Examples of critical and major observations from GMP
inspections of Manufacturing, QC and Contract
Research Organisations
Prequalification Programme: Priority Essential Medicines
Essential Medicines Policies, WHO, Geneva.
Presented by
Ian Thrussell
Head of Inspections
thrusselli@[Link]
Session Outline
This presentation provides a summary of those
areas of FPP and API manufacture and their
control where deficiencies versus GMP are most
commonly found
Questions
Quality Matters.
In 2012 Poor quality continues to impact on the patient
LAHORE: Isotab contaminated isosorbide tablets supplied by a
major cardiac care clinic
Mystery behind the factors which have caused THE DEATH OF OVER
100 PATIENTS.
Several thousand patients hospitalized
Each of them had consumed a chronic overdose of Pyrimethamine every
day, which caused immediate bone marrow suppression and a terrible drop
in platelet and white blood cell counts, ultimately leading to their deaths.
Root cause a simple mix up of an excipient and an API during
manufacture
THE PRODUCT COMPLIED WITH ITS SPECIFICATION!!!!!!!!
BUT WAS LETHAL!
GMP: assuring the consistency of quality
Since the establishment of GMP the prime objectives set out
in law and guidance has been to:
Ensure that products are manufactured batch upon batch,
year upon year, to the appropriate and consistent quality
standards and in accordance with regulatory requirements
by requiring that there be a pharmaceutical quality system.
HAVING A QMS IS NOT NEW!
Require Marketing Authorisation holders to regularly
review their products and their manufacturing processes to
ensure that they keep up to date with scientific and
technological progress
CONTINUAL IMPROVEMENT HAS ALWAYS BEEN A
REQUIREMENT of most GMPs!
Prequalification: Inspection Processes
By a team of qualified and experienced inspectors
WHO representative (qualified inspector)
Inspector from well-established inspectorate (Pharmaceutical
Inspection Cooperation Scheme countries PIC/S)
National inspector/s invited to be part and observe the
inspection
Observer from recipient/developing countries (nominated by
DRA of the country)
Scope:
Compliance with specific GXP guidelines:
GMP for API and FPP sites,
GCP for CROs,
GLP for FPP/API factory QCL, CRO-BAL, NQCL, IQCL
Data verification data manipulation, falsification,
(validation, stability, clinical, bioanalytical)
Risk-based approach in:
definition and classification of deficiencies
Deficiencies are descriptions of non-compliance
with GMP requirements.
A distinction is made between deficiencies as a
result of: a defective system or,
failure to comply with the system.
Deficiencies may be classified as:
Critical Observation potential risk harm to the user
Major Observation major deviation from GMP/GCP
Minor or Other Observation departure from good
practice
Classification of observations
Critical Observation
An observation that has produced, or may result in a significant risk of producing, an API that, when
used in a finished product, is harmful to the user.
Major Observation
A non-critical observation that:
has produced or may produce a product which does not comply with its prequalification application
(including variations); and/or
indicates a major deviation from the GMP guide; and/or
indicates a failure to carry out satisfactory procedures for release of batches; and/or
indicates a failure of the person responsible for QA/QC to fulfill his/her duties; and/or
consists of several other deficiencies, none of which on its own may be major, but which may together
represent a major deficiency and should be explained and reported as such.
Other Observation
An observation that cannot be classified as either critical or major, but indicates a departure from good
manufacturing practice.
A deficiency may be other either because it is judged as minor, or because there is insufficient
information to classify it as major or critical.
WHO-PQ offers new avenues for
collaboration in inspection
WHO-PQ Collaborative Procedure in Inspections
nominated inspectors from NMRAs of selected member states
are invited to participate in WHO-PQ organized inspections and
in turn, the NMRAs is given appropriate access to outcomes of
these inspections.
Capacity building of NMRAs inspectors.
Facilitating use of WHO-PQ inspection results in national regulatory
environment for information and decision making.
Facilitation of harmonization through joint inspections and sharing of
outcomes.
Share the workload and promote avoiding duplicative inspections.
[Link]
Prequalification Programme: International norms,
standards and guidelines used in inspection activities
to ensure wide applicability
USP
BP
Ph. Eur.
Ph. Int.
Other guidelines
e.g. ICH, ISO
[Link]
[Link]#2
9
Quality Assurance and Quality Management
Investigations
Deviations
Out of specification
and out of trend
results
Root cause analysis
Change Management
Continual
Improvement
Quality Risk
Management
Quality Review APRs
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Pharmaceutical
Development
Technology
Transfer
Manufacturing
Discontinuation
Management Responsibilities
PQS
Process Performance & Product Quality monitoring
CAPA
Change Management
elements
Management review
Enablers
Knowledge Management
Quality risk Management
GMP
ICH Q10 Management
commitment(2.1)
Senior management has the ultimate
responsibility to ensure an effective
pharmaceutical quality system is in place to
achieve the quality objectives and that the roles,
responsibilities, and authorities are defined,
communicated and implemented throughout the
company
The concept of corporate governance
12
Why do inspectors already look at an organisations
QMS and QRM programmes during inspections?
Looking at how companies react when things go wrong or are
changing and are under pressure is a major diagnostic
indicator of the robustness of the scientific and organisational
integrity of a companys operations
Do they investigate to improve knowledge or simply build
arguments for release of product
Quality of investigations- appropriateness of depth of
investigation
Reactive rather than proactive usage of knowledge
Quality is everyones responsibility Is this true when things go
wrong?
Is the company a learning organisation? And where is it on the
learning curve?
Managing Knowledge: Out of Specification,
deviations and process failures
OOS results may indicate a flaw in product or process
design
Lack of robustness in product formulation
Inadequate raw material characterization or control
Substantial variation introduced by one or more unit
operations of the manufacturing process
Combination of these factors
In such cases, it is essential that redesign of the product
or process be undertaken to ensure reproducible
product quality
)
Importance of root cause
investigations and risk management
Have we identified and do we understand factors that
impact product quality?
Information is not knowledge.
Lets not confuse the two.
- W. Edwards Deming
We are drowning in information
but starved for knowledge.
- John Naisbitt
Quality philosophy After
W Edwards Deming
Learning is not compulsory!
Adaptation and improvement is not compulsory
SURVIVAL IS NOT COMPULSORY
ICH Q10 ( Management
responsibility) :
Leadership is essential to establish and maintain a
companywide commitment to quality and for the
performance of the pharmaceutical quality
system
18
Inspection of FPP manufacturers
Poorly understood and poorly designed
processes
Poor understanding of
requirements
Poor product
understanding due to
inadequate
development
Unvalidated blending
at the unit dose level
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Poorly designed processes
Materials transferred
between unit
processes with
inadequate assurance
of integrity and
contamination risks
Inadequate dust
extraction and
containment
Excessive holding
times for
intermediates that are
unvalidated
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Drying Oven designs!
Failure to use easy to
clean equipment and
closed transfers
No or inadequate
filters on the oven
Difficult to load and
unload cleanly without
liberating dusts
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
An open tray drying process where
containment is difficult
;
Closed systems where containment
is excellent
;
Poorly designed processes
Raw material
suppliers not audited
but acceptance of side
samples or CoAs
accepted with no
justification
No understanding of
ingredient variability
and its effect on FPP
Container suppliers
and packaging
material suppliers
never audited
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Poorly designed or maintained equipment
Equipment not easy to
clean especially
dust extracts
No traps in dust
extract systems
Un-validated cleaning
and re-use of filters
Inappropriate filtration
grades for the
materials handled
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Procedures!
Incomplete process
descriptions
No verification of
tablet punch length
(leading to greater
variability of tablet
weight and hardness)
Sealing parameters
inadequately defined
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Equipment
Poorly designed or maintained equipment
Poor control over
metal items
inparticular seives
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Construction activities
Major construction in room next to personnel
entry airlock (e.g., gowning).
Construction occurred over approximately onemonth period and coincided with continued
production
Premises!
Inadequate
containment or
dedication to those
materials that are
recognised as highly
potent or sensitising
Inadequate dust
extraction
Inadequate filtration of
recirculated air
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Deficiencies observed during PQ Inspections
PREMISES
Inadequate segregation.
Illogical process flow.
Inadequate provision for Utilities: HVAC,
water, compressed gases
Poor design and management of
the HVAC system:
Multipurpose plant used re-circulated air
but had no HEPA filters.
Adequate pressure differentials: reversal
of air flow.
No sequence of switching on and off of
AHUs of adjacent areas.
Mix-ups
Contamination
Cross contamination
Poor design and construction of
premises:
Lack of awareness on current guideline in TRS 957 WHO good manufacturing practices for pharmaceutical
products
containing hazardous substances
Inadequate facilities and equipment for handling
potent hormone products
Inadequate containment from both a GMP
standpoint BUT also safety and environmental
perspective (which are present in the WHO
guidance unlike other GMPs)
Inadequate HVAC systems
Lack of training including hygiene practices, gowning
Lack of awareness on current guideline in TRS 957 WHO good manufacturing practices for pharmaceutical
products
containing hazardous substances
Not all products containing hazardous substances are
equally potent and risk assessments should be carried
out to determine the potential hazards to operators and
to the environment.
This guidance gives standards for the most potent but it
is possible to justify other approaches depending upon
risk.
Areas of the facility where exposed product presents a risk should be maintained
at a negative air pressure relative to the environment.
The facility should be a well-sealed structure with no air leakage through ceilings,
cracks or service areas.
TRS 957 Expectations
Where possible, single-pass air-handling systems with
no recirculation
Exhaust air or return air should be filtered through a
safe-change or bagin-bag-out filter housing.
Airlocks, pass-through hatches, etc., should have supply
and extract air to provide the necessary air pressure
cascade and containment.
The starting and stopping of the supply and exhaust air
fans, and associated system ventilation fans, should be
synchronized such that the premises retain their design
pressure
Deficiencies observed during PQ Inspections
MATERIALS
Inadequate goods and materials
management
Starting materials: sourcing and
sampling ID per container.
Packaging materials: inadequate
sampling ISO2859 or BS6001.
Intermediate and bulk products
holding time not set, or justified, or
respected.
Finished products: Release
procedures no adequate review
by QA or QP.
Rejected materials and products:
not adequate segregation or
disposal.
Reagents and culture media: no
GPT, positive and negative control
Reference Standards: inadequate
standardisation, storage and use.
Poorly designed or executed micro
monitoring
Water TVC sample
points for water not
close to point of use
Materials in use that
are at risk of spoilage
coating solutions
Monitoring is not
risked based and too
routine
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Packaging
Packaging material control!
No 100% verification
of issued packaging
materials at the point
of use
No 100% verification
of filled blisters
No in-process check
for the integrity testing
of blisters.
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Raw Materials material control!
No 100% verification of
the identity of received
raw materials
Dispensing of materials
carried out in a way tat
does not minimise the risk
of cross contamination
Water hoses not drained
fully after use. Common to
see a number of hoses
containing pooled water.
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Validation!
Non-risk based validation
leading to a failure to
concentrate on risks and
doing non-value added
validation by rote!
Poor practices for usage
and cleaning accepted as
covered & justified by
passing results of
manual cleaning or
residue testing!
Good history does not
mean failures do need not
be investigated
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Validation
Incomplete validation
of content uniformity
and blending due to
sample size taken
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Poor cleaning practices
Un-validated cleaning
Heavy use of manual
cleaning techniques
which are difficult if
not impossible to
validate
Risks from machine
lubricants
Long campaigns
during which
contamination
accumulates
Personnel
Validated processes
Procedures
Raw Materials
Equipment
Packing Materials
Environment
Premises
Deficiencies observed during PQ Inspections
FPP manufacturers: sterile products
Poor aseptic techniques:
Alternative dosage forms:
Asepsis compromised by
safety design
Safe collection systems and
vacuum can and have failed
leading to contamination of
cytotoxic injectables
Inadequate evidence of validity
of media fill tests due to
residues of otent materials
The nature of the vehicle not
taken into account when
designing sterilisation validation
E.g. Does the sterilant reach the
locations where microrganisms
may be protected.
Deficiencies observed during PQ Inspections
FPP manufacturers: sterile products
Poor aseptic techniques:
Extensive movement of
operators in Grade A close to
the open vials.
Vials that were not stoppered by
the machine taken from the
conveyor belt into class B area
and manually placed back into
class A to be manually
stoppered.
Inadequate Media Fill Tests
Environmental monitoring:
The viable particle continuous
monitoring for Grade A zone
does not cover the whole time
period of setting up of the
equipment and the vial fillingcapping process.
Personnel garments and gloves
were not monitored after
manufacturing operations in
grade A/B areas
Inspection of API manufacturers
Deficiencies observed during PQ Inspections
API manufacturers
The most frequently found
deficiencies were:
Material management
SOPs
Cleaning
Others included:
Batch records
Labelling
Cross contamination
10
9
Cross
contamination
Batch records
8
7
6
SOPs
5
Material
Management
Cleaning
4
3
2
1
Labeling
0
Major deficiencies
WHO GMP for APIs: Buildings, utilities and equipment
Facilities,equipment
and utilities system
Facilities designed to prevent
mix-ups and contamination (4.10)
Precautions implemented based
on a risk assessment
Utilities (HVAC, compressed air and
other gases etc) qualified and
monitored, as appropriate.
Buildings and equipment
cleaning methodology and
intervals appropriate to prevent
build-up and carry-over of
contaminants (degradants)
Critical operation with
prolonged exposure to the
environment
Non critical operation with
prolonged exposure to the
environment
Non critical or critical
operation in a closed
equipment
Why is a Split Unit bad news?
RETURN AIR
Poor quality
Air filter
Cooling Coil
Condensate drip tray
SUPPLY AIR
Wards?
Fan liberates dust
into the air
49
WHO GMP for APIs: Production
Production
Blending operations (section
8.4)
Only batches meeting
established specifications
Expiry or retest date of the
blended batch based on the
manufacturing date of the
oldest batch included.
Should be controlled and
documented traceability
Validation for homogeneity
following blending
OOS batches
blended with
others to meet
1. Blending small batches
tospecifications
se batch size
2. Blending tailings
APIs for OSDs/ Suspensions
1. Particle size distribution
2. Bulk density
3. Tap density
WHO GMP for APIs: Reprocessing & Reworking
Reprocessing or reworking for intermediates or APIs which
do not conform to standards or specifications
Reprocessing (s. 14.2)
Repeating a step of the
established manufacturing
process
Crystallization, distillation,
filtration, chromatography, milling,
etc
Continuation to completes process
after IPQC in not reprocessing
Introducing unreacted material into
reaction is reprocessing
Included in the standard
manufacturing process if
reprocessing used for a
majority batches
Reworking (section 14.3)
Reason for non conformance
determined prior to any
reworking
Involves a treatment different
from the established one
Recrystallization with a a different
solvent
Reworked batches to be
subjected to appropriate
evaluation, testing stability
testing
Concurrent validation
Should have comparable impurity
profile
WHO GMP for APIs: Recovery of materials
Recovery of Materials and
solvents
Reactants, intermediates or APIs
may be recovered from mother
liquor or filtrates.
Must use approved procedures
and specifications.
Recovered solvents may be
reused in same process or in
different process if confirmed to
meet appropriate standards.
Fresh and recovered solvents and
reagents can be combined if their
adequacy is confirmed
1. No approved procedures
2. Specs carry over
impurities
3. Not adequately tested
4. Use not documented
1. Approved procedures
2. Suitable specs
3. Adequate testing
5. Use documented
Inspections of Contract Research
Organizations (CROs)
CRO/BE Inspections: Problems with integrity,
archiving and retrieval of documents
CRO/BE Inspections: Inadequate data integrity
Source data either not available or authenticity
questionable:
Source data could not be located to verify entries in VRFs
destroyed accidently by fire or rain
Sponsor claims the data were kept by the CRO, and the CRO
claims the data were kept by the sponsor
Two of the ECGs shown to the inspectors, bearing different
subject numbers and initials, were found to be identical.
Other ECGs bearing different subject numbers and initials
appear to have been recorded from a single subject. Out of
95 ECGs copied by the inspectors, 43 appear to have
been recorded from the same and single subject during
a single session
CRO/BE Inspections: Data manipulation
inappropriate manual integration of peaks
Manual reintegration of peak was
done
inappropriately
and
inconsistently
for
all
peaks
inclusive internal standard
For some samples checked, especially QCs or
standards close or outside the 15% of their
nominal concentration, the baseline of the
chromatograms were modified manually. This was
not done appropriately and consistently for all
peaks inclusive internal standard. For modified
integration, initial integration was not available.
No paper or electronic audit trail of
manual integration available.
Each analytical run did not include
calibration and quality control
samples.
CRO/BE Inspections: Data manipulation - Identical
chromatograms had different peak areas but the same
area percent
Deficiencies observed during PQ Inspections
QC Laboratories: Conclusions
Data manipulation and misrepresentation is not
acceptable to the WHO and according to the law
of most national regulatory authorities (could
result in the publication of NOC or NOS on
behalf of the WHO).
The honest way is always the "right way".
Good ethics are key to reliable data.
Always prioritize data integrity not quick batch
release at any cost.
Questions?