 Mar 1994]
[CNOTES vol. 2 no. 2 Jun 1994]
[CNOTES vol. 2 no. 3 Sep 1994]
[CNOTES vol. 2 no. 4 Dec 1994]
►TO FIND, GO TO WEBSITE: http://www.fda.gov/cder/dmpq/index.htm
Other Resources
• Guidance for Industry: CGMPs (Pharmaceutical CGMPs for the 21st Century)
–
Questions and Answers on Current Good Manufacturing Practices (cGMP) for Drugs (Posted
8/4/2004)
►TO FIND, GO TO WEBSITE: http://www.fda.gov/cder/guidance/cGMPs/default.htm
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
Good Luck!!
• Think soundly
• Operate under control
Oral Solid Dosage Forms/Michael
O'Meara/ 2004
FDA API Inspections
Robert C. Horan, PhD
FDA Pharmaceutical Inspectorate
New York District
Quality System observations
FDA 483 Observations for Product Quality
Reviews range from:
„
No SOP for Product Quality Reviews
„
No Product Quality Reviews conducted to:
„
various components of the reviews not done
„
inadequate investigations
„
no corrective actions or other conclusions
Quality System observations
Regarding the annual product reviews:
„
„
The reports do not identify the specific batches
which were covered by the review period and there
is no evaluation of specific data from the batches
covered.
The annual report from 200X was found to contain
some conclusions regarding out of specification data
and corrective actions without providing specific
information such as batch numbers, actual events,
specific data, conclusions and any specific
corrections made.
Quality System observations
An example is on page 3 which states:
“The main unqualified item in 200X is the
XXX content out of the specific range. We
take relative measures to strengthen the
control of manufacturing process, training
the workers, strengthening the workers’
quality sense”.
Quality System observations
„
„
Many of the firm’s written procedures (SOPs) have not
been periodically reviewed and revised where needed to
ensure that they accurately describe current procedures
at the firm and are in compliance with cGMPs. Some of
the SOPs were found to have approval dates as far back
as 1994. Examples include but not limited to:
a)
**********, revision 1, approved 10 Jan 1994
b)
XXXXXXXXX, revision 1, approved 23 March 1998
Further, review of SOP XX found that it describes
equipment which had been removed two years ago and
the attachments “C” and “D” are no longer used for
documentation and were replaced by other forms which
were not attached to the SOP.
Quality System observations
From a Warning Letter:
“Failure to establish corrective and preventive
actions (CAPA) procedures for investigating the
cause of non-conformities relating to product,
processes and the quality system.
Specifically, the firm received – complaints
related to……. You failed to follow SOP # -- in
that investigations were inadequate and no
CAPAs were implemented.
Quality System observations
„
„
Change control forms for changes in
Master Batch Production records fail to
identify specific changes made.
Further, there is no written evaluation of
the significance of the change, need for
re-validation etc.
Quality System observations
Software change control reports were
found to have multiple text changes made
by means of “white-out” rather than by
following the firm’s written procedure of
crossing out the original text and initialing
(stamp) the correction. Further, there
were no written explanations given for the
specific changes made.
Quality System observations
There is no control over the use of
signature stamps by production and
quality control personnel used in the
signing of documents.
Quality System observations
Process validation reports for API *** did not
have criteria for acceptable reduction of the two
specified impurities “eimp” and “fimp”. Batch
record review (20 consecutive batches) found
that post-validation batches showed typical levels
of both impurities were much higher than in the
validation batches. A number of batches
exhibited “eimp” values that were more than
double that in validation batches and approached
the limit of 1.0%.
Quality System observations
SOP “QA Inspector in the Workshop”
describes a twice daily check of
equipment readings versus data recorded
in batch records. Examination of several
entries in the QA inspector’s log and
corresponding batch records from those
same dates/times found discrepancies
between the QA inspector’s record and
batch record data.
Quality System observations
Further, on (date), the QA inspector recorded a
temperature of 0 C for the critical **** reaction
step ------ for batch ***, however, my
examination of the batch record found that for
that step which lasts 5 hours, the temperature
never reached 0 C. In fact, the critical
temperature range is 12 to 20 C and examination
of 25 batch records close to dates for batch ***
found
1) Examples of temperature exceed upper limit
2) No batches recorded a temperature of 0C.
Cited on warning letter
The firm’s procedures for identifying and
documenting problems that occur in
manufacturing are deficient. For example, 235
“minor” deviations were logged year-to-date, of
which only one was fully documented as a
deviation investigation. Minor deviations that
were not fully investigated and documented
included:
Quality System observations
1) API ^^^ production lot *** failed to form final
product crystals. The cause was attributed to an
operator error and the charging of excess
solvent. Non-validated measures were used to
attempt to force the formation of crystals. The
in-process lot was subsequently divided into
thirds and blended into three other production
lots that became finished API ^^^ lots ***, ***
and ***. This was listed as a minor deviation
and a full investigation was not performed.
continued
2) API ^^^ production lot *** yielded only 57%.
The yield was approximately 30% below
average. The cause was attributed to an initial
high processing temperature caused by the
computer system. No additional information or
justification was provided; this was listed as a
minor deviation and a full investigation was not
performed.
Quality System observations
Review of a number of “oos” for potency in API ***,
it was found that this was attributed to failure of
temperature sensors on manufacturing equipment
XXX and that the temperature had been out of the
critical control range. In reviewing other deviation
reports, it was found that following earlier episodes
of “oos” potency values, there were corrective
actions recommended including one to increase the
frequency of calibrations of the sensing devices.
Examination of the applicable SOPs found these
recommended had not been implemented and no
other corrective action taken.
Quality System observations
Action limits for testing of Purified Water have been
exceeded several times without any investigations
or completion of non-conformance reports. The test
results were included in the Purified Water System
Qualification report dated (date). For example, Use
Point XX sampled on (date), results were
“Unsatisfactory” for absence of clinically significant
organisms (pathogens), User Point YY sampled on
(date, three months earlier) had Total Viable Counts
which were more than 10 times the action limit of X
cfu/mL. This data was recorded in the final report
signed by quality management.
Quality System observations
„
„
„
The written procedure (SOP XX-Y) for training of
employees does not address the conduct of job
specific, performance based training and there is no
documented record of such training for quality
control laboratory and production personnel.
Inspection found many production deviations where
the cause was reported to be operator error and
retraining was conducted. SOP XX-Y does not
address the retraining of personnel and there is no
documentation of retraining.
There are no individual training records for
personnel.
Laboratory observations
„
„
Calibration of pH meter #__ is done using
buffers at pH 4.0, 7.0 and 9.0, however, it is
used to measure the pH of *** which has an
expected pH around 12.
Balance # ___ used in the testing of *** is
calibrated at ___ intervals using weights in the
range *-*, however, sample weights as per the
method for testing of *** are considerably
below the lower end of the calibration.
Laboratory observations
„
„
The identification test used for XX@-Na by FTIR
compared the spectrum of XX@-Na against the
spectrum for USP XX@. These spectra are not
equivalent and are in fact quite different.
Identification testing of API ***
batches …,…,…,…,… using IR was not actually
done. The analyst simply used a previous
spectrum and changed the batch number each
time.
Laboratory observations
„
Regarding the computerized and paper systems
used in the recording of quality control testing
data for chemistry, microbiology and in-process
production testing the following was observed:
a)
The computerized (LIMS) system is not secure in that
it is possible for data to be changed. This was
observed following a request during inspection for a
challenge to be performed. In performing the
requested challenge, the analyst was able to change
previously recorded input including sample gross and
net weights resulting in changed assay results.
Laboratory observations
b)
There is no system such as the use of
pre-coded sheets, signed and distributed
by a responsible quality employee for
assuring the integrity of loose paper data
sheets used in the recording of test
results
Laboratory observations
„
„
Inspection of the QC and Microbiology laboratories
found that analysts use loose printed sheets for
recording raw data, there were stacks or pads of
blank pages readily available.
In the microbiology laboratory, in response to a
question about how the name of the product is
stamped on the data page, an analyst took out a
stamp and ink pad and demonstrated how it would
be done. There is no procedure in place to insure
the integrity of data sheets used in the QC
laboratory.
Laboratory observations
„
„
„
Examination of the HPLC systems in the API
testing laboratory found that for the ***
systems, the audit trail function was not enabled.
For the *** HPLCs, the audit trail function was
enabled, however, the laboratory management
has never conducted an examination of the
audit trail on any of these instruments.
No training of analysts regarding audit trail.
Laboratory observations
Generic Statement – details withheld
FDA inspections sometimes find evidence
of data in computer files which is not
recorded in laboratory notebooks, lab
worksheets or final written reports.
Laboratory observations
„
„
The firm’s QC chemistry laboratory has
three HPLC systems and reportedly tests
about 2000 samples per year, however,
the calibration is done only once every
two years (by government agency).
There is no established basis for not
conducting more frequent full equipment
calibration related to the high equipment
usage.
Laboratory observations
Note:
At least several FDA 483s have cited
observations regarding incomplete information
provided on certificates following their
calibrations. It has also been cited several times
that the factories receive no other information
and that it is not possible for an adequate
review to be done of the instrument calibration –
either by the factory or outside auditor - such as
FDA).
Laboratory observations
„
Calibration of HPLC is inadequate in that
the lamp energy was not determined to
assure that it is capable of detecting low
concentration of impurities during impurity
determination.
Laboratory observations
„
„
„
System suitability is not performed each
time the HPLC assay method is run.
The firm has conducted system suitability
only once in the history of testing API***.
The firm does no conduct system
suitability each time testing is done as per
USP.
Laboratory observations
„
The firm has not demonstrated that the
assay method used for stability testing of
API *** is stability indicating.
Laboratory observations
‹
‹
There is no data available from the forced
degradation studies which serve as the basis for
demonstrating that the stability test method for
testing of API stability samples is stabilityindicating.
The management stated that at the time the
studies were conducted in 200X, the factory was
not retaining raw data.
(continued)
Laboratory observations
‹ Further,
there is no record of preparation
of samples, sample stress treatments or
the actual testing.
‹ Finally,
there is no record of the subdividing of stressed samples to prepare a
sub-sample to be sent to a contract
laboratory for the peak purity studies.
Laboratory observations
„
For the related compounds methods for *** API,
the procedure states to run the chromatogram
for NLT 2.5 times the retention time of the API.
Review of earlier test data shows that a
significant recurring impurity elutes at
approximately five times the retention time of
the API, which could go undetected when
following the instructions for chromatographic
run time.
Laboratory observations
„
For several tests from the USP monograph for
API ^^^, USP, the firm either did not perform
the test or did not conduct it as per USP. For
example, the UV identity test was not done and
the IR identity scan in the batch records was
simply a copy of a “representative” batch run
previously; “the test for the specified impurity 4XXXXX was not conducted for any of the batches
examined (batches ***, *** and ***) and the
“Crystallinity” test was not done.
Laboratory observations
„
„
„
„
The firm’s “out of trend” (“OOT”) investigation for stability
testing on three consecutive validation batches ****1,
****2 and ****3 concluded that the “OOT” result was due
to analyses being conducted by different analysts on
different instruments. The following is noted:
The analysts were also reportedly trained and the
instruments calibrated and deemed acceptable for the
testing
There is no documented basis for the investigation
conclusion
The conclusion suggests the method is not robust, however,
the investigation did not address the significance for all
other previous testing
Laboratory observations
„
For the related compounds method for
***, several errors exist in the procedure
that were not detected during the review
process. These include the incorrect
concentration listed for the stock standard
and the incorrect dilution for the low level
standard preparation.
Laboratory observations
„
Following an out of specification result for
*** in the 6 month stability sample of ***,
lot ***, the analyst reported that the
"Test FAILED" on the report sheet and
forwarded this to the group leader,
however, no action was taken. According
to the laboratory manager, the sheet must
have been missed and was not discovered
for more than two months.
Laboratory observations
„
„
There is no written procedure which requires the
investigation, review and trending of laboratory
deviations not covered by “oos” investigations.
Inspection of product *** found that there were
HPLC assays discontinued when an outdated
reference standard solution introduced unknown
peaks. The firm has stability data for 15 days
use of *** reference standard solution and
supervisor stated “We would not normally use
such an old solution. It was done because
standard is expensive”.
“oos”
‹
‹
The firm’s investigation of “oos’ test results for
assay,, related substances and residual solvents
for the two consecutive batches *** and *** of
API ^^^ was limited to verifying that there was
no laboratory error and the results were valid.
There was no evaluation to determine the root
cause of the multiple critical specification failure,
no extension of the investigation to consider the
potential significance for other batches. The
only further action taken was to reprocess the
batches and sell them to the local market
instead of U.S.
“oos”
‹
‹
The firm received complaint of batches **** and
*** of the API product ^^^ failing the related
substances test for the single largest related
substance. The API manufacturer investigated the
original test records from (date) and found that the
analyst had selected the wrong peak as the largest
related substance peak.
The investigation was not extended to other batches.
Review during the current inspection of test results
from other batches found that the same analyst
made the same mistake for several other batches.
This had not been discovered by the API
manufactuer’s investigation.
“oos”
‹
Inspection found that an “oos” for potency of
API ^^^, lot *** was invalidated based solely
on the testing of a new sample. Examination
of the firm’s SOP PP-T, found the following
regarding the procedure for “oos”
investigations:
a)
If an identified cause for the “oos” is not
determined or not confirmed, then a second analyst
will test a new sample.
b)
If the second sample meets specification, the
conclusion is made that the original sampling was
flawed. (continued next slide)
“oos”
c)
d)
If the new sample failed, only then would
the lab supervisor prepare an “oos”
reporting form which would be copied to
production, QC and QA.
The SOP does not address retesting the
original sample.
“oos”
‹ Regarding
the firm’s procedure for
investigation of “oos” test results:
a)
There is no log, file or other cumulative
record of the firm’s “oos” investigations.
b)
The annual product reviews do not include
review of these investigations.
c)
There is no time frame identified in the SOP
for completion of “oos” investigations.
“oos”
(From an FDA letter sent to factory to indicate inadequate
written response to FDA 483):
‹
‹
Specifically, we remain concerned regarding the
consistency of the manufacturing process and/or
analytical procedures.
The inspection revealed numerous “oos” assay results in
different samples from batch *** as well as “oos” for
two other batches within the same campaign. Some of
the “oos” values were attributed to analytical error but
the cause of others remain undetermined. (continued
next slide)
“oos”
‹
‹
Your written response indicates that the “oos”
investigations will be closed out within 30 days
and that new laboratory SOPs have been written,
training has been provided to laboratory
personnel, and additional laboratory personnel
have been recruited.
Please provide the documentation that the “oos”
investigations have been completed and that the
cause of the “oos” assay results have been
identified as either process related or analysis
related. (continued next slide)
“oos”
Please address any process or analytical
changes which may have been necessary
to address this issue.
Facilites & Equipment
„
The firm’s written procedures for preventive
maintenance (PM) do not include examination
and evaluation of all equipment components or
schedule for replacement of parts. In this
regard, there were three batches (***, *** and
***) which were reported in the annual product
review to be contaminated with particles from a
shredded Teflon gasket associated with the --mixer. Inspection found: (continued…..)
Facilites & Equipment
a)
b)
There was no extension of the investigation to
determine if previous batches may have been
contaminated. In addition, the investigation
does not document the identification of the
contamination being consistent with Teflon
particles.
The engineering management stated that while
they are responsible for equipment
maintenance, they have no PM procedures and
stated PM should be the responsibility of
production.
Facilites & Equipment
c)
d)
There are no PM SOPs in the production
department.
The production department has a
machine log for each piece of equipment,
however, review of the machine log for
the mixer found no record of the Teflon
gasket replacement in the period
following the reported contamination.
Facilites & Equipment
The investigation into lots of API ^^^
returned due to the presence of metallic
particles does not include a measure to
prevent future recurrence.
Please note:
The following two slides list other
observations on that same FDA 483.
Facilites & Equipment
‹ Facilities
& equipment in which crude APIs
are exposed during processing are not
maintained in a clean and sanitary manner
and are not designed to prevent
contamination of the crude APIs from
foreign particles like dirt, rust, dust, paint
chips and metal.
Facilites & Equipment
‹
Then 483 lists a number of examples…..transfer
of crude API from ----- reactor to centrifuge is
performed underneath a metal platform in a
building which is open to the outside; transfer
to the multimill is performed in a room with
peeling and flaking paint on walls/ ceiling;
inside of the multimill granulator is corroded
toward the bottom of the chute and was missing
knives; interior of the vacuum dryer for crude
API is rusted; transfer room of API to drums has
peeling/ flaking paint on wall/ceilings.
Facilites & Equipment
‹ In
the warehouse for storage of
replacement parts such as valves for the
process water system and reverse osmosis
membranes, there were numerous
pigeons observed flying above the
equipment parts and evidence of bird
droppings. This included in the locked
cage which contained the stored reverse
osmosis membranes.
Facilites & Equipment
‹ There
are no piping or instrument
drawings of the incoming source water,
deionized water or Ultrafiltration Water
systems to show current “as-built”
components, treatment or distribution
systems of water, for the purpose of
system maintenance, monitoring and
operation.
Facilites & Equipment
‹ Welds
used in the initial installation or
replacement of critical equipment
components are not examined, not
electropolished or in any other manner
evaluated against acceptance criteria.
‹ Several
investigations of microbial
contamination implicated residual weld
material as a principal contributing factor.
Facilites & Equipment
‹ There
is a dead leg of at least 1 foot in
length between the crystallization vessel
XX (for purified API) and the centrifuge.
‹ (Note:
This was from a previously used
connection to another piece of equipment
– no longer is use – now capped)
Facilites & Equipment
‹ The
firm recently introduced and qualified
a new delivery system for nitrogen
blanketing of a critical step in the ***
process.
‹ The
system including new valves and flow
meters was qualified as reported in IQ,
OQ reports.
Facilites & Equipment
‹
‹
Inspection on (date) found that although the
replacement valves associated with lines X and Y
were closed, the nitrogen flow meter display
indicated a significant nitrogen flow to line X.
(NOTE: The initial change was made to deal
with intermittent flow problem. Following the
inspection, the firm determined that the new
valve design was faulty/ not appropriate for the
intended use and replaced all of the valves).
Facilites & Equipment
„
Equipment cleaning deficiencies
include:
a)
Product residues were visible in numerous
pieces of equipment labeled as clean
(including fluid bed dryers, centrifuges; one
vessel which was stated to have not been
used in several weeks had yellow-brown
residue, no status label)
Facilites & Equipment
b)
c)
„
Tape on discharge chutes of centrifuges and
other surfaces with potential for product
contact.
There were rough welds on the product
contact surface of the hopper used to
charge purified product to the dryer.
(Risk for next batch ? Degradants ?)
Facilites & Equipment
„
According to the firm’s written procedure
(SOP XX-Y), the cleaning of Sparkler filters
requires that at the completion of a
campaign, the equipment is dismantled
and all components thoroughly cleaned.
Examination of Sparkler filters #s *** and
*** found the bolts to be worn/ stripped.
Facilites & Equipment
„
The firm’s maintenance employees in the
presence of the plant manager and the
FDA investigator were unable to remove
the bolts using dedicated tools. The firm
has no individual equipment cleaning
record and the batch documentation
records only that all equipment in the
“train” was cleaned.
Facilites & Equipment
„
The Ultra-Filtered (UF) Water system which
produces water used in the critical steps of API
production was observed to have ball-type
valves at numerous locations including in the
finishing area for the final API ******. These
valves are potential “dead-legs” in the UF Water
system. (API ****** is intended to further
processing to manufacture sterile products for
injection.)
Facilites & Equipment
„
The piping throughout the purified/UF water
system is ABS plastic pipe and elbows and the
line leading to the stainless steel holding tank
(ABS) attaches to a stainless steel line by means
of a flange. It was stated that the water in the
line before the storage tank is drained at times
when the system is not producing water,
however, it was noted that the ABS line to the
flange slopes in a manner which would not
promote adequate drainage and, therefore,
could promote biofilm production.
Production observations
„
The firm’s SOP XX states that batch production
records for use in production are photocopied
from the master record, however, examination
of executed batches found that:
•
Batch production records are not an accurate
reproduction of the master.
•
The following steps lacked instruction details given in
the master records:
(6 examples listed on FDA 483)
Production observations
„
This observation was on FDA 483 and
then cited in a letter from FDQ CDER to
firm:
“The master production and batch production
records for APIs ***, ^^^ and +++ are
deficient in that they do not require
documentation of all significant steps and in
many cases are unclear. (Ten examples given
on FDA 483).”
Production observations
From an FDA 483:
Stage IV master production record does
not specify the mill speed nor the screen
to be used during milling and this
information is not recorded in the batch
record. Additionally, the master record
does not specify the screen to be used
during seiving.
Production observations
From Regulatory Letter:
We also have concerns regarding particle size
specifications in which all four prospective validation
batches failed to meet the release specification.
Note:
The letter then reports the fact that inspection found
that firm actually used different equipment from that
described in manufacturing instructions and validation
protocol.
Production observations
„
In the crystallization step to obtain crude ***,
the manufacturing instructions state to add 100
Liters of xxx dropwise within 5 to 10 minutes.
When it was pointed out that this would be more
than 3000 drops per second (in 10 minutes) and
that the same instruction is given in the (original
language version), the firm’s (management title)
stated that discussion with the production
personnel found that this is accomplished
“roughly” in the time period mentioned in the
batch record by means of a valve.
Production observations
„
It was noted that, in contrast to other
manufacturing steps which provide details, there
is no instruction regarding use of valves or other
means of controlling the flow.
(Note: There was suggestion at one point that
the word “dropwise” came from pilot scale
batches but no documented evaluation of the
criticality of the rate of addition and how
“dropwise” should have been converted to an
accurate instruction for the scaled-up batches).
Production observations
„
Inspection of first batches of new product
*** found that the first batch failed
specification for --- and this was related to
a critical step. Batch rejected. Corrective
action, change critical process step time
from 20 minutes to 30 minutes.
(see next slide)
Production observations
„
Examination of batch records for product +++
which has similar critical step states in the
manufacturing instruction:
“ Perform operation --- for twenty (30) minutes”.
„ There is no record of the actual time it took for
the operation, yet every batch record has two
signatures verifying step done as described.
Production observations
From Warning Letter (“***” from FDA not by RCH)
Several batches of API are *** in a *** to produce
one large batch. The individual batches are not
tested for residual solvents and found to meet
appropriate specifications prior to ***. This process
has not been validated for *** of the combined
batch. The *** is tested for residual solvents, but
the sampling method, one composite sample, does
not provide evidence of ***.
Production observations
„
„
Inspection of the manufacturing facility on (date)
at (time) found that while the two batches of
***, lots ----- and ----- had just begun the
XXXXX step, the BPRs were signed by two
operators verifying that the 9 step process had
been completed.
Further, the production QA employee signed the
sheet stating that the above was reviewed and
approved.
Production observations
‹
Examination of reactor GLR # XXX in use for
the ****** step (critical step) for batch $$$$$
of the API ***** found that the thermometer
which extends into the reaction mass could not
be read. The QA Manager who was
accompanying the inspection examined the
batch record for that batch, then leaned forward,
examined the thermometer and stated that the
temperature was XX C which she stated was
“right on target”. (continued)
Production observations
‹I
asked for the production manager to
examine the thermometer and it was
determined that not only could it not be
read, the thermometer bulb was broken
and the fluid had emptied. It could not be
determined when the thermometer had
broken nor where the contents of the
thermometer had gone.
Production observations
„
Inspection found that the initial production
deviation report # D-XX stated that batches
##### and +++++ of the product *** from a
campaign in (time period) were rejected due to
failing potency results. An amended deviation
report prepared just the week before the current
inspection reported that operators admitted to
not adequately monitoring the critical step X.00Y
and simply recorded results typical of previous
batches.
(continued)
Production observations
„
The amended deviation report:
a) Failed to explain how the workshop supervisor
was able to sign the batch record stating that he
had observed the monitoring of the batches and
that it had been done as per written instructions
b) Failed to document an extension of the
investigation to determine if there were other
batches for which the operators had not
properly monitored and documented the
reaction progress.
Production observations
Related to the previous observation, a production
employee from that shift who was reprimanded
reported that for a previous batch ***, there was a
spill of the final product blend from the blender onto
the floor of production room XX and the employees
swept the batch with broom and with scoops and
reloaded the material back into the blender.
According to the investigation report written five
months after the event, the team leader was
confronted and acknowledged this had happened.
This incident had not been documented or reported
at the time it occurred.
Production observations
Note:
A deviation report examined at another
factory stated that certain deviations and
batch rejections were related to “More
experienced workers know what to do but
take short cuts and do not follow
procedures.”
Materials observations
From a Warning Letter
Sampling and Testing of incoming xxx used in
the manufacture of API *** were inadequate:
„
„
At least one specific identity test to verify the identity
of the incoming material was not conducted.
The reliability of the supplier’s certificate of analysis
(COA) was not established in that a complete analysis
was not performed and compared with the COA at
appropriate intervals.
Materials observations
From a Warning Letter
Procedures for the recovery of solvents were
inadequate:
Procedures for solvent recovery had not been
established to ensure that solvents are controlled and
monitored to assure they meet appropriate standards
before reuse or commingling with other approved
materials. (FDA 483 observation concerned co-mingling
recovered solvent with fresh solvent before testing of
the recovered solvent).
Materials observations
„
Recovered solvents were not adequately
controlled in that a drum of recovered
chloroform was observed stored in the
area identified for storage of recovered
ethyl acetate.
(From a Warning Letter; the actual FDA 483
observation also pointed out that the
recovered chloroform was in the middle of
several drums of the other solvent).
Materials observations
„
Raw material sampling was not
performed in an appropriately
controlled area and foreign material
was noted on the surface of bags of
approved materials.
Materials observations
„
Sterile PE film used during production to form
sterile bags for the finished product is gamma
irradiated in a validated sterilization at another
firm, however, the integrity of this film may
potentially be compromised prior to use due to
the practice employed in sampling for release for
production. The PE film is transferred to the
production area (class 100), sampled, resealed
and transferred back to the warehouse with
“Release” stickers place of the original cardboard
boxes in which the rolls of PE film are stored.
Materials observations
„
The firm has out-sourced the testing of API
^^^ for residual solvents and does not request
testing of residual solvent for every batch of
product manufactured. In addition, review of
two test reports from the contract laboratory,
selected at random, found that despite the fact
that the firm’s batch records and the DMF show
ethanol to be the only solvent used in the
process, the test results showed benzene to be
present at levels more than 20 PPM. (continued)
Materials observations
„
Finally, the firm reportedly sends
recovered solvent to a contract firm which
performs further purification, however,
there were no records present to support
this arrangement and in response to my
inquiry, it was stated the factory has never
audited the contract firm which purifies
the solvents.
Materials observations
„
The computer software designed by
the firm’s IT department for raw
material inventory control has not
been validated and has no user
controls.
Materials observations
„
There is no password security for the two
computer terminals (Materials Section and
Synthesis Section) which are used for
entering and monitoring information
regarding the receipt, use and inventory
records for raw materials and
intermediates.
Packaging & Labeling
observations
„
„
„
Failure to have a written procedure for receipt,
identification, quarantine, sampling, release
and handling of labels
Incoming labels are not proofed against a
master label.
There is no specimen labels placed in the
executed batch records.
Packaging & Labeling
observations
„
„
„
There is no procedure to reconcile the quantities
of labels issued and returned or destroyed.
Final product labeling for API *** lacks retest
date and storage temperature.
Labels on drums of finished API not sticking.
(Note: Inspection found solution employed was
use two labels – hope one sticks).
Packaging & Labeling
observations
„
The written procedure (SOP) covering labeling of
finished product, i.e., printed bags stamped with
lot number does not address the details of label
issuance or reconciliation following the labeling
operation.
(Inspection found printed bags with two API batch
numbers in packaging staged for use in packaging of
those batches. The accompanying paperwork recorded
numbers of bags issued and returned even though
operation not yet started.)