FDA cGMP Inspections

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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

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Foreign Inspections by Country in FY 2004
India
Others 14%
19%

Germany
Ireland 14%
4%

Spain
4%

Switzerland
4% Italy
10%
Japan
5%
China
France 7%
5%
Canada
United Kingdom
7%
7%

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Foreign Inspection in FY 2004 by Firm
Type

Both API and Dosage Control Lab

2% Micronizer
9%
1%

Intermediates
10%

API
51%

Dosage
27%

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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

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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 (risk-based;
geared toward GMP documents)

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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

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 Pharmaceutical Inspectorate
FDA Review staff, Compliance Officers and PI candidates
attended training modules which focused on:
Current Regulatory Programs
Advanced Quality Systems
PAT and Modern Pharmaceutical Technology
Risk Management

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Pharmaceutical Inspectorate
Field Investigators (18) from across U.S. make up the
Pharmaceutical Inspectorate
Screening process with certification board
Completed training with HQ personnel
One month detail working with HQ staff
Level III certification (highest level)
Conduct PAIs, complex drug inspections

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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

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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

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Process Analytical Technology
A process is generally considered well understood when:
 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.”

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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)

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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

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System Inspections
Quality
Facilities and Equipment
Materials
Production
Packaging/Labeling
Laboratory Controls

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Most Common GMP Deficiencies by System – API/
Dosage Inspections for 2004/5

Materials
6%
Packaging and Labeling Laboratory
1% 19%

Facilities & Equipment

17%
Production
11%

Quality
46%

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“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

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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

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Role of Management in QS
Management is responsible for:

Organizational structure
All Processes
All Procedures
Facilities & Resources

In short, everything to insure product quality,

customer satisfaction and continuous improvement

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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)

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Quality system (continued)

6) Reprocess/ Rework
7) Validation/ Revalidation
8) Rejects
9) Stability Failures/ Out of trend data
10) Quarantine products
11) Documented GMP & Job Related Training

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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

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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

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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

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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

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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 in-process
controls, tests, and examinations

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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

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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.)

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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

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Facilities & Equipment System
Defined areas or other control systems to prevent mix-
ups or contamination
Incoming materials (id, quarantine)
Sampling area (prevent contamination)
Quarantine (intermediates, APIs)
Released materials
Rejection

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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

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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.)

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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

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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

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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

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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

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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

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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

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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

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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

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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)

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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.”

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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”.

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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

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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”)

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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

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More Similarities…..
Science based approach for the establishment of
processes
Knowledge of process based on Process
Development work
Design Of Experiments (DOE)
Quality System (review/ trending)
Continuous Improvement possible within well
characterized process

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